Evaluation and Assessing Resectability Not Add Much Additional Value and Are Not Routinely Performed in the Initial Assessment for Resectability

664 Practice of Oncology / Cancers of the Gastrointestinal Tract

Evaluation and Assessing Resectability not add much additional value and are not routinely performed in the initial assessment for resectability. Although periampullary cancer (adenocarcinoma of the pan- Resection is attempted if (1) patients are medically fit for a pancreas, ampulla of Vater, bile duct, or periampullary duode- createctomy, (2) there is no evidence of metastases, and (3) patients num) should be considered in any patient who presents with are believed to have resectable disease. Resectability is ultimately a conjugated hyperbilirubinemia, the likelihood is highest in decided by the operating surgeon, but general guidelines have been older patients (e.g., >55 years). In individuals with an expected proposed and are based on the likelihood of achieving a complete, pancreatic cancer, a thorough history and physical should be margin-negative resection.81,82 Resectability equates to a high prob- performed, followed by appropriate imaging for staging and to ability of an R0 resection; borderline resectability equates to a likely assess resectability. Critical findings on physical exam include result of an R1 resection (positive microscopic margins); and unre- scleral icterus, jaundice, and lymphadenopathy (e.g., Sister sectable (or locally advanced) PDA is likely to result in R2 resection Mary Joseph or Virchow nodes). A chest x-ray or chest CT (residual macroscopic disease). Resectable lesions do not invade the scan is performed to assess for pulmonary metastases and as a superior mesenteric artery (SMA), celiac axis (CA), common hepatic baseline study. Either a high-quality MRI or CT scan of the artery (CHA), or superior mesenteric–portal vein axis (SMV-PV). In abdomen is performed to evaluate the pancreas and measure contrast, locally advanced lesions encase (i.e., >180° invasion) any the extent of disease. We typically prefer CT for its superior of the previously mentioned arteries or occlude the SMV-PV such resolution and detailed depiction of the relevant vasculature. that no reconstructive options remain. Borderline resectable lesions Water is administered as oral contrast, and nonionic intrave- involve the visceral vessels to a lesser extent; they can abut the vis- nous contrast is rapidly injected. Slices are captured at 1-mm ceral arteries (<180° invasion), distort the visceral veins, or even oc- intervals from the diaphragm to the iliac crests at three different clude the SMV-PV, but with venous reconstruction still technically times or phases: early arterial, late arterial, and venous. Multi- feasible (Table 49.3).83 Most pancreatic surgeons offer patients with planar reformatting and three-dimensional (3D) surface render- resectable lesions an attempt at resection (although some centers ad- ing is performed during the early arterial and venous phases vocate neoadjvuant treatment prior to resection even for resectable (Fig. 49.4).80 Positron-emission tomography (PET)/CT scans do lesions84). Patients with locally advanced lesions are recommended

A B

C D Figure 49.4 Slices from a triphasic CT scan in a patient with resectable pancreatic cancer. (A) Late arterial phase. Double duct sign with dilated common bile and pancreatic ducts, and an atrophic pancreatic body. (B) Mass. (C) Coronal reconstructions, venous phase, with the mass apparent, and (D) clearly away from the superior mesenteric–portal vein axis (SMV/PV) axis. Yellow arrow = PDA; green arrow = common bile duct; red arrow = pancreatic duct; and blue arrow = SMV. (Courtesy of Jennifer Brumbaugh, Department of Surgery, Thomas Jefferson University.)

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TABLE 49.3 Criteria for Reseectability

Resectable Borderline Resectable Locally Advanced

Vessel R0 Resection Likely R1 Resection Likely R2 Resection Likely SMA No abutment Tumor abutment Tumor encasement Celiac axis/ No abutment Tumor abutment Tumor encasement hepatic artery SMV–PV Abutment may be Vein Distortion or short- Occluded and no present but no vein segment occlusion with suitable technical option for distortion vessel above and below reconstruction

Note: R0 = gross total resection; histologically negative margins. R1 resection = gross total resection; one or more histologically positive margins. R2 resection = subtotal resection, visible tumor unresected. Abutment is ≤180° vessel circumference; encasement is >180° vessel circumference. SMA, superior mesenteric artery; SMV–PV, superior mesenteric vein–portal vein. Modified from Varadhachary GR, Tamm EP, Abbruzzese JL, et al. Borderline resectable pancreatic cancer: definitions, management, and role of preoperative therapy. Ann Surg Oncol 2006;13:1035–1046. to undergo palliative treatment without the intent to cure. Consider- pancreatic remnant is closed with suture (Fig. 49.5B) or staples. able debate remains for borderline PDAs; resection may be offered, A central pancreatectomy or local excision for a PDA is seldom if but increasingly, neoadjuvant treatment is recommended for even ever performed for PDA due to inadequate lymph node harvest. abutment or narrowing of the SMV-PV.81 Neoadjuvant chemo- A minimally invasive pancreatectomy using laparoscopy or a therapy (± radiation) can facilitate resection, and may improve the robotic-assisted approach may be safely performed. Although a likelihood of a complete resection with negative margins, even in minimally invasive approach is more common for benign and pre- the absence of a radiographic response.85 malignant lesions, a presumed diagnosis of PDA is not a contra- Obtaining a tissue diagnosis is not essential for all cases. Indica- indication.87 A meta-analysis comparing open versus laparoscopic tions include instances when (1) neoadjuvant treatment is advised distal pancreatectomies for PDA revealed similar oncologic and or (2) the pretest probability of an alternative diagnosis is consider- pathologic outcomes in the two groups. Patients undergoing lapa- able (e.g., suspicion for benign causes of pancreatitis, medically roscopy had a shorter postoperative stay by 4 days, less blood loss, OF ONCOLOGY PRACTICE managed neoplasms such as lymphoma, or a benign stricture). In and fewer surgical site infections.88 Importantly, studies compar- these instances, an EUS with fine-needle aspiration (FNA) biopsy ing the two techniques have not been prospective and random- is an effective method for obtaining tissue and has an accuracy in ized, and are, therefore, all subject to selection bias, with the more excess of 90%.86 When the diagnosis is clear based on imaging and difficult resections falling into the open group. Although most history, it is appropriate to proceed to attempted resection without high-volume pancreatic centers offer minimally invasive left-sided a preoperative tissue diagnosis. Similarly, placement of an endo- resections, laparoscopic PD is more technically challenging, and scopic biliary stent is frequently performed in jaundiced patients only a handful of centers have a significant experience.89 These preoperatively, but is essential in only selected cases. A multicenter centers report comparable outcomes with minimally invasive ver- prospective and randomized trial compared routine preoperative sus open pancreatic surgery in their own experience, although an biliary drainage with delayed resection to early surgery without advantage of laparoscopic PD has not yet been proven in a pro- stenting in jaundiced patients with pancreatic cancer. Serious spective and randomized study. complications were increased nearly twofold in the routine biliary drainage group (74% versus 39%; p <0.001), suggesting that International Study Group of Pancreatic biliary decompression be reserved for jaundiced patients unable Surgery Contributions to undergo resection in a short-time frame (1 to 2 weeks).86 A pancreaticoduodenectomy is safely performed, even when the total Surgically related mortality after PD has improved dramatically bilirubin is markedly elevated. Patients, who are otherwise healthy, over the last 3 decades, and is lower than 5% at most high volume with normal renal function and clotting parameters will usually centers.27 However, morbidity remains high (∼40%). The most tolerate a safely performed pancreaticoduodenectomy with a total common complications include pancreatic leak (20%), delayed bilirubin as high as 20 mg/dL. gastric emptying (15%), and wound infection (10%). Bile and duodenal leaks occur in roughly 3% and 1% of patients, respec- Surgery tively.27 The greatest limitation to studies focused on pancreatectomy-related complications has been a lack of standard definitions Technical aspects of a pancreatectomy are detailed elsewhere across institutions, making comparisons between institutions’ re- and are well beyond the scope of this chapter, hence will only ports difficult. The formation of an International Study Group of be reviewed briefly here. For right-sided pancreatic cancers, a Pancreatic Surgery (ISGPS) to address this issue has been a great pancreaticoduodenectomy (PD) is performed. The specimen advance in pancreatic surgery–related outcomes research. The includes the gallbladder, duodenum, head of the pancreas (the group has published consensus criteria and definitions for com- pancreatic transection typically is at the level of the neck), proxi- plication grading on the following pancreatic-specific morbidities: mal jejunum, and distal common bile duct. The most proximal postoperative pancreatic fistula (leak),90 delayed gastric emptying,91 retained jejunum is brought up into the right upper quadrant, and and postpancreatectomy hemorrhage.92 In addition, the group es- three anastomoses to the pancreas remnant, common hepatic duct, tablished concrete guidelines on reporting features and manage- and proximal duodenum (or stomach) are performed (Fig. 49.5A). ment of the pancreatic remnant/anastomosis (e.g., duct size, gland A distal pancreatectomy for PDA involves resection of the pan- texture, mobilization distance, type of anastomosis, suture used, creatic body and tail, with an en bloc splenectomy performed to use of stent).93 Definitions of postpancreatectomy-related mortal- ensure a proper lymphadenectomy. The transected surface of the ity, bile leak,94 and wound infection also vary in the literature, and 666 Practice of Oncology / Cancers of the Gastrointestinal Tract

Jejunum anastomosed to: 1. Pancreas 2. Common hepatic duct 3. Proximal duodenum or stomach Portal vein

Aorta

3 1

SMV

Figure 49.5 (A) Standard reconstruction after a pancreaticoduodenectomy, with an end-to-side pancreaticojejunostomy, an end-to-side hepatic jejunostomy, and a retro-colic and end-to-side duodenojejunostomy. (B) Suture closure of the pancreatic remnant after distal pancreatectomy.

a strategy to standardize terms and complication grading for these examined the location of the enteroenterostomy (antecolic versus outcomes would enhance the surgical literature. retrocolic), and no significant differences were observed.103–107 A postoperative pancreatic fistula (POPF) remains the most Surgical Trials challenging complication after PD. Clinically significant leaks (e.g., requiring treatment intervention) occur in roughly 10% of cases. Risk factors include soft pancreatic texture, a fatty pan- There have been numerous prospective and randomized surgi- creas, a small pancreatic duct, high intraoperative blood loss, cal trials that have shaped the surgical management of PDA. A and a high postoperative serum amylase level.108,109 Numerous trial unique to PDA, compared to other common cancers, is a randomized trials have attempted to reduce the pancreatic leak study demonstrating superiority of resection over best nonopera- 95 rate, although few have succeeded. Ineffective interventions in- tive therapy for the management of resectable disease. A total clude fibrin glue,110,111 octreotide,112–119 and internal pancreatic of 42 patients in Japan with resectable PDA were randomized to stenting.27 Mixed results have been reported with pancreatico- either standard pancreatectomy without adjuvant treatment or gastrostomy (versus standard pancreaticojejunostomy).120–126 to chemoradiation alone (50.4 Gy with continuous fluorouracil 2 The pancreaticojejunostomy technique was recently examined, [5-FU] at 200 mg/m per day) without surgery. Randomization oc- comparing a two-layered invagination technique with inter- curred at laparotomy and patients randomized to chemoradiation rupted outer stitches and a continuous inner layer, against a duct- had only an open biopsy and abdominal closure. The only multi- to-mucosa technique. The pancreatic leak rate was more than variate predictor of survival in the study was the treatment group = = twofold higher with the latter approach (7% grade B/C versus (hazard ratio [HR] 0.4; p 0.02), with the group undergoing 17%; p = 0.03).127 A binding pancreaticojejunostomy (versus resecting having superior survival (median overall survival (OS), invagination) is a second technique shown to have a decreased 13 versus 9 months). pancreatic leak rate. With this technique, an end-to-end pancre- Pancreaticoduodenectomy aticojejunostomy is performed; 3 cm of the pancreatic remnant is mobilized and telescoped within the jejunum. No leaks were A comprehensive list of surgical trials in patients undergoing pan- observed in 106 patients in the latter group, although these data creaticoduodenectomy is provided in Table 49.4. Regarding tech- have not yet been replicated.128 Interestingly, there now have nical aspects of the operation, one of the more studied questions been three randomized trials showing a lower pancreatic leak compares pylorus preserving pancreaticoduodenectomy (PPPD) rate associated with external pancreatic duct stenting (the pan- to distal gastrectomy plus pancreaticoduodenectomy (classic creatic duct stent is brought out through the bowel and skin as PD).96–102 Karanicolas et al.97 performed a meta-analysis of six ran- a drain),129–131 whereas a fourth study revealed no benefit.132 In domized trials including 574 patients. PPPD was associated with a the past, trials using somatostatin or its analogs have had mixed reduced operative time by more than 1 hour (p <0.001), less blood outcomes in lowering pancreatic leak rates. Recently, a phase III loss (284 mL; p <0.001), and fewer blood transfusions. There was trial using pasireotide (SOM230, a potent somatostatin analog) a nonsignificant trend toward improved mortality in the same di- was completed at Memorial Sloan-Kettering Cancer Center, rection (0.4; p = 0.09). There was not a significant difference in and revealed a statistically significant lower pancreatic leak rate delayed gastric emptying. Multiple randomized studies have also in patients receiving subcutaneous injections of the study drug

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TABLE 49.4 Randomized Surgical Trials with Pancreaticoduodenectomy

Author Year Trial Result Doi95 2008 Surgery vs. chemoradiation for PDA ↑ Survival with surgery Riall137 2005 PD vs. PD with lymphadenectomy = Survival Pedrazzoli136 1998 PD vs. PD with lymphadenectomy = Survival Farnell135 2005 PD vs. PD with lymphadenectomy = Survival Brennan138 1994 Preoperative TPN vs. none ↑ Morbidity with TPN Ke133 2013 Roux-en-Y PJ vs. standard ↓Grade B POPF with Roux-en-Y Fischer281 2010 Hemodilution vs. standard intraoperative IVF ↑ POPF with hemodilution Uemura282 2008 Ulinastatin vs. placebo ↓ Pancreatitis with ulinastatin Jo283 2006 Glutamine supplement vs. none = Morbidity Conlon139 2001 Drain vs. no drain = Complications and mortality Bassi284 2010 Late vs. early drain removal ↑ Complications with late Van Buren140 2013 Drain vs. no drain ↑ Mortality with drain Van der Gaag86 2010 Preoperative biliary drainage vs. none ↑ Morbidity with drainage Poon130 2007 External MPD stent vs. no stent ↓ POPF with external stent Kuroki285 2011 External MPD stent vs. no stent = POPF Pessaux129 2011 External MPD stent vs. no stent ↓ POPF with external stent Motoi131 2012 External MPD stent vs. no stent ↓ POPF with external stent Kamoda286 2008 External MPD stent vs. internal stent = POPF Tani287 2010 External MPD stent vs. internal stent = POPF PRACTICE OF ONCOLOGY PRACTICE Winter27 2006 Internal MPD stent vs. no stent = POPF Ye o 126 1995 PG vs. PJ = POPF Arnaud121 1999 PG vs. PJ ↓ POPF with PG Takano125 2000 PG vs. PJ ↓ POPF with PG Duffas123 2005 PG vs. PJ = POPF Bassi122 2005 PG vs. PJ = POPF Fernandez-Cruz124 2008 PG vs. PJ ↓ POPF with PG Klempa119 1991 Octreotide vs. none = POPF Beguiristain113 1995 Octreotide vs. none = POPF Ye o 112 2000 Octreotide vs. placebo = POPF Gouillat115 2001 Octreotide vs. placebo = POPF Shan117 2003 Octreotide vs. none = POPF Kollmar116 2008 Octreotide vs. placebo = POPF Fernandez-Cruz114 2013 Octreotide vs. placebo = POPF Wang118 2013 Octreotide vs. placebo = POPF Allena 2013 SOM230 vs. placebo ↓ POPF with SOM230 Reissman288 1995 MPD duct ligation vs. PJ ↑ POPF with ligation Tran289 2002 MPD duct ligation vs. PJ = POPF Lillemoe110 2004 Fibrin glue to PJ vs. none = POPF Martin111 2013 Fibrin glue to PJ vs. none = POPF Bassi290 2003 Invagination PJ vs. duct-to-mucosa = POPF Berger127 2009 Invagination PJ vs. duct-to-mucosa ↓ POPF with invagination Peng128 2007 Binding PJ vs. invagination ↓ POPF with binding PJ Ye o 291 1993 Erythromycin vs. placebo ↓ DGE with erythromycin Tani107 2006 Antecolic vs. retrocolic DJ ↓ DGE with antecolic DJ Gangavatiker104 2011 Antecolic vs. retrocolic DJ = DGE (continued) 668 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 49.4 Randomized Surgical Trials with Pancreaticoduodenectomy (continued)

Author Year Trial Result Imamura103 2013 Antecolic vs. retrocolic DJ = DGE Tamandl106 2013 Antecolic vs. retrocolic DJ = DGE Eshuis105 2014 Antecolic vs. retrocolic DJ = DGE Paquet99 1998 PPPD vs. classic = DGE Bloechle96 1999 PPPD vs. classic = DGE Wenger102 1999 PPPD vs. classic = Morbidity Tran101 2004 PPPD vs. classic = DGE Lin98 2005 PPPD vs. classic ↑ DGE with PPPD Seiler107 2005 PPPD vs. classic = DGE

Note: Shading pattern highlights similar trials. a Personal communication with senior author. TPN, total parenteral nutrition; PJ, pancreaticojejunostomy; POPF, postoperative pancreatic fistula; IVF, intravenous fluid; MPD, main pancreatic duct; PG, pancreaticogastrostomy; DJ, duodenojejunostomy; DGE, delayed gastric emptying; PPPD, pylorus preserving pancreaticoduodenectomy.

(Peter J. Allen, email communication, January 2014). Roux-en-Y A meta-analysis revealed that OS is the same between the groups, reconstruction performed to isolate the pancreaticojejunostomy although total hospital days after randomization was twofold more (PJ) from the other two anastomoses did not decrease the overall in the stenting group, principally related to recurrent biliary ob- leak rate, but the proportion of clinically significant leaks was struction requiring intervention. The authors recommend that for substantially reduced (74% versus 29% of all leaks; p = 0.01).133 patients projected to live more than 6 months, a surgical biliary In addition to these important technical trials relevant to the (as well as gastric bypass) be considered. Two separate randomized management of right-sided pancreatic neoplasms, other studies studies have demonstrated that prophylactic gastrojejunostomy have informed the management of patients undergoing PD. A in nonobstructed patients decreased the absolute risk of subse- group of studies established that a radical retroperitoneal lymphad- quent gastric outlet obstruction by roughly 20%, but did not affect enectomy does not confer improved cancer-specific survival (four OS.146,147 Finally, there is evidence that celiac neurolysis with al- randomized trials).134–137 Additionally, routine adjuvant parenteral cohol injected at laparotomy in patients with unresectable disease nutrition has proven to be detrimental.138 A previous single-insti- improves quality of life and OS.148 tution randomized trial suggested that routine nondrainage after a 139 pancreatic resection is safe, whereas a recent multi-institution Operative and Surgical Pathology Reporting and randomized study revealed a much higher mortality rate in patients without drains,140 leaving this issue unresolved. Just as the ISGPS has sought to standardize complication reporting, there have been efforts to standardize operative and pathology Distal Pancreatectomy reporting to facilitate collaboration between institutions, establish A distal pancreatectomy and splenectomy for left-sided PDA is a a minimum standard of quality, and provide consistency to the simpler operation than pancreaticoduodenectomy, yet also car- literature. With regard to the operative dictation, a description of ries significant risk. POPF is the principal morbidity associated the clinical stage (relationship to mesenteric vessels and evidence of with distal pancreatectomy. Clinically significant leaks occur in metastatic disease) is important. Specific mention of the liver, peri- roughly 10% of cases. In 10% to 20% of cases, a leak is appreciable toneum, and small intestines is necessary. Blood loss and the need as amylase-rich fluid in surgical drains, but does not add morbid- for transfusion are recorded. The surgical technique used to dissect ity. There are now roughly a half-dozen randomized clinical trials the uncinate process should be described, as well as the manage- examining the effect of pancreatic stump management on POPF, ment of the SMA and SMV (e.g., were they skeletonized? resected? ranging from staplers to mattress sutures. In summary, no posi- the method of visceral vessel repair?). The anastomotic techniques tive interventions have been discovered. The DISPACT trial was need to be described. The important elements of the pancreaticoje- the largest of these trials. This European multi-institution study junostomy have been addressed by the ISGPS, as mentioned previ- 93 analyzed 352 patients, and compared stapled and hand-sewn clo- ously. If a frozen section analysis was performed, the results should 149 sures. The pancreatic leak rate was roughly 30% in both groups be stated. Similarly, any gross residual disease must be reported. (p = 0.56).141 Fibrin sealant and falciform ligament patches have Standards for pathology reporting have been established by also been tested, with no observed benefit.142, 143 Interestingly, ul- the College of American Pathologists, and protocols are available trasonic dissection of the pancreas with ligation of all visualized at the Web site (http://www.cap.org/apps/cap.portal). On the ducts in nonfibrotic glands was associated with improved pancre- pathology review, tumor site (e.g., head, uncinate, body, tail), atic leak rates compared to conventional division and suturing maximum tumor diameter (in centimeters), histologic type or sub- (n = 58, 4% versus 26%, p = 0.02). Roughly 20 4-0 silk ligatures type, and histologic grade (well, moderate, or poor) are provided. were used per neck transection in the ultrasonic dissection group, Extension into extrapancreatic tissue is described. Margins are and transection took 10 extra minutes, on average.144 assessed (e.g., involvement or distance), including the uncinate, pancreatic neck, common bile duct, and duodenum. The distance Palliative Surgery to the margin (in millimeters) from the tumor should be stated. The posterior pancreatic surface margin is also reported, although There have been five randomized trials directly comparing hepati- this is not a transected or surgical margin. Microscopic invasion of cojejunostomy with endoscopic or percutaneous biliary decom- the lymphatics, small vessels, and nerves are indicated. The TNM pression for patients with malignant periampullary obstruction.145 stage and the component elements are provided according to the

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AJCC 7th edition staging system. A minimum of 12 lymph nodes occur early after resection. A study of recurrence patterns out of should be evaluated. Treatment effect is described if the patient Memorial Sloan-Kettering revealed that 12% of resected patients has received neoadjuvant therapy. developed a local-only recurrence pattern; 33% had metastatic disease only and 46% had both local and metastatic disease (recur- 160 Assessing Prognosis rence status was unknown in the remaining patients). Identifying biomarkers to predict patterns of recurrence could help select the patients who are most likely to benefit from intensive Although PDA is widely viewed as an aggressive cancer, like other local therapy (radiation). The most intriguing biomarker to date in common cancers, tumors display a wide range of biology. The me- this area of research has been SMAD4. A study of pancreatic ade- dian survival after resection for PDA is around 18 months in large nocarcinomas from an autopsy series (n = 65) revealed that a local series27; roughly 20% of patients survive more than 5 years, and predominant pattern was associated with intact SMAD4 expres- a comparable number suffer cancer-specific mortality within just sion (7 of 9 cases), whereas a disseminated pattern was associated 1 year of surgery.5 There would be substantial value in accurately with absent SMAD4 expression (16 of 22 cases).49 This pattern predicting patients’ cancer-specific outcome; at the present time, was confirmed in tissue samples of patients from a phase II trial of there are no reliable tests to predict prognosis. The most frequently locally advanced PDA.161 Out of 15 patients with SMAD4-positive considered adverse prognostic factors include conventional patho- tumors, 11 had progression in a local-predominant pattern. In con- logic features (lymph node metastases, poor differentiation, tumor trast, 10 of 14 patients with absent SMAD4 had significant distant size >3cm, and positive resection margins). The approximate pro- spread. These studies suggest that patients having tumors with portions of resected PDAs that fulfill each criterion are 75%, 40%, intact SMAD4 are most likely to benefit from radiation, whereas 50%, and 40%, respectively.27 It must be remembered that each of those patients with absent SMAD4 should only receive systemic these individual prognostic factors are weak predictors of outcome, therapy. However, a study of resected PDA samples revealed that with multivariate Cox proportional hazards ratios only around resection alters the natural history of PDA recurrence, such that 1.5. Winter et al.,162 studied 137 patients who underwent resec- SMAD4 status is no longer predictive of recurrence pattern in this tion for PDA and died within 1 year from their disease or survived setting.160 Other biomarkers162 were examined as part of that study, more than 30 months (patients with intermediate survival were and MUC1 expression was associated with a metastatic recurrence excluded). Adverse pathologic features were frequently present in pattern. In a multivariate analysis, lymph node spread was the only long-term survivors; for instance, 65% of patients in the long sur- variable (including the tested biomarkers) associated with pattern vivor group had lymph node metastases in the resected specimen. of failure. Patients without regional lymph node metastases had Conversely, lymph node metastases were not detected in 17% of an increased risk of a local-only recurrence, typically in a rela- the short survivor group, yet they still recurred early after resection tively delayed fashion.160 These data highlight that some patients and succumbed to their disease. would likely benefit from intensified local therapy, whereas others Perhaps the most robust prognostic marker routinely used in

are best suited to receive systemic therapy only. Future studies are OF ONCOLOGY PRACTICE patients with localized and resectable PDA is the postoperative CA needed to define a personalized approach. 19-9 level. CA 19-9 is a high–molecular-weight glycolipid that is a sialylated derivative of the Lewis a antigen (normally expressed by epithelial cells and absorbed onto the surface of erythrocytes). Adjuvant Therapy The oligosaccharide epitope is also present on mucins secreted by pancreatic cancer cells and detectable in the serum. A markedly According to the National Comprehensive Cancer Network elevated preoperative CA 19-9 level has some prognostic value (on (NCCN) guidelines, adjuvant chemotherapy is recommended for par with conventional pathologic features). Preoperative CA 19-9 patients who recover well from pancreatic resection. Acceptable has also been used by some surgeons as a predictor of unresectable strategies include chemotherapy alone (gemcitabine, 5-FU, or disease when the lesion appears resectable on imaging. Roughly capecitabine monotherapy), or chemoradiation plus chemotherapy 30% of patients with serum values above 300 U/mL were found (gemcitabine or 5-FU monotherapy, either given before or after to have a contraindication to resection on staging laparoscopy.150 chemoradiation).157 Unfortunately, these regimens all consist of However, preoperative CA 19-9 is particularly limited in patients single-agent therapy with minimally effective agents. A meta-analysis with biliary obstruction because the antigen is falsely elevated in of five randomized adjuvant trials including 951 patients concluded this setting.151–153 In addition, the sensitivity suffers because 5% to that adjuvant therapy provides a 3-month median survival advantage, 10% of the population are unable to express CA 19-9 due to Lewis and a 3% absolute improvement in 5-year survival. To put these find- antigen variability (related to the presence or absence of a fucosyl- ings in perspective, patients typically require a 6-month course of transferase).154–156 As noted previously, CA 19-9 is most informative adjuvant treatment to achieve a 3-month survival.158 Although these after resection when biliary obstruction is no longer a confounding figures may appear unappealing to many patients, the reality is more variable and there has been macroscopic clearance of the disease. complex; many patients receive no benefit at all, and may even be In a landmark ad hoc analysis of the Radiation Therapy Oncol- harmed with treatment, whereas a subset of patients receive a robust ogy Group (RTOG) 9704 adjuvant trial, an elevated postoperative and durable survival benefit with these adjuvant treatments. Identify- CA 19-9 level (≥180 U/mL, drawn 1 to 2 months after resec- ing which patients are most likely to experience a survival benefit is tion) was associated with a multivariate proportional HR of 3.6.154 as important as discovering superior treatment regimens. Interestingly, Lewis antigen-negative individuals (who cannot express elevated serum CA 19-9) had the same survival as patients Adjuvant Trials with low CA 19-9 levels for unclear reasons. There have been eight prospective and randomized adjuvant trials Patterns of Failure that have shaped current treatment recommendations, including: five European trials, two in the United States, and one in Japan Although OS after resection for PDA is roughly 18 months,27 (Table 49.5).163–170 Out of these eight trials, only four were consid- patients typically recur by 1 year,159 indicating a short survival time ered positive with respect to the planned primary end point (one in once a recurrence is detected (comparable in survival to patients the United States and three in Europe).164,165,168,169 The continent with metastatic disease). Recurrences have been reported in virtu- where these trials were performed has played an important factor ally every organ site, but most commonly occur in the retroperi- in defining the standard of care adjuvant treatment strategy around toneum (57%), liver (51%), peritoneum (35%), and lung (15%). the world; chemoradiation is commonly performed in addition Interestingly, lung recurrences are typically delayed, and rarely to chemotherapy in the United States, whereas chemotherapy 670 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 49.5 Prospective and Randomized Adjuvant Trials for Pancreatic Cancer

Trial Year N Randomization OS (Months) P GITSG168 1985 43 Bolus 5-FU/4,000 cGy vs. observation 20 vs. 11 0.04 Bakkevold169a 1993 61 AMF vs. observation 23 vs. 11 0.04 EORTC163a 1999 218 Continuous 5-FU/4,000 cGy vs. observation 21.6 vs. 19.2 0.5 ESPAC-1165 2004 289 Bolus 5-FU vs. observation (2 × 2 design) 20.1 vs. 15.5 0.009 Japan167 2006 89 5-FU/cisplatin vs. observation 12.5 vs. 15.8 0.9 ESPAC-3166 2010 1088 Gemcitabine vs. 5-FU 23.6 vs. 23.0 0.4 RTOG 9704170 2011 451 Gemcitabine + ChemoXRT vs. 5-FU + ChemoXRT 18.7 vs. 17.3 0.9 CONKO-001164 2013 368 Gemcitabine vs. observation 22.8 vs. 20.2 0.01

Note: Statistically significant findings in bold (p <0.05). a Included all periampullary cancers. OS, overall survival; AMF, adriamycin, mitomycin C, 5-FU; ChemoXRT, Chemoradiation.

( without radiation) is the standard in Europe. The principal adju- followed by chemotherapy (bolus leucovorin at 20 mg/m2 and 5-FU vant trials will briefly be reviewed, emphasizing the strengths and at 425 mg/m2 daily for 5 days, every 28 days for six cycles); (2) ad- weaknesses of the studies. juvant chemotherapy only (without chemoradiation) as previously The Gastrointestinal Tumor Study Group (GITSG) trial was defined for group 1; (3) chemoradiation only (without chemother- the first of the adjuvant trials and was a small phase III trial (by apy) as previously defined for group 1; and (4) no treatment. The today’s standards, n = 49 patients treated between 1974 and 1982) two groups receiving chemotherapy (groups 1 and 2) had superior performed in the United States. Patients in the experimental arm survival as compared to those who did not (20.1 versus 15.5 months; received 40 Gy (split course with 20 Gy in each course, and a p = 0.009). When chemoradiation was analyzed separately, the OS 2-week break in the middle). Bolus 5-FU was administered weekly were 15.9 months with the two chemoradiation groups (groups 1 for 2 years as maintenance therapy (500 mg/m2), but was given and 3) and 17.9 months without chemoradiation (groups 2 and 4; daily for the first 3 days of each radiation course. The treatment arm p = 0.05). When patients who received chemotherapy only were was compared to an observation only arm, and the chemoradiation excluded from the no chemoradiation group (leaving just patients in group had superior survival (20 versus 11 months; p = 0.04). The the observation group), there was still a strong trend toward improved study has been criticized for its small sample size. Furthermore, it is survival without chemoradiation. The results have been widely ques- not known whether the observed benefit was attributable to chemo- tioned because of the complex study design and because patients radiation, to maintenance chemotherapy, or to both. Nevertheless, apparently received suboptimal radiation therapy (split course, no this landmark study established a role for adjuvant chemoradiation central quality of radiation control, 9% protocol violation, a very as an acceptable treatment for resected PDA in the United States. high [62%] local failure rate compared to recent trials). Although Two small trials (in Norway169 and Japan167) were performed this study established chemotherapy alone as an acceptable standard over the last 15 years that provided equivocal results for chemo- of care in Europe and other parts of the world, oncologists in North therapy alone, compared to surgery only. In the Norwegian trial, America remain largely divided on the role of chemoradiation. authored by Bakkevold et al.,169 61 patients with periampullary The Charité Onkologie (CONKO-001) trial primarily took cancer (only 47 with PDA) were randomized to receive doxorubi- place in German centers between 1998 and 2004,159 with updated cin, mitomycin C, and 5-FU (six cycles), or observation. Patients results recently reported.164 The trial was an appropriate follow-up receiving adjuvant chemotherapy had an improved median sur- to ESPAC-1, which was interpreted in Europe as evidence in favor vival (23 versus 11 months; p = 0.04), but 2-year survival was simi- of adjuvant chemotherapy (without chemoradiation). Moreover, lar (43% versus 32%; p = 0.1). In the Japanese trial, 89 patients only 5-FU–based adjuvant chemotherapy had been tested up to were randomized to just two cycles (separated by 4 to 8 weeks) of that point, whereas the superiority of gemcitabine over 5-FU had 5-FU (500 mg/m2 as a continuous infusion over 5 days) plus cispla- been established for patients with advanced PDA (discussed in the tin (80 mg/m2 on day 1 of each cycle), versus observation. OS was Stage IV: Metastatic Disease section).171 A total of 368 patients similar in the two groups (12.5 versus 15.8, respectively; p = 0.9). were randomized to receive six cycles of gemcitabine (4-week cy- The European Organization for Research and Treatment of cles) at a weekly dose of 1,000 mg/m2 every 3 weeks with a 1 week Cancer (EORTC) trial was Europe’s response to the GITSG trial break versus observation alone. Chemoradiation was not included and proved to be the largest adjuvant trial for PDA at that time.163 in the treatment arm. The initial report reached its primary end A total of 218 patients with either PDA or other periampullary point of disease-free survival (13.4 versus 6.9 months; p <0.001), cancer were randomized to chemoradiation or observation. The but OS was not significantly different.159 However, the updated treatment arm received split-course radiation for 40 Gy (as with analysis demonstrated improved OS with gemcitabine (22.8 versus GITSG). However, 5-FU was given as a continuous infusion (as 20.2 months; p = 0.01).164 The small absolute difference in sur- opposed to bolus) on days 1 through 5 of each radiation course (for vival could be explained, in part, by the fact that 38% of patients a total of 125 mg/m2). No maintenance chemotherapy was admin- did not receive the planned dose of gemcitabine and 13% did not istered. OS was 21.6 months with treatment and 19.2 months with receive at least one full cycle. In addition, most patients in the observation (p = 0.5). control arm received palliative chemotherapy once a recurrence The European Study Group for Pancreatic Cancer (ESPAC-1) was detected. Grade 3 through 4 toxicities were extremely rare was the next large randomized adjuvant trial.165 A total of 289 pain the treatment arm (no specific toxicity occurred in more than tients were randomized to a 2×2 design, with one of the four 3% of patients in the gemcitabine group). Although the median groups receiving no treatment. Treatment groups included (1) survival advantage is modest, it should be emphasized that the chemoradiation (40 Gy split-course radiation with bolus 5-FU 5-year survival advantage was 10% (20.7% versus 10.2%; p <0.05) at 500 mg/m2 on days 1 through 3 of radiation, as with GITSG) and the 10-year survival advantage was 5% (12.2% versus 7.7%).

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Overall survival 70% of patients, and local–regional in 30% (a low figure relative to 100 the local recurrence rate reported in ESPAC-1). Subsequent sites of Log-rank P = .01 recurrence were not reported. The RTOG-9704 study had several additional informative findings. Patients treated at centers that did 80 not meet the quality assurance standards had inferior outcomes.173 As previously described, postoperative CA 19-9 was identified as an 60 important prognostic variable and should be considered in planning future adjuvant trials.154 Finally, the inferior outcomes in Gemcitabine patients with PDA of the left side of the pancreas raises questions 40

Survival, % Survival, about whether this group should be included in adjuvant trials with chemoradiation. 20 Observation Future Questions and Ongoing Adjuvant Trials 0 Based on these trials, 6 months of adjuvant therapy is clearly sup- 0246810ported as the standard of care for patients with resected PDA. Years Whether adjuvant chemoradiation is important remains an unan- swered question, and is the subject of an ongoing randomized trial Figure 49.6 Improved long-term survival with gemcitabine monotherapy, in the CONKO-001 trial. The highlighted area represents patients who in the United States (RTOG 0848, NCT01013649). The study likely had a substantial benefit from gemcitabine monotherapy. (Modified compares the impact of chemotherapy alone to chemotherapy from Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy plus chemoradiation. Patients in the radiation arm will receive 28 with gemcitabine and long-term outcomes among patients with resec- fractions of 1.8 Gy (50.4 Gy total, either 3-D conformal or inten- ted pancreatic cancer: the CONKO-001 randomized trial. JAMA 2013;310: sity-modulated radiotherapy) and either capecitabine (825 mg/m2 1473–1481.) twice daily) or 5-FU (250 mg/m2 per day as a continuous infusion for the duration of radiation) as a radiosensitizer. Unlike the RTOG 9704 trial, chemoradiation is administered after five cycles of gemcitabine-based chemotherapy have been completed. This These data provide very strong evidence that, in a small subset of trial design reflects an emerging trend in many centers toward de- patients (i.e., 1 in 10), gemcitabine monotherapy is highly effec- ferring chemoradiation until after chemotherapy is completed in tive (Fig. 49.6). The opportunity to achieve long-term survival due order to maximize systemic control early on and to spare patients to gemcitabine (albeit uncommon) is an important consideration who recur early at distant sites the cost and morbidity of radiation. for patients contemplating adjuvant treatment, despite the meager The next ESPAC trial (ESPAC-4, ISRCTN96397434) is evaluating improvement in median survival. OF ONCOLOGY PRACTICE the role of doublet therapy (gemcitabine plus capecitabine versus The European ESPAC-3 trial is the largest adjuvant trial to gemcitabine alone) in the adjuvant setting. It is worth pointing date, and directly compared chemotherapy with gemcitabine out that this regimen did not improve OS in advanced pancreatic (1,000 mg/m2 over 30 minutes weekly, 3 out of 4 weeks) versus 5-FU cancer (see the Stage IV: Metastatic Disease section).174 CONKO- (bolus folinic acid at 20 mg/m2 plus bolus 5-FU at 425 mg/m2 on 005 (DRKS00000247) is testing the addition of erlotinib to the days 1 to 5, every 28 days for six cycles as administered in ESPAC-1). standard-of-care gemcitabine (versus gemcitabine alone) based As with CONKO-001, no adjuvant chemoradiation was given. Me- on a small, but statistically significant improvement in survival in dian OS were 23.6 and 23.0 months, respectively (p = 0.4), dem- the metastatic setting.175,176 As discussed later in detail, two regi- onstrating equivalence between the two agents. However, this study mens, (1) gemcitabine plus nab-paclitaxel and (2) FOLFIRINOX, did not change the emerging paradigm of frontline gemcitabine were recently shown to be superior to gemcitabine in the meta- monotherapy at most centers, because toxicity was less with gem- static setting.177,178 In light of these encouraging results, there are citabine (14% serious adverse events with 5-FU versus 7.5% with plans to test both regimens in the adjuvant setting (NCT01964430 gemcitabine; p <0.001). The increased toxicity due to 5-FU was and NCT01526135, respectively), using a similar control arm in primarily related to increased stomatitis and diarrhea. both studies (gemcitabine monotherapy). Finally, the role of neo- Finally, RTOG 9704 was the second United States adjuvant trial, adjuvant chemotherapy in patients with resectable disease is not completed in 2002172 and updated in 2011.170 The trial’s treatment known. There are selected centers that routinely treat patients with arms paralleled the ESPAC-3 study (5-FU versus gemcitabine), resectable disease with neoadjuvant therapy,84 and the NCCN except patients in both treatment groups received 5-FU–based guidelines recommend that such an approach be conducted as chemoradiation in the middle of their adjuvant chemotherapy part of a clinical trial. In one of the largest series, from the M.D. course. Total treatment duration in both groups was 6 months, Anderson Cancer Center,84 outcomes are favorable (34 months) and the study question related to chemotherapy (5-FU versus gem- for patients who ultimately make it to pancreatic resection. The citabine), and not the role of chemoradiation. A total of 451 pa- median survival of the entire cohort (22.7 months) in an intent-to- tients were randomized to chemotherapy with 5-FU at 250 mg/m2 treat analysis is similar to historical controls with localized disease per day given as a continuous infusion (different from ESPAC-3) (see Table 49.5). Proponents argue that a neoadjuvant approach al- or gemcitabine 1,000 mg/m2 given weekly. Patients received one lows for an objective assessment of treatment response, early treat- chemotherapy cycle prior to chemoradiation (3 weeks) and 12 ad- ment of microscopic metastases, and an additional 3 to 6 months ditional weeks afterwards (two cycles of 5-FU consisting of 4 weeks to monitor disease biology before committing to an operation with on and 2 weeks off; three cycles of gemcitabine with 3 weeks on substantial risk. It is likely that as adjuvant treatment improves, and 1 week off). Chemoradiation was given to all study patients more centers will move to a neoadjuvant paradigm, similar to the as 50.4 Gy with continuous infusion 5-FU (250 mg/m2 per day), treatment of other upper gastrointestinal cancers. and prospective quality assurance was performed. The primary end points of the study were OS for the whole cohort and for pancreatic Surveillance Postresection head cancers. For all patients, OS was similar in the gemcitabine and 5-FU arms (18.5 versus 16.4 months; p = 0.5). In patients with The current NCCN guidelines recommend that patient follow- pancreatic head tumors (86% of the total study population), those up after resection should include visits every 3 to 6 months for receiving gemcitabine had a trend toward superior survival in the 2 years, and then annually. Surveillance CT scans and serial tumor multivariate analysis (20.5 versus 17.1 months; p = 0.08). The site markers (CA 19-9 at minimum) should be assessed, along with a of first relapse was recorded in this study, and was distant in roughly history and physical exam. These recommendations are not based 672 Practice of Oncology / Cancers of the Gastrointestinal Tract on Level 1 evidence, but rather expert consensus.179 In practice, defined as a “tumor [that] involves the celiac axis or the superior surveillance patterns range widely from close follow-up with CT mesenteric artery (unresectable primary tumor).” A representative imaging and CA 19-9 levels every 3 months, to no routine sur- CT scan of stage III PDA is provided in Figure 49.7. These presen- veillance at all.180 Poor outcomes after recurrence (roughly 6 to tations account for about 30% of all pancreatic cancers and typi- 12 months in the adjuvant trials discussed previously), and a lack cally have an average survival of 1 year or less, even when treated of proven benefit for salvage chemotherapy, argue against close (see Table 49.1). However, it is problematic to lump these patients surveillance. However, as the number of second-line agents with into a single group with regard to treatment decisions, because of activity against PDA increases, so will the opportunity to prolong heterogeneous biology and differences in other relevant clinical survival with early detection of recurrence and intervention. It factors. Management decisions for patients with locally advanced should be noted that a rise in CA 19-9 often precedes radiographic tumors are based on both the local extent of involvement of the evidence of recurrence by 3 to 12 months.181 However, initiating celiac and/or SMA arteries and critical primary branches, such as chemotherapy based on changes in tumor marker levels alone is the proper hepatic artery, as well as the clinician’s answer to the not currently recommended (although widely practiced), due to following questions: the risk of false positive and false negative results.153,154 1. What therapeutic goal appears to be most rational based not There are a few reports that support the benefit of close surveil- only on the tumor staging, but also on performance status, lance and early intervention. One study, presented in abstract form, weight loss, and significant comorbid illnesses? Along these described 139 patients who underwent resection for PDA. All pa- lines, is the treatment potentially curative? Is minimal or mod- tients were advised to have CT scan and CA 19-9 surveillance every erate antineoplastic intensity more appropriate? Or is treatment 3 months in the first year, every 6 months in the 2nd year, and annu- supportive and purely palliative? ally thereafter. The patients were retrospectively analyzed in three 2. What is the level of treatment intensity that this patient would groups: those who followed the recommendations, those who un- be able to accept and withstand psychologically and emotion- derwent surveillance but with less frequency than recommended, ally in addition to physiologically? and those who did not follow up. Survivals in the three groups were 3. What are the support structures surrounding this patient, and 16.6, 15.7, and 8.7 months, respectively. The authors concluded are they up to the challenges that will be incurred by the man- that close follow-up is advisable. Notably, the proportions of patients agement selected? who received adjuvant treatment in each group were not reported. Selected patients may even benefit from a metastasectomy. Pragmatically, stage III clinical presentations have been divided Pulmonary metastases (as compared to liver or peritoneal metasta- into borderline resectable and clearly unresectable (introduced pre- ses) typically occur in a delayed fashion after surgery.160 Therefore, viously in the section Stage I, II: Localized Disease, Evaluation the biology and natural history of patients who develop isolated and Assessing Resectability), with the conceptual distinction being pulmonary metastases may represent a unique subgroup where the probability of safely and successfully resecting the tumor with- resection of these lesions is beneficial. The Johns Hopkins group out antecedent chemotherapy or chemoradiotherapy. identified 31 patients with isolated lung metastases at a median of 34 months post pancreatectomy. A total of 9 had the lung lesion re- Basic Management Considerations sected, and these patients survived an additional 19 months (range 5 to 29 months) after the intervention.182 The initial evaluation of patients with presumed pancreatic adenocarcinoma will be the same whether the patient ultimately is STAGE III: LOCALLY ADVANCED DISEASE demonstrated to have a resectable, borderline resectable, or locally unresectable disease at presentation. This component of management has been addressed previously in the chapter (see AJCC Staging Versus “Intent of Stage I, II: Localized Disease, Presentation and Evaluation and Management”–Based Staging Assessing Resectability). For patients treated initially with chemotherapy or chemoradiation, several additional management In the current (7th) edition of AJCC staging for pancreatic adeno- considerations need to be considered (also relevant for patients carcinoma, stage III cancers are T4, Nany M0 malignancies, with T4 with resectable disease who are to receive neoadjuvant treatment).

LGA Mass CHA Mass PV SMV SMA

A B Figure 49.7 CT scans of a locally advanced, stage III PDA in the pancreatic body. Coronal images. (A) The arterial phase. Visceral arteries named are left gastric artery (LGA), common hepatic artery (CHA), and superior mesenteric artery (SMA). The CHA is encased. (B) The venous phase. The portal splenic confluence is completely occluded.

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Patients generally require histologic confirmation of a pancreatic Evolution of Management for Local–Regional cancer diagnosis prior to treatment. Additionally, relief of ob- Unresectable Disease structive jaundice and duodenal obstruction is necessary when present. These interventions will be concurrent with other basic The early, practice defining, randomized experiences have been 188 assessments and interventions such as nutritional optimization, reviewed in many prior publications and textbooks, and key treatment of dehydration and electrolyte abnormalities, pain man- ones are highlighted in Table 49.6. It is important to remember agement, and attention to depression if present. It is important how dated some studies are with respect to patient selection and to emphasize that multidisciplinary teams with focused, manage- evaluation, chemotherapy selection, and radiation planning and ment experience for gastrointestinal (GI) malignancies of the delivery (typically delivered as 2-D nonconformal, split course, upper abdomen achieve the best results, and include expertise in low-dose therapy). Nevertheless, these papers established proof of pathology, chemotherapeutic, radiotherapeutics, surgical manage- principle for treatment feasibility with acceptable toxicity, and the ment, interventional radiology, and endoscopy, as mentioned in value of 5-FU–based radiosensitization in this context. the opening of the chapter.183 From the mid 1990s through the first decade of the current century, there have been a series of important lessons learned in the management of locally advanced pancreatic cancer. Accept- Local–Regional Unresectable Disease able chemoradiation strategies integrating insights gained from past studies are summarized in Table 49.7. There is a biologic basis Impact of Prognostic Factors in the Management for needing both improved local control and improved systemic of Locally Unresectable Patients control to optimize results. Improved local control in pancreatic cancer has been strongly Patients with locally advanced, or stage III, PDA have an average suggested by the autopsy studies by Iacobuzio-Donahue et al.,49 OS between 7 and 12 months (Table 49.6). Several patient-specific previously described (see the Stage I, II: Localized Disease, factors have been adversely associated with outcome in this con- Adjuvant Therapy section), and validated in patients with locally text, including anemia, poor performance status, elevated CA advanced disease.161 Investigators observed that patients with tu- 19-9, and elevated Charlson Comorbidity Score. In addition, use mors having intact SMAD4 expression were more likely to have and response to systemic chemotherapy as the initial treatment, locally destructive tumors and a lower burden of metastatic disease prior to chemoradiotherapy, appears to favorably predict (and pos- than patients with tumors showing SMAD4 loss. Recently, Oshima sibly impact) survival.184–187 et al.189 found that abnormal TP53 expression (either absence or

TABLE 49.6 PRACTICE OF ONCOLOGY PRACTICE Selected Locally Advanced Pancreatic Ductal Adenocarcinoma Randomized Trials

Patient Median Survival Year Study Name Number Radiation (Gy) Chemotherapy (Months) 1980292 SWOG 33 60 MeC, 5-FU, SMF 8.8 29 60 MeC, 5-FU, testolactone 6.9 1981293 GITSG 83 60 5-FU 9.4 86 40 5-FU 9.8 25 60 None 5.3 1985192 ECOG 37 40 5-FU 8.3 34 None 5-FU 8.2 1985294 GITSG 73 60 5-FU 8.5 70 40 Doxorubicin 7.6 1988190 GITSG 22 54 5-FU, SMF 9.7 21 None SMF 7.4 1994295 Mayo Clinic 44 50–60 5-FU 7.8 43 50–60 Hycanthone 7.8 2005296 ECOG 62 60 None 8.4 64 60 5-FU, MMC 7.1 2008191 FFCD/SFRO 59 60 Gemcitabine 8.6 60 None Gemcitabine 13 2011193 ECOG 34 50 Gemcitabine 11.1 37 None Gemcitabine 9.2 2013207 SCALOP 38 50, Gemcitabine Gemcitabine, Capecitabine 15.2 36 50, Capecitabine Gemcitabine, Capecitabine 13.4

Note: Statistically significant findings are in bold (p <0.05). MeC, Methyl-CCNU; SMF, streptozotocin, mitomycin C, 5-FU. 674 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 49.7 Recommended Radiation Treatment Volumes in Commonly Used Chemoradiation Regimens for Localized Pancreatic Cancer

No Arterial Involvement Extensive Arterial Involvement with Chemotherapy Chemotherapy Dose Radiation Dose or Abutment with Likely Uncertain Resectability or Arterial Choice and Schedule and Schedule Resectability (T3 or T4) Encasement/Unresectable (T4) Gemcitabine 400–500 mg/m2 weekly 50.4 Gy over 5.5 wks GTV only GTV only (good PS) or 30 Gy over 2 wks (poor PS) 1 g/m2 weekly 36 Gy over 3 wks GTV only GTV only 40 mg/m2 twice weekly 50.4 Gy over 5.5 wks GTV + ENI GTV only Capecitabine 800–825 mg/m2 twice 50.4 Gy over 5.5 wks GTV + ENI GTV only per day on days of (good PS) or 30 Gy radiation over 2 wks (poor PS) PVI 5-FU 225 mg/m2 daily or 300 50.4 Gy over 5.5 wks GTV + ENI GTV only mg/m2 on days of (good PS) or 30 Gy radiation over 2 wks (poor PS)

PS, performance status; GTV, gross tumor volume; ENI, elective nodal irradiation; PVI, protracted venous infusion. Modified from Royal RE, Wolfe RA, Crane CH. Cancer of the pancreas. In: DeVita VT Jr, Lawrence TS, Rosenberg SA, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles & Practice of Oncology. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2011. nuclear accumulation) was associated with a local–regional recur- (chemoradiotherapy plus chemoradiation, median survival 13.0 rence pattern in patients with resected PDA, whereas CDKN2A months versus 8.0 months without additional chemotherapy).195 loss was associated with widespread metastases.189 Similar to an On further analysis, the authors could not find prognostic factor aforementioned study by Winter et al.,160 SMAD4 expression was variation between to the two groups to explain this difference. not associated with pattern of failure in this patient cohort follow- Gemcitabine has been found to be marginally superior to 5-FU ing resection.189 in the metastatic setting.171 The drug also has marginal efficacy as Past studies suggest that the controversy of using chemotherapy a single-agent adjuvant therapy after resection for PDA.164 There alone versus chemoradiotherapy should be reframed to acknowl- is some suggestion that it may be better than 5-FU in the adjuvant edge that there might be potential roles of each. There have been setting, when chemoradiation is included,170 although there is no several randomized trials comparing chemotherapy to chemother- such trend in a European trial comparing these agents without apy plus chemoradiation,190–193 with mixed results (each appear in chemoradiation.166,170 Thus, there has been interest in exploring Table 49.6). An older ECOG study published in 1985 (with the gemcitabine as a radiation sensitizer; indeed, the drug is potent aforementioned limitations) compared weekly 5-FU against the in this role based on preclinical and clinical data.196 Investiga- same chemotherapy treatment preceded by 40 Gy radiation (com- tors from the M.D. Anderson Cancer Center, the University of bined with 5-FU) and found no difference in survival. The multi- Michigan, and other sites explored the use of gemcitabine with institution French Fédération Francophone de Cancérologie radiotherapy in various contexts, with the following observations: Digestive-Société Française de Radiothérapie Oncologie (FFCD/ Radiotherapy fields designed to cover gross tumor and at risk nodal SFRO) study found decreased survival in patients receiving 60 Gy basins cannot safely be targeted with concurrent gemcitabine un- radiation concomitantly with 5-FU and cisplatin, and followed less the gemcitabine dose is reduced from the chemotherapy-only with maintenance gemcitabine, compared to gemcitabine alone level of 1,000 mg/m2 to 300 to 600 mg/m2. Additionally, the daily (8.6 versus 13 months). The chemoradiation regimen used in this fraction size should not exceed 1.8 Gy when targeting expanded trial has been criticized as being particularly toxic (more on this fields with draining lymph nodes. If the desire is to administer in the following).191 The LAP-07 trial with gemcitabine or gem- full-dose gemcitabine (1,000 mg/m2) weekly with higher radiation citabine plus erlotinib for four cycles, followed by either chemora- doses (e.g., 2.4 Gy fractions), then radiotherapy must be limited to diotherapy or additional chemotherapy (two cycles), failed to show gross tumor only with tight margins, and special attention must be any difference in survival between the two arms. About one-third given toward inadvertent targeting organs such as the duodenum, of patients had progressed by the time of the second randomiza- stomach, and small bowel. Subsequent studies have demonstrated tion. The trial results, although final, have only been reported in that respecting these guidelines allows for acceptable toxicity, espe- abstract form.194 However, a GITSG study from 1988 comparing cially when combined with appropriate supportive care measures, 5-FU and radiation followed by streptozotocin, mitomycin C, and treatment planning that accounts for target and organ movement 5-FU chemotherapy to the same chemotherapy alone showed an with respiration, and intensity modulated planning and delivery improved median survival (9.7 versus 7.4 months) with multi- aimed at minimizing doses to sensitive critical organs.196–200 modality therapy.190 Most recently, ECOG 4201 from 2011 sug- The work of Ben Joseph et al.197 at the University of Michigan gested that locally advanced patients randomly assigned to receive validates this approach. Investigators conducted a phase I/II dose chemoradiotherapy with gemcitabine followed by five cycles of escalating study of radiotherapy dose over 25 fractions (totaling gemcitabine alone did better than patients receiving gemcitabine 50 to 60 Gy) in 50 patients, all deemed to have locally advanced without radiotherapy (11.1 versus 9.2 months; p = 0.016).193 It PDA (not borderline resectable). The maximal tolerated dose was is noted that this trial was closed, with only 71 patients accrued 55 Gy (2.2 Gy per fraction) in combination with fixed-dose rate and analyzed, a potential criticism of the results. Other nonran- gemcitabine (1,000 mg/m2). Patients had a median survival of 14.8 domized studies suggesting benefit to using a combination of mo- months and 24% (12 of 50 patients, a very high rate compared to 161,191,201,202 dalities, rather than one modality, include the recently reported previous studies ) underwent resection (10 R0 and 2 R1). Massachusetts General Hospital experience (improved survival Among resected patients, the median survival was 32 months. A with chemotherapy plus chemoradiation versus chemoradiation meta-analysis of three randomized trials and one comparative ret- alone, HR = 0.46; p <0.001),184 and a German study in which rospective study (including 229 patients) revealed a small but sig- treatment decisions were assigned from tumor board discussions nificant survival advantage with gemcitabine-based chemoradiation

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(at 12 months: HR, 1.5; p = 0.03), over 5-FU–based treatment, al- leucovorin, and irinotecan) has a response rate of 27% in the locally 210 though toxicity was higher.203 advanced setting, which rivals the best results with multimodal- 197,207 Technologic advances combined with greater understanding ity therapy. Planned and ongoing trials with FOLFIRINOX, of the mechanisms and impact of acute radiation toxicity have as well as with nab-paclitaxel plus gemcitabine (with or without ra- improved the safety profile of treatment. Excessive acute toxicity diation), will help establish the role of these treatments for locally quickly results when the radiation fractional dose increases, the advanced PDA. total dose increases, the field sizes are too large for the degree of drug sensitization or intensity, or radiation is delivered without Management of Borderline Resectable careful consideration of limiting dose volume to the stomach, duodenum, small bowel, or other critical organs. There is increasing Patients consensus that such toxicity can be associated with symptoms, increased costs, and decreased survival.191,200 Current NCCN guidelines for borderline resectable patients Capecitabine is an appealing alternative to 5-FU or gem- favor neoadjuvant therapy over directly going to surgery, while acknowledging the validity of both approaches and the absence of citabine as a radiosensitizer. Capecitabine is a prodrug of 5-FU 157 with near-complete oral bioavailability. It is converted to its ac- phase III data to definitively answer the issue. A meta-analysis tive form through a three-step process, with the last step occur- of 182 patients from 10 prospective trials of borderline resectable ring more reliably within tumor cells than in nonmalignant cells, patients included seven studies reporting on the impact of chemoradiation (with or without chemotherapy) and three on chemo- due to higher thymidine phosphorylase levels. Thus, systemic 211 levels of active 5-FU are actually decreased with capecitabine, therapy alone. At restaging following neoadjuvant therapy, 16% theoretically widening the therapeutic window of the drug. Aside of patients responded to treatment, 69% had stable disease, and from hand–foot syndrome associated with capecitabine, clinical 19% showed progression. The median survival for the cohort was trials reproducibly demonstrate an improved safety profile. The 22.0 months, and treatment-related grade 3 to 4 toxicity was ob- efficacy of capecitabine is comparable to 5-FU, at least in studies served in 32% of patients. Surgical exploration was performed in of other cancer types that directly compare them.204 Importantly, 69% of patients, and 80% of surgically explored patients were re- oral dosing obviates the need for semipermanent venous access sected. Moreover, 83% of resected specimens had microscopically and the attendant risks of thrombosis and infection. Nonrandom- negative resection margins. Among resected patients, 61% were ized data demonstrate that capecitabine (typically administered alive at 1 year, and 44% were alive at 2 years. The median survival at a daily dose of around 1,600 mg/m2) has comparable efficacy in this highly selected and favorable group was 22.0 months. to continuous infusion 5-FU, and an improved toxicity profile, as Although the survival of patients with borderline PDA after neoadjuvant treatment and resection is comparable to patients a radiosensitizer in patients with locally advanced PDA receiving 27 intensity-modulated radiation therapy (IMRT).205,206 Finally, the with resectable PDA, these data should be interpreted with a few recently published SCALOP I randomized trial in patients with points of caution. First, the study was underpowered and not de- OF ONCOLOGY PRACTICE locally advanced PDA, has suggested mildly increased efficacy signed to determine the best neoadjuvant regimen; thus, treatment (OS 15.2 versus 13.4 months; p = 0.01) and decreased toxicity choice is largely dependent on institutional preferences. Second, of capecitabine with irradiation, as compared to gemcitabine. In resected patients represent 56% of the total cohort, and are en- this study, sensitized radiation was administered after four cycles riched for patients with tumors that have favorable biology. In of gemcitabine and capecitabine chemotherapy (randomization these nonrandomized studies, it is possible that intrinsic biologic was performed after three cycles).207 Note that the chemosensitiz- factors were more important determinants of survival than neoad- ing dose of gemcitabine (300 mg/m2) was lower than the fixed- juvant treatment. Notably, nonresected patients with borderline PDA have a survival around 1 year, which is similar to patients dose rate levels successfully used in the abovementioned Ben 212 Josef study.197 with locally advanced disease. Finally, roughly 40% of patients A final lesson from previous studies of chemoradiation for locally with potentially resectable tumors do not undergo resection when advanced pancreatic adenocarcinoma demonstrate that induction a neoadjuvant approach is used. Whether unresected patients suf- chemotherapy prior to chemoradiation has advantages. Neverthe- fered a missed opportunity for resection (and therefore for long- less, chemotherapy, chemoradiation, or both have been studied and term survival) or were spared ineffective surgery is unknown. Most are acceptable approaches for locally advanced PDA. There are likely, the answer lies somewhere in the middle. no level 1 data conclusively supporting one approach over the other. However, several studies provide a meaningful rationale for beginning with induction chemotherapy. Roughly two-thirds EMERGING ROLE OF STEREOTACTIC BODY of patients with locally advanced PDA develop systemic metas- RADIOTHERAPY tases during treatment. Some of these individuals are less likely to benefit from radiation, and the costs and side effects of local SBRT is hypofractionated (one to five fractions) radiotherapy given radiation therapy may be avoided.208 An ad hoc analysis of a pro- in doses that, in aggregate, do not exceed 50 to 60 Gy per course. spective, nonrandomized study (GERCOR), revealed that patients Single fraction courses are usually in the dose range of 20 to 25 Gy. with locally advanced PDA who received consolidation chemora- The number of fractions and dose per fraction is determined by diation after induction chemotherapy had improved survival, as tumor size and radiation tolerance of the involved and/or adjacent compared to those who had chemotherapy alone (15.0 versus 11.7 organs. To be safe, these large-dose fractions are given with extra months; p <0.001).208 This has been validated by other retrospec- attention to immobilization, controlling for respiratory movement, tive data.209 The SCALOP trial, as previously described, showed image guidance, and dose shaping around critical structures. that sequenced chemoradiation after chemotherapy achieves The risk of severe or lethal normal organ damage is substantial very good results with locally advanced PDA.207 The GERCOR in the absence of proper attention to all required, relevant con- LAP-07, described previously, warrants additional mention here, siderations. In pancreatic applications, the primary dose-limiting because no benefit was observed with chemoradiation (50.4 Gy structure is the duodenum, followed by the stomach, remaining plus capecitabine) after chemotherapy (gemcitabine plus erlotinib small bowel, and other adjacent organs/structures. This approach of gemcitabine alone), as compared to additional chemotherapy has been applied with and without chemotherapy in a variety of (n = 269; OS, 15.2 versus 16.4 months; p = 0.8).194 pancreatic contexts, including locally unresectable, borderline re- Along these lines, certain multidrug combinations with higher sectable, locally recurrent, and as an adjuvant management boost response rates for advanced PDA than gemcitabine monotherapy after conventional radiotherapy.213–215 These studies demonstrated (see the Stage IV: Metastatic Disease section) are also promising reg- feasibility and acceptable toxicity in experienced hands, although imens for locally advanced PDA. FOLFIRINOX (5-FU, oxaliplatin, the exact role of this modality remains to be defined. 676 Practice of Oncology / Cancers of the Gastrointestinal Tract

STAGE IV: METASTATIC DISEASE phate (dFdCDP) and triphosphate (dFdCTP) forms. The active metabolites incorporate into DNA and inhibit chain elongation. Approximately 50% of patients with PDA will be diagnosed with Moreover, they deplete nucleotide pools by competitively inhibit- distant metastatic (stage IV) disease at the time of presentation.1 ing ribonucleotide reductase.218 Prognosis is dismal, with a median OS of less than 6 months and In the 1997 Burris trial, 126 patients with advanced pancreas an estimated 2-year survival of only 2%.3,7 Chemotherapy in this cancer were randomized to either of two arms: (1) gemcitabine setting improves survival by just a few additional months. There- 1,000 mg/m2 weekly for 7 weeks followed by 1 week of rest, then fore, the goals of therapy in this patient population are to prolong 3 doses per week every 4 weeks thereafter, or (2) bolus 5-FU 600 survival, as well as to palliate symptoms. mg/m2 once per week.171 Patients primarily had metastatic disease, although 26% had locally advanced disease. Treatment in both arms was generally well tolerated. Grade 3 through 4 hema- Gemcitabine as a Gold-Standard Therapy for tologic toxicities were higher with gemcitabine, including neutro- Metastatic Pancreatic Adenocarcinoma penia (25.9% versus 4.9%), thrombocytopenia (9.7% versus 0%) and anemia (9.7% versus 0%). Grade 3 through 4 nausea was also 5-FU was the principal treatment option for metastatic pancreatic more frequent in the gemcitabine arm (9.5% versus 4.8%). Clini- cancer through the 1990s, although response rates were under cal benefit, based on pain score, performance status, and weight, 20% and median survival was just 6 months.216 Other agents or was noted in 23.8% of patients in the gemcitabine arm versus only combinations of drugs failed to show any improvement over 5-FU 4.8% in the 5-FU arm (p = 0.0022). The survival advantage with monotherapy until a landmark study in 1997 by Burris et al.171 gemcitabine was just over 5 weeks, with median OS of 5.65 and demonstrating the superiority of gemcitabine for advanced PDA. 4.41 months, respectively (p = 0.0025). Survival at 12 months Since that study, gemcitabine has become the single most impor- was 18% in the gemcitabine arm versus 2% in the 5-FU arm. tant pancreatic cancer therapy, and the standard treatment arm in Partial tumor responses were observed in 5% of patients in the at least 19 phase III studies (Table 49.8). gemcitabine group, and stable disease was observed in 39%. In Gemcitabine (difluorodeoxycytidine [dFdC]) is a nucleoside contrast, no partial tumor responses were observed with 5-FU, and analog of deoxycytidine, and it is administered as a prodrug. Upon only 19% of patients experienced stable disease. As a result, gem- entry into the cell, gemcitabine is phosphorylated by deoxycyti- citabine was approved by the U.S. Food and Drug Administration dine kinase (DCK) to a monophosphate form (dFdCMP). Similar (FDA) in 1997 for first-line treatment for locally advanced unre- to the association between thymidine phosphorylase and the sectable or metastatic pancreas cancer. prodrug capecitabine, elevated DCK levels in tumor cells (com- Two studies have focused on modifying the dosing and infusion pared to normal tissues)217 enhance the therapeutic window of rates of gemcitabine in order to increase the concentration of in- gemcitabine. dFdCMP is then phosphorylated into active diphos- tracellular, activated gemcitabine. Tempero et al.219 compared two

TABLE 49.8

Phase III Studies of Gemcitabine + Drug “X”, Compared to Gemcitabine

Gemcitabine Combination Author Year N Drug “X” OS (Months) OS (Months) P Value Collucci223 2002 107 Cisplatin 5.0 7.5 0.43 Berlin199 2002 327 5-FU 5.4 6.7 0.09 Bramhall229 2002 239 Marimastat 5.8 5.98 0.95 Rocha Lima227 2004 360 Irinotecan 6.6 6.3 0.79 Richards297 2004 565 Pemetrexed 6.3 6.2 0.85 Van Cutsem233 2004 688 Tipifarnib 6.5 6.9 0.75 Louvet226 2005 300 Oxaliplatin 7.1 9.0 0.13 Herrmann174 2005 319 Capecitabine 7.3 8.4 0.31 Heinemann225 2006 192 Cisplatin 6.0 7.5 0.15 Stathopoulous228 2006 130 Irinotecan 6.5 6.4 0.97 Abou-Alfa221 2006 349 Exatecan 6.2 6.7 0.52 Moore175 2007 569 Erlotinib 6.2 5.9 0.04 Poplin220 2009 574 Oxaliplatin 4.9 5.7 0.10 Cunningham224 2009 533 Capecitabine 6.2 7.1 0.08 Philip232 2010 745 Cetuximab 5.9 6.3 0.23 Kindler231 2010 602 Bevacizumab 5.9 5.8 0.95 Kindler230 2011 632 Axitinib 8.3 8.5 0.54 Conroy177 2011 342 FOLFIRINOXa 6.8 11.1 <0.001 Von Hoff178 2013 861 Nab-paclitaxel 6.7 8.5 <0.001

Note: Statistically significant findings are in bold (p <0.05). a The experimental arm was FOLFIRINOX alone; all other experimental arms listed in this table include a drugs in combination with gemcitabine.

tahir99 - UnitedVRG Chapter 49 Cancer of the Pancreas 677 different dose-intense regimens (compared to the Burris regimen) to gemcitabine alone. A total of 745 patients were accrued, with in a randomized phase II study. A total of 92 patients were random- median survivals of 6.3 (combination) and 5.9 months, respec- ized to either standard 30 minute infusion at a dose of 2,200 mg/ tively (p = 0.23). Objective response rates and progression-free m2 versus 1,500 mg/m2 over 150 minutes at a fixed-dose rate (FDR) survival were also similar between the two groups. of 10 mg/m2 per minute.219 All patients had locally advanced (8%) Angiogenesis has proven to be a worthy target in the solid or metastatic pancreatic cancer (92%). Although there was no tumor arena, and prior successes served as the impetus for the difference in the primary end point (i.e., time to treatment fail- Cancer and Leukemia Group B (CALGB 80303) double-blind, ure), patients in the standard arm had a median OS of 5 months, placebo-controlled randomized phase III trial comparing gem- whereas those in the FDR had a median survival of 8 months citabine plus bevacizumab versus gemcitabine alone.231 A total (p = 0.013). Pharmacokinetic analyses showed a twofold increase of 602 treatment-naïve patients with advanced pancreatic cancer in the intracellular (peripheral mononuclear cells) concentration were accrued. The median OS were 5.8 and 5.9 months, respec- of gemcitabine triphosphate with FDR gemcitabine, even though tively (p = 0.95). Again, response rates and progression-free sur- the total dose given was 30% less. Consistent with these data, grade vival were similar. Axitinib is another antiangiogenic factor, and 3 to 4 hematologic toxicity was also greater with FDR gemcitabine. a potent inhibitor of vascular endothelial growth factor receptor Subsequently, the Eastern Cooperative Oncology Group (ECOG) (VEGFR)1, 2, and 3. A randomized phase II trial with 103 patients conducted a three-arm phase III study (E6201) comparing gem- demonstrated a nonsignificant improvement in OS; this prompted citabine (1,000 mg/m2) plus oxaliplatin (100 mg/m2) every 2 weeks a larger phase III trial comparing gemcitabine 1,000 mg/m2 on versus a weekly 30-minute infusion of gemcitabine (1,000 mg/m2) days 1, 8, and 15 every 28 days plus axitinib 5 to 10 mg orally daily, versus weekly FDR gemcitabine (1,500 mg/m2 as previous).220 A or gemcitabine plus placebo.230 There were 632 patients in the total of 832 patients were enrolled. The study confirmed an in- trial, which closed at an interim analysis when the futility bound- crease in OS for the FDR arm compared to the 30-minute infusion ary was crossed. Median OS was 8.5 months in the gemcitabine/ of gemcitabine arm (6.2 months versus 4.9 months; p = 0.04). axitinib arm and 8.3 months in the gemcitabine/placebo arm. However, the OS benefit actually did not meet the prespecified Two recently published meta-analyses examined the numer- criteria for significance (a 33% decrease in survival). In addition, ous randomized controlled clinical trials of gemcitabine-based patients experienced greater toxicities with grade 3 to 4 neutrope- combination therapy in aggregate. These studies included more nia and thrombocytopenia in the FDR gemcitabine arm, consis- than 8,000 patients enrolled in over 25 trials.236,237 Despite the tent with the earlier phase II trial. Of note, there was no survival fact that virtually all of these studies were negative independently, advantage with the combination of gemcitabine and oxaliplatin. both meta-analyses found a small survival benefit (OR> 0.9 with Based on these data, the fixed-dose rate of gemcitabine can be p <0.05) with combination therapy, although toxicity was higher. considered a reasonable alternative to the standard 30-minute Although these findings do not justify routine use of the examined gemcitabine infusion, albeit with greater toxicity. regimens, they suggest that a small subset of patients (∼10% to

20%) do receive a benefit and affirm that further work to identify OF ONCOLOGY PRACTICE the best candidates for specific combination therapies is warranted. A Decade of Failed Attempts to Move Beyond Gemcitabine Monotherapy Modest Breakthroughs in the Treatment of In addition to oxaliplatin, there have been numerous attempts over Advanced Pancreatic Cancer the past decade to augment the therapeutic benefit of gemcitabine in patients with advanced disease, using additional therapeutic Two additional treatments have been approved for the treatment agents in combination with gemcitabine (see Table 49.8). Con- of advanced PDA by the FDA: erlotinib and nab-paclitaxel. The ventional cytotoxic agents that have been tested include cisplatin, former drug is an oral tyrosine kinase inhibitor of the EGFR that oxaliplatin, 5-FU, capecitabine, irinotecan, and exatecan. Despite was approved in 2005 for use in combination with gemcitabine for promising phase II data, the aforementioned doublets all failed locally advanced unresectable or metastatic pancreatic cancer.175 to show any benefit over gemcitabine monotherapy.174,220–228 In The National Cancer Institute of Canada Clinical Trials Group addition, novel targeted or biologic therapies have been tested (NCIC-CTG) conducted a large international phase III double- in combination with gemcitabine, including marimastat (metal- blind randomized trial of 569 patients with advanced or metastatic loproteinase inhibitor), tipifarnib (a farnesyltransferase inhibitor, pancreatic adenocarcinoma, comparing gemcitabine intravenous targeting Kras signaling), cetuximab (epidermal growth factor re- (IV) 1,000 mg/m2 weekly × 7 weeks followed by 1 week of rest, ceptor [EGFR] inhibitor), bevacizumab (angiogenesis inhibitor), then weekly × 3 every 4 weeks plus erlotinib 100 mg or 150 mg and axitinib (multitarget tyrosine kinase inhibitor).229–233 In gen- per day orally versus gemcitabine plus placebo. Toxicities, includ- eral, the addition of these agents to gemcitabine failed to markedly ing diarrhea and the typical acneiform rash associated with EGFR change OS. inhibitors, were slightly worse in the erlotinib arm. Nevertheless, A few of the biologic agents warrant special mention based these toxicities were mostly grade 1 to 2 and easily manageable. on the promise of therapeutic efficacy in other cancer types or in The gemcitabine/erlotinib arm experienced an improved median early phase clinical trial data in the treatment of advanced PDA. OS (6.24 months versus 5.91 month), with 1-year OS of 23% and EGFR is expressed in 60% of PDAs,162 and amplification or high 17%, respectively. Based on this study, combination gemcitabine polysomy at the EGFR locus is identified in half of the affected pa- and erlotinib became a standard of care in the first-line treatment tients.234 Moreover, targeting EGFR is effective in certain nonpan- of locally advanced or metastatic pancreas cancer in patients with creatic cancers (e.g., lung, colorectal, head and neck). Therefore, a reasonably good performance status at many centers. Enthusi- there is a strong therapeutic rationale for targeting EGFR in the asm for the combination has certainly been tempered by the fact treatment of PDA. Cetuximab is a monoclonal antibody with affin- that the survival benefit amounted to just 10 days with the com- ity for EGFR, which was tested in a small phase II study in patients bination therapy. Moreover, erlotinib adds roughly $10,000 per with advanced pancreatic cancer as a combination therapy with month to the cost of treatment.238 With that said, gemcitabine/ gemcitabine.235 In the 41 patients with EGFR-positive tumors, the erlotinib is clearly a more effective treatment for a subgroup of 5% median OS was 7.1 months with a 1-year OS of 31.7%, suggest- to 10% of patients than gemcitabine monotherapy, and identifying ing a potential benefit when compared to historical controls.171 predictive markers to select these individuals would be a signifi- However, in the large and definitive phase III trial conducted by cant advance and a step towards personalized treatment for pan- the Southwest Oncology Group (SWOG S0205),232 this combina- creatic cancer. Notably, individuals who experienced a skin rash tion failed to improve the outcome of patients when compared had improved disease control (p = 0.05) and improved survival 678 Practice of Oncology / Cancers of the Gastrointestinal Tract

(Cox regression HR = 0.37; p = 0.04). Kras mutation status was gemcitabine. Paclitaxel binds with high affinity to microtubules, tested based on prior data that wild-type Kras in colorectal cancers thereby stabilizing tubule polymerization and inhibiting cell mi- is predictive of response to anti-EGR therapy.239 Unfortunately, no tosis. Nab-Paclitaxel is bound to albumin, resulting in improved such correlation was found, although the study was underpowered, pharmokinetic efficiency and higher intratumoral drug levels, com- in large part because nearly all PDAs harbor Kras mutations.234 pared to the standard solvent-based paclitaxel formulation (standard Building on the modest success of the gemcitabine/erlotinib paclitaxel pharmokinetics is otherwise limited by the hydrophobic 241 doublet, Van Cutsem et al.240 evaluated the same combination nature of the molecule). The exact mechanism of improved nab- with or without bevacizumab in a randomized phase III study (pub- paclitaxel delivery is not completely understood, but evidence points lished prior to the negative phase III gemcitabine/ bevacizumab to protein–protein interactions between albumin and receptors study).240 Six hundred and seven patients were randomized to re- that mediate transport (e.g., gp60) or that enhance drug targeting 242 ceive gemcitabine 1,000 mg/m2 per week × 7 weeks over 8 weeks in the stroma (secreted protein, acidic, cysteine-rich [SPARC]). and × 3 every 4 weeks for subsequent cycles plus erlotinib 100 mg Interestingly, a recent study of drug pharmokinetics in a genetically per day and bevacizumab 5 mg/kg every 2 weeks, or gemcitabine/ engineered SPARC-null mouse demonstrated that intratumoral erlotinib plus placebo. The median OS were 7.1 months for the nab-paclitaxel levels were not dependent on SPARC expression and 243 bevacizumab arm and 6.0 months for the control arm (p = 0.2). Of that the drug does not target the stroma in this model. 2 note, there was an improvement in progression-free survival with In an early phase I/II study, gemcitabine 1,000 mg/m with nab- 2 the experimental treatment (4.6 versus 3.6 months; p = 0.0002). paclitaxel 125 mg/m weekly × 3 every 28 days, resulted in tumor Grade 3 through 5 adverse events were comparable. Although the shrinkage in 48% of patients (substantially higher than the 5% rate 171 primary end point of OS was not met, there was an apparent favor- previously seen with gemcitabine alone ) and a median OS of 244 able trend across all end points, providing a modicum of optimism 12.2 months (more than twice the survival with gemcitabine). that the gateway towards improved outcomes was opening, if ever With these promising results, a large international phase III study so slightly. was conducted, randomizing 861 patients with advanced PDA to 178 Nab-paclitaxel was approved by the FDA in September receive either gemcitabine/nab-paclitaxel or gemcitabine alone. 2013 as a second agent indicated for combination therapy with The MPACT study met its primary end point (Fig. 49.8), with a

Overall survival 100 90 Hazard ratio for death, 0.72 (95% Cl, 0.62–0.83) P <0.001 by stratified log-rank test 80 70 60 50 40 nab-paclitaxel–gemcitabine 30 20 Gemcitabine

Patients who were alive (%) 10 0 0 3 6 9 121518212427 36 33 36 39 Months No. at risk nab-Paclitaxel–Gemcitabine 431357 269 169 108 67 40 27 16 9 4 1 1 0 Gemcitabine 430340 220 124 69 40 26 15 7 3 1 0 0 0 A

Progression-free survival, according to independent review 100 Hazard ratio for disease progression or death, 90 0.69 (95% Cl, 0.58–0.82) 80 P <0.001 by stratified log-rank test 70 60 50 nab-paclitaxel–gemcitabine 40 30 20 10 Gemcitabine progression or death (%) 0 Figure 49.8 Kaplan–Meier curves for 0 3 6 9 12 15 18 21 24 survival and progression-free survival Patients who were free from disease for nab-paclitaxel versus gemcitabine. Months No. at risk CI, confidence interval. (From Von Hoff nab-Paclitaxel–Gemcitabine 431281 122 62 24 8 4 2 0 DD, Ervin T, Arena FP, et al. Increased Gemcitabine 430209 51 23 10 6 4 0 0 survival in pancreatic cancer with nab- paclitaxel plus gemcitabine. N Engl J Med B 2013;369:1691–1703.)

tahir99 - UnitedVRG Chapter 49 Cancer of the Pancreas 679 median OS of 8.5 months in the gemcitabine/nab-paclitaxel arm cancer.210 In the 46 evaluable patients, the overall response rate was and 6.7 months in the gemcitabine group (p <0.001). Progression- 26%, with a 4% complete response rate. Median time to progression free survivals were 5.5 and 3.7 months, respectively (p <0.001). was 8.2 months and the median OS was 10 months. A randomized The 1-year OS were 35% versus 22%, and the 2-year OS were 9% phase II trial was initiated, comparing the regimen to gemcitabine. versus 4%, respectively. Patients receiving combination therapy Promising results in 88 patients were presented at the American So- had a higher response rate as well (23% versus 7%; p <0.001). ciety of Clinical Oncology (ASCO) 2007 conference (response rate Grade 3 or higher toxicities that were more common in the nab- of 38.7% versus 11.7%), and the study continued on as the large, paclitaxel arm included neutropenia (38% versus 27%), fatigue randomized phase III PRODIGE 4/ACCORD 11 study.246 (17% versus 7%), and neuropathy (17% versus 1%). Given the The PRODIGE 4/ACCORD 11 study randomized 342 pa- results of this trial, gemcitabine combined with nab-paclitaxel tients with a performance status of ECOG 0-1 to receive FOLFIRI- has eclipsed gemcitabine plus erlotinib as a standard of care in NOX (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, leucovorin the first-line treatment of advanced, unresectable, or metastatic 400 mg/m2, and 5-FU 400 mg/m2 IV bolus followed by 5-FU 2,400 pancreatic adenocarcinoma. Importantly, the cost of adding nab- mg/m2 as a 46- hour continuous infusion every 2 weeks) versus paclitaxel is not trivial ($8,000 per month). gemcitabine 1,000 mg/m2 weekly × 7 weeks followed by 1 week Although gemcitabine has served as the principal backbone for of rest, then 3 times per weekly × 3 every 4 weeks.177 The primary pancreatic cancer therapy in most clinical trials, including patients end point was overall survival OS (Fig. 49.9). The FOLFIRINOX with advanced PDA, studies were also being conducted on a com- group had a median OS of 11.1 months compared to 6.8 months bination of other drugs with proven success in colorectal cancer, in the gemcitabine alone arm (p <0.001). Median progression- including FOLFIRINOX. In 2003, the results of a phase I study free survivals were 6.4 months and 3.3 months (p <0.001), re- were reported, which included 34 evaluable patients in total, and 6 spectively. Objective response rates were 31.6% versus 9.4% with advanced pancreatic cancer. Two of the patients with pancre- (p <0.001), and disease control rates (response + disease stability) atic cancer experienced an objective response, with one complete were 70.2% and 50.9%, respectively. The FOLFIRINOX regimen responder.245 These observations spawned a single-arm phase II resulted in substantially more toxicity, including higher grade 3 trial in 47 chemotherapy-naïve patients with advanced pancreatic and 4 neutropenia (45% versus 21%), febrile neutropenia (5.4%

Overall survival 100 Hazard ratio, 0.57 (95% Cl, 0.45–0.73) P <0.001 by stratified log-rank test 75 PRACTICE OF ONCOLOGY PRACTICE

50 Folfirinox

Probability (%) Probability 25 Gemcitabine

0 0 3 6 9 1215182124273033 36 39 42 Months No. at risk Gemcitabine 171134 89 48 28 14 7 6 3 3 2 2 2 2 1 FOLFIRINOX 171146 116 62 34 20 13 9 5 3 2 2 2 2 2 A

Progression-free survival 100 Hazard ratio, 0.47 (95% Cl, 0.37–0.59) P <0.001 75

50 Folfirinox

Probability (%) Probability 25

Gemcitabine 0 0 3 6 9 1215182124273033 36 Months No. at risk Figure 49.9 Kaplan–Meier curves for survival and Gemcitabine 17188 26 8 5 2 0 0 0 0 0 0 0 progression-free survival for FOLIRINOX. (From Conroy FOLFIRINOX 171121 85 42 17 7 4 1 1 0 0 0 0 T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J B Med 2011;364:1817–1825.) 680 Practice of Oncology / Cancers of the Gastrointestinal Tract versus 1.2%), thrombocytopenia (9.1% versus 3.6%), diarrhea requires minimally invasive interventions such as celiac plexus (12.7% versus 1.8%), and sensory neuropathy (9% versus 0%). neurolysis (endoscopic or percutaneous), in addition to systemic Despite these significant side effects, only 31% of patients in the narcotics. Active surveillance and prompt treatment of thrombo- FOLFIRINOX group had a definitive degradation in quality of life embolic events, biliary obstruction, and gastric outlet obstruction (QoL), as compared to 66% in the gemcitabine group. The time to are critical. Psychosocial issues for the patient and family must be definitive deterioration (based on the EORTC QoL questionnaire) addressed. Often, the extent of symptoms and deterioration in per- was also significantly longer for the FOLFIRINOX group in the formance status precludes additional antitumor-directed therapy. areas of global health status; physical, cognitive, and social func- Even with expert care, there is a 1% to 4% mortality rate related to tioning; and multiple symptom domains (e.g., fatigue and pain).247 treatment.177,178 Therefore, oncologists need to have frank discus- Finally, a recently reported phase III trial in Japan compared sions with patients and family members about best supportive care gemcitabine alone (standard dosing) versus S-1 alone (80 to 120 mg (e.g., no chemotherapy or radiation) when appropriate. per day for 28 days every 42 days) versus the combination of gemcitabine (1,000 mg/m2 × 2 every 21 days) plus S-1 (60 to 100 mg per day for 14 days every 21 days). S-1 is an oral fluoropyrimidine FUTURE DIRECTIONS AND CHALLENGES derivative available in Japan with activity against PDA. A total of 832 patients with locally advanced or metastatic PDA were included The timeline of pancreatic cancer therapy can be summarized in the analysis. OS were 8.8, 9.7, and 10.1 months (p = 0.15 for as follows (Fig. 49.10): Through the 1970s, no effective therapies combination therapy compared to gemcitabine alone), respectively. existed; between 1980 and 2000, surgical outcomes markedly im- Objective responses were higher with S-1 monotherapy (21%) proved, permitting safe treatment of early stage PDA at high vol- and combination therapy (29%), than gemcitabine alone (13%). ume centers; between 2000 and the present, modest improvements Gemcitabine was associated with more hematologic toxicities com- in chemotherapy and radiation have improved outcomes and the pared to S-1, whereas S-1 was associated with more diarrhea.248 safety profile of these treatments. Over the same time span, there Combination therapy was the most toxic regimen. have been dramatic advances in the genetic and molecular under- Taken together, these trials establish gemcitabine alone, S-1 standing of pancreatic cancer development and survival, although (in Japan), gemcitabine plus nab-paclitaxel, gemcitabine plus this new knowledge has not yet translated into improved patient erlotinib, and FOLFIRINOX as the current standard of care outcomes. It is becoming more apparent, however, that the field treatments for metastatic pancreatic cancer. The latter regimen is on the cusp of substantial breakthroughs, similar to those expe- is recommended for patients with excellent performance status rienced recently in many other cancer types (e.g., breast, colon, (ECOG 0 or 1), whereas the other regimens are applicable for a melanoma). The next decade will likely produce improved molec- broader patient population (ECOG 0–2). ular diagnostics (markers for detection, prognosis, and treatment response), targeted therapies (personalized oncology), antistromal Monitoring Treatment Response agents used in tandem with antineoplastic agents, and immunotherapies (e.g., vaccines and immune checkpoint inhibitors). There is a growing trend toward multi-institutional collaboration In the current era, with multiple active drugs available to treat fostered by the National Cancer Institute (NCI), private founda- PDA, patients increasingly have second-line options after a tions, and industry, as well as scheduled national meetings focused first-line therapy fails. Therefore, it is important for oncologists to entirely on pancreatic cancer research. This surge in collaboration closely monitor patients for signs of progression. Patients typically and communication between thought leaders, coupled with in- have weekly laboratory testing, and are seen biweekly or monthly creased national attention (e.g., the Recalcitrant Cancer Research by medical oncologists who assess for signs of treatment toxicity. Act of 2012, which identified pancreatic cancer as a high priority), With regard to treatment response, patients undergo repeat im- will undoubtedly jolt the field forward in the coming years. aging (CT scans or magnetic resonance imaging [MRI]) every 8 In this closing section, we will broadly discuss some of the most weeks and responses are assessed by Response Evaluation Crite- encouraging areas of research, address some of the greatest chal- ria in Solid Tumors (RECIST) criteria. CA 19-9 levels are seri- lenges, and highlight areas that warrant investigative pursuit. ally drawn every 8 weeks. A falling CA 19-9 level in response to treatment is associated with improved survival, with the greatest decreases being associated with the best outcomes.249–253 CEA and Biomarkers: Diagnostic, Prognostic, and CA-125 are not FDA-approved biomarkers for PDA, and have far Predictive less accuracy then CA 19-9. Nevertheless, they may be helpful to monitor response to therapy, particularly in patients who do not Biomarkers can be separated into three categories. Diagnostic express CA 19-9 due to Lewis antigen polymorphism variability. biomarkers detect the presence of disease. They are relevant for In the face of rising tumor markers and tumor progression, on- early detection, as well as to measure disease burden in response to cologists should pay close attention to performance status, because therapy. Prognostic markers gauge disease aggressiveness or tumor patients with an ECOG status of 2 or greater have an expected sur- biology, and are used to forecast outcome or recurrence pattern. vival around 2 months and are not likely to benefit from additional 231 Predictive markers predict treatment response, and are the key in- chemotherapy. gredient to a personalized therapeutic approach. Symptom Palliation New molecular Although extending survival is a primary objective in patients with insights into PDA, the palliation of symptoms is equally important. As with PDA biology other aspects of care, palliative-focused therapy in the patient with 1970 1980 1990 2000 2010 PDA requires a multidisciplinary team approach. Treatment recommendations are often based on the etiology of the symptoms, which may be multifactorial. Contributing factors include the No effective Improved Modest metabolic burden of the tumor, treatment toxicity, or mechani- therapies surgical improvements in outcomes chemotherapy cal obstruction from the tumor. Optimization of nutritional intake and radiation is paramount and could be exacerbated by cancer cachexia and pancreatic insufficiency. Aggressive pain management frequently Figure 49.10 Timeline of advances in PDA-related therapy and science.

tahir99 - UnitedVRG Chapter 49 Cancer of the Pancreas 681

Effective early detection of PDA could have the greatest impact rate cohorts of patients with resected disease and found that the on PDA-specific outcomes, but may also be the least likely to come panel predicted poor survival. The gene signature has not yet been to fruition. Such a test would need to identify premalignant le- validated by a separate group.258 In a separate study, protein expressions that are at very high risk of developing into an invasive lesion sion patterns of 13 putative PDA biomarkers were examined in a (PanIN-3). Genetically engineered mouse data suggest that tumor large cohort of short- and long-term survivors after resection. The dissemination can still occur even at the premalignant stage254; investigators found that MUC1 and mesothelin (MSLN) expres- nevertheless, it is still believed (albeit unproven) that treatment sion were far more predictive of early cancer-specific death than of PanIN-3 lesions would be curative for most patients. Moreover, conventional pathologic features. Again, these findings require PanIN-3 (i.e., carcinoma in situ) lesions are likely far enough along validation.162 in the tumor progression sequence that the risk of overtreatment There are no proven predictive markers for standard pan- would not outweigh the potential benefit of treatment (including creatic cancer therapies. Data from the phase II gemcitabine/ surgical intervention).33,255 nab-paclitaxel study suggested that stromal SPARC expression There are several challenges associated with early detection is associated with improved outcome.244 Data from the more re- research. First, most diagnostic biomarker research to date merely cent phase III study are forthcoming. No predictive markers of distinguishes invasive PDA (in resected patients) from normal gemcitabine have been consistently validated in samples from controls. This research largely misses the point, because the index randomized trials. Human equilibrative nucleoside transporter 1 lesions are not curable precursor lesions. Most individuals with (hENT1) is a nucleoside transporter involved in gemcitabine up- localized invasive cancer already harbor occult metastases. Pres- take. Increased expression was associated with improved survival ently, only 6% of resected PDAs (and <1% of all PDAs) are di- in patients receiving gemcitabine in the RTOG 9704 study,259 agnosed at stage I, and the resection of PanIN-3 disease in the but no association was observed in a randomized study compar- absence of invasive carcinoma is exceedingly rare.27,256 Second, ing gemcitabine and an hENT1-independent gemcitabine deriva- current CT scanning technology fails to reliably detect PDAs tive.260 Brody et al. have identified the RNA binding protein, HuR, below 2 cm, because PDAs are poorly demarcated and are hy- as a candidate predictive marker of gemcitabine efficacy in two ret- podense compared to normal pancreata.80 Curable lesions (i.e., rospective institutional cohorts.261,262 HuR regulates and stabilizes PanIN-3 lesions) are likely one-quarter the size of this lower DCK, which phosphorylates and activates gemcitabine. Investiga- limit.224 Third, the sensitivity required for effective screening tors are currently evaluating samples from the adjuvant ESPAC3 tests is much higher than commonly appreciated. Pannala et al.79 trial (gemcitabine versus 5-FU) to validate this finding. Finally, calculated that an early detection biomarker with 99% sensitivity our group at Thomas Jefferson recently observed that DCK expres- and specificity would detect all PDAs in the general population, sion was associated with improved survival in patients receiving but would also result in a 1% false positive rate due to the rela- 5-FU chemotherapy in the RTOG 9704 trial. This finding was re- tively low prevalence of PDA (false positives outnumbering true capitulated in cell lines (unpublished).

positives by an astounding 25:1). Restricting early detection tests to OF ONCOLOGY PRACTICE high-risk individuals would improve the positive predictive value, but of course end up missing sporadic PDAs, which comprise the Targeted Therapy large majority of cases. Finally, serum based tests have a low pretest probability of detecting molecular analytes derived from non- As a result of whole-exome sequencing, the vast majority of genes invasive lesions that do not have access to the circulatory system. mutated in PDA with high frequency are now known. Unfortu- As an illustration of this point, we recently prepared plasma from nately, no novel high frequency druggable targets were identified. fresh phlebotomy draws in patients with PDA, and performed a Many mutated genes can be categorized within core signaling Kras mutation screen using a high-sensitivity commercial muta- pathway (12 were initially described),35 and there have growing tion detection assay (BEAMing, which detects mutant genes in a efforts to try to develop therapies targeting these pathways (as op- background of wild-type DNA at ratios >1:10,000).257 Mutations posed to a specific genetically altered gene). In addition, there has were detected at low rates even in patients with high invasive dis- been a redoubling of efforts to target Kras, as a result of the empty ease burden: two out of nine patients with metastatic disease and genetic search for promising new targets. As stated, Kras is mutated zero out of three with localized disease (Jordan M. Winter, un- in virtually every PDA, as well as most cells within each PDA. Al- published observation). With improved high-throughput instru- though attempts to inhibit Kras have eluded researchers thus far, mentation and bioinformatics strategies available, researchers are numerous innovative approaches are currently under investiga- now better equipped to interrogate analytes beyond DNA (e.g., tion. These include developing novel compounds to directly bind metabolome, transcriptome, proteome) in search of a molecular and inhibit RAS through rational drug design; developing drugs beacon of early PDA. National tissue banking programs, such as that restore GTP hydrolytic function in mutant RAS; interference the NCI-sponsored Early Detection Research Network, are criti- with RAS posttranslational modification (e.g., prenylation, pro- cal to this pursuit. teolytic processing, carboxyl methylation); inhibition of RAS ex- There are currently no effective prognostic panels for PDA, pression (e.g., RNA interference); inhibition of downstream RAS akin to the validated Oncotype Dx panels for breast, colon, and signaling (e.g., Raf-MEK-ERK and PI3K pathways); and identify- prostate cancers. Limitations are primarily due to relatively low ing pathways that are required for survival in Kras mutant cells tissue availability and to a tighter survival distribution necessitating (synthetic lethal approach). As evidence of the importance that even higher sample numbers for analyses. Nevertheless, the tech- the NCI has placed on this research, the NCI recently announced nology currently exists (e.g., gene expression arrays or Nanostring an initiative focused on targeting Kras, and plans to divert $10 mil- multiplex gene expression analyses [Seattle, WA]) to develop lion annually to support the program (http://frederick.cancer.gov/ prognostic panels for PDA. Improved prognostics could identify News/RASCancerGeneticsInitiative.aspx). patients who harbor particularly aggressive tumors that may appear resectable by imaging, yet are best managed with neoadjuvant chemotherapy to treat occult metastases and perhaps avoid ineffective Heterogeneity as an Obstacle to Targeted surgery. Therapy There has been some intriguing work in this area. Stratford et al.258 used fresh frozen tumors from 15 resected PDAs and PDAs exhibit tremendous molecular heterogeneity, both between 15 metastatic PDAs (from autopsies) to identify a gene expression and within tumors. The genetic fingerprint of each tumor is signature using cDNA microarrays associated with metastatic dis- unique: each with a different set of mutated genes and chromo- ease. The researchers then tested the derived signature in two sepa- some copy number changes.35,41 Yachida et al.255 revealed that 682 Practice of Oncology / Cancers of the Gastrointestinal Tract

MUC1+ xenografts (with low stromal content), but ineffective in autoch- 268 MUC1- thonous genetically engineered mouse models of PDA. Stromal depletion in KPC mice (mice with conditional and pancreatic- specific expression of mutant Kras and TP53) with a Hedgehog pathway inhibitor improved gemcitabine delivery to tumors and decreased tumor burden. The same effects were observed in a separate study that used a drug targeting the extracellular matrix protein, hyaluronic acid.269 Thus, targeting the tumor stroma is a promising strategy to improve the efficacy of conventional pancreatic cancer treatments and is a high research priority.

Metabolism

There is a growing appreciation and understanding of the malignant metabolic phenotype, although Otto Warburg first observed fundamental metabolic differences between cancer and normal cells nearly 100 years ago. The proliferative demands of pancreatic cancer cells, along with the adaptive requirements for survival in an austere tumor microenvironment (characterized by an abundant, yet nutrient-deprived stroma), require complex mechanisms to reprogram metabolic pathways.270 In fact, PDA cells are particularly tolerant to nutrient deprivation compared to other cancers.31 Recently, mutant Kras was found to alter metabolic pathways, leading to increased glycolysis,271 altered amino acid metabolism through noncanonical enzyme pathways,272 and macropinocytosis of protein as an additional fuel source.273 Figure 49.11 MUC1 expression in a pancreatic cancer. A focus of Metabolic reprogramming through posttranscriptional regulation invasive cancer reveals areas of positive (+) and negative (−) MUC1 of metabolic enzymes by a stress response RNA-binding protein expression (arrows). was found to be an independent survival mechanism of PDA cells under nutrient deprivation.274 A better understanding of PDA metabolism will likely expose metabolic dependencies as important genetic abnormalities differ across a given pancreatic tumor, with therapeutic targets. genetically distinct foci in the primary, that give rise to clonal populations in metastatic deposits. An immunohistochemical survey Immunotherapy of pancreatic cancer biomarkers illustrates the diversity in protein expression.162 For instance, MUC1 is absent in 15% of PDAs, but Immunotherapy was the 2013 Science Breakthrough of the is diffusely expressed (>75% of neoplastic cells) in 30%. Even a Year,275 as a result of multiple new therapies for nonpancreatic ma- single focus of PDA containing both MUC1-positive and MUC1- lignancies (especially melanoma). Many of the treatments work negative cells illustrates biologic variation within a given tumor by targeting immunologic checkpoints (i.e., immunosuppressive (Fig. 49.11). Keeping with this pattern, metabolic gradients exist pathways induced by cancer cells). Inhibition of these molecules in tumors due to the proximity of neoplastic cells to patent blood with antibodies unleashes the body’s immune system against the vessels as well as due to the dynamic nature of the tumor microen- tumor in some patients.276,277 T-cell adoptive therapy is another vironment. Microecologic niches result,263 which are reflected in emerging immunotherapy with successes in nonpancreatic can- the varied expression patterns of metabolic enzymes across tumor cers, where T cells from patients are genetically engineered ex vivo sites (e.g., primary and metastases) in patients with PDA.264 Basic to target the patient’s own tumor.278 Thus, there is an urgent need cell cycle dynamics drive proteomic changes in a single cell over to understand how these strategies can be used or modified to treat time, even in the most stable circumstances. PDA heterogeneity is, pancreatic cancer. therefore, a certainty, yet has emerged as the unaddressed truth, as There are immunotherapies that have had some preclinical the cancer field pursues apersonalized approach to cancer therapy. and early clinical trial success against pancreatic cancer. CD40 is Single molecule targeting is likely to fail because of PDA heteroge- a molecule on the surface of tumor-associated macrophages that neity. An example from another cancer type is illustrative. Extreme stimulates T-cell–dependent antitumor immunity. In a recent heterogeneity, based on the expression pattern of the estrogen phase I study, patients with treatment-naïve advanced PDA were receptor, was observed in a human ovarian cancer prior to treat- treated with gemcitabine and a monoclonal antibody that binds ment. After treatment, the expression pattern was dramatically al- and stimulates CD40. There was a 19% response rate and biologic tered in the same tumor sample, when only chemoresistant clones indicators of a strong immune response (e.g., increased cytokine survived.265 A multitargeted approach may be necessary, similar to levels).279 A pancreatic cancer vaccine (algenpantucel-L, New- the standard treatment strategy against HIV. Therapeutic strategies Link Genetics Corporation, Ames, IA) has also been developed that are significantly more tunable than conventional medicinal in which pancreatic cancer cell lines are genetically engineered pharmacology may also be useful, such as nanoparticle-delivered to express an immunogenic nonhuman epitope. The vaccine is gene therapy.266 delivered intradermally, and was given to 70 patients as part of a phase II study, along with gemcitabine and chemoradiation (simi- Targeting the Stroma lar to the RTOG 9704 regimen). The 12-month OS of patients who received the vaccine and conventional adjuvant treatment Over 70% of a PDA is comprised of stroma, and a worse outcome was 86%, which compared favorably with historical controls.280 was observed in patients with tumors exhibiting a higher stromal Vaccine-related toxicity was minimal. A phase III adjuvant trial content.267 The hypovascular stroma is viewed as an obstacle to was recently completed in North America, and the results are drug delivery, and explains why gemcitabine is potent against pending.

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CONCLUSION is still lethal in most patients and survival beyond 2 years is a rare event. For those of us who routinely treat this disease, progress Improvements in pancreatic cancer treatment over the past 2 cannot come soon enough. However, advances are imminent, decades include safer surgical management, safer radiation treat- and there is reason for optimism. The Pancreatic Cancer Action ment, and modest but notable improvements in systemic treat- Network has publicized its desire to dramatically improve patient ments. With modern chemotherapy, roughly half of patients outcomes by the year 2020, and the scientific community is rally- experience temporary disease control. Nevertheless, the disease ing to the charge.

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Treatment of locally unre- tion alone, moderate dose radiation (4000 rads + 5-fluorouracil), and high sectable cancer of the stomach and pancreas: a randomized comparison dose radiation + 5-fluorouracil: The Gastrointestinal Tumor Study Group. of 5-fluorouracil alone with radiation plus concurrent and maintenance Cancer 1981;48:1705–1710. 5-fluorouracil—an Eastern Cooperative Oncology Group study. J Clin Oncol 294. Radiation therapy combined with Adriamycin or 5-fluorouracil for the treat- 1985;3:373–378. ment of locally unresectable pancreatic carcinoma. Gastrointestinal Tumor 193. Loehrer PJ, Sr., Feng Y, Cardenes H, et al. Gemcitabine alone versus Study Group. Cancer 1985;56:2563–2568. gemcitabine plus radiotherapy in patients with locally advanced pancre- 295. Earle JD, Foley JF, Wieand HS, et al. Evaluation of external-beam radiation atic cancer: an Eastern Cooperative Oncology Group trial. J Clin Oncol therapy plus 5-fluorouracil (5-FU) versus external-beam radiation therapy 2011;29:4105–4112. plus hycanthone (HYC) in confined, unresectable pancreatic cancer. Int J 194. Hammel P, Florence H, Van Lathem J, et al. Comparison of chemoradio- Radiat Oncol Biol Phys 1994;28:207–211. therapy (CRT) and chemotherapy (CT) in patients with a locally advanced 296. Cohen SJ, Dobelbower R, Jr., Lipsitz S, et al. A randomized phase III study of pancreatic cancer (LAPC) controlled after 4 months of gemcitabine with or radiotherapy alone or with 5-fluorouracil and mitomycin-C in patients with without erlotinib: Final results of the international phase III LAP 07 study. locally advanced adenocarcinoma of the pancreas: Eastern Cooperative On- J Clin Oncol 2013;31:suppl; abstr LBA4003. cology Group study E8282. Int J Radiat Oncol Biol Phys 2005;62:1345–1350.

tahir99 - UnitedVRG Genetic Testing in 50 Pancreatic Cancer

Jennifer E. Axilbund and Elizabeth L. Wiley

INTRODUCTION BRCA1

It is estimated that 5% to 10% of pancreatic cancer (adenocarcinoma) Similar to BRCA2, mutations in BRCA1 are associated with a is familial,1,2 and individuals with a family history of pancreatic can- markedly increased risk for premenopausal breast cancer and ovar- cer are at a greater risk of developing pancreatic cancer themselves.3 ian cancer. The Breast Cancer Linkage Consortium reported a Although there is evidence of a major pancreatic cancer suscepti- 2.26-fold (95% CI, 1.26 to 4.06) increased risk of pancreatic cancer bility gene,4 it remains elusive. Therefore, the majority of families in families with a BRCA1 mutation,19 and Brose et al.20 estimated with multiple cases of pancreatic cancer do not have an identifiable a threefold higher lifetime risk. However, more recently, in the causative gene or syndrome, making risk assessment and counseling United Kingdom, Moran et al.6found no elevation in pancreatic challenging. However, a subset of pancreatic cancer is attributable cancer risk in 268 families with a known BRCA1 mutation. A to known inherited cancer predisposition syndromes (Table 50.1). United States–based study reported that 11% (24 out of 219) of their families with a BRCA1 mutation had at least one individual with pancreatic cancer, with median ages at diagnosis of 59 years SELECTED GENES THAT MAY CAUSE for males and 68 years for females. Again, this was significantly PANCREATIC CANCER younger than reported in the SEER database (p = 0.0014).8 Al- Sukhni et al.21 molecularly evaluated pancreatic tumors from seven known BRCA1 mutation carriers and found a loss of hetero- BRCA2 zygosity of BRCA1 in five (71%), with confirmed loss of the wild- type allele in three of the five compared with only one (11%) of OF ONCOLOGY PRACTICE The BRCA2 gene is associated with hereditary breast and ovar- nine sporadic controls. This suggests that BRCA1 germ-line muta- ian cancer syndrome, and often presents as premenopausal breast tions do, in fact, predispose some individuals to pancreatic cancers. cancer, ovarian cancer, and/or male breast cancer. The Breast Familial breast cancer registries in the United States and Is- 5 Cancer Linkage Consortium reported a 3.5-fold (95% confidence rael have evaluated the mutation status of families that reported interval [CI], 1.9 to 6.6) increased risk of pancreatic cancer in pancreatic cancer in addition to breast cancer and ovarian cancer. BRCA2 gene mutation carriers. Subsequent studies in the United In the US study of 19 families with breast, ovarian, and pancre- Kingdom and the Netherlands showed a relative risk of 4.1 and atic cancer, 15 carried a deleterious mutation in BRCA1 and 4 in 6,7 5.9, respectively. In a United States–based study, 10.9% (17 out BRCA2,22 whereas the Israeli study reported an equal number of of 156) of families with a BRCA2 mutation reported a family his- BRCA1 and BRCA2 families.23 tory of pancreatic cancer. The median ages at diagnosis for males Another study, specifically of Ashkenazi Jewish families, re- and females were 67 and 59 years, respectively, which differed ported a BRCA1 mutation in 7% of probands with breast cancer statistically from the Surveillance, Epidemiology and End Results who also had a family history of pancreatic cancer,16 which was, (SEER) database (70 years old for males and 74 years old for fe- again, equal to the prevalence of BRCA2 mutations. Thus, within = 8 males; p 0.011). Although genotype–phenotype data remain the Ashkenazi Jewish population, BRCA1 and BRCA2 mutations sparse, the BRCA2 K3326X variant was found in 5.6% (8 out of may contribute more equally to risk in families with both breast 144) of familial pancreatic cancer patients compared with 1.2% and pancreatic cancer. However, these studies all examined co- (3 out of 250) of those with sporadic pancreatic cancer (odds ratio horts of families selected because of clustering of breast and/or < 9 [OR], 4.84; 95% CI, 1.27 to 18.55; p 0.01). ovarian cancer with pancreatic cancer. When families were se- Approximately 17% of pancreatic cancer patients who have at lected on the basis of familial pancreatic cancer alone, BRCA1 least two additional relatives with pancreatic cancer carry deleteri- mutations were less prevalent. None of the sixty-six families with 10 ous mutations in the BRCA2 gene. Estimates for the prevalence three or more cases of pancreatic cancer had a deleterious BRCA1 of BRCA2 mutations with two first-degree relatives with pancreatic mutation, including those who also reported a family history of 11,12 cancer are 6% to 12%, and BRCA2 mutations also explain a breast and/or ovarian cancer.24 An evaluation of Ashkenazi Jew- 13 portion of apparently sporadic pancreatic cancers. However, ish patients ascertained on the basis of pancreatic cancer alone prevalence varies between populations. Out of 145 Ashkenazi Jews showed a 1.3% (2 out of 145) prevalence of BRCA1 mutations.14 with pancreatic cancer, 6 (4.1%) were found to have a deleterious Therefore, BRCA1 may explain a small subset of families show- BRCA2 mutation when compared with cancer-free controls (OR, ing a clustering of pancreatic cancer with breast and/or ovarian = 3.85; 95% CI, 2.1 to 10.8; p 0.007), although no differences were cancer, but is unlikely to explain most families with site-specific 14 noted in age at diagnosis or clinical pathologic features. An earlier, pancreatic cancer. smaller study found a deleterious BRCA2 mutation in 3 (13%) of 23 Ashkenazi Jews with pancreatic cancer, unselected for family history.15 Among Ashkenazi Jewish probands with breast cancer who PALB2 reported a family history of pancreatic cancer, 7.6% (16 out of 211) had a BRCA2 mutation.16 By comparison, no BRCA2 mutations PALB2 (partner and localizer of BRCA2) was recognized as the were found in studies of pancreatic cancer in Korea or Italy.17,18 FANCN gene in 2007, and biallelic mutation carriers develop

685 686 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 50.1 Inherited Cancer Predisposition Syndromes that Increase the Risk for Pancreatic Cancer

Syndrome Gene(s) Risk of Pancreatic Cancer Predominant Features Hereditary breast and ovarian cancer BRCA1 RR, 2.26–3 Malignancies: Breast (particularly premenopausal), ovary, male breast, prostate BRCA2 RR, 3.5–5.9 Malignancies: Breast (particularly premenopausal), ovary, male breast, prostate, melanoma (cutaneous and ocular) Familial atypical multiple mole and CDKN2A RR, 7.4–47.8 Malignancies: Melanoma (often multiple and early onset) melanoma Other: Dysplastic nevi

Hereditary pancreatitis PRSS1 SIR, 57 Other: Chronic pancreatitis Hereditary nonpolyposis colorectal MLH1 SIR, 0–8.6 Malignancies: Colorectum, endometrium, ovary, cancer (Lynch syndrome) MSH2 stomach, small bowel, urinary tract (ureter, renal MSH6 pelvis), biliary, brain (glioblastoma), skin (sebaceous) PMS2 EPCAM

PJS STK11 SIR, 132 Malignancies: Colorectum, small bowel, stomach, breast, gynecologic Other: Melanin pigmentation (mucocutaneous), small- bowel intussusception

SIR, standardized incidence ratio.

Fanconi anemia.25,26 Monoallelic mutation carriers were shown to cancer proband, and subsequently found PALB2 mutations in be at an increased risk for breast cancer (relative risk [RR], 2.3; 3 out of 96 additional families, suggesting that 3% to 4% of fa- 95% CI, 1.4 to 3.9).27 The prevalence of PALB2 mutations among milial pancreatic cancer may be attributed to this gene. Other familial breast cancer cases is low across ethnicities; PALB2 muta- populations have found lower mutation frequencies, ranging tions are relatively nonexistent in breast cancers in the Irish and from absent in the Dutch (0 out of 31) to 3.7% (3 out of 81) in Icelandic populations and are found in approximately 1% of Ital- Germans.45,46 When ascertained on the basis of co-occurrence ians, African Americans, Chinese, and Spanish breast cancer fami- of breast and pancreatic cancer in the same individual or family, lies, and in 2% of young South African breast cancer patients.28–35 prevalence varied, again, from absent in the Dutch (0 out of 45) An analysis of 1,144 US familial breast cancer cases found a and United States–based studies (0 out of 77) to 4.8% (3 out of PALB2 mutation in 3.4% (33 out of 972) of non-Ashkenazi Jews 62) in Italians. 42,47,48 and none (0 out of 172) of Ashkenazi Jews. The estimated risk for breast cancer was 2.3-fold by the age of 55 years (95% CI, 1.5 to 4.2) and 3.4-fold by the age of 85 years (95% CI, 2.4 to 5.9). There CDKN2A was also a fourfold risk for male breast cancer (p = 0.0003) and a sixfold risk for pancreatic cancer (p = 0.002).36 Among French The p16 transcript of the CDKN2A gene is an important cell cycle Canadian women with bilateral breast cancer, a PALB2 mutation regulator. Germ-line mutations in the CDKN2A gene predispose was found in 0.9% (5 out of 559) compared with none of the 565 individuals to multiple early-onset melanomas. Somatic CDKN2A women with unilateral breast cancer (p = 0.04), and first-degree mutations are also frequently identified in pancreatic adenocar- relatives of PALB2 mutation carriers had a 5.3-fold risk for breast cinomas and precursor lesions, indicating a role for this gene in cancer (95% CI, 1.8 to 13.2).37 pancreatic cancer development and progression.49–51 PALB2 founder mutations have been identified in several The risk of pancreatic cancer with CDKN2A mutations var- populations, including the c.2323C>T (Q775X) mutation in ies based on genotype. In a study of 22 families with the Dutch French Canadians.38 Another example is the Finnish founder founder mutation, p16-Leiden, which is a 19–base-pair deletion mutation c.1592delT. This mutation was found in 2.7% (3 out of in exon 2, the relative risk of pancreatic cancer was 47.8 (95% CI, 113) of familial breast and/or breast/ovarian cancer families com- 28.4 to 74.7).52 The age-related risks have been shown to be less pared with 0.2% (6 out of 2,501) of controls (OR, 11.3; 95% CI, than 1%, 4%, 5%, 12%, and 17% by ages 40, 50, 60, 70, and 75 1.8 to 57.8; p = 0.005).39 One percent (18 out of 1,918) of breast years, respectively.53 Regarding other mutations, the Genes, Envi- cancer cases unselected for family history also had this founder ronment and Melanoma Study assessed relative risks for nonmela- mutation. The hazard ratio for breast cancer was estimated at 6.1 noma cancers in 429 first-degree relatives of 65 melanoma patients (95% CI, 2.2 to 17.2; p = 0.01), with a penetrance of 40% by the with a CDKN2A mutation. Five pancreatic cancers were reported age of 70 years.40 compared with 41 pancreatic cancers among 23,452 first-degree PALB2 has not been shown to be a significant contributor relatives of 3,537 noncarriers, for a relative risk of 7.4 (95% CI, to familial clustering of other cancers, including melanoma, 2.3 to 18.7; p = 0.002).54 A United States–based study estimated ovarian cancer, and prostate cancer,41–43 but has been identi- penetrance to be 58% by the age of 80 years (95% CI, 8% to 86%) fied in familial pancreatic cancer kindreds. Specifically, Jones and noted a hazard ratio of 25.8 (p = 2.1 × 10213) in those who et al.44 identified a PALB2 mutation in a familial pancreatic ever smoked cigarettes.55

tahir99 - UnitedVRG Chapter 50 Genetic Testing in Pancreatic Cancer 687

Mutation prevalence in pancreatic cancer families varies by analysis, only one deleterious MMR mutation was found. Thus, population. In an Italian study, 5.7% of 225 consecutive patients MMR mutations presumably account for only a small proportion with pancreatic cancer had an identifiedCDKN2A mutation.56 of pancreatic cancer patients. The predominant mutations were the E27X and G101W founder mutations, although others were also represented. Of 16 patients Hereditary Pancreatitis classified as having familial pancreatic cancer, 5 (31%) carried CDKN2A mutations, leading the authors to conclude that this Hereditary pancreatitis (HP) is a rare form of chronic pancreatitis. gene may account for a sizeable subset of Italian familial pancre- Several genes have been linked to chronic pancreatitis, including atic families. By comparison, no CDKN2A mutations were found SPINK1, CTFR, and CTRC, but the PRSS1 gene on chromosome in 51 Polish pancreatic cancer patients diagnosed at younger than 7q35 accounts for the majority of hereditary cases. PRSS1 muta- 50 years.57 Similarly, an analysis of 94 German pancreatic cancer tions are inherited in an autosomal-dominant fashion and have an patients who had at least one other first-degree relative with pan- 80% penetrance for pancreatitis. Affected individuals begin expe- creatic cancer revealed no CDKN2A mutations.58 However, two riencing symptoms of pancreatic pain and acute pancreatitis early of five families with at least one pancreatic cancer and at least one in life. Several studies have shown an increase in pancreatic can- melanoma had an identified mutation.59 Similarly, a Canadian cer risk associated with HP, and cumulative lifetime risk estimates study found a CDKN2A mutation in 2 of 14 families with both range from 18.8% to 53.5%.70–72 Lowenfels et al.71 observed an in- pancreatic cancer and melanoma.60 Finally, a United States–based creased risk associated with paternal inheritance. Tobacco use in study found 9 CDKN2A mutations in an unselected series of 1,537 patients with HP has been shown to increase the risk for pancreatic pancreatic cancer cases (0.6%). The prevalence increased to 3.3% cancer twofold (95% CI, 0.7 to 6.1), pancreatic and HP patients and 5.3% for those who reported a first-degree relative with pan- who smoke developed cancer 20 years earlier than did their non- creatic cancer or melanoma, respectively.55 Thus, in the majority smoking counterparts.73 of populations, the co-occurrence of melanoma appears to be a significant indicator of an underlyingCDKN2A mutation. Peutz–Jeghers Syndrome

SELECTED SYNDROMES THAT INCREASE Peutz–Jeghers syndrome (PJS) is an autosomal-dominant condi- THE RISK OF PANCREATIC CANCER tion characterized by mucocutaneous pigmentation and hamartomatous polyps of the gastrointestinal tract. PJS is caused by mutations on the STK11 (LKB1) gene. The lifetime risk to develop Hereditary Nonpolyposis Colorectal Cancer any cancer has been estimated to be as high as 93%,74 with no sex difference in cancer risk noted.74,75 Risk for pancreatic cancer 74–76 Hereditary nonpolyposis colorectal cancer (HNPCC), also re- in PJS is estimated to be 8% to 36% by the age of 70 years. OF ONCOLOGY PRACTICE ferred to as Lynch syndrome, is the most common form of he- Grützmann et al.77 analyzed 39 individuals with familial pancre- reditary colon cancer, and it accounts for 2% to 5% of colorectal atic cancer, and none were found to carry mutations in STK11. cancers. In addition to a high lifetime risk for colorectal cancer, In 2011, Schneider et al.58 confirmed these findings in their study affected individuals are at an increased risk for multiple other can- of 94 familial pancreatic cancer kindreds. Therefore, although cers. HNPCC results from mutations in mismatch repair (MMR) STK11 mutations confer a high lifetime risk for pancreatic can- genes, and colon cancers that arise in Lynch syndrome typically cer in individuals with PJS, germ-line STK11 mutations are not demonstrate microsatellite instability (MSI). Four percent of all thought to account for hereditary pancreatic cancer. pancreatic adenocarcinomas demonstrate MSI.61 Yamamoto et al.62 assessed tumor characteristics in three MLH1 mutation carriers with both colon and pancreatic cancer, and found that both EMPIRIC RISK COUNSELING AND tumor types had similar properties, including high MSI, loss of MANAGEMENT MLH1 protein expression, wild-type KRAS and p53, and poor differentiation. These findings support an inherited basis for the de- Having a first-degree relative with apparently sporadic pancreatic 62 velopment of both types of cancer. cancer has a moderate effect on risk (OR, 1.76; 95% CI, 1.19 to Pancreatic cancer has been described in HNPCC kindreds as 2.61).78 In familial pancreatic cancer kindreds (defined as a family early as 1985, although data regarding the risk of pancreatic cancer with a pair of affected first-degree relatives), the risk of pancreatic 63–68 64 in HNPCC have varied. Barrow et al. studied 121 families cancer increases with the number of affected first-degree relatives with known MMR mutations; 2 of 282 extracolonic cancers were (Table 50.2).3 These findings suggest that high-penetrance genes pancreatic, leading to a 0.4% cumulative lifetime risk for pancre- may be causing the clustering of pancreatic cancer in families with 65 atic cancer (95% CI, 0% to 0.8%). By comparison, Geary et al. two or three pancreatic cancer cases. Thus, individuals with multiple studied 130 families with MMR mutations and found 22 cases of affected first-degree relatives are at an appreciably increased risk for pancreatic cancer, half of which were in confirmed or obligate pancreatic cancer and may be candidates for increased surveillance. carriers. Pancreatic cancer in these families was seven times more common than expected, and the familial relative risk was 3.8 (p = 0.02). In addition, these tumors were 15 times more common in individuals younger than 60 years, suggesting an earlier TABLE 50.2 average age at diagnosis as compared with the general popula- 65 Risk of Pancreatic Cancer in Familial Pancreatic tion. Another United States–based study of HNPCC families Cancer Kindreds Based on Number of Affected found the lifetime risk for pancreatic cancer to be 1.31% by the First-Degree Relatives age of 50 years (95% CI, 0.31% to 2.32%) and 3.68% by the age of 70 years (95% CI, 1.45% to 5.88%). These risks are higher than Number of Affected FDRs SIR (95% CI) those from the SEER data of 0.04% and 0.52% at ages 50 and 70 years, respectively. 66 1 4.5 (0.54–16.3) Regarding the prevalence of HNPCC in pancreatic cancer, 2 6.4 (1.8–16.4) Gargiulo et al.69 assessed 135 pancreatic cancer patients. Nine- 3 32 (10.4–74.7) teen of these patients had a family history that was suggestive of HNPCC, and of the 11 patients whose DNA was available for FDR, first-degree relatives; SIR, standardized incidence ratio. 688 Practice of Oncology / Cancers of the Gastrointestinal Tract

Ideally, high-risk patients would be able to undergo noninva- malignant.79–82 However, it is unknown if these methods actually sive, inexpensive pancreatic cancer screening; however, to date, prevent pancreatic cancer or improve overall survival by detect- a highly sensitive and specific method for pancreas surveillance ing presymptomatic disease. In addition, there is great interest in has not been recognized. Screening of high-risk patients with developing a biomarker for premalignant or early-stage disease, endoscopic ultrasound, magnetic resonance imaging, and/or although none, including CA19-9, have been proven effective.83 magnetic resonance cholangiopancreatogram has been shown Thus, whenever possible, it is recommended that high-risk patients to be effective at identifying early neoplasms, both benign and undergo pancreatic screening through a research study.

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BRCA1 and pancreatic cancer: early-stage pancreatic intraepithelial neoplasia. Gastroenterology 2012;142: pedigree findings and their causal relationships. Cancer Genet Cytogenet 730–733. 2005;158:119–125. 50. Remmers N, Bailey JM, Mohr AM, et al. Molecular pathology of early pan- 23. Danes BS, Lynch HT. A familial aggregation of pancreatic cancer. An in creatic cancer. Cancer Biomark 2011;9:421–440. vitro study. JAMA 1982;247:2798–2802. 51. Bartsch D, Shevlin DW, Tung WS, et al. Frequent mutations of CDKN2 24. Axilbund JE, Argani P, Kamiyama M, et al. Absence of germline BRCA1 in primary pancreatic adenocarcinomas. Genes Chromosomes Cancer 1995; mutations in familial pancreatic cancer patients. Cancer Biol Ther 2009;8: 14:189–195. 131–135. 52. de Snoo FA, Bishop DT, Bergman W, et al. Increased risk of cancer other 25. Reid S, Schindler D, Hanenberg H, et al. Biallelic mutations in PALB2 than melanoma in CDKN2A founder mutation (p16-Leiden)-positive mela- cause Fanconi anemia subtype FA-N and predispose to childhood cancer. noma families. Clin Cancer Res 2008;14:7151–7157. Nat Genet 2007;39:162–164. 53. Vasen HF, Gruis NA, Frants RR, et al. Risk of developing pancreatic cancer 26. Xia B, Dorsman JC, Ameziane N, et al. Fanconi anemia is associated with a in families with familial atypical multiple mole melanoma associated with a defect in the BRCA2 partner PALB2. Nat Genet 2007;39:159–161. specific 19 deletion of p16 (p16-Leiden). Int J Cancer 2000;87:809–811. 27. Rahman N, Seal S, Thompson D, et al. PALB2, which encodes a BR- 54. Mukherjee B, Delancey JO, Raskin L, et al. Risk of non-melanoma cancers CA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet in first-degree relatives of CDKN2A mutation carriers. J Natl Cancer Inst 2007;39:165–167. 2012;104:953–956.

tahir99 - UnitedVRG Chapter 50 Genetic Testing in Pancreatic Cancer 689

55. McWilliams RR, Wieben ED, Rabe KG, et al. Prevalence of CDKN2A mu- 70. Howes N, Lerch MM, Greenhalf W, et al. Clinical and genetic charac- tations in pancreatic cancer patients: Implications for genetic counseling. teristics of hereditary pancreatitis in Europe. Clin Gastroenterol Hepatol Eur J Hum Genet 2011;19:472–478. 2004;2:252–261. 56. Ghiorzo P, Fornarini G, Sciallero S, et al. CDKN2A is the main susceptibility 71. Lowenfels AB, Maisonneuve P, Di Magno EP, et al. Hereditary pancreatitis gene in Italian pancreatic cancer families. J Med Genet 2012;49:164–170. and the risk of pancreatic cancer. International Hereditary Pancreatitis Study 57. Debniak T, van de Wetering T, Scott R, et al. Low prevalence of CDKN2A/ Group. J Natl Cancer Inst 1997;89:442–446. ARF mutations among early-onset cancers of breast, pancreas and malignant 72. Rebours V, Boutron-Ruault MC, Schnee MF, et al. Risk of pancreatic ad- melanoma in Poland. Eur J Cancer Prev 2008;17:389–391. enocarcinoma in patients with hereditary pancreatitis: a national exhaustive 58. Schneider R, Slater EP, Sina M, et al. German national case collection for series. Am J Gastroenterol 2008;103:111–119. familial pancreatic cancer (FaPaCa): ten years experience. Fam Cancer 2011; 73. Lowenfels AB, Maisonneuve P, Whitcomb DC, et al. Cigarette smoking as 10:323–330. a risk factor for pancreatic cancer in patients with hereditary pancreatitis. 59. Bartsch DK, Sina-Frey M, Lang S, et al. CDKN2A germline mutations in JAMA 2001;286:169–170. familial pancreatic cancer. Ann Surg 2002;236:730–737. 74. Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of 60. Lal G, Liu L, Hogg D, et al. Patients with both pancreatic adenocarcinoma cancer in familial Peutz–Jeghers syndrome. Gastroenterology 2000;119: and melanoma may harbor germline CDKN2A mutations. Genes Chromo- 1447–1453. somes Cancer 2000;27:358–361. 75. Lim W, Olschwang S, Keller JJ, et al. Relative frequency and morphology 61. Goggins M, Offerhaus GJ, Hilgers W, et al. Pancreatic adenocarcinomas of cancers in STK11 mutation carriers. Gastroenterology 2004;126: with DNA replication errors (RER+) are associated with wild-type K-ras and 1788–1794. characteristic histopathology. Poor differentiation, a syncytial growth pattern, 76. Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum and pushing borders suggest RER+. Am J Pathol 1998;152:1501–1507. of cancers in the Peutz–Jeghers syndrome. Clin Cancer Res 2006;12: 62. Yamamoto H, Itoh F, Nakamura H, et al. Genetic and clinical features of 3209–3215. human pancreatic ductal adenocarcinomas with widespread microsatellite 77. Grützmann R, McFaul C, Bartsch DK, et al. No evidence for germline muta- instability. Cancer Res 2001;61:3136–3144. tions of the LKB1/STK11 gene in familial pancreatic carcinoma. Cancer Lett 63. Lynch HT, Voorhees GJ, Lanspa SJ, et al. Pancreatic carcinoma and hereditary 2004;214:63–68. nonpolyposis colorectal cancer: a family study. Br J Cancer 1985;52:271–273. 78. Jacobs EJ, Chanock SJ, Fuchs CS, et al. Family history of cancer and risk 64. Barrow E, Robinson L, Alduaij W, et al. Cumulative lifetime incidence of ex- of pancreatic cancer: A pooled analysis from the Pancreatic Cancer Cohort tracolonic cancers in Lynch syndrome: A report of 121 families with proven Consortium (PanScan). Int J Cancer 2010;127:1421–1428. mutations. Clin Genet 2009;75:141–149. 79. Canto MI, Hruban RH, Fishman EK, et al. Frequent detection of pan- 65. Geary J, Sasieni P, Houlston R, et al. Gene-related cancer spectrum in fami- creatic lesions in asymptomatic high-risk individuals. Gastroenterology lies with hereditary non-polyposis colorectal cancer (HNPCC). Fam Cancer 2012;142:796–804. 2008;7:163–172. 80. Ludwig E, Olson SH, Bayuga S, et al. Feasibility and yield of screening 66. Kastrinos F, Mukherjee B, Tayob N, et al. Risk of pancreatic cancer in fami- in relatives from familial pancreatic cancer families. Am J Gastroenterol lies with Lynch syndrome. JAMA 2009;302:1790–1795. 2011;106:946–954. 67. Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of 81. Verna EC, Hwang C, Stevens PD, et al. Pancreatic cancer screening in a DNA-mismatch-repair genes. Int J Cancer 1999;81:214–218. prospective cohort of high-risk patients: A comprehensive strategy of imaging 68. Vasen HF, Offerhaus GJ, den Hartog Jager FH, et al. The tumor spectrum and genetics. Clin Cancer Res 2010;16:5028–5037. in hereditary non-polyposis colorectal cancer: a study of 24 kindreds in the 82. Langer P, Kann PH, Fendrich V, et al. Five years of prospective screening Netherlands. Int J Cancer 1990;46:31–34. of high-risk individuals from families with familial pancreatic cancer. Gut

69. Gargiulo S, Torrini M, Ollila S, et al. Germline MLH1 and MSH2 muta- 2009;58:1410–1418. OF ONCOLOGY PRACTICE tions in Italian pancreatic cancer patients with suspected Lynch syndrome. 83. Goggins M. Markers of pancreatic cancer: working toward early detection. Fam Cancer 2009;8:547–553. Clin Cancer Res 2011;17:635–637. Molecular Biology of Liver 51 Cancer

Jens U. Marquardt and Snorri S. Thorgeirsson

INTRODUCTION approaches of diagnosis and therapy, providing the foundation for predictive and preventive personalized medicine.10 Hepatocellular carcinoma (HCC) is the fifth most common In this chapter we discuss both the molecular hallmarks of cancer in men and the seventh most common cancer in women hepatocarcinogenesis in the context of next-generation high- worldwide, accounting for at least 600,000 deaths annually.1 Al- throughput genomic technologies, and the implications for clini- though rates in traditionally high-incidence regions such as south- cal and translational efforts. east Asia and sub-Sahara Africa has stabilized and slowly declined due to generalized vaccination programs, the incidence and mortality rates of HCC have doubled in the United States and Europe GENETIC ALTERATIONS IN LIVER CANCER in the past 4 decades and are predicted to continue rising.2 Sev- eral confounding factors (e.g., immigration from high-incidence During the last decade, a detailed map of the structural variation countries) contribute to these high numbers in the western world, in the human cancer genome has been generated.11 This map and HCC is currently among the fastest growing causes of cancer reveals that tumor development is the consequence of intragenic related deaths in the United States. Small HCCs can be cured mutations in approximately 140 genes belonging to 12 signaling by resection and/or liver transplantation. However, at the time of pathways regulating three core cellular processes—cell fate, cell diagnosis, less than 20% of patients are eligible for these treatment survival, and genome maintenance—that can promote or “drive” options.3 These observations make it clear that liver cancer is a tumorigenesis in the majority of human cancers.11 Hepatocarcino- major health problem in the United States and Europe and high- genesis can, therefore, be considered a multistep process that is light the critical need for both improved understanding and treat- orchestrated by a sequence of epigenetic and genetic alterations ment options of this deadly disease. leading to disruption in these core processes by the activation or in- The major etiologic agents responsible for chronic liver disease, hibition of key downstream signaling such as p53, WNT, β-catenin, cirrhosis, and ultimately, HCC are known and well characterized MYC, the ErbB family, as well as chromatin modifications.11 (e.g., hepatitis B virus [HBV], hepatitis C virus [HCV], ethanol Structural variation and chromosomal aberrations in tumors abuse). Other etiologic factors include nonalcoholic fatty liver dis- are traditionally regarded as evidence of gene deregulation and ease (NAFLD) and other metabolic disorders that have become genome instability, and may facilitate the identification of crucial particularly relevant in Western countries due to a sharp increase genes and regulatory pathways that are perturbed in diseases.12 in prevalence and a high number of HCCs without underlying Large, genomewide association studies (GWAS) recently identified cirrhosis.4 liver disease–specific susceptibility loci, including in HCC.13,14 Over the last decades, molecular mechanisms of liver diseases Most of these studies employed powerful high-throughput mi- that are associated with increased risk of HCC as well as several croarray technology for single nucleotide polymorphism (SNP) cellular alterations that precede HCC have been identified.5,6 genotyping and array-based comparative genomic hybridization Research into the molecular pathogenesis of HCC is currently (aCGH). These technologies enable a high-throughput analysis focused on the interrelationship of abnormal genomics, epig- of DNA copy number and yield comprehensive information for enomics, proteomics, and downstream alterations in molecular determining the molecular pathogenesis of human HCC. signaling pathways. The primary goal of this research is to integrate A meta-analysis of aCGH studies of chromosome aberrations the new data with clinicopathologic features of HCC in order to in human HCC shows that specific chromosomal gains and losses uncover new diagnostic tools, improve treatment options, and im- correlate with etiology and histologic grade.15 In HCC, the most plement effective prevention strategies.7 frequent amplifications of genomic material involve 1q (57.1%), The recent introduction of next-generation whole genomic 8q (46.6%), 6p (22.3%), and 17q (22.2%), whereas losses are most technologies permits simultaneously detection of the expression common in 8p (38%), 16q (35.9%), 4q (34.3%), 17p (32.1%), and of tens of thousands of genes in small samples from normal and 13q (26.2%). Deletions of 4q, 16q, 13q, and 8p correlate with diseased tissues.8 High-throughput microarray-based technologies HBV infection and a lack of HCV infection. Chromosomes 13q and the recent advent of next-generation whole genome DNA and 4q are significantly underrepresented in poorly differentiated sequencing offer a unique opportunity to define the descriptive HCC, and gains of 1q correlate with other high-frequency altera- characteristics (i.e., phenotype) of a biologic system in terms of the tions.16 Amplifications and deletions often occur on chromosome genomic readout (e.g., gene expression, coding mutations, inser- arms at sites of oncogenes (e.g., MYC on 8q24) and tumor sup- tions and deletions in DNA, splicing variants, copy number varia- pressor genes (e.g., RB1 on 13q14), as well as at several loci that tions, chromosomal translocations). Integrated analyses and the contain genes with known and/or suspected oncogenic functions interpretation of biologic systems has caused a paradigm shift in bi- (e.g., FZD3, WISP1, SIAH-1, and AXIN2), all of which modulate ologic research, from the classic reductionism to systems biology.9 the WNT signaling pathway. In these meta-analyses, etiology and Fundamental to the systems approach is the hypothesis that disease poor differentiation of HCC correlated with specific genomic al- processes are driven by aberrant regulatory networks of genes and terations. In preneoplastic dysplastic nodules (DN), amplifications proteins that differ from the normal counterparts. The application are most frequent in 1q and 8q, whereas deletions occur in 8p, of multiparametric measurements promises to transform current 17p, 5p, 13q, 14q, and 16q.16 A gain of 1q appears to be an early

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tahir99 - UnitedVRG Chapter 51 Molecular Biology of Liver Cancer 691 event that develops in DN, possibly predisposing affected cells to described genes was seen from cirrhotic nodules over dysplastic acquire additional chromosomal aberrations. nodules (low and high grade) to early carcinoma (eHCC) and, A comprehensive collection of common aberrations from both finally, progressed HCC (pHCC).28 human and rodent HCC is provided in the OncoDB.HCC data- More recently, integrative genome-wide methylation analyses base (http://oncodb.hcc.ibms.sinica.edu.tw).17 This database pro- have been applied to 71 human HCC patients.29 The methyla- vides a useful, validated, and graphic integration of published data tion data were combined with those from a microarray analysis of derived from loss of heterozygosity (LOH) analyses, aCGH, gene gene reexpression in four hepatoma cell lines following their ex- expression microarrays, as well as proteomics, which is publically posure to DNA methylation inhibitors. A total of 13 candidate assessable for the validation of possible molecular targets. tumor suppressor genes were identified using this approach and, Recently, a systematic strategy to identify potential driver genes subsequently, SMPD3 and NEFH were functionally validated as by integrating whole genome copy number data with gene expres- tumor suppressor genes in HCC. The authors could further show sion profiles of HCC patients was introduced.18 Using regional that SMPD3 not only affects tumor aggressiveness, but also that pattern recognition approaches, the authors discovered the most reduced levels are an independent prognostic factor for early re- probable copy number–dependent regions and 50 potential driver currence of HCC. genes. At each step of the process, the functional relevance of the se- Although genetic changes in chromatin modulators are among lected genes was evaluated by estimating the prognostic significance the most common alterations in HCC (see the following), the role of the selected genes. Further validation using small interference of epigenetic alterations beyond DNA methylation such as modifi- RNA-mediated knockdown experiments showed proof-of-principle cation of histones (e.g., acetylation, methylation, phosphorylation, evidence for the potential driver roles of the genes in HCC progres- ubiquitylation, SUMOylation) are not well studied in HCC.30 The sion (i.e., NCSTN, SCRIB). In addition, the systemic prediction of fact that modifications of both repressing (e.g., H3 lysine 27 and drug responses using the Connectivity Map,19 a compendium of histone H3 Lysine 9) and activating histone marks (e.g., H3 lysines functional connections between drugs and genes, implicated the 4) have a significant impact on the expression of critical genes as- association of the 50 genes with specific signaling molecules associated with hepatocarcinogenesis highlight the need for whole sociated with hepatocarcinogenesis (mTOR, AMPK, and EGFR). genomic approaches such as chromatin immunoprecipitation It was concluded that the application of an unbiased and integra- with microarray technology (ChIP-chip) and ChIP sequencing tive analysis of multidimensional genomic data sets can effectively (ChIP-seq) to address the role of these changes in a more global screen for potential driver genes and provide novel mechanistic perspective.31 and clinical insight into the pathobiology of HCC. MicroRNAs are epigenetically active, small RNAs that are In a similar approach, a recent study used an integrative ap- critically involved to regulate protein expression.32 Distinct Mi- proach combining information from high-resolution aCGH and croRNA expression patterns contribute to the definition of the gene expression profiling with clinical data from HCC patients to cellular phenotype, including the regulation of proliferation, cell

identify copy-number variations (CNV) in HCC with functional rel- signaling, and apoptosis. Not surprisingly, the aberrant expression OF ONCOLOGY PRACTICE evance for tumor progression.20 The investigation was restricted to of microRNAs is associated with cancer initiation, propagation, genes that showed (1) recurrent CNVs, (2) correlation of the CNVs and progression. Several microRNAs are frequently deregulated and the transcriptome, and (3) a selective association to patients’ in HCC and associated with certain clinicopathologic features.33 outcomes to distinguish “drivers” from passengers. The authors were Several studies have demonstrated that microRNAs play an es- able to demonstrate significant differences in CNVs between patients sential role in HCC progression by directly contributing to cell with good and poor outcome and generated a 10-gene signature as a proliferation, apoptosis, and metastasis of HCC as well as by tar- molecular predictor of patient survival and validated the signature in geting a large number of critical protein-coding genes involved in several independent cohorts. Both these studies elegantly illustrate hepatocarciongenesis.34 The profiling of microRNA expression by the power of multilayer integrative analyses to identify the functional microarray revealed subclasses associated with clinicopathologic significance of genomic alterations in human HCC. features as well as mutations in several oncogenic pathways such as β-catenin and HNF1A.35 Furthermore, microRNA profiling of 89 HCC samples using a ligation-mediated amplification method re- EPIGENETIC ALTERATIONS IN LIVER vealed three distinct clusters HCCs reflecting the clinical behavior CANCER of the tumors as well as identifying the microRNAs family mir-517 with increased tumorigenicity of HCC cells.36 37 Epigenetic alterations such as DNA methylation are important fac- Ji and colleagues confirmed the therapeutic potential of tors in tumor development for many cancers.21 Changes in DNA microRNA-based treatment modalities in HCC. The authors demonstrated that miR-26 levels are associated with a response to methylation patterns are believed to be early events in hepatocar- α α cinogenesis, preceding allelic imbalances and ultimately leading adjuvant therapy with interferon (IFN- ) and, more recently, developed a simple and reliable companion diagnostic (MIR26-DX) to cancer progression, thereby adding considerable complexity to α the pathogenesis of liver cancer.22 to select HCC patients for adjuvant IFN- therapy as a first step to successfully translate information from large scale analyses into Global hypomethylation and promoter hypermethylation in 38 certain cancer-related genes are known drivers of hepatocarcino- the clinics. genesis with an association to biologic behavior and prognosis.23 Methylation patterns can further be used to classify patients according to different etiological factors (e.g. HBV, HCV, alco- MUTATIONAL LANDSCAPE OF GENETIC hol).24,25 Moreover, in addition to changes in global methylation ALTERATIONS IN HCC: THE NEXT patterns, distinct methylation patterns strongly correlate with clini- GENERATION cal characteristics of HCC patients.23 Methylation patterns in a 807 cancer-related gene panel could successfully separate primary Sophisticated next-generation sequencing (NGS) technologies HCC samples according to their biologic subtype.26 Consistent are now applied in cancer research for complete and cost-efficient with previous studies, patients with progenitor cell origin displayed analyses of cancer genomes at a single nucleotide resolution and the worst clinical outcome.27 The confirmation of a multistep, have advanced into valuable tools in translational medicine.12 The epigenetic-driven sequence of molecular alteration in hepatocar- implementation of NGS to solid tumors like HCC is challenging cinogenesis could further be demonstrated in HBV-related liver because the proportion of normal cells or the stromal composi- cancers. A stepwise hypermethylation of CpG islands of nine well- tion within a given sample contributes to the genomic signature 692 Practice of Oncology / Cancers of the Gastrointestinal Tract and, therefore, may require additional coverage (i.e., read depth). firmed the previous studies that β-catenin (10% and 15.9%) and Also, HCCs often arise in the background of a chronically diseased TP53 (18% and 35.2%) are the most frequently mutated oncogene liver with underlying cirrhosis, fibrosis, or HBV or HCV infec- and tumor suppressor, respectively, in HCC.46,47 The study by Kan tion, which may complicate the tumor/normal variant discovery et al.47 also detected several drugable mutations, including activat- when compared to the peritumoral liver tissue or even blood.39 ing mutations of Janus kinase 1 (9.1%), which might provide an Therefore, the number of studies where NGS technologies—in option for novel individualized therapeutic interventions. Interest- particular, whole exome sequencing—have been applied to in- ingly, Nault et al.,48 using traditional Sanger sequencing, identi- vestigate HCC is, so far, limited and only conducted on a few fied somatic mutations activating telomerase reverse transcriptase patients.40 However, all the studies revealed that the landscape of as both the earliest and the most frequent mutations in human molecular alterations in HCC is relatively broad, with the number preneoplastic lesions (25%) as well as hepatocellular carcinomas of mutations found ranging from 5 to 121 mutations per tumor. (59%) and is associated with activating CTNNB1 mutations.48 Thus, due to the genetic heterogeneity, a rather complex interac- Compared to whole-genome sequencing, the application tion of multiple mutations in the development of a singular HCC of RNA sequencing in liver cancer is currently limited to three has to be assumed.41–44 Although no clear oncogenic addiction studies. One study investigated the transcriptomes of 10 matched has been demonstrated, a high number of mutations in p53 and HBV-related HCC cases, identifying a total of 1,378 differentially Wnt/β-catenin signaling were detected (Fig. 51.1). Thus, results expressed genes with a specific enrichment of chromosome loca- from in-depth analyses strengthen existing evidence that p53 and tion on 8q21.3 to 24.3.49 Another study investigated three paired Wnt/β-catenin signaling are among the most common molecular nontumor and tumor specimens demonstrating that ADAR1-medi- changes involved in HCC development. Another interesting find- ated AZIN1 RNA editing is linked to tumor initiation and developing is the high frequency of genetic alteration in genes involved ment in liver cancer.50 in chromatin remodeling. Overall, 16% to 24% of HCCs showed Sequential molecular alterations during human hepatocar- genetic alterations in these pathways, thereby suggesting a caus- cinogenesis from dysplastic lesions to eHCC and, ultimately, ative association with hepatocyte transformation and highlighting pHCC are not clearly defined. This lack of information represents recent evidence for the key role of epigenetics in hepatocarcino- a major challenge in the clinical management of patients at risk. genesis.45 Although recent results associating MYC activation with early Two recent studies on whole exome/genome sequencing of 87 stages of malignant conversion into HCC, detailed molecular se- and 88 human HCCs as well as matched normal tissue46,47 con- quences that drive premalignant lesions into pHCC still remain

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Figure 51.1 Major oncogenic pathways and genetic landscape in hepatocellular carcinoma (HCC). The scheme shows the major disrupted pathways in HCC patients (outer circle). The inner circle emphasizes the frequency of genetic alterations within the corresponding pathways and their putative contribution to hepatocarcinogenesis. Frequencies are based on results from recent whole genomic studies.41–44 Representative members of each pathway most frequently altered in HCC are also shown.

tahir99 - UnitedVRG Chapter 51 Molecular Biology of Liver Cancer 693 to be clarified.51 In the third study, integrative transcriptome se- patocarcinogenesis. Among the most prominent factors involved quencing to the tumor-free surrounding liver (n = 7), low-grade in the so called inflammation-fibrosis-cancer axis is the nuclear (n = 4) and high-grade dysplastic lesions (n = 9), eHCC (n = 5), factor kappa B (NF-κB) pathway.54 The dominant role of this path- and pHCC (n = 3) from eight HCC patients with HBV infections way for hepatocarcinogenesis is well documented.54 However, the was applied.52 The results of the study indicate that molecular pro- absence of NF-κB by genetic loss of the NF-κB master regulator files of dysplastic lesions and eHCC are quite uniform. In contrast, NEMO significantly enhanced liver cancer development in a a sharp increase in heterogeneity on both mRNA and DNA levels mouse model, indicating that inhibition of NF-κB may not only is observed in progressed HCC. These molecular alterations result exert beneficial effects, but also may negatively impact hepatocyte in massive deregulation of key oncogenic molecules such as trans- viability, especially when NF-κB inhibition is pronounced.55 forming growth factor beta 1 (TGF-β1), MYC, PI3K/AKT, and The importance of the microenvironment is further high- suggest that activation of prognostically adverse signaling pathways lighted in a recent study demonstrating that transplantation of is a late event during hepatocarcinogenesis (Fig. 51.2). hepatic progenitor cells gave rise to cancer only when introduced into a liver with chronic damage and compensatory proliferation.56 Interestingly, similar to observations made in human hepatocar- THE MICROENVIRONMENT OF LIVER cinogenesis, the cells resembling these progenitor cells quies- CANCER cently resided within dysplastic lesions for several months before the appearance of HCC. During this time, the progenitor cells HCC develops on the basis of chronic liver disease and, in more acquired autocrine interleukin (IL)-6 signaling that stimulated in than 80% of the cases, with preexisting liver cirrhosis. For a com- vivo growth and malignant progression, which might be a general plete understanding of the molecular mechanisms of hepatocar- mechanism of progenitor cell–induced HCC. cinogenesis, the underlying liver disease leading to a chronically However, the microenvironment does not only contribute to altered inflamed liver microenvironment has to be appreciated.53 tumor initiation. Although gene-expression profiles of tumor tissue Recent research efforts have focused on the identification of key failed to yield a significant association with survival, a 186-gene factors that contribute to the disruption of the liver microenviron- signature generated from the surrounding nontumoral liver tissue ment and the generation of an adverse niche(s) that promotes he- was highly correlated with outcomes in a cohort of more than 300 PRACTICE OF ONCOLOGY PRACTICE

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Figure 51.2 Sequential evolution of liver cancer. The current concept considers hepatocarcinogenesis as a multistep process that develops on the basis of a chronically altered microenvironment (i.e., cirrhosis) and progresses from dysplastic nodules (high grade and low grade) over early HCC to progressed HCC (upper panels). On the molecular level, the different stages are characterized by progressive activation of signaling pathways related to oxidative stress, immune response, and proliferation (middle panel). However, the activation of prognostically adverse signaling occurs late during the evolution of liver cancer. During this process, a progressive loss of differentiation with a concomitant acquisition of malignant and invasive properties is observed (lower panel). LGDN, low-grade dysplastic nodule; HGDN, high-grade dysplastic nodule; EMT, epithelial-mesenchymal transition. 694 Practice of Oncology / Cancers of the Gastrointestinal Tract

HCC patients.57 Consistently, this poor-prognosis signature con- better define the intratumoral genetic heterogeneity of HCC that tained gene sets associated with inflammation, such as IFN sig- is likely to contribute to the high tumor recurrence and chemore- naling, NF-κB, and tumor necrosis factor α (TNF–α). Further, a sistance of the disease.62,63 gene set enrichment analysis showed that the downstream targets Nault et al.64 aimed to identifying a robust molecular signature of IL-6 were strongly associated with the poor-prognosis signature, to accurately predict the clinical outcome of HCC patients who again confirming the importance of this signaling for hepatocar- underwent curative surgical resection. They identified a panel of cinogenesis. five genes (TAF9, RAMP3, HN1, KRT19, and RAN) in a training Together, these studies demonstrate the complexity of molecu- cohort of 314 HCC patients with a strong prognostic relevance lar mechanisms influencing the development and progression of and further validated this panel in two independent validation co- liver cancer that are exerted by epigenetic and genetic alterations horts with different HCC etiologies.64 The five-genes panel was and a cross-talk between microenvironment and damaged hepato- associated with disease-specific survival both in the training and cytes and/or cancer cells, respectively. in the validation cohort, and was found to be significantly more accurate in predicting the patients’ prognosis (i.e., survival and recurrence) when compared to known gene expression signatures. Due to the simplicity of the panel and its reproducibility in differ- CLASSIFICATION AND PROGNOSTIC ent technologies (i.e., gene expression microarray and real-time PREDICTION OF HEPATOCELLULAR reverse-transcription polymerase chain reaction [qRT-PCR]), the CARCINOMA work by Nault et al. has a high potential for implementation into the clinical management of HCC. In particular, the score may The application of microarray technologies to characterize tumors be helpful to stratify patients at high risk for relapse and tumor- on the basis of global gene expression has had a significant impact related death before the decision of liver resection or transplanta- on both basic and clinical oncology.10 The goal of tumor microar- tion is made. However, independent validation of this prognostic ray studies generally includes the discovery of subsets of tumors algorithm by different groups and independent cohorts is needed (class discovery), which enables diagnostic classification (class before the panel can be used for clinical decision making. comparison), a prediction of clinical outcome (class prediction), Two independent studies provide evidence that the oncofetal and mechanistic analysis. Verification and validation of the pri- marker SALL4 could be an attractive therapeutic target in HCC mary results are essential for the discovery of oncogenic pathways with progenitor cell origin.65,66 High SALL4 expression was sig- and the identification of therapeutic targets.8 nificantly associated with overall survival of patients in large inde- The goal of all staging systems is to separate patients into ho- pendent cohorts. Further, and consistent with its oncofetal role, mogeneous prognostic groups to permit the selection of the most SALL4 overexpressing tumors shared similar molecular profiles appropriate surveillance as well as to find a specific therapy for with fetal progenitor cells and stemness-associated HCC. Finally, each subtype. Although much work has been devoted to establish- by using RNAi and a specific inhibitory 12-AA peptide against ing prognostic models for HCC by using clinical information and SALL4, the authors could convincingly show that SALL4 pos- pathologic classification, many issues still remain unresolved.58 sessed therapeutic potential in HCC by interacting with PTEN/ More than 20 studies on prognostic HCC gene expression profil- PI3K-AKT signaling via the interaction with the NuRD complex.67 ing, as well as several reviews, have appeared during the last 10 These studies confirm several recent observations indicating that years.4 However, results from these studies are quite heterogeneous HCCs harboring phenotypic features of stem/progenitor cells con- and, besides disruption in general cancer-related processes such as stitute a subclass of therapeutically challenged cancer patients that proliferation, apoptosis, neoangiogenesis as well as prometastatic have a particularly poor prognosis.27,68,69 and proinflammatory gene sets, the overall similarity was low, thus Contrary to HCCs, the molecular pathology of intrahepatic limiting a successful implementation into clinical practice. A po- cholangiocellular carcinoma (ICC) is less well investigated. Most tential explanation is the fact that the interpretation of molecular of the studies on cholangiocarcinogenesis focused on the inves- profiling studies of HCC poses more challenges than other human tigation of few candidate genes.70 In a seminal work on both ge- tumors, mainly because of the complex pathogenesis of this nomic and genetic features of ICC gene expression, profiles of 104 cancer.59As already emphasized, HCC arises in diverse settings surgically resected cholangiocarcinoma samples were collected ranging from infection with HBV or HCV to chronic metabolic and analyzed from patients in Australia, Europe, and the United diseases as varied as diabetes, NAFLD, and hemochromatosis. States.71 The authors discovered new two prognostic subclasses of These different disease stages represent complex assortments of patients defined by a 238-gene classifier as well as KRAS muta- genetic and epigenetic aberrations as well as altered molecular tions and increased levels of EGFR and HER2, and concomi- pathways.39,60 tantly validated promising therapeutic strategies in different ICC A recent study aimed to generate a composite prognostic model cell lines, which resembled the different prognostic subtypes. Fur- by evaluating 22 prognostic gene expression signatures generated thermore, this study also addressed the importance of the stromal from tumors as well as cirrhotic tissues in a cohort of 287 patients component of ICC by laser capture microdissection of epithelial with early stage HCC (BCLC 0/A).61 Overall, most previously and stromal compartments from 23 tumors. Although the tumor reported signatures retained their prognostic ability in this inde- epithelium was defined by deregulation of the HER2 network and pendent data set. Out of these 22 signatures, 17 were able to ad- frequent overexpression of EGFR, c-MET, pRPS6 as well as pro- equately subclassify patients according to their prognostic trait. It liferation, the stroma was predominantly enriched for inflamma- is noteworthy that none of the signatures reflecting a progenitor tory gene sets. In another study, gene expression analyses of 149 cell origin (i.e., EpCAM, hepatoblastoma-C2, CK19-rat, CK19- patients with ICC from formalin-fixed paraffin-embedded samples human signature) could be confirmed to be of prognostic value. were performed.72 A Gene Set Enrichment Analysis (GSEA) and However, these signatures have not been generated for the clas- functional characteristics of the patients again revealed two broad sification of early stages of HCC. molecular subclasses—proliferation and inflammation—defined Another important finding of this study was the observation that by the differential expression of 1,565 significant genes. The pro- gene expression profiles obtained from paired biopsies from the liferation class was associated with aggressive tumor biology as center and periphery of the same tumor in 15 tumor specimens well as a poor prognosis and was characterized by molecular en- showed a high (>80%) transcriptomic concordance. Although richment of oncogenic pathways (e.g., RAS/RAF/MAPK, VEGF, these observation provide at least some evidence for stability of and PDGF). The inflammation class displayed a better prognosis gene expression signatures in paired biopsies and suggests a low and enrichment of immune-related signaling, in particular IL-10 influence of sampling error, more in-depth analyses are needed to and signal transducer and activator of transcription 3 (STAT3)

tahir99 - UnitedVRG Chapter 51 Molecular Biology of Liver Cancer 695 signaling. Furthermore, a subgroup of ICCs in the proliferation of these new analytical approaches, comparative and/or integrative class shared features of several previously published prognostic functional genomics, suggests that integration of independent data HCC signatures with a possible progenitor cell origin, which sup- sets will enhance our ability to identify robust predictive markers. ported the hypothesis that these tumors may be derived from a Despite the success of these approaches in preclinical translational common origin or precursor cell(s). This hypothesis is supported studies, the clinical application of gene expression profiling is still by recent work by Woo et al.,73 which applied an integrative on- immature. Although current signatures accurately classify HCCs cogenomic approach to address the clinical and functional impli- according to their natural biology, they are unable to predict the cations of the overlapping phenotype of combined hepatocellular response to currently used therapies.59 Furthermore, HCC with cholangiocarcinoma (CHC), a histopathologic intermediate be- progenitor cell features display a particular aggressive behavior, tween HCC and cholangiocellular carcinoma (CC). which might indicate that tumor heterogeneity and resulting chemoresistance might be generated in molecularly plastic cancer stem cells (CSCs).76 Because CSCs by definition are a rare sub- CONCLUSION AND PERSPECTIVE population of cells, their molecular profile might be diluted by the bulk of tumor cells, which further hampers therapeutic progress.77 Next-generation technologies, in particular gene expression micro- However, based on the exciting results of recent studies and the arrays and, more recently, next-generation sequencing, have pro- advent of NGS technologies that offer unprecedented depths and vided an extraordinary opportunity for integrative analyses of the resolution, it seems reasonable to predict that the genomic tech- cancer (epi-) genome as well as transcriptome. Array-based gene nologies will play an increasingly important role in clinical oncol- expression profiling not only has advanced our understanding of ogy. The immediate focus undoubtedly will be on incorporating cancer biology, but also has begun to influence decision making these whole-genomic technologies into clinical trials. To achieve in clinical oncology, which may ultimately allow for the develop- this ambitious goal, systematic and standardized collections of tis- ment of more effective therapies. The power of gene expression sue specimens from HCC patients (e.g., mandatory biopsies) for profiling of HCC can be further enhanced by cross-comparison subsequent prospective molecular analyses are urgently needed analyses of multiple gene expression data sets from human HCC to ultimately improve the diagnosis and treatment of liver cancer and the rich database of HCC in animal models.74,75 The success patients.

SELECTED REFERENCES

The full reference list can be accessed at lwwhealthlibrary.com/oncology. 43. Li M, Zhao H, Zhang X, et al. Inactivating mutations of the chromatin remodeling gene ARID2 in hepatocellular carcinoma. Nat Genet 2. El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011;365:1118–1127. 2011;43:828–829. OF ONCOLOGY PRACTICE 3. Bruix J, Sherman M, American Association for the Study of Liver D. Manage- 44. Totoki Y, Tatsuno K, Yamamoto S, et al. High-resolution characterization of ment of hepatocellular carcinoma: an update. Hepatology 2011;53:1020–1022. a hepatocellular carcinoma genome. Nat Genet 2011;43:464–469. 4. Marquardt JU, Galle PR, Teufel A. Molecular diagnosis and therapy of hepa- 46. Cleary SP, Jeck WR, Zhao X, et al. Identification of driver genes in hepato- tocellular carcinoma (HCC): an emerging field for advanced technologies.J cellular carcinoma by exome sequencing. Hepatology 2013;58:1693–1702. Hepatol 2012;56:267–275. 47. Kan Z, Zheng H, Liu X, et al. Whole-genome sequencing identifies re- 6. Thorgeirsson SS, Grisham JW. Molecular pathogenesis of human hepatocel- current mutations in hepatocellular carcinoma. Genome Res 2013;23: lular carcinoma. Nature Genet 2002;31:339–346. 1422–1433. 8. Quackenbush J. Microarray analysis and tumor classification. N Engl J Med 48. Nault JC, Mallet M, Pilati C, et al. High frequency of telomerase reverse- 2006;354:2463–2472. transcriptase promoter somatic mutations in hepatocellular carcinoma and 11. Vogelstein B, Papadopoulos N, Velculescu VE, et al. Cancer genome land- preneoplastic lesions. Nat Commun 2013;4:2218. scapes. Science 2013;339:1546–1558. 52. Marquardt JU, Seo D, Andersen JB, et al. Sequential transcriptome analysis 15. Moinzadeh P, Breuhahn K, Stutzer H, et al. Chromosome alterations in human of human liver cancer indicates late stage acquisition of malignant traits. J hepatocellular carcinomas correlate with aetiology and histological grade—re- Hepatol 2014;60:346–353. sults of an explorative CGH meta-analysis. Br J Cancer 2005;92:935–941. 54. Karin M. Nuclear factor-kappaB in cancer development and progression. 18. Woo HG, Park ES, Lee JS, et al. Identification of potential driver genes in human Nature 2006;441:431–436. liver carcinoma by genomewide screening. Cancer Res 2009;69:4059–4066. 56. He G, Dhar D, Nakagawa H, et al. Identification of liver cancer progeni- 22. Feinberg AP, Ohlsson R, Henikoff S. The epigenetic progenitor origin of tors whose malignant progression depends on autocrine IL-6 signaling. Cell human cancer. Nat Rev Genet 2006;7:21–33. 2013;155:384–396. 23. Calvisi DF, Ladu S, Gorden A, et al. Mechanistic and prognostic significance 57. Hoshida Y, Villanueva A, Kobayashi M, et al. Gene expression in fixed tis- of aberrant methylation in the molecular pathogenesis of human hepatocel- sues and outcome in hepatocellular carcinoma. N Engl J Med. 2008;359: lular carcinoma. J Clin Invest 2007;117:2713–2722. 1995–2004. 27. Lee JS, Heo J, Libbrecht L, et al. A novel prognostic subtype of human 58. Thorgeirsson SS. Genomic decoding of hepatocellular carcinoma. Gastroen- hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med terology 2006;131:1344–1346. 2006;12:410–416. 60. Farazi PA, DePinho RA. Hepatocellular carcinoma pathogenesis: from genes 29. Revill K, Wang T, Lachenmayer A, et al. Genome-wide methylation analysis to environment. Nat Rev Cancer 2006;6:674–687. and epigenetic unmasking identify tumor suppressor genes in hepatocellular 61. Villanueva A, Hoshida Y, Battiston C, et al. Combining clinical, pathology, carcinoma. Gastroenterology 2013;145:1424–1435.e1–25. and gene expression data to predict recurrence of hepatocellular carcinoma. 30. Esteller M. Epigenetics in cancer. N Engl J Med 2008;358:1148–1159. Gastroenterology 2011;140:1501–1512.e2. 32. Lujambio A, Lowe SW. The microcosmos of cancer. Nature 2012;482: 64. Nault JC, De Reynies A, Villanueva A, et al. A hepatocellular carcinoma 347–355. 5-gene score associated with survival of patients after liver resection. Gastro- 36. Toffanin S, Hoshida Y, Lachenmayer A, et al. MicroRNA-based classification enterology 2013;145:176–187. of hepatocellular carcinoma and oncogenic role of miR-517a. Gastroenterol- 66. Yong KJ, Gao C, Lim JS, et al. Oncofetal gene SALL4 in aggressive hepato- ogy 2011;140:1618–1628.e16. cellular carcinoma. N Engl J Med 2013;368:2266–2276. 37. Ji J, Shi J, Budhu A, et al. MicroRNA expression, survival, and response to 71. Andersen JB, Spee B, Blechacz BR, et al. Genomic and genetic characteriza- interferon in liver cancer. N Engl J Med 2009;361:1437–1447. tion of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase 41. Fujimoto A, Totoki Y, Abe T, et al. Whole-genome sequencing of liver can- inhibitors. Gastroenterology 2012;142:1021–1031.e15. cers identifies etiological influences on mutation patterns and recurrent mu- 72. Sia D, Hoshida Y, Villanueva A, et al. Integrative molecular analysis of intra- tations in chromatin regulators. Nat Genet 2012;44:760–764. hepatic cholangiocarcinoma reveals 2 classes that have different outcomes. 42. Guichard C, Amaddeo G, Imbeaud S, et al. Integrated analysis of somatic Gastroenterology 2013;144:829–840. mutations and focal copy-number changes identifies key genes and pathways 76. Marquardt JU, Thorgeirsson SS. Stem cells in hepatocarcinogenesis: evi- in hepatocellular carcinoma. Nat Genet 2012;44:694–698. dence from genomic data. Semin Liver Dis 2010;30:26–34. 52 Cancer of the Liver

Yuman Fong, Damian E. Dupuy, Mary Feng, and Ghassan Abou-Alfa

INTRODUCTION account for 75% of the world’s cases. Both case control studies and cohort studies have shown a strong association between chronic Primary cancers of the liver represent the fifth most common ma- hepatitis B carriage rates and increased incidence of HCC. Beasley lignancy worldwide and the second most common cause of death et al.8 followed Taiwanese male postal carriers who were hepatitis B from cancer. This is due the relationship of hepatocellular car- surface antigen (HBsAg)-positive and found an annual HCC inci- cinoma to chronic hepatitis B virus (HBV) and hepatitis C virus dence of 495 per 100,000. This represented a 98-fold greater risk than (HCV) infections.1 The prognosis of untreated hepatocellular observed in HBsAg-negative individuals. By evaluating apparently carcinoma (HCC) has a dismal prognosis, with a 5-year survival asymptomatic HBsAg-positive blood donors at American Red Cross rate below 10%.2 The combination of cancer and chronic liver dis- centers, a relative risk of 12.7 was noted for liver cancer compared ease add significant complexity to treatment. The great progress in with HBsAg-negative individuals. A multivariate analysis has been understanding the natural history, pathogenesis, and tumor biol- used to determine risk scores for the development of HCC.9 Factors ogy of HCC has resulted in effective treatment options. For local- predictive of HCC include male gender, advanced age, specific pro- ized HCC, surgical resection and orthotopic liver transplantation moter mutations, the presence of cirrhosis, and higher viremia levels. (OLT) are the gold standard therapies. Formidable radiologic di- If validated, this may improve patient selection for surveillance. rected local and regional therapies, radiation therapy, and systemic The exact mechanism by which HBV infection causes HCC therapies now round out a full arsenal of treatments even for dis- is not known.10,11 Some have postulated that the effect of HBV on seminated disease. There have also been marked advances in ther- hepatic carcinogenesis is indirect, through the process of inflam- apies for hepatitis3 and in care of the associated liver parenchymal mation, regeneration, and fibrosis associated with chronic hepati- disease. However, this optimism may be negated by the continued tis and cirrhosis. Consistent with this hypothesis, 70% of cases of lack of a true breakthrough in screening and early detection, and HBV-related HCC occur in association with cirrhosis. It is well the continued rising incidence of HCC globally. known that cirrhosis of all causes may result in HCC. There is evidence that the effect may be a direct viral effect. HBV DNA may become integrated within the chromosomes of EPIDEMIOLOGY infected hepatocytes, and in some HCCs, this integration of viral genetic material may occur in a critical location within the cel- The annual number of worldwide liver cancer cases (748,300) lular genome. For example, integration of HBV DNA has been closely resembles the number of deaths (695,900). Long-term sur- observed within the retinoic acid receptor alpha gene and within vival rates are 3% to 5% in most cancer registries. In the United the human cyclin A gene, both of which play crucial roles in cel- States, approximately 30,640 new tumors of the liver and intrahe- lular growth. However, in most cases, the HBV DNA integration patic bile ducts are diagnosed each year, with 21,670 deaths esti- appears to be random. The hepatitis B x gene (HBx) product has mated annually.1 HCC is 2.3 times more common in men than in been implicated in causing HCC because it is a transcriptional women, and this difference is consistent globally. Androgen and activator of various cellular genes associated with growth control. androgen receptor (AR) have long been implicated in this male- HBx has been found to interact with p53, interfering with its func- dominance feature.4 In the United States, rates of HCC are two tion as a tumor suppressor. times higher in Asians than African Americans, which are two HCV is an RNA virus without a DNA intermediate form, and times higher than those in Caucasians. There has been a signifi- therefore, cannot integrate into hepatocyte DNA. In contrast to HBV, HCV is more likely to lead to chronic infection (10% versus cant overall increase in the incidence of HCC in the United States 12 during the past 25 years.5 This parallels the increase in HCV in- 60% to 80%), and cirrhosis (20-fold increase). The typical inter- fection, the increase in immigrants from HBV-endemic countries, val between HCV-associated transfusion and subsequent HCC is and an increase in nonalcoholic fatty liver disease. The widespread only about 30 years (compared with 40 to 50 years for HBV). The utilization of HBV vaccination is leading to a decrease in liver can- state of the liver also differs in that HCV-associated HCC patients cer in some areas. A dramatic demonstration of this is available tend to have more frequent and more advanced cirrhosis. In HBV- from Taiwan, where an HBV vaccine was introduced in 1984, and associated HCC, only half the patients have cirrhosis. The risk of a reduction of liver cancer was observed in children from 0.54 per developing HCC in a patient with HCV-related cirrhosis is 5% per 100,000 to 0.2 per 100,000 during a 16-year period.6 year versus 0.5% per year for HBV-related cirrhosis. There have been extensive efforts to establish the molecular pathways involved in the pathogenesis of HCC.13,14 Some of the ETIOLOGIC FACTORS abnormalities that are commonly found in HCC include (1) cell- cycle dysregulation associated with somatic mutations or loss of heterozygosity in TP53, silencing of CDKN2A or RB1, or CCND1 Viral Hepatitis and Hepatocellular Carcinoma overexpression; (2) increased angiogenesis accompanied by overexpression or amplification ofVEGF, PDGF, and ANGPT2; (3) eva- The variable geographic incidence of liver cancer7 reflects the vari- sion of apoptosis as a result of activation of survival signals such as able geographic incidence in HCV and HBV infections, which nuclear factor kappa B (NF-κB); and (4) reactivation of TERT.

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tahir99 - UnitedVRG Chapter 52 Cancer of the Liver 697

There is emerging evidence of the importance of microRNAs TABLE 52.1 and epigenetic alterations such as hypermethylation in the pathogenesis of HCC. MicroRNA-155 (miR-155) levels were sig- Conditions Associated with Human nificantly increased in patients infected with HCV, and overex- Hepatocellular Carcinoma pression of miR-155 was associated with nuclear accumulation of Condition Risk beta-catenin by increased Wnt signaling, thereby implicating this pathway in HCV-associated hepatocellular carcinogenesis.15 Cirrhosis Hepatitis B virus High Alcohol-Induced Hepatocarcinogenesis Hepatitis C virus High There is a strong association between alcoholic cirrhosis and the Alcohol High development of HCC. By itself, chronic alcohol consumption has Autoimmune chronic active hepatitis High carcinogenic effects. Thus, chronic alcohol intake is known to lead Cryptogenic cirrhosis High to oxidative stress in the liver, inflammation, and cirrhosis. Etha- nol is metabolized by alcohol dehydrogenases and cytochrome Cirrhosis due to nonalcoholic fatty liver High P-450, producing acetaldehyde and reactive oxygen species. Ac- disease etaldehyde binds directly to proteins and DNA. It damages mito- Primary biliary cirrhosis Low chondria, initiating apoptosis. P-450 metabolism leads to reactive oxygen species, which lead to lipid consumption peroxidation, Hereditary hemochromatosis High 16 protein oxidation, and DNA adducts. Alcohol leads to monocyte α1-Antitrypsin deficiency High activation and inflammatory cytokine production. Oxidative stress Wilson disease Low has been demonstrated in alcoholic cirrhosis through increased isoprostane, a marker of lipid peroxidation.17 Oxidative stress pro- Metabolic Diseases (without Cirrhosis) motes the development of fibrosis and cirrhosis, creating a per- Hereditary tyrosinemia High missive HCC microenvironment. Oxidative stress may also lead α -Antitrypsin deficiency Moderate to decreased Signal Transducers and Activators of Transcription 1 1 (STAT1)-directed activation of interferon gamma (IFNγ) signal- Ataxia telangiectasia Moderate 18 ing with consequent hepatocyte damage. Types 1 and 3 glycogen storage disease Moderate Nonalcoholic Fatty Liver Disease Galactosemia Moderate Citrullinemia Moderate PRACTICE OFPRACTICE ONCOLOGY HCC has been linked to nonalcoholic fatty liver disease (NAFLD). Hereditary hemorrhagic telangiectasia Moderate NAFLD is present in 30% of the general adult population, in 90% Porphyria cutanea tarda Moderate of morbidly obese adults (body mass index [BMI] ≥40 kg/m2), and in close to 74% of those with diabetes.19–21 The risk of HCC due to Orotic aciduria Moderate NAFLD appears to be less than that of chronic hepatitis C. A recent Alagille syndrome (congenital cholestatic Moderate US study reported a 2.6% yearly cumulative incidence of HCC in syndrome) NAFLD and 4% in HCV cirrhosis.22 Similarly, a prospective 5-year study from Japan reported a rate of HCC of 11.3% among patients Environmental with NAFLD cirrhosis compared to 30.5% among those with HCV- Thorotrast Moderate 23 associated cirrhosis. A recent study from Germany identified non- Androgenic steroids Moderate alcoholic steatohepatitis (NASH) as the most common etiology of HCC (24%), surpassing chronic hepatitis C (23.3%), chronic hepa- Cigarette smoking Low to moderate 24 titis B (19.3%), and alcoholic liver disease (12.7%). Aflatoxin Moderate Diabetes and obesity have been established as independent risk factors for HCC, and that association holds true in the setting of NAFLD and associated NASH.25,26 However, there is also increasing evidence suggesting that NAFLD contributes to noncirrhotic HCC, and that HCC can develop in patients with metabolic syn- called aflatoxin B .28 Aspergillus flavus mold and aflatoxin prod- drome and NAFLD in the absence of NASH and fibrosis.27 1 uct can be found in a variety of stored grains, particularly in hot, humid parts of the world, where grains such as rice are stored Other Etiologic Considerations in unrefrigerated conditions. In the months following the mon- soons in Southeast Asia, most village-based grains can be seen to In addition to alcoholic cirrhosis and viral hepatitis, several un- be covered by a white layer of aflatoxin that is consumed with derlying conditions have been found to be associated with an the grain. Data on aflatoxin contamination of foodstuffs correlate increased risk for the development of HCC (Table 52.1). These in- well with incidence rates of HCC in Africa and to some extent clude autoimmune chronic active hepatitis, cryptogenic cirrhosis, in China. and metabolic diseases. Metabolic diseases include hemochroma- There is considerable literature on the hepatocarcinogenicity tosis (iron accumulation), Wilson disease (copper accumulation), of anabolic steroids as well as the induction of benign adenomas α 1-antitrypsin deficiency, tyrosinemia, porphyria cutanea tarda, by estrogens.29 Although estrogens are capable of causing HCC glycogenesis types 1 and 3, citrullinemia, and orotic acid urea. In in rodents, an epidemiologic association in humans has never children, congenital cholestatic syndrome (Alagille syndrome) is been clearly shown. In an industrial society, a large number of associated with a familial type of HCC. environmental pollutants, particularly pesticides and insecticides, are known rodent hepatic carcinogens. In a recent case-control Chemical Carcinogens study, cumulative lifetime tobacco use of more than 11,000 packs and Asian ethnicity were independent predictors of HCC devel- Probably the best-studied and most potent ubiquitous natural opment amongst a cohort of patients with chronic liver disease, chemical carcinogen is a product of the Aspergillus fungus, including HCV.30 698 Practice of Oncology / Cancers of the Gastrointestinal Tract

STAGING TABLE 52.2B Child-Pugh Grading of Cirrhosisa Multiple clinical staging systems for hepatic tumors have been described. The most widely used is the American Joint Committee Measurement 1 Point 2 Points 3 Points on Cancer/tumor-node-metastasis (AJCC/TNM) (Table 52.2).31 Ad- > verse prognostic features include large size, multiple tumors, vascular Bilirubin (mg/dL) 1–1.9 2–2.9 2.9 invasion, and lymph node spread. Macroscopic or microscopic vascu- Prolongation of PT 1–3 4–6 >6 lar invasions, in particular, have profound effects on prognosis. Stage Albumin (g/dL) >3.5 2.8–3.4 <2.8 III disease contains a mixture of lymph node–positive and –negative tumors. Stage III patients with positive lymph node or stage IV dis- Ascites None Mild Moderate/severe ease have a poor prognosis, and few patients survive 1 year. Encephalopathy None Grade 1 or 2 Grade 3 or 4 The prognosis in patients with HCC is very much influenced by the presence and severity of underlying liver disease as well. a Grade A = 5–6 points; grade B = 7–9 points; grade C = 10–15 points. The Child-Pugh scoring system is the most commonly used tool PT, prothrombin time. for assessing cirrhosis (see Table 52.2).32 It encompasses five parameters—bilirubin, albumin, prothrombin time, clinical ascites, and clinical encephalopathy—each of which is scored from one Cancer of the Liver Italian Program (CLIP) score was defined to three depending on severity. The key limitation of the Child- and studied prospectively in patients with HCC mainly caused by Pugh scoring system is its lack of any parameters pertaining to HCV.33,34 The CLIP score consists of the Child-Pugh score pa- the cancer itself. Despite that, it remains incorporated into many rameters combined with a subjective assessment of tumor in the HCC clinical trials as a tool to measure the extent of liver disease liver, the presence or absence of portal vein thrombosis, and the in the study populations, and thus, its use may not fade away any alpha-fetoprotein (AFP) level. The addition of vascular endothelial time soon. However, this main limitation of the Child-Pugh scor- growth factor levels to the CLIP parameters (V-CLIP) has been ing system has been overcome by other scoring systems. Among shown to provide a significantly more precise prognosis, but has those, the first to be established is the Okuda staging system. The yet to be prospectively validated.35 The Chinese University Prog- nostic Index (CUPI) scoring system was developed in patients with mainly HBV-related HCC.36 The CUPI parameters are bilirubin, ascites, AFP, alkaline phosphatase, the tumor extent (AJCC/TNM TABLE 52.2A 5th edition), and clinical symptoms at presentation. A French system called the Groupe d’Etude et de Traitement du Carcinoma Staging for Liver Function and Cancer: Hepatocellulaire (GETCH) staging system consists of bilirubin, American Joint Commission on Cancer Karnofsky performance score, AFP, alkaline phosphatase, and por- Staging for Hepatocellular Cancer tal vein thrombosis.37 Another scoring system that is mainly used in Japan is the Japan Integrated Staging (JIS) score.38 T TX Primary tumor cannot be assessed Another commonly used scoring system is the Barcelona 39 T0 No evidence of primary tumor Clinic Liver Cancer (BCLC) classification system. The BCLC couples prognosis with treatment assignment and has been vali- T1 Solitary tumor without vascular invasion dated prospectively.40 However, it has been shown to be less valu- T2 Solitary tumor with vascular invasion, or multiple able in the setting of more advanced disease, defined as BCLC tumors no more than 5 cm category C.41,42 In retrospective analyses of patients with advanced- T3a Multiple tumors more than 5 cm stage HCC seen by medical oncologists, the CLIP scoring system was noted to be the most informative regarding the outcome of this T3b Tumor involving a major branch of the portal or hepatic specific patient population. vein(s) T4 Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral DIAGNOSIS peritoneum The tests used to diagnose HCC include radiologic studies and N NX Regional lymph nodes cannot be assessed pathologic diagnosis with biopsy. Core biopsies are most preferred N0 No regional lymph node metastasis because of the tissue architecture given by this technique. For pa- N1 Regional lymph node metastasis tients suspected of having portal vein involvement, a core biopsy of the portal vein may be performed.43 Morphologic features, such M MX Distant metastasis cannot be assessed as stromal invasion, help distinguish high-grade dysplastic nodules M0 No distant metastasis from HCC.44 M1 Distant metastasis The American Association for the Study of Liver Diseases (AASLD),45 and the European Association for the Study of the Stage Grouping Liver (EASL)46 have outlined noninvasive criteria for the diagno- IT1 N0 M0 sis of HCC. EASL recommends that lesions that are greater than 2 cm with characteristic radiologic features of arterial hyperen- II T2 N0 M0 hancement on two different imaging modalities, or on one imag- IIIA T3a N0 M0 ing modality alongside with a serum AFP of 400 ng/dL or more, IIIB T3b N0 M0 are diagnostic of HCC, and no biopsy is needed. The AASLD added venous washout as a requisite radiologic feature. Detec- IIIC T4 N0 M0 tion of a lesion larger than 2 cm that exhibits both arterial hyper- IVA Any T N1 M0 enhancement and venous washout in a single imaging modality concomitant with an AFP >200 ng/mL is sufficient to diagnose IVB Any T Any N M1 HCC.47 Bialecki et al.48 found a sensitivity and specificity of 89.1% Edge SB, Byrd DR, Compton CC, et al., eds. The American Joint Committee and 100%, respectively, for liver biopsy compared to 64.9% and on Cancer: AJCC Cancer Staging Manual, 7th ed. New York:Springer;2010:197. 62.8%, respectively, for the noninvasive EASL criteria. The fear of

tahir99 - UnitedVRG Chapter 52 Cancer of the Liver 699 biopsy-related hemorrhage is dissuaded by a 0.4% rate, and tumor (Child-Turcotte-Pugh class A) were candidates for hepatic resection, seeding occurs at a low rate of 1.6%. When seeding does occur, it whereas patients with significant hepatic functional dysfunction can be treated by local resection and is seldom a cause of morbidity (Child class B or C) are generally not selected for resection because and mortality.49,50 of poor outcome.51 Portal hypertension can be indirectly assessed clinically by the presence of splenomegaly, esophagogastric varices, and thrombocytopenia (platelet count <100.000/mm3) or directly TREATMENT OF HEPATOCELLULAR determined by hepatic venous wedge pressures (≥10 mmHg). CARCINOMA With recent advances in perioperative care, there is growing evidence that liver resection for HCC in well-selected patients with Many treatment options for HCC are available (Table 52.3). Re- mild portal hypertension is safe and can achieve a comparable out- 52,53 section and liver transplantation represent the potentially curative come as in patients without portal hypertension. options with the longest track record. For small tumors, ablation The future remnant liver mass is another important factor to and radiotherapy (RT) are quite effective and may be curative. be considered in cirrhotic patients before resection. A too small remnant liver volume is associated with an increased risk for postresectional liver failure.54 There is a general consensus that Surgical Resection for Hepatocellular the critical remnant liver volume in cirrhotic patients is 50%,55 Carcinoma and portal vein embolization should be considered if the future remnant liver volume is expected to be below 50%.56–59 Some in- Patient Selection vestigators have even attempted to sequential employ transarterial chemoembolization (TACE) to control the tumor or portal vein Liver resection is the preferred treatment for the noncirrhotic embolization (PVE) to increase residual liver volume, followed by patient with HCC. These patients generally have normal liver definitive surgical resection.56,57 The sequential use of TACE and function, no portal hypertension, and can tolerate major liver re- PVE results in more efficient hypertrophy of the future remnant sections with acceptable morbidity and low mortality. The selec- liver compared to PVE alone.51 tion of noncirrhotic patients with HCC for resection is as for other In other parts of the world, dynamic liver function tests are also malignant lesions. Resection should be considered for patients employed for the assessment of suitability for liver resection. These where a complete resection of tumor is possible while preserving include the indocyanine green (ICG) test and technetium-99m greater than 30% functional liver. If the potential remnant liver diethylenetriaminepentaacetic acid-galactosyl human serum albu- volume may be less than 30%, portal vein embolization is now a min (technetium-99m galactosyl human serum albumin [99mTc- well-accepted preoperative preparatory method for increasing the 51,55 51 GSA] scintigraphy). An ICG retention rate of less than 14% potential remnant liver volume and safety of the resection. proved to be a safe indicator for major hepatectomy in cirrhotic For cirrhotic patients, the primary determinant of outcome patients, whereas retention rates above 20% are considered a con- OFPRACTICE ONCOLOGY and selection of therapy is the degree of hepatic dysfunction and traindication for major hepatectomy.60–62 portal hypertension. Traditionally, only compensated cirrhotics Patient medical comorbidities considered are similar to an assessment for any major surgery. Some studies have reported age and gender to be independent risk factors for poor outcome after 63 TABLE 52.3 resection of HCC. Other studies indicate that advanced age is more a surrogate for medical fitness, and that, with careful patient Treatment Options for Hepatocellular Carcinoma selection, elderly patients benefit as much from resection as younger patients.64 Comorbidities as represented by American Society of ■ Surgery Anesthesia (ASA) grade have been shown to correlate with survival.65 ■ Partial hepatectomy ■ Liver transplantation Outcomes of Resection and Prognostic Factors ■ Local ablative therapies ■ Cryosurgery With improving patient selection and perioperative care, the out- ■ Microwave ablation come of hepatic resection for HCC has been continuously improved ■ Ethanol injection during the past 2 decades. Many large series of the past 10 years ■ Acetic acid injection show that resection is associated with a perioperative mortality rate ■ Radiofrequency ablation of less than 7%, and patients achieve an overall survival rate of 30% to 50% (Table 52.4).65–75 Many major centers are recently reporting ■ Regional therapies: hepatic artery transcatheter treatments operative mortalities less than 2%,68,70,74 even in cirrhotic patients. ■ Transarterial chemotherapy Tumor factors most important for outcome are TNM stag- ■ Transarterial embolization ing at presentation, macro- and microvascular invasion, and the ■ Transarterial chemoembolization number of tumors. Large HCC has a propensity for vascular inva- ■ Transarterial yttrium-90 microspheres 131 sion and growth of tumor intraluminally. This is associated with ■ Transarterial I-lipiodol intrahepatic satellite metastases via the portal venous system and ■ Proton or carbon ion therapy is frequently associated with small satellite tumors. Intraluminal ■ Conformal radiation therapy spread through the hepatic veins leads to pulmonary metastases. ■ Stereotactic radiation therapy One surgical factor prognostic for outcome is surgical margins. ■ Palliative low-dose radiation therapy There is no clear margin size that has been universally agreed ■ Systemic therapies upon, but there is consensus on importance of an R0 resection.76 ■ Chemotherapy Most surgeons prefer at least a 1-cm margin. In one 225 patient ■ Targeted therapy (sorafenib)a study, a 1-cm margin was associated with a 77% 3-year survival ver- ■ Immunotherapy sus 21% for those with less than a 1-cm margin.72 It must be noted ■ Hormonal therapy that in a randomized controlled trial, a 2-cm margin was associated with a decrease in recurrence as well as improved survival.77 ■ Supportive care Studies have demonstrated improved outcome for anatomic 78 a Sorafenib is the only systemic therapy with level 1 evidence, proving a versus nonanatomic resections for HCC. In a series of 210 pa- survival benefit. tients, 5-year survival rates were 66% for anatomic versus 35% in 700 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 52.4 Results of Surgical Resection for Hepatocellular Carcinoma

Number of Minor 5-Year Overall First Author Year Published Patients Cirrhosis Resectionsa Mortality Survival Rate Zhou66 2001 2,366 — 72% 2.7% 50% Kanematsu68 2002 303 55% 76% 1.6% 51% Belghiti67 2002 328 50% — 6.4% 37% Wayne69 2002 249 73% 73% 6.1% 41% Ercolani65 2003 224 100% — — 42% Wu70 2005 426 100% 55% 1.6% 46%–61%b Capussotti71 2005 216 100% 24% 8.3% 34% Hasegawa72 2005 210 39% — 0.0% 35%–66%b Nathan73 2009 788 — — — 39% Yang74 2009 481 77% — 1.7% 20%–48%b Wang75 2010 438 — — 7.5% 43%

Note: Selected series with more than 200 patients over the past decade. Areas marked by a dash are not defined. a Minor resections are defined as≤ segmentectomy. b Range of 5-year overall survival among different subgroups.

nonanatomic resections.72 For small solitary tumors, anatomic re- (UCLA).96 In this study of 467 transplants performed for HCC, sections seem to be less important.79 Choice of margin and the the overall 1-, 3-, and 5-year survivals were 82%, 65%, and 52%, anatomic approach for cancer clearance must be weighed against respectively. Transplanted patients with tumors beyond the UCSF better perioperative outcome for limited parenchymal resection in criteria had a survival below 50%. cirrhotic patients. Living Donor Liver Transplant Liver Transplantation for Hepatocellular Because of the shortage of cadaveric livers, living donor liver trans- Carcinoma plant (LDLT) has become an increasingly utilized modality for the treatment of patients with decompensated cirrhosis. In many Asian Patient Selection countries, where prevalence of HCC is high, living related transplants are the most common liver transplants performed. Survival Theoretically, liver transplantation is the ideal therapy for HCC in cirrhotic patients because it treats both the cancer as well as the underlying parenchymal disease. However, early experience with transplants produced dismal results. Bismuth et al.80 was one of the first groups to consider that, in advanced disease, the likelihood of Milan UCSF Criteria Criteria systemic disease was so high that recurrence rates, and therefore long-term outcomes, were unacceptably poor. They demonstrated that patients with limited disease (uninodular or binodular <3 cm tumors) had much better outcomes with transplant than resection Single lesion Single lesion (83% 5-year survival versus 18%).80 < 5 cm < 6.5 cm The landmark works of Mazzaferro et al.81 have defined the most commonly used criteria for the selection of patients with HCC for transplantation. In their paper they defined the Milan criteria for transplantation as a single tumor less than 5 cm or three or fewer tumors all individually less than 3 cm (Fig. 52.1). Using these criteria for selection, patients transplanted had a very favorable outcome, including a 4-year actuarial survival rate of 85% and a recurrence-free survival rate of 92%. The suitability of these criteria for the selection of patients for transplant has been confirmed by numerous studies (Table 52.5).81–94 ≤ 3 lesion The excellent outcomes of HCC patients within the Milan cri- ≤ 3 lesion ≤ 4.5 cm each teria led many to explore more expansive and inclusive criteria.90 ≤ 3 cm each Total diameter ≤ 8 cm The most accepted of the expanded criteria is that from the Uni- versity of California San Francisco (UCSF) group. They reported excellent results after transplant for solitary tumor ≤6.5 cm, three or fewer nodules with the largest ≤4.5 cm, and total tumor diam- ≤ eter 8 cm (see Fig. 52.1). The UCSF criteria was associated with Figure 52.1 Milan (single lesion ≤5 cm, or no more than 3 lesions 90,95 a survival of 90% and 75% at 1 and 5 years, respectively. ≤3 cm) and University of California, San Francisco (UCSF) criteria (single The largest experience to date using transplantation for HCC lesion ≤6.5 cm, or no more than 3 lesions ≤4.5 cm and a total diameter of was reported from the University of California, Los Angeles 8 cm) for patients with HCC and who are undergoing liver transplantation.

tahir99 - UnitedVRG Chapter 52 Cancer of the Liver 701

TABLE 52.5 Results of Liver Transplantation for Early Hepatocellular Carcinoma

Study Number of Patients Tumor Number and Size Neoadjuvant Therapy Survival (%)a Mazzaferro et al., 200981 444 1 ≤5 cm; 3 ≤3 cm None 73 1,112 Beyond Milan criteria None 54 Pelletier et al., 200985 2,790 1≤5 cm; 3 ≤3 cm None 61 346 Beyond Milan criteria None 32 Herrero et al., 200886 47 1 ≤5 cm; 3 ≤3 cm None 70 26 Beyond Milan criteria None 73 Onaca et al., 200787 631 1 ≤5 cm; 3 ≤3 cm None 62 (5 y RFS) 575 Beyond Milan criteria None 43 (5 y RFS) Decaens et al., 200688 279 1 ≤5 cm; 3 ≤3 cm None 60 44 UCSF criteria None 46 145 Beyond UCSF criteria None 35 Bigourdan et al., 200389 17 1 ≤5 cm; 3 ≤3 cm TACE 71 Yao et al., 200190 46 1 ≤5 cm; 3 ≤3 cm TACE/ETOH 72 Tamura et al., 200191 56 <5 cm ± TACE 71 Regalia et al., 200192 122 1 ≤5 cm; 3 ≤3 cm TACE 80 Jonas et al., 200193 120 1 ≤5 cm; 3 ≤3 cm None 71 Llovet et al., 199894 58 <5 cm None 74 Mazzaferro et al., 199681 48 1 ≤5 cm; 3 ≤3 cm TACE 75 (4 y) a All are 5-year survivals, except where noted. RFS, recurrence-free survival; ETOH, alcohol. PRACTICE OFPRACTICE ONCOLOGY outcomes for all patients undergoing LDLT are comparable to the be assessed every 3 months by CT scans or MRI to rule out pro- results with deceased donors (Table 52.6).97–102 The disadvantage gression of disease beyond the established criteria. is clearly the risk to the living donor, with morbidity as high as 40% To reduce the likelihood of tumor progression while on the wait and a 0.5% mortality. The greatest concern is that LDLT may en- list, many local treatments are used, including TACE, percutane- courage transplants for patients with unfavorable biology (outside ous radiofrequency ablation (RFA), or percutaneous ethanol injec- of the established Milan or UCSF criteria) and pose unjustified tion (PEI). TACE involves selective embolization of the arterial risk to two lives, including the healthy individual. feeding vessels for the hepatoma with occlusive particles with or without admixed chemotherapeutic agents. TACE limits wait list Multimodality Management While Awaiting dropout, decreases posttransplant recurrence, and can downstage 103 Transplant HCC that is beyond transplant criteria. A dropout rate of 14% was found in a series of patients treated with TACE as bridge to To qualify for the wait list, a biopsy or one of the following criteria transplant, which compared very favorably to a dropout rate of 38% must be fulfilled: AFP> 200 mg/mL, arteriogram confirming the for an untreated group of patients reported by the Barcelona Liver tumor or arterial enhancement followed by portal venous wash- Cancer study group.104,105 out on computed tomography (CT) scans or magnetic resonance For small, solitary tumor, PEI106 or RFA can be effective treat- imaging (MRI), or a history of local–regional treatment. Patients ment options for use as a bridge to transplant. In a series of 52 pa- should be assessed radiologically for number and size of tumors, tients treated with RFA, the dropout rate was 6% at 12 months to rule out extrahepatic disease and vascular involvement. Patients due to tumor progression with a 3-year disease-free survival of 76% with tumors less than 2 cm in size or patients who do not qualify for the 41 patients eventually transplanted.107 Mazzaferro et al.108 for the Milan criteria can be listed for transplant, but they will re- reported no dropout for their patients treated with RFA as bridge to ceive no additional priority points for the tumor. The tumor should transplant, with a 3-year survival of 83%.

TABLE 52.6 Results of Living Donor Liver Transplantation for Hepatocellular Carcinoma with Patient Selection Based on the Milan Criteria

Patients Meeting Milan Criteria Patients Exceeding Milan Criteria Study Number 3-Year Survival (%) Number 3-Year Survival (%) Todo et al., 200499 137 80 172 60 Hwang et al., 2005100 151 91 62 62 Takada et al., 2006101 49 68 44 59 Sugawara et al., 2007102 68 79 10 60 702 Practice of Oncology / Cancers of the Gastrointestinal Tract

ADJUVANT AND NEOADJUVANT THERAPY possible use of PIAF as neoadjuvant therapy for medically fit patients with good liver function in whom cytoreduction might permit future resectability. The potential for cure would justify the Adjuvant Therapy risk of the significant toxicity profile of PIAF. A recent report of a randomized trial of adjuvant IFNα-2b described an improved 5-year survival in patients with stage III/IVA Choice of Resection, Ablation, or tumor from 24% to 68% (p = 0.038).109 In a separate, larger study, Transplantation IFNα-2b therapy was not associated with reducing postoperative recurrence in a population at risk for viral hepatitis–induced he- Although liver resection versus liver transplantation as primary patocellular carcinoma. In this study of 268 patients, the median therapy for patients with small HCC and adequate hepatic reserve recurrence-free survival was 42.2 and 48.6 months with observa- is hotly debated, in most cases resection and OLT are complemen- tion and IFNα-2b therapy, respectively (p = 0.828).110 tary and not competing therapies. A number of studies report com- Another approach that has been evaluated is intrahepatic parable overall survival rates for primary resection and primary 131I-lipiodol. In a randomized study of 43 patients, adjuvant 131I- OLT for transplantable HCC (Table 52.7).89,124–134 lipiodol administered via the hepatic artery was compared with Patients with limited disease have potentially curative treat- observation after resection of HCC. There was an improvement ment options. There is general consensus that in patients with no in median disease-free survival noted in favor of the 131I-lipiodol underlying liver dysfunction, limited disease should be resected arm (57.2 versus 13.6 months; p = 0.037).111 However, a long-term because this gives the best chance of cure without an ongoing follow-up of this trial at 10 years failed to show the same survival need of immunosuppression dictated by transplantation. The out- advantage.112 comes of resection are quite good, with 5-year survivals of 30% to The best-studied systemic adjuvant therapy so far is acyclic 50% (see Table 52.4). retinoid, which was evaluated against placebo following surgical For patients with end-stage liver disease (ESLD) and limited resection in 89 patients.113 Patients who received acyclic retinoid HCC, OLT is currently the best treatment modality. However, had a recurrence rate of 27% compared with 49% for patients who OLT can only be offered only to a small proportion of patients due received placebo (p = 0.04) after a median follow-up period of to donor organ shortage. Therefore, liver resection remains the 38 months. The prevention of second primary HCC was more most important surgical therapy in patients with HCC and well- marked after a median follow-up of 62 months (p = 0.002, log rank preserved liver function (Child class A).51 Using resection as first- test), but the difference in survival rates did not reach significance line therapy with salvage transplantation saved for recurrence is a until after 6 years, with an estimated 6-year survival of 74% versus common approach, especially for geographic regions with a high 46%, respectively (p = 0.04).114 incidence of HCC and a low liver donation rate.135,136 Resection Sorafenib, which will be discussed at length in the Systemic can, therefore, be used as bridge therapy before OLT to control the Therapy section, was also studied in the adjuvant setting. In a pilot tumor burden in patients who fulfill the Milan81 or UCSF90 crite- study of 31 patients with HCC who had undergone curative resec- ria. In a study from a large Asian transplant center, the majority of tion and were at high risk of recurrence, sorafenib prolonged the patients (79%) who developed tumor recurrence after resection of time to recurrence (21.5 versus 13.4 months; p = 0.006) and signifi- small HCC were still eligible for salvage transplantation.137 Pri- cantly lowered recurrence rate (29.4% versus 70.7%; p = 0.006).115 mary resection also allows the opportunity to pathologically assess A currently fully accrued yet not reported phase III trial (STORM) the tumor and adjacent liver tissue.136 Pathologic prognostic fac- randomized patients to adjuvant sorafenib versus placebo after sur- tors such as micro- or macrovascular invasion, satellitosis, or occult gery, radiofrequency ablation, or percutaneous alcohol injection tumors can be used as selection criteria for salvage liver transplan- with a primary end point of recurrence-free survival (Clinical Trial: tation in the case of recurrent tumor disease. NCT00692770). A phase II randomized, placebo-controlled study Patients with large HCC beyond the Milan or UCSF criteria evaluating whether adjuvant sorafenib can prevent recurrence of have a less favorable outcome than those with small HCC.81,90 HCC in high-risk orthotopic liver transplant recipients is currently Patients in the United States outside the accepted criteria can be enrolling (Clinical Trial: NCT01624285). transplanted based on the physiologic Model for End-Stage Liver Disease (MELD) score but do not receive any exception points for Neoadjuvant Therapy HCC. In an analysis of 94 patients with HCC exceeding the Milan criteria, results of resection was compared to OLT.138 The overall survival rate was 66% for both groups even though the mean Two randomized controlled trials and seven nonrandomized trials tumor size was 10 cm for the resection group and 6.4 cm for the have evaluated preoperative transarterial chemotherapy. No clear OLT group. The results suggest that resection and OLT in patients advantage in disease-free or overall survival was found in these with HCC beyond the Milan criteria have similar outcomes. A studies.116–118 Postoperative transarterial chemotherapy has been proposed algorithm of care from the Barcelona Clinic is shown in examined in four randomized controlled trials and three nonran- Figure 52.2. domized controlled trials. A meta-analysis of these trials revealed a significant improvement in disease-free and overall survival.117 The regimens consisted of Lipiodol and chemotherapy agents, Ablative Therapy For Localized Hepatocellular including doxorubicin, mitomycin, and cisplatin. An analysis Cancer of postoperative adjuvant systemic chemotherapy trials demonstrated no consistent advantage in terms of disease-free or overall Chemical Ablation survival.113,119–122 A combination regimen of systemic therapy that has been Chemicals destroy tumor tissue by direct dehydration of the cy- studied extensively in advanced HCC provided input for its po- toplasm, protein denaturation, and consequent coagulation ne- tential use in the neoadjuvant setting. PIAF (cisplatin, IFNα-2b, crosis as well as from indirect ischemia from vascular thrombosis doxorubicin, and 5-fluorouracil) have shown in a phase II study from endothelial damage.139,140 The direct instillation of chemi- a response rate of 26% with a median survival of approximately cals such as absolute ethanol or acetic acid has been long stud- 9 months.123 Of the 13 patients (26%) who had a partial response, ied for the treatment of HCC.141–143 Chemical ablation is very 9 underwent surgery and 4 (9%) achieved a complete pathologic inexpensive and, therefore, it is more widely used in developing response to chemotherapy. These results illustrated that chemo- countries with a high incidence of HCC. Intratumoral instilla- therapy for HCC is effective in selected patients and suggest the tion of acetic acid for the treatment of HCC compares favorably

tahir99 - UnitedVRG Chapter 52 Cancer of the Liver 703

TABLE 52.7 Recent Studies Comparing Long-Term Outcome of Patients with Hepatocellular Carcinoma Treated Primarily with Resection (and Salvage Transplantation) or Primary Liver Transplantation

5-Year Overall 5-Year Disease-Free First Author Year Published Primary Therapy Sample Size Survival Rate (%) Survival Rate (%) Lee127 2010 Transplantation 78 68 75a Resection 130 52 50 Facciuto128b 2009 Transplantation 119 62 — Resection 60 61 — Del Gaudio129 2008 Transplantation 147 58 54 Resection 80 66 41 Shah130 2007 Transplantation 140 64 78a Resection 121 56 60 Poon131 2007 Transplantation 85 44 — Resection 228 60 — Margarit126 2005 Transplantation 36 50 64a Resection 37 78 39 Bigourdan89 2003 Transplantation 17 71 80a Resection 20 36 40a Adam132 2003 Transplantation 195 61b 58a Resection 98 50 18 Belghiti133 2003 Transplantation 70 — 59 Resection 18 — 61 Figueras134 2000 Transplantation 85 60 60a Resection 35 51 31 a

Significant difference as reported in the original study. OFPRACTICE ONCOLOGY b Fourth-year survival rates are reported for patients meeting the Milan criteria. Adapted from Rahbari NN, Mehrabi A, Mollberg NM, et al. Hepatocellular carcinoma: current management and perspectives for the future. Ann Surg 2011;253:453–469, Table 3, with permission from Lippincott Williams & Wilkins.

with that of ethanol treatment.144,145 Moderate quality evidence on the energy balance between heat conduction of the local RF supports that RFA is superior to chemical ablation for the treat- energy applied and heat convection from the circulating blood ment of HCC.146 Chemical ablation requires multiple applica- and extracellular fluid. tions, and thus, thermal ablation has largely replaced chemical In the United States, there are three commercially available ablation in many cases. In certain anatomic locations, such as percutaneous RFA systems (Fig. 52.3). Two of the systems (Boston adjacent to the major biliary tree or gallbladder, the combina- Scientific/RadioTherapeutics and RITA Medical Systems) use a tion of thermal ablation and ethanol ablation has shown some deployable RF array electrode that consists of 4 to 16 small wires benefit.147,148 (tines) deployed through a 14- to 17-G needle. Because the tines of the Boston Scientific device (LeVeen electrode) curve back toward Radiofrequency Ablation the handle (see Fig. 52.3), the array is initially deployed in the deep portion of the tumor. In contrast, the RITA electrode tines RFA is currently the most widely used ablative technique for the course forward and laterally so the probe is deployed on the near treatment of liver malignancies. The term radiofrequency applies surface of the tumor. The LeVeen electrode measures impedance to all electromagnetic energy sources with frequencies less than only, and treatment time depends on repeated increases in imped- 30 MHz, although most clinically available devices function in ance during active heating, which is a measure of tissue desicca- the 375 to 500 kHz range. The technique for thermal ablation in tion indicative of adequate thermocoagulation. With the RITA the liver by using RFA was first described in animal liver models system, temperature readings are obtained throughout the ablation in 1990149,150 and was later reported in a patient in 1995.151 cycle from multiple peripheral thermocouples. The RITA system In this technique, the RF electrode is placed into the tumor also has perfusion electrodes (see Fig. 52.3) that introduce small with imaging guidance. The electrode is coupled to an RF amounts of saline into the tissue to enhance the distribution of generator and is grounded by means of a grounding pad or tissue heating. The third RF system (Cool-tip; Covidien) utilizes pads applied to the thighs. The RF generator produces a volt- a single or triple “cluster” perfusion electrode (three single elec- age between the active electrode (applicator) and the reference trodes spaced 5 mm apart; see Fig. 52.3), the tip of which is posi- electrode (grounding pad), establishing electric field lines that tioned in the deepest part of the tumor. oscillate with the alternating current. This oscillating electric Cold saline or water is pumped internally within the shaft of field causes electron collisions with the adjacent molecules the electrode to keep its tip cooler than the adjacent heated tissue, closest to the applicator, inducing frictional heating.152 Tissue thus reducing charring, which in turn helps the thermal conduc- heating to temperatures greater than 60°C leads to immediate tion to occur at a greater distance from its source. The single or cell death. Thus, for any given RFA procedure, the application cluster RF electrode contains a thermocouple embedded in its of energy from the applicator is maximized to create a zone of tip, which is used to measure intratumoral temperature. A switch- tissue necrosis that encompasses the tumor and a margin of nor- ing controller can be used with the Covidien system, allowing the mal parenchyma.153 The volume of ablation achieved is based placement of up to three separate single electrodes spaced 1.5 to 704 Practice of Oncology / Cancers of the Gastrointestinal Tract

HCC

Stage 0 Stage A-C Stage D PST 0 and Child-Pugh A PST 0-2 and Child-Pugh A-B PST > 2 or Child-Pugh C

Very early stage (0) Early stage (A) Intermediate stage (B) Advanced stage (C) End stage (D) single < 2 cm, single or 3 nodules multinodular, PST 0 portal invasion, N1, carcinoma in situ < 3 cm, PS 0 M1, PST 1-2

Single 3 nodules ≤ 3 cm

Portal pressure/ bilirubin

Increased Associated diseases

Normal No Yes

Resection Liver transplantation PEI/RF TACE Sorafenib (CLT/LDLT)

Curative treatments (30%) Randomized controlled trials (50%) Symptomatic tx (20%) 5-yr survival: 40%–70% 3-yr survival: 10%–40% Survival < 3 mo

Figure 52.2 Strategy for staging and treatment assignment for patients with HCC according to the BCLC staging system. PST, performance status; CLT, cadaveric liver transplantation; tx, treatment.

2.5 cm apart, thus increasing the duty cycle of the generator to en- Microwave Ablation able the creation of a greater volume of tissue thermocoagulation in a single application, as compared with three separate ablations Like RFA, microwave ablation (MWA) uses electromagnetic waves that might be required with a single electrode. Most of the ther- to produce heating. Unlike RFA, the MW energy is not an electri- mal ablation data regarding the treatment of liver tumors has been cal current and is in a much higher frequency range that extends reported with RFA.154–156 from 300 MHz to 300 GHz. The broader deposition of MW energy creates a much larger zone of active heating. MW applicators available for clinical use generally operate in the 900 to 2,450 MHz range.157 Microwave tissue heating occurs because of the induction of kinetic energy in surrounding water molecules. Because of their electron configuration, water molecules have highly polar properties and function as small electric dipoles, with the negative charges preferentially localized around the oxygen nucleus. The rapidly alternating electric field of the MW antenna causes water molecules to spin rapidly in an attempt to align with electromagnetic charges of opposite polarity. These spinning water molecules interact with neighboring tissues, transferring a portion of their kinetic energy. Because temperature is merely a proxy measurement of molecular kinetic energy, this energy transfer results in local tissue hyperthermia. Currently, there are six MWA systems that are commercially available in the United States and Europe.158 These systems use either a 915-MHz generator (Evident, Covidien; MicrothermX, BSD Medical, Salt Lake City, UT; Avecure, MedWaves, San Diego, CA) or a 2,450-MHz generator (Certus 140, NeuWave Medical, Madison, WI; Amica, Hospital Service, Rome, Italy; Acculis MTA, Microsulis Medical, Hampshire, England) and straight antennae with varying active tips 0.6 to 4.0 cm in length. Figure 52.3 Radiofrequency ablation equipment currently available in Perfusion of the antenna shaft is required for five of the six systems, the United States. The three most popular generators (left) and needle with either room-temperature fluid or carbon dioxide to reduce designs (right) are shown. conductive heating of the nonactive portion of the antenna, thus

tahir99 - UnitedVRG Chapter 52 Cancer of the Liver 705 preventing damage to the skin and tissues proximal to the active Regardless, many institutions around the world perform liver abla- tip. A single applicator is used with a single generator in four of tion for primary and metastatic liver tumors given its relative safety, the systems. Two have the ability to power up to three antennae low cost, and low toxicity. Many factors affect the success of ther- with a single generator and treat large tumors (Fig. 52.4). Because mal ablation treatment for liver malignancies, some of which in- most of the microwave systems have only recently received U.S. clude: tumor size, proximity to blood vessels, operator experience, Food and Drug Administration approval, there are no published the presence of underlying liver disease, extrahepatic disease in data at this time on the differences between systems in clinical patients with secondary liver malignancies, overall patient health, safety or effectiveness. Similar safety and efficacy results for the and implementation alongside synergistic therapies in a collegial, treatment of metastatic colorectal liver metastases have been re- multidisciplinary treatment clinic. The ever present argument for ported.159 Perceived advantages of MW over RF energy include a surgery as first-line treatment in these patients would be to prop- greater heating profile and less severe heat sink effects.160 Less heat erly stage the patient because preoperative imaging can underes- sink effects may reduce local recurrences, and the larger resultant timate the extent of liver and extrahepatic disease.164 Of course, ablative volume when using the synergistic effect of multiple ap- not all patients are fit for surgery, and ablation is an attractive plicators simultaneously will allow a faster treatment time when minimally invasive option for older and frailer patients. Tumors compared to RFA.161,162 Large trials evaluating safety show a simi- adjacent to larger (>3 mm) blood vessels may be undertreated due lar safety profile compared with RF.163 In Asia, MWA technology to the thermal sink effect.165 Proper device selection to effectively has been used for the treatment of liver tumors for a long period of eradicate tumors adjacent to vessels should be improved, in theory, time, and their extensive experience has created the development with hotter energy sources such as MWA compared to RFA.166 A of appropriate treatment guidelines.163 novel, largely, nonthermal electrical ablation technology called irreversible electroporation that is purported to be unaffected by Outcomes of Ablations thermal sink effects may play a role in treating tumors adjacent to blood vessels and critical structures, but there are no mature data To date, the literature is replete with retrospective, single and at this time.167 multicenter cohorts with very few randomized controlled or co- With a myriad of thermal ablation devices available to hepatic operative group trials evaluating the benefits of liver ablation. surgeons, hepatologists, and interventional radiologists, studies PRACTICE OF ONCOLOGY PRACTICE

Figure 52.4 A 73-year-old man with previously resected colorectal metastatic disease in the left lobe of the liver who recurred in the right lobe despite 5-flourouracil, oxaliplatin, leukovorin (FOLFOX) chemotherapy. An axial contrast enhanced CT scan and coronal fludeoxyglucose–positron-emission tomography (FDG-PET) CT scan (top panel) show a large heterogeneous colorectal cancer (CRC) metastasis in the right lobe. The patient refused additional chemotherapy and ablation was offered as palliative therapy. Given the size of the mass, microwave ablation was performed with multiple antennas under CT guidance (bottom left). The patient responded to the treatment extremely well, and a current 20-month follow-up contrast enhanced CT scan (bottom right) shows a large coagulation defect (small arrows) without evidence of recurrence in the liver. 706 Practice of Oncology / Cancers of the Gastrointestinal Tract have shown that it is incumbent upon these operators to gain ex- methods have emerged as the most commonly used treatment perience with a particular device before optimal results can be ex- worldwide. These techniques rely on the dual blood supply of the pected.164,168 This can be difficult not only in low patient volume liver: arterial and portal venous. The portal vein provides over 75% ablation practices, but also in general given the rapid technologic of the blood flow to the hepatic parenchyma, whereas the hepatic changes that occur in this arena whereby a newer technology is artery is the primary nutrient supply of tumors. Selectively deliver- perceived to be an improvement over an existing technology prior ing agents transarterially targets the tumor while sparing the liver. to rigorous scientific study. The presence of underlying cirrhosis There are currently three main categories of percutaneously will affect treatment options and outcomes in patients present- administered transcatheter intra-arterial therapies: TACE, bland ing with HCC. In general, HCC patients with Child-Pugh class hepatic artery embolization (HAE), and radioembolization (RAE). C cirrhosis who are not on a liver transplant list and do not un- The usual chemotherapeutic agents used are mitomycin C, doxo- dergo liver-directed therapies have a median survival of less than rubicin, and aclarubicin. The majority of the effects of embolic 4 months. Therefore, treatment with thermal ablation is unlikely therapies derive from tumor ischemia produced by occlusion of going to affect long-term survival.169 In patients with Child-Pugh the arterial vessels. Thus, bland embolizations (without chemo- class A cirrhosis, data suggest thermal ablation can rival surgery therapy), even with a nonpermanent agent such as Gelfoam, can when tumors are solitary and smaller (<5 cm) and less in number produce a high likelihood of tumor killing. RAE involves the ad- (< three tumors each under 3 cm).170 However, for patients who ministration of yttrium-90 (a pure β emitter) that can be loaded are healthier with a normal performance status, surgical resection in glass or resin microspheres intra-arterially.179 This is really not may provide better long-term survival compared to RFA.171 It makes an embolization, in that the goal is not occlusion of the arterial clinical sense that in patients with limited extrahepatic disease, inflow, but more brachytherapy. RAE will be further discussed. liver-directed therapy could improve outcomes, although the outcomes themselves may be as much due to underlying tumor biol- Patient Selection ogy and not necessarily the treatment.154,155 Given the complexity of any given patient with hepatic malignancy, it is important to first Performance status, underlying liver disease, and degree of portal and foremost apply any treatment or treatments under the supervi- hypertension are important patient selection criteria. Although sion of a team of experts whose primary goal is to provide the most minimally invasive, following embolization, patients commonly cost-effective, comprehensive treatment based on evidenced-based experience a postembolization syndrome of pain, fever, and nau- medicine when available alongside patient centered outcomes. sea that may last for several days to a few weeks. It often takes 4 to 6 weeks to recover to baseline performance status. Although embolization in patients with normal liver, or well- Liver Resection Versus Ablative Therapy for compensated cirrhosis, has a low risk of liver failure, the risk of Hepatocellular Carcinoma further compromising liver function and hastening death in poorly compensated cirrhosis is significant. This is because a basis of With recent improvements in imaging that allows for the early TACE is that the portal blood flow will protect the noncancerous diagnosis of cancer and facile guidance for interventional thera- liver from the treatment agents and ischemia. Thus, portal vein pies, ablative modalities such as RFA are increasingly accepted as occlusion is considered a contraindication to both TACE180 and effective treatment for small tumors. Ablative techniques are less HAE because of the risk of liver failure. Ascites, which is an indica- invasive and have the promise of being better tolerated than resection of severe portal hypertension, or measured reversal of portal tions or transplantation. In retrospective studies, data suggest that blood flow is a relative contraindication. for small HCCs (≤2 to 3 cm), RFAs result in similar outcomes as resections.172–174 Results of Treatment Recently, four randomized trials comparing RFA and hepatic It has always been apparent that embolic therapies can result in a resection have been reported (Table 52.8).175–178 Two of them, high rate of tumor response (>50%). Excellent results (level IIa Chen et al. and Huang et al., compared tumors fulfilling the evidence) following chemoembolization have also been reported Milan tumor criteria for transplantation. Chen et al.175 compared from Japan in 8510 patients treated between 1994 and 2001, with resection to RFA for tumors less than 5 cm in size. The 1-, 3- and 1-, 3-, and 5-year survival of 82%, 47%, and 26%, respectively.29 4-year survivals were 93%, 73% and 64%, respectively, for resec- With well-designed trials, there is also now level I evidence of a tion, and 96%, 71%, and 68%, respectively, for RFA. The authors survival benefit to conventional TACE as demonstrated in ran- concluded that RFA was as effective as surgical resection in the domized trials published by Llovett et al.,181 Lo et al.,182 and treatment of solitary HCCs ≤5 cm in terms of overall and disease- Becker et al.183 In the trial by Lo et al.,182 patients were random- free survival after 4 years with no significant difference in outcome ized to TACE (cisplatin + Lipiodol + Gelfoam) versus control between the two groups on follow-up. Huang et al.177 concluded (no treatment). The 2-year survival was 31% for TACE versus 11% that surgical resections have better outcomes than RFAs. This for controls. In the trial by Llovet et al.,181 patients randomized to conclusion was based on a recurrence rate at 5 years of 63% in the TACE (doxorubicin + Lipiodol + Gelfoam) had a 2-year survival RFA group and 41% in the resection group. However, it must be of 63% versus 27% for control. In the study from Becker et al.,183 pointed out that more patients in the resected group had tumors TACE (mitomycin C [MMC] + Lipiodol + Gelfoam) + PEI re- less than 3 cm in size. In addition, the overall survival was not sulted in a 39% 2-year survival compared to 18% for TACE. What statistically different between the two treatment groups. seems clear from these data is that arterial embolotherapy is an Feng et al.178 and Liang et al.176 confirmed the similar efficacy effective method of treating HCC and can prolong the patient’s of RFA to resection in tumors <4 cm. Both groups found RFA and survival. Comparable, or better, survival results have been demon- resection to have similar overall survival in a follow-up period after strated with bland embolization.119 3 years. It appears that for small HCCs, particularly in patients with cirrhosis, RFA can produce similar cancer outcomes with much lower morbidity. Figure 52.5 illustrates a recommended Radiation Therapy for Hepatocellular algorithm of care for small HCCs. Carcinoma

Embolic Therapies for Regional Disease Radiation therapy for liver tumors was historically limited by hepatic toxicity but, with improved imaging, treatment planning, and For patients with multifocal liver-predominant disease who are not treatment delivery, it now is an excellent option, particularly for candidates for resection or transplantation, transcatheter ablative patients with unresectable tumors or who are medical inoperable.

tahir99 - UnitedVRG Chapter 52 Cancer of the Liver 707 p NS NS 0.8 0.3 — — — — 76 28 40 55 — — — — 31 40 64 68 45 49 92 70 75 67 73 71 79 77 98 87 96 93 93 96 — — — — — — 51 29 — — — — — — 46 52 — — 61 50 61 46 69 64 Disease-Free Survival (%) Survival Disease-Free (%) Survival Overall — — 91 86 85 82 87 86 PRACTICE OFPRACTICE ONCOLOGY 1 Year 3 Years 4 Years 5 Years 1 Year 3 Years 4 Years 5 Years 5 cm 5 cm 4 cm 4 cm 5 cm (77%) 5 cm (73%) 5 cm 5 cm Characteristics Characteristics Diameter ≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤ 3 3 2 2 3 3 1 1 ≤ ≤ ≤ ≤ ≤ ≤ Tumor Tumor Number 13 14 11 11 12 11 ± ± ± ± ± ± 49 52 49 55 47(18–76) 51(24–83) 56 57 90 71 44 66 84 84 115 115 RES RFA RES RFA RES RFA RES RFA a 177 176 175 178 TABLE 52.8 TABLE Randomized Controlled Trials of Hepatic Resection Versus RF Ablations for HCC Reported After 2000 After HCC Reported Ablations for RF Versus of Hepatic Resection Trials Controlled Randomized Huang (2010) Feng (2012) Feng Chen (2006) Author/Year Author/Year Country Treatment Number Age Liang (2008) Treatments for recurrent disease. recurrent for Treatments a not significant. disease-free survival; survival; NS, DFS, overall resected patients; OS, RES, 708 Practice of Oncology / Cancers of the Gastrointestinal Tract

of RT, similar to its use for the safety of liver resection.188,189 In Small HCC the United States, the University of Michigan has pioneered its (< 5 cm) use to measure individual tolerance to radiation, which can be quite variable. Even some patients with good pretreatment liver Liver function can experience rapid decline, so customizing treatment 190 function is crucial. At the University of Michigan, investigators created the normal-tissue complication probability (NTCP) model that quantitatively described the relationship between radiation Childs A Childs B Childs C dose and liver volumes and the probability of developing RILD.191 Dose was customized per patient to give an anticipated risk of 5% to 15%. Due to the variety of tumor and liver sizes and geometries, prescribed doses ranged from 40 to 90 Gy. Peripheral Central Deep Medical optimization Patients who received 75 Gy or more had a higher median survival of 24 versus 15 months. Progression-free survival was also improved with higher doses.192–195 A prospective phase II trial Improvement No from France treated patients to 66 Gy in 2 Gy fractions, with a response rate of 92%.196 The largest published experiences Resection Ablation Supportive care are from Asia, which has a very high incidence of HCC. In a multicenter retrospective patterns-of-care study among 10 institutions in Korea, 398 patients with HCC were described. Of Figure 52.5 The treatment algorithm for a small HCC. those, 70% were Child class A, 54% had tumors >5 cm, and 40% had portal vein thrombosis. Nearly all had received prior treatment, mostly TACE. In this series, higher dose (biologic effective dose over 53 Gy) also correlated with better survival.197 Tumors not likely to be effectively treated by radiofrequency abla- Other groups have combined TACE and RT, with various tion due to size over 3 cm or proximity to the diaphragm, large schedules, although mostly using RT to treat residual disease. vessel, or gallbladder are also good candidates for RT. With proper In a Korean study of 73 patients with incomplete response to care, tumors near gastrointestinal (GI) structures can also be TACE, 38 received RT, whereas the rest received additional treated. Side effects are typically minimal, and commonly include TACE. Patients who received radiation had a higher 2-year sur- mild fatigue, and less commonly include nausea, mild radiation vival of 37% versus 14% (p = 0.001).198,199 dermatitis, pain associated with tumor edema, or worsening liver Another use for RT is to treat tumor thrombus in the portal dysfunction. Radiation can be delivered using external beam or vein, with the goals of decreasing portal pressure and allowing the brachytherapy. Patients with metastases to the bone, brain, adre- safe delivery of embolic therapies. The largest series from Taiwan nals, or other locations can be effectively palliated with RT, as can reports a 25% response rate. Compared with a dismal 1-year sur- 184 patients with pain from large primary tumors. vival of 9% for nonresponders, responders had a better survival of 21% for those still not eligible for definitive therapies, and 29% for External Beam Radiotherapy those who ultimately had additional therapy.200 Other crucial components of a liver RT program not always Fractionated Treatment available for standard RT include adequate imaging with arterial and portal venous phase imaging with CT scans and MRI for Because the liver is one of the most radiosensitive organs in the tumor delineation, motion assessment, and management tools body, treatment planning and delivery must be done carefully to four-dimensional computed tomography (4D-CT) scan, treatment maximize dose to the tumor and to minimize dose to the normal gating), and precise image guidance (cone beam CT scan) on the liver. The primary toxicity of concern is radiation-induced liver dis- treatment machine. Because liver tumors move with respiration, ease (RILD), which can be categorized as classic and nonclassic. accurate assessment and management of this will aid in proper Classic RILD is a constellation of anicteric ascites, hepatomegaly, tumor targeting and normal tissue avoidance. Some common and elevated liver enzymes (particularly alkaline phosphatase), methods include forced breath hold for tumor immobilization and which typically occurs within 4 months of therapy and is a type 4D-CT scans to assess and help account for motion.201,202 Fidu- of veno-occlusive disease, similar to that which can be seen after cials can also be placed within or near the tumor percutaneously high-dose chemotherapy conditioning for bone marrow transplan- prior to treatment planning, with daily alignment on the treatment tation.185 Nonclassic RILD, a recently coined classification, can machine, because external anatomy is a poor surrogate for internal occur in patients with hepatitis and cirrhosis, and is characterized anatomy and tumor location. by jaundice and markedly elevated serum transaminases (>5 times the upper limit of normal) within 3 months of completion of Stereotactic Body Radiotherapy therapy. This is thought to represent direct hepatocyte rather than endothelial injury.186 RILD is typically self-limited, but can be se- Stereotactic body radiotherapy (SBRT) is a relatively new method rious, even leading to mortality. It is managed symptomatically, of delivering high-dose, high-precision therapy in just a few treat- using diuretics and paracentesis. Even low doses to the whole liver ments, rather than spread out daily over a course of several weeks. of 25 Gy in 10 fractions or 32 Gy in 1.5 Gy per fraction twice daily With high doses per fraction, the biologic effect is much more are associated with a more than 5% risk of radiation-induced liver than with the same total dose delivered in a standard fractionated disease, particularly for patients with cirrhosis and already com- course, up to the equivalent to 80 to 150 Gy in 2-Gy fractions (see promised liver function. Other toxicities that can occur include Fig. 52.5). This technique was pioneered by Blomgren et al.,203 gastric or duodenal bleeding,187 although both of these risks can be who treated 20 liver tumors, including 8 HCCs in the 1990s. Since minimized using careful treatment planning, image guidance, and then, the literature has mostly been populated by small retrospec- treatment delivery. It is important to consider factors including cir- tive studies. A few prospective studies have been quite informative. rhosis, prior liver-directed therapies, and hepatitis B and C, which Mendez-Romero et al.204 initially started treating patients with a add to the dose and volume models for the prediction of RILD. schedule of 25 Gy in five fractions, but after two patients experi- ICG is also used in Asia as a pretreatment assessment for the safety enced local failure, the dose was raised to 30 Gy in three fractions

tahir99 - UnitedVRG Chapter 52 Cancer of the Liver 709 for the rest of the study. The 1-year local control was 75%, with all either the right or the left HA, although with favorable anatomy, failures in the low-dose group. One Child-Pugh class B patient exit can be delivered more selectively. Whole liver treatment is usu- perienced grade 5 nonclassic RILD, leading the authors to advise ally reserved for metastases rather than HCC due to the risk of others to be very cautious with similar patients.204 The next and liver injury. The most common isotope is yttrium-90, a pure beta largest studies were a phase I and II trial from Princess Margaret emitter, with an effective path length of 5 mm and a half-life of Hospital.205,206 Of 41 initial patients, 31 had HCC. Patients were 65 hours. Ninety percent of the energy is deposited within 5 mm treated with a six-fraction course of SBRT delivered over 2 weeks, of the sphere, therefore, side effects are quite localized. The dose with the dose individualized based on the University of Michigan to the individual tumors is not well characterized, but is prescribed NTCP model, escalated from 5% to 20%. The median dose was to 80 to 150 Gy, depending on liver function, to the entire treated 36 Gy (range, 24 to 54 Gy) and the median tumor volume was portion of the liver, assuming equal distribution and based on pre- 173 mL (range, 9 to 1,913 mL). Even for these relatively large treatment angiography. Side effects are typically quite tolerable and tumors, approximately 50% had a response to treatment, and 42% consist of mild nausea, pain, and fatigue. Rare complications could had stable disease. Median survival was 12 months. No patients include hepatobiliary dysfunction, radiation pneumonitis, and GI developed classic RILD, although 26% had grade 3 elevation of ulceration. Risk factors associated with early mortality include an liver enzymes and 16% had a decline from Child class A to B infiltrative tumor, a tumor encompassing over 50% to 70% of the within 3 months after treatment. Recently, the results from the full liver, albumin <3 g/dL, bilirubin >2 mg/dL, and lung dose >30 102 patients from both the phase I and II portions of the trial were Gy.216 With proper patient selection, this procedure is relatively reported.206 Of the patients, 93% had underlying liver disease, 52% safe. Although both RAE and chemoembolization can deliver re- had received prior therapy, and 55% had tumor vascular throm- gional therapy, which is particularly useful for multifocal HCC, it is bosis. The 1-year local control was excellent, at 87%. However, currently unclear which treatment may be preferred for which pa- 30% of patients had grade 3 or higher toxicity, some of which pos- tients. No randomized trials comparing these two modalities have sibly contributed to mortality. This illustrates the tenuous balance been completed; however, a retrospective comparison suggests that between treatment safety and efficacy and the need for improved RAE may have a longer time to progression with reduced toxicity predictive models of safety for individual patients. and similar overall survival.179 In general, response rates are 30% to Another phase I study reported 100% local control after 36 to 50%, with a time to progression of 6 to 16 months depending on 48 Gy in three to five fractions. Similar to what was seen in the stage and portal vein thrombus.217,218 Treatment may be repeated.219 Mendez-Romero study, patients with Child-Pugh class B liver failure were prone to liver toxicity.207 Truly, these patients need extra Toxicities attention and consideration. Many larger retrospective studies RT is typically very well tolerated. Mild fatigue can be attributed have confirmed these smaller prospective results.208–210 both to the treatment itself and to the travel related to multiple Charged particles, including protons and carbon ions, are appointments for the treatment. Mild nausea can be prevented by being investigated for treatment of HCC. These have the advan- OF ONCOLOGY PRACTICE premedicating with an antiemetic. Radiation dermatitis is highly tage of lower entrance and minimal exit dose, due to a difference unusual due to the extremely conformal distribution of radiation in dose deposition properties. In a Japanese retrospective review, dose. Occasionally, the treatment of large tumors can cause a pain 162 patients were treated with 72 Gy in 16 fractions using protons flare due to local edema. These acute effects typically resolve with a 5-year local control and survival of 87% and 24%, respec- within a few weeks after treatment. Late effects could include tively. There were no grade 3 or higher toxicities.211 In a phase RILD, as discussed previously, in addition to GI ulceration and II proton study, 51 patients received 66 Gy in 10 fractions. The renal dysfunction, although these risks can be avoided by minimiz- 5-year local control and survival rates were 88% and 39%, respec- ing the dose to these structures to below acceptable levels.187 tively. There were no cases of RILD, although 26% had a decline in liver function.212 Currently, carbon-ion therapy is only available in a few centers worldwide. In Japan, 24 patients were treated on Systemic Therapy for Hepatocellular a phase I/II dose-escalation study. Twenty-four patients received Carcinoma from 50 to 80 Gy in 15 fractions, with local control and survival 213 similar to other reports, at 81% and 25%, respectively. Despite First-Line Single-Agent Therapies the technologic imperative that newer is better, charged particles are not the miracle treatment some may assume. The high-dose A large number of controlled and uncontrolled clinical studies treatment region cannot be shaped as conformably as with stan- have been performed with most of the major classes of cancer dard photon radiotherapy (SBRT and intensity modulated radiochemotherapy, given intravenously as single agent or in combina- therapy [IMRT]), and image guidance is currently rudimentary, tion. However, these systemic therapies, and other chemotherapy therefore, ensuring the accuracy of treatment is difficult. However, combinations studied, have had no proven benefits on survival in because the liver is extremely sensitive to radiation, reducing the HCC.220 Many other nonchemotherapeutic agents have also been moderate and low-dose regions could potentially aid in protecting tried without definitive success, including luteinizing hormone-re- the normal liver and allowing for escalation of tumor dose. The leasing hormone agonists, tamoxifen, IFN, Sandostatin, megestrol, next few years should yield exciting developments. vitamin K, thalidomide, interleukin-2, 131I-lipiodol, and 131I-ferritin. Given the vascular nature of HCC and that vascular endothe- Brachytherapy lial growth factor (VEGF) promotes HCC development and metastasis, antiangiogenic agents have been studied extensively in the In contrast to other tumor sites such as prostate, gynecologic, and setting of advanced HCC. Increased levels of VEGF have been breast, liver brachytherapy typically involves an injection of a ra- observed and have been associated with inferior survival.221 dioisotope for regional therapy, rather than interstitial or intracavi- Sorafenib a multi–tyrosine kinase inhibitor with antiangiogenic tary therapy, although small experiences in interstitial therapy have effects are thought to be mediated by the blockade of VEGFR-2/-3, been reported.214,215 Radioembolization, like chemoembolization, platelet-derived growth factor receptor (PDGFR)-β, and other takes advantage of the liver’s dual blood supply and the arterial en- receptor tyrosine kinases.222 The clinical efficacy of sorafenib in hancement of HCC. Rather than chemotherapy and embolic ma- HCC was first reported in a multicenter phase II study of 137 pa- terial, radioisotopes linked to either glass (TheraSphere, Nordion, tients with systemic treatment-naïve, inoperable HCC and varying Canada) or resin (SIRTeX Medical, Inc., Lane Cove, New South hepatic reserve (72% Child-Pugh class A, 28% Child-Pugh class B) Wales, Australia) microspheres are injected into the hepatic artery received the agent, with a primary end point of evaluating response (HA). This outpatient treatment is typically delivered through by World Health Organization (WHO) criteria.223 Although only 710 Practice of Oncology / Cancers of the Gastrointestinal Tract

2.2% of the study population achieved a confirmed objective re- is not undercut by this observation, and it remains an effective and sponse by WHO criteria, 42% of the study population had extended life prolonging therapy for HCC, irrespective of etiologic factor. disease control. There was a median overall survival of 9.2 months, Several other small receptor tyrosine kinase inhibitors have which was encouraging when compared to historical controls. Sub- been studied. Thus far, emerging results have been disappoint- sequently, the Sorafenib Hepatocellular Carcinoma Assessment ing with the major phase III studies of antiangiogenic therapy Randomized Protocol (SHARP) trial enrolled 602 patients with failing to improve upon sorafenib in the first-line setting. Suni- advanced HCC, Child-Pugh class A, and who had not received tinib, an inhibitor of vascular endothelial growth factor receptor prior systemic therapy.224 The majority of the study population was (VEGFR)-1/-2 with greater potency than sorafenib, plus an in- recruited from the Western Hemisphere. Patients were randomly hibitor of PDGFR-α/β, c-KIT, FLT3, RET, and other kinases, has assigned to receive sorafenib at 400 mg orally twice a day (N = been studied in three phase II studies with three different dosing 299) or best supportive care (N = 303). The coprimary end points schedules of the agent as a treatment for advanced HCC.231–233 of the study were overall survival and time to symptomatic progres- A subsequent randomized phase III study of sunitinib, dosed con- sion. Median overall survival was 10.7 months in the sorafenib arm tinuously, versus sorafenib in patients with advanced HCC and versus 7.9 months in the placebo arm (hazard ratio [HR] = 0.69; Child Pugh class A liver function was initiated and rapidly en- 95% confidence interval [CI], 0.55 to 0.87). A predefined subset rolled 530 patients on the sunitinib arm and 544 on the sorafenib analysis indicated that the survival benefit of sorafenib was inde- arm.227 The study, powered to test the dual hypotheses of nonin- pendent of performance status and disease burden. feriority and superiority with regard to overall survival, was halted Parallel to the SHARP trial, the Asia-Pacific study assessed the by an independent data monitoring committee due to futility and efficacy and tolerability of sorafenib in comparison with best sup- safety concerns. The median overall survival for the sunitinib arm portive care in the patients with advanced HCC geographically lo- was 7.9 versus 10.2 months for the sorafenib arm (HR, 1.30; one- calized to Asia.225 As expected and in contrast to the SHARP trial, sided p = 0.9990; two-sided p = 0.0014). the Asia-Pacific study was enriched with patients with HBV-related Brivanib, a dual inhibitor of VEGFR and fibroblast growth HCC (73% of the total study population). The trial confirmed factor receptor (FGFR), demonstrated modest antitumor activ- that sorafenib, when compared to best supportive care, was toler- ity in both treatment-naïve and in those patients who had failed able and led to a statistically significant improvement in disease prior antiangiogenic therapy in two separate phase II studies.234,235 control, time to radiographic progression, and overall survival. Based on these data, a large randomized phase III study compared However, the magnitude of the overall survival benefit on the brivanib to sorafenib in patients with systemic treatment-naïve, ad- Asia-Pacific study was not as substantial as observed on the SHARP vanced HCC.236 This noninferiority trial did not meet its primary study—the median overall survival was only 6.5 and 4.2 months for end point; median overall survival with brivanib treatment was patients receiving sorafenib and placebo, respectively. The inclu- 9.5 months versus 9.9 months with sorafenib (HR, 1.06; 95% CI, sion of patients who were more ill prior to beginning therapy than 0.93 to 1.22; p = 0.3730). those patients on the SHARP study might explain this difference. Linifanib, a selective inhibitor of VEGFR and PDGFR, also Another postulate is that the observed differential outcomes on the failed to improve upon the modest survival advantage of sorafenib two trials were due to differing treatment patterns between Asia despite early encouraging efficacy data.237 A large multicenter, ran- and Western countries. Intense local–regional therapies might be domized, phase III study of sorafenib versus linifanib as a first-line more common in Asia, thus leading to the selection of patients therapy for advanced HCC, failed to meet both prespecified end on the Asia-Pacific study who are presenting later in the course points of superiority and noninferiority. The median overall sur- of their disease. The inclusion criteria for the Asia-Pacific study, vival for linifanib was 9.1 months versus 9.8 months for sorafenib however, do not necessarily support this assertion. Alternatively, (HR = 1.046; 95%, CI 0.896 to 1.221). specific viral etiologic factors might affect prognosis and influence Over 20 separate clinical trials have assessed or are assessing the responsiveness of liver cancer to sorafenib. bevacizumab, a monoclonal antibody directed against VEGF, in In an unplanned subset analysis of the SHARP study, patients patients with advanced HCC. Evaluated regimens include mono- with HBV-related HCC who were treated with sorafenib had therapy and combination therapy with chemotherapy, targeted a modest prolongation in median overall survival over placebo agents, and embolization procedures. In general, completed stud- (9.7 versus 6.1 months).226 However, HCV-related HCC patients ies have reported higher response rates than those observed with treated with sorafenib appeared to derive a more substantial sur- other tyrosine kinase inhibitors; however, adverse events such as vival improvement over placebo (14.0 versus 7.4 months). A retro- arterial/venous thrombotic events and variceal hemorrhage (some spective analysis of the initial phase II study of sorafenib observed fatal) are more common. A phase II study in advanced HCC with similar etiologic-dependent trends in survival. Patients who were extrahepatic disease found a 14% overall response rate with beva- infected with HCV lived longer (N = 13, 12.4 months) than did cizumab monotherapy.238 It has not moved to later stage trials due patients infected with HBV (N = 33, 7.3 months; p = 0.29). The to concerns regarding bleeding. recently reported phase III study of first-line sunitinib indicates that there may in fact be differential outcomes relative to disease cause First-Line Combination Therapies and ethnic origin, with median overall survival for HCV-associated HCC ranging from 18.3 months for patients with living outside of The addition of cytotoxic chemotherapy or targeted therapy to Asia to 7.9 months for patients living in Asia.227 Etiologic-depen- bevacizumab may augment antitumor activity. Response pro- dent genomic differences in HCC might explain improved out- portions with various cytotoxic combinations range from 9% to comes to sorafenib in patients with HCV-related HCC. CTNNB1 20%, with disease control rates reportedly as high as 78%.239–241 mutations are more commonly observed in HCV-related HCC but Bevacizumab and erlotinib may offer enhanced antitumor activ- not in HBV-related HCC and are associated with a specific WNT ity with a response rate of 24% and favorable patient outcomes gene expression profile.228 Sorafenib can modulate this gene sig- with a median overall survival of 13.7 months.242 A multicenter, nature, interfere with WNT signaling output, and lead to HCC randomized phase II trial of bevacizumab combined with erlo- growth suppression in preclinical models. Etiologic-dependent dif- tinib (Clinical Trial: NCT00881751) versus sorafenib monother- ferences in outcome might also be explained by HCV core protein- apy is ongoing. Similarly, the SEARCH trial confirmed that the induced upregulation of the sorafenib target CRAF, among other addition of erlotinib to sorafenib provided no benefit in HCC. kinases.229 Finally, in vitro data suggest that sorafenib can directly In this randomized, placebo-controlled, double-blind, phase III inhibit HCV viral replication, although the clinical importance of study the combination of sorafenib and erlotinib were compared this observation is debatable.230 Although more exploration is cer- to sorafenib alone in the first-line setting in 720 patients with tainly required, it should be emphasized that the utility of sorafenib advanced HCC. There was no statistically significant difference

tahir99 - UnitedVRG Chapter 52 Cancer of the Liver 711 between study arms with regard to the primary end point of evaluated at two doses in a randomized, placebo-controlled phase overall survival (combination 9.5 months, sorafenib 8.5 months; II in advanced HCC patients who had progressed after first-line HR = 0.93; 95%, CI 0.78 to 1.11). therapy.252 This study reported a statistically significant difference In the attempt to improve upon the modest results observed with in outcomes between high-MET expressing tumors in favor of ti- sorafenib, investigators have proposed combination strategies with vantinib. For patients with high MET-expressing tumors (defined as cytotoxic chemotherapy and novel biologic agents. Prior to the ap- ≥50% 3 to 4+ expression), tivantinib therapy resulted in a median proval of sorafenib, doxorubicin was evaluated as monotherapy or in time to progression of 2.7 months in comparisons to 1.4 months for combination with sorafenib in a randomized, double-blind, phase placebo (HR, 0.43; 95% CI, 0.19 to 0.97) and a median overall sur- II study.243 The trial enrolled 96 patients with treatment-naïve ad- vival of 7.2 months versus 3.8 months for placebo (HR, 0.38, 0.18 to vanced HCC and Child-Pugh class A liver function. The primary 0.81). Importantly, no such differences between the agent and pla- end point of the study was time to progression. In a planned ex- cebo were observed in low-MET expression tumors. This strongly ploratory analysis, both time to progression, as determined by in- suggests that MET expression is a predictive biomarker for MET- dependent review, and progression-free survival were increased by directed targeted therapy in HCC. Additionally, in patients on the approximately 4 months, and the median overall survival doubled in placebo arm, high tumoral MET expression was associated with an favor of combined therapy (13.7 versus 6.5 months; p = 0.006). Car- improved overall survival when compared with low tumoral MET diac toxicity was notable, with a higher proportion of patients on the expression (3.8 months versus 9 months; HR, 2.94; 95% CI, 1.16 combination experiencing left ventricular systolic dysfunction (19% to 7.43). This observation indicates that MET expression may also versus 2%). Although the majority of such cases were asymptomatic, be prognostic in this disease. Given these data, tivantinib is being the median cumulative doxorubicin dose was limited to 165 mg/m2. compared with placebo in a double-blind, randomized phase III The dramatic increase in survival over placebo was striking; how- study in patients with advanced HCC and high-MET expressing ever, the lack of sorafenib as a comparator arm limits the interpreta- tumors in the second-line setting (Clinical Trial: NCT01755767). tion of the trial. Doxorubicin may contribute little to outcome. The Cabozantinib, an inhibitor of MET and VEGFR-2, has also shown observed benefit in the doxorubicin–sorafenib group may be due to promising efficacy data in a cohort of 41 patients with advanced the effects of sorafenib alone. Alternatively, the combination may HCC.253 In 78% of patients, tumor regression was observed by Re- be synergistic. Inhibition of the mitogen-activated protein kinase sponse Evaluation Criteria in Solid Tumors (RECIST) with a 5% (MAPK) pathway by sorafenib may restore chemosensitivity by en- confirmed partial response rate. Median progression-free survival hancing proapoptotic pathways and dampening multidrug resistance for the cohort was estimated at 4.2 months, and median overall (MDR) pathways. Anthracycline-induced cytotoxicity is mediated by survival 15.1 months. A phase III study of cabozantinib versus pla- the proapoptotic kinase ASK1.244 Growth factor–induced MAPK ac- cebo in patients with advanced HCC in the second-line setting is tivation, via FGF, has been shown to abrogate ASK1 activity. Block- underway (Clinical Trial: NCT01908426). A different view on the ade of the RAF kinases by sorafenib might, therefore, augment the biology of met inhibition differs between those two studies, where

antitumor activity of doxorubicin. Furthermore, MAPK activation the tivantinib approach is to treat only patients with met-positive OF ONCOLOGY PRACTICE leads to the induction of the MDR-1 pump.245 Sorafenib decreases tumors defined as ≥50% 3 to 4+ expression, whereas the cabozan- ATP-binding cassette/MDR protein gene expression, thereby restor- tinib study will take all comers, arguing that it is not known yet how ing HCC sensitivity to doxorubicin in vitro.246 A randomized phase much met positivity is needed, if at all, considering the multikinase III study of sorafenib versus sorafenib and doxorubicin in the first- nature of both drugs. line setting is currently underway (Clinical Trial: NCT01015833). The mammalian target of rapamycin (mTOR) pathway plays a A phase II study of doxorubicin plus sorafenib in second-line set- critical role in hepatocarcinogenesis, and in xenograft mouse models, ting after sorafenib failure is currently underway (Clinical Trial: blockade of this pathway results in HCC growth suppression—but NCT01840592). not regression or cellular apoptosis—and in lengthening of sur- Gemcitabine and oxaliplatin (GEMOX) therapy has established vival.254 These observations, as well as retrospective data indicating efficacy in HCC,247 and there is reason to believe that addition of enhanced survival among patients receiving sirolimus immunosup- sorafenib to gemcitabine might offer synergistic antitumor effects.246 pression following liver transplantation for HCC, led to the devel- The GEMOX–sorafenib versus sorafenib was recently tested in a ran- opment of a phase I/II study of everolimus established that 10 mg domized phase II study (GONEXT).248 The trial enrolled 95 patients daily was a safe dose.255 The phase II portion, a two-stage efficacy with advanced HCC. The primary end point was 4-month progres- design, did not meet its prespecified boundary for expansion to the sion-free survival of greater than or equal to 50%. The combination second stage. Of 25 evaluable patients, 1 (4%) had a partial response of GEMOX plus sorafenib resulted in a 4-month progression-free and 10 (40%) had stable disease. Median time to progression was survival rate of 61% compared to 54% in the sorafenib monotherapy 3.9 months and median overall survival was 8.4 months. Nonethe- group. The combination was feasible, and efficacy data were encour- less, everolimus was investigated in the second-line setting after aging (overall response rate [ORR] 16%, DCR 77%). sorafenib failure in the phase III, randomized, placebo-controlled EVOLVE-1 study (Clinical Trial: NCT01035229) that was recently Second-Line Therapies reported as negative. A randomized phase III study of brivanib after progression The interest in developing novel agents for advanced HCC and of disease on sorafenib versus best supportive care also failed to the positive outlook on improved outcome led to a rapidly evolving meet its primary end point of improved overall survival.256 Among field studying second-line therapies, with already several phase III 395 randomized patients, 87% had disease progression while on clinical trials reported, still on-going, or planned. sorafenib, median overall survival was 9.4 months in the brivanib Overexpression of c-MET and its ligand hepatocyte growth fac- group versus 8.2 months in the placebo group (HR, 0.89; 95.8% tor (HGF) occur in up to 80% of human HCC tumors.249 Trans- CI, 0.69 to 1.15; p = 0.3307). This study’s importance lies in de- genic mice that overexpress MET in hepatocytes developed HCC, fining what may be the true and current median survival of pa- and inactivation of this transgene leads to tumor regression, medi- tients with advanced HCC, preserved liver function, and who have ated by apoptosis and growth suppression.250 Blocking MET with failed at least one prior line of therapy. The median survival of several different multitargeted tyrosine kinase inhibitors small mol- such population seems to be better than anticipated and may be ecules induce in vitro HCC growth suppression, cell-cycle arrest, reflective of the involvement of multidisciplines, ensuring better and decreased viability as well as growth suppression and survival management of patients with advanced HCC. A selection bias, prolongation in vivo.251 Based on these data, several MET inhibi- of course, could not be ruled out in the brivanib study as portal tors are already being studied in the setting of advanced HCC. Ti- invasion and/or thrombosis was noted in 12% of placebo patients vantinib, a selective MET receptor tyrosine kinase inhibitor, was versus 25% on the brivanib arm.256 712 Practice of Oncology / Cancers of the Gastrointestinal Tract

Ramucirumab, a monoclonal antibody blocking VEGFR-2, with a bilirubin >3 × ULN. Other antiangiogenic therapies have was recently assessed in a phase II study comprised of 43 patients shown to be detrimental in cirrhotics (Fig. 52.6).237 with systemic treatment-naïve advanced HCC.257 The median progression-free survival was 4 months and the median survival was 12 months. Based on these data, a randomized phase III study of TREATMENT OF OTHER PRIMARY LIVER ramucirumab versus best supportive care in the second-line setting TUMORS is ongoing (Clinical Trial: NCT01140347). The biosynthesis of the nonessential amino acid arginine occurs as part of the urea cycle and is dependent upon the enzymes Fibrolamellar Hepatocellular Carcinoma argininosuccinate synthetase and argininosuccinate lyase. Mes- senger RNA encoding argininosuccinate synthetase is not present Fibrolamellar HCC is a rare primary liver cancer that differs sig- in subsets of hepatocellular carcinomas; therefore, arginine must nificantly from the usual HCC. Fibrolamellar HCC occurs in a be extracted from the circulation.258 Pegylated arginine deiminase much younger age group (peak incidence, 3rd decade), is usually (ADI-PEG 20) is an arginine-degrading enzyme isolated from My- not associated with cirrhosis or viral hepatitis, and affects males coplasma that is formulated with polyethylene glycol (molecular and females equally. Additionally, a much higher percentage weight: 20 kDa). In preclinical models, ADI-PEG 20 decreases (>15%) of patients with fibrolamellar HCC presents with positive HCC cell viability at low nanomolar concentrations, reduces lymph nodes than normal variant HCC. serum arginine levels to undetectable levels, and prolongs survival Whether the diagnosis of fibrolamellar HCC portends a more in HCC xenograft mouse models. A phase I/II study demonstrated favorable outcome after surgical treatment remains controversial.266–269 an excellent safety profile in a patient population comprised with Resection is the first-line of therapy. For those patients in whom the a high burden of disease and impaired hepatic function.259 The tumor is thought to be unresectable, liver transplantation provides an most common events were injection site reactions and isolated lab effective alternative. Pinna et al.269 described 13 patients with fibrola- abnormalities, such as elevated fibrinogen. Of 19 patients evalu- mellar HCC who received transplantation between 1968 and 1995 able, 2 (10.5%) had a complete response, 7 (36.8%) had a partial and reported 1-, 3-, and 5-year patient survival rates of approximately response, and 7 (36.8%) had stable disease. The duration of re- 90%, 75%, and 38%, respectively.269 Given that most patients trans- sponse ranged from 37 to more than 680 days. A subsequent study planted presented as young patients with advanced disease, this is not reported a disease control rate of 63.1%, a 2.6% objective response an unacceptable survival rate. El-Gazzaz et al.270 reported similar sur- rate, and a median overall survival of 11.4 months.260 This exclu- vival rates. Contrary to what was previously reported, in a large 95 pa- sively European patient population was composed predominately tient retrospective analysis, with 50% presented with stage IV disease, of HCV-associated (79%) HCC confined to the liver (84%) with median survival was limited to 6.7 years. Factors significantly associ- otherwise excellent hepatic function (81%). In contrast, Yang and ated with poor survival were female sex, advanced stage, lymph node colleagues261 tested the agent in a heavily pretreated Asian popula- metastases, macrovascular invasion, and unresectable disease.271 tion with HBV-associated (69%) extrahepatic (58%) hepatocellular There is a great need for new, effective systemic therapies for ad- carcinoma. In this study, no objective responses were noted and vanced fibrolamellar HCC. A study is underway evaluating evero- the median overall survival was 7.3 months. Currently, a double- limus plus estrogen deprivation with leuprolide and letrozole for blind placebo-controlled study of ADI-PEG 20 after prior systemic unresectable fibrolamellar HCC (Clinical Trial: NCT01642186). therapy is ongoing (Clinical Trial: NCT01287585). Hepatoblastoma Systemic Treatments for Patients with Advanced Liver Cirrhosis Hepatoblastoma is the most common primary cancer of the liver occurring in childhood. The annual incidence of hepatoblastoma Both the SHARP and Asia-Pacific studies were limited to patients ranges from 0.5 to 1.5 cases per million children, with a peak in- with unresectable or metastatic HCC who also had preserved liver cidence occurring within the first 2 years of life.272 Hepatoblas- function. The benefit of sorafenib in patients with Child-Pugh class toma is highly sensitive to chemotherapy, which often renders B and C has not been established. Sorafenib’s safety in patients who unresectable tumors resectable. Surgical resection is considered are not Child-Pugh class A is of concern. A subgroup analysis of the the first line of therapy. However, for those tumors that cannot be phase II sorafenib study reported higher rates of hepatic decompen- converted to resectable lesions but without distant metastasis, most sation, represented by worse hyperbilirubinemia, encephalopathy, can be rescued with liver transplantation. Survival rates for these and ascites in Child-Pugh class B compared to Child-Pugh class A children after liver transplantation is excellent, with 1-, 3-, and patients.262 Patients in this subgroup had a shorter treatment dura- 5-year survivals reported at 92%, 92%, and 83%, respectively.272 tion as well as shorter survival in Child-Pugh class B (3.2 months) versus Child-Pugh class A patients (9.5 months). In a Japanese study, there were no differences in the incidence of adverse events between Epithelioid Hemangioendothelioma Child-Pugh class A and B groups, despite a geometric means of area under the curve (AUC0–12) and maximum serum concentra- Epithelioid hemangioendothelioma is a very rare tumor of vascu- tion (Cmax) at steady state that were slightly lower in patients with lar origin that can originate in the liver; it occurs predominantly Child-Pugh class B cirrhosis compared with Child-Pugh class A.263 in females. The tumor is often confused with other more aggres- Similar findings have been reported from the phase IV study of sive cancers, particularly cholangiocarcinoma, angiosarcoma, and sorafenib known as GIDEON.264 Child-Pugh class B and C patients HCC. The clinical course of epithelioid hemangioendothelioma were treated for a shorter duration, had a shorter median survival on is quite variable. In the review by Makhlouf et al.,273 137 cases were sorafenib, and were more likely to develop hepatic and serious drug- described, and survival ranged from 4 months to 28 years. Of interrelated adverse events. A phase I study of sorafenib pharmacokinetics est, one patient who received no treatment survived for 27 years in patients with hepatic dysfunction helped establish some guid- without evidence of metastasis. Surgical resection is considered to ance on the use of sorafenib among patients with advanced Child- be the treatment of choice. However, in multifocal disease, a short Pugh score.265 For a serum bilirubin ≤1.5 × upper limit of normal observation may be reasonable to help decide between observa- (ULN), sorafenib at the full dose of 400 mg twice daily can be given, tion, ablation, resection, or transplant as the course of action. The whereas for a bilirubin 1.6 to 3 × ULN, half that dose should be presence of metastatic disease does not seem to influence survival considered. For albumin <2.5 mg/dL, no more than 200 mg once and should not be considered an absolute contraindication to ei- daily should be given. There was no safe dose identified for patients ther surgical resection or transplantation.

tahir99 - UnitedVRG Chapter 52 Cancer of the Liver 713

B PRACTICE OF ONCOLOGY PRACTICE

D Figure 52.6 An SBRT can be used to treat single (A, B) or multiple (C, D) tumors in three to five high- dose, highly focused treatments. Planning is typically performed by fusing MRI images (A, C) with a planning CT scan (B, D) for accurate targeting. Special attention must be given to minimizing radiation dose to the remaining liver, particularly for patients with preexisting liver dysfunction. 714 Practice of Oncology / Cancers of the Gastrointestinal Tract

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tahir99 - UnitedVRG 53 Cancer of the Biliary Tree

Tushar Patel and Mitesh J. Borad

INTRODUCTION Within the liver, bile ducts along with branches of the hepatic artery and portal vein constitute the portal triad, which is directed The biliary tract or the biliary drainage system includes the intra- to each lobule of the liver. The adult liver is divided into eight and extrahepatic bile ducts and the gallbladder. Cancers associated segments delineated by blood supply and venous drainage. These with the biliary tract may be associated with biliary tract epithelia segments delineate and guide the resections of the liver. The main along the entire biliary tract from the intrahepatic ductules to the left hepatic duct exits the liver at the base of the umbilical fissure, ampulla of Vater. and the main right hepatic duct exits the liver between segments V Cholangiocarcinomas are cancers of the biliary tract that are and VI. The caudate lobe drains directly into the left main hepatic associated with the intrahepatic or extrahepatic bile ducts. The duct via numerous small branches. term cholangiocarcinoma encompasses three distinct tumor types The confluence of the right and left hepatic ducts occurs in the that vary in their risk factors, presentation, natural history, and hilum. The porta hepatis consists of the bile duct, the portal vein, management.1,2 Intrahepatic cholangiocarcinomas (iCCA) arise and the hepatic artery, from right to left. At the hilum, the portal from the intrahepatic biliary tract beyond the second order ducts. vein is posterior; the right hepatic artery generally passes between Distal extrahepatic cholangiocarcinomas (dCCA) arise from the the common bile duct and the portal vein; and the cystic artery common hepatic duct extending up to the junction with the cystic passes anterior to the bile duct. The proximity of the portal vein duct up to the papilla. Perihilar cholangiocarcinomas (pCCA) and hepatic artery to the bile duct in the hilum leads to early vessel arise from the second order ductal division within the liver and the involvement or occlusion from pCCA, which affects the options large extracellular ducts up to the confluence with the cystic duct. for surgical resection. Arterial anomalies are common, and if not In addition to cholangiocarcinomas, cancers such as gallbladder recognized, could lead to inadvertent injury during dissection OF ONCOLOGY PRACTICE cancer and some ampullary cancers also arise from the biliary tract. within the porta hepatis. The presentation, diagnosis, and management of intrahepatic, The cystic duct may enter the common duct near the conflu- perihilar, and distal cholangiocarcinomas and of gallbladder can- ence of the right and left ducts, or distally near the duodenum. It cer are separately described in this chapter. may also enter the right hepatic duct. The distal bile duct travels Periampullary tumors can arise from biliary as well as pancre- posterior within the head of the pancreas and then joins the pan- atic, duodenal, or ampullary tissues. The presentation, evaluation, creatic duct in a common channel leading to the ampulla of Vater. and management of periampullary tumors of biliary tract origin The lymph node drainage of the bile ducts involves the su- are identical to those of any of the other types of periampullary perior pancreaticoduodenal, retroportal, or proper hepatic nodes tumors, namely pancreatic, duodenal, or ampullary tumors. In first, then the peripancreatic, celiac, and interaortocaval lymph most instances, the distinction between the tissue type of origin is nodes.3 Lymph nodes in the porta hepatis may be difficult to re- obscure or may only be made on a histopathologic examination. move because of attached venous branches from the portal vein These cancers will not be described in this chapter. or fixation of tumor-involved lymph nodes to the bile duct, portal As a group, cancers of the biliary tract are rare. They are often vein, hepatic artery, or the head of the pancreas. However, a multi- diagnosed at an advanced stage and are associated with a poor institutional cohort study reported that the presence of lymph prognosis. Management of these patients requires a multidisci- node metastases significantly and adversely affected patient sur- plinary approach by a team with experience in their management vival (hazard ratio [HR], 2.21; p <0.001), and may explain the and which includes hepatobiliary surgeons, hepatologists, gastro- survival benefit of a lymphadenectomy for iCCA. enterologists, diagnostic and interventional radiologists, patholo- The location of the primary tumor within the gallbladder and gists, medical oncologists, and radiation oncologists. If the relevant the proximity of the portal vein, hepatic artery, and bile duct are and necessary expertise is not available locally, an early referral to all important factors in the surgical management of this tumor. experienced centers should be considered. The gallbladder is attached to segments IVb and V of the liver, and these segments may be involved early in tumors of the fundus and body of the gallbladder. The gallbladder has a thin mucosal wall, ANATOMY OF THE BILIARY TRACT a narrow lamina propria, and only a single muscle layer. Once this is penetrated, the tumor can access major lymphatic and vascular The biliary tract consists of the intrahepatic and extrahepatic bile channels leading to early lymphatic and hematogenous spread. ducts and is responsible for transporting bile from the liver to the Tumors of the infundibulum or cystic duct can also obstruct the intestine. Development of bile ducts requires complex intercellular common bile duct and may involve the portal vein. interactions and signaling. Notch signaling is a critical determinant The lymphatic drainage of the gallbladder first involves cys- of both biliary differentiation and morphogenesis leading to the for- tic and pericholedochal nodes, before extending to nodes pos- mation of normal bile ducts. Activation of Notch in liver progenitor terior to the pancreas, portal vein, and common hepatic artery. cells results in differentiation to biliary ductal cells, whereas activa- Finally, the flow reaches the interaortocaval, celiac, and supe- tion of Notch signaling in the hepatic lobule promotes ectopic biliary rior mesenteric artery lymph nodes. Node-bearing adipose tissue differentiation and duct formation. Experimentally enforced Notch posterior to the head of the pancreas and portal vein may be signaling in adult murine hepatocytes causes them to reprogram to a involved early, whereas drainage to the hilum does not occur.4 biliary phenotype and can result in cholangiocarcinoma formation. Direct connections may exist from the pericholedochal nodes to 715 716 Practice of Oncology / Cancers of the Gastrointestinal Tract the interaortocaval nodes, limiting the ability to control disease per 100,000 in the United States.13 Liver fluke infection with O. spread with a regional lymph node dissection. viverrini or C. sinensis species is associated with ingestion of raw The upper abdomen contains many organs with relative low fish containing the larva of liver flukes. Infestation is reversible tolerance to radiation, such as the spinal cord, kidneys, liver, with treatment with praziquantel. The degree of infestation as stomach, duodenum, and small bowel. The tolerance of these measured by stool egg count is related to the risk for CCA. Liver at-risk organs poses significant limitations to the dose used in radia- fluke infestation is associated with intrahepatic stones as well as tion therapy. with elevated nitrates, and animal and human studies suggest that N-nitroso compounds may be involved in carcinogenesis. The diagnosis of cancer is often difficult and delayed. Once cancer CHOLANGIOCARCINOMA develops, the prognosis is similar to that of CCA in patients that do not have a fluke infestation. Other infectious diseases that have been associated with CCA Nomenclature of Cholangiocarcinoma include HIV, and chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections.14 A recent meta-analysis of case-control The nomenclature used for cholangiocarcinomas has evolved over studies reported an increased risk of iCCA in patients with HBV time and has been variably applied. As an example, epidemiologi- and HCV infection.15,16 There appear to be regional differences in cal reports have either included perihilar tumors with iCCA or as the risk of chronic hepatitis associated iCCA, although these are extrahepatic tumors with dCCA. In addition, iCCA have long been not well characterized. reported along with other primary tumors of the liver. Because of Inflammatory conditions are less common, but their preva- the failure to recognize the different tumor types, the true inci- lence is more widely distributed. Primary sclerosing cholangitis dence, prevalence, and natural history are not well established. (PSC) is an autoimmune condition affecting the biliary tract and The relative distribution of tumors within the biliary tract is also characterized by inflammation within the biliary tract and subse- unclear. pCCA are the most common type of cholangiocarcinoma quent development of diffuse multifocal biliary ductal strictures. (CCA) worldwide. In one study, only 8% of cholangiocarcinomas 17 5 CCA can occur in 5% to 10% of patients with PSC and occurs seen were iCCA. However, these data are not supported by clini- more frequently in patients with chronic ulcerative colitis than in cal observations in practice and do not accurately reflect disease the general population.18 A high incidence of CCA occurs in pa- distribution because they are from a single center series and influ- 19 5 tients with coexisting PSC and ulcerative colitis. Up to 50% of enced by referral patterns. The seventh edition of 2010 American patients with PSC with CCA have this diagnosed within a year of Joint Committee on Cancer (AJCC) staging system classifies each their initial diagnosis with PSC.20 The presence of underlying liver of type of cancer of the biliary tract as separate entities with distinct 6 dysfunction resulting from biliary tract disease complicates surgery staging and biologic properties. or chemotherapy.21 Classification of all of these diverse cancers as a single group Chronic calculi of the intrahepatic and extrahepatic bile of biliary tract cancers has resulted in a lack of recognition of their ducts (hepatolithiasis) outside the gallbladder is rare, but predis- distinctive clinical behavior, nature, and management. The indi- poses one to cancer formation. In Southeast Asia, chronic portal vidual risk factors and specific molecular pathogenesis of iCCA, bacteremia and portal phlebitis are associated with intrahepatic pCCA, or dCCA are also not well understood. Likewise, a lack of pigmented stones, and subsequently, increased risk of cholangio- distinction between these cancers in therapeutic clinical trials has carcinoma. Cancers may develop even after stone removal, poten- limited progress in identifying useful and optimal therapies for the tially related to stasis and cholangitis related to fibrosis induced by individual types of cancers. Most clinical studies have included stone disease.22 all types of biliary tract cancers, including gallbladder cancer and An anomalous pancreatic–biliary duct junction may lead to a ampullary cancer, and have reported results in an aggregate fash- chronic inflammatory state in the bile duct via reflux of pancre- ion. Although specific etiologic and molecular differences are now atic juice into the biliary tree. This has been associated with an becoming recognized, an improved understanding will emerge increased risk of CCA.23 only once these distinctive cancer types are recognized as separate Biliary tract cystic diseases are associated with an increased risk cancers in future population-based reports, patient-based studies, of malignancy, which can arise in noncystic portions of the biliary or laboratory investigations. tract. Tumors can occur in patients with untreated choledochal cyst disease.24,25 A choledochal cyst is a rare condition, manifest Etiology of Cholangiocarcinoma by congenital cystic dilatation(s) of the bile ducts. Bile stasis in the cysts leads to chronic inflammation of the duct. Of patients Risk Factors with choledochal cysts, 10% to 20% will develop CCA if left untreated or managed with surgical drainage alone.26 Early exci- Although these cancers often occur sporadically without any iden- sion of the choledochal cyst has been proposed to reduce the risk tifiable risk factors, there are some well-defined risk factors. These of CCA. Caroli disease is a rare variant of choledochal cysts that include infections, conditions resulting in chronic biliary tract results in intrahepatic ductal dilatation and an increased risk of inflammation, drug/toxins, or congenital causes.1,7–11 Because developing CCA.27 the individual risk factors for the different types of cholangiocar- Recent epidemiologic studies indicate that occupational expo- cinoma have not yet been delineated, we will review common sure to asbestos or to certain volatile compounds used in the print- risk factors associated with these cancers in this section. Where ing industry such as 1,2-dichloropropane may also increase the tumor specific risk factors are known, they will be discussed in the risk of cancer.28,29 Exposure to dioxin has also been implicated, relevant sections. although the data are not conclusive. Other potential carcino- Infestation with Opisthorchis viverrini and Clonorchis sinensis gens include radionuclides, radon, and nitrosamines.30 Thorotrast results in chronic inflammation of the bile duct, and are asso- (thorium dioxide) is a vascular contrast agent that is associated ciated with CCAs. These two parasitic liver flukes are classified with an increased risk of cancer, but has not been used since the as group 1 carcinogens by the International Agency for Research 1940s.31 The risks associated with cigarette smoking are not well on Cancer.12 These liver flukes are highly prevalent in certain quantified.15,30 geographic regions such as Southeast Asia and, in particular, in Recently, liver cirrhosis has been identified as a risk factor for Northeast Thailand. The geographic restriction of liver flukes has iCCA.15 Consistent with this observation, risk factors for cirrhosis, resulted in a highly variable disease prevalence in different parts such as chronic hepatitis C, chronic hepatitis B, and alcohol, are of the world varying from 87 per 100,000 in Thailand to 1 to 2 also associated with a higher risk for iCCA.15,32,33 Because these are

tahir99 - UnitedVRG Chapter 53 Cancer of the Biliary Tree 717 also dominant risk factors for hepatocellular cancers, these obser- of these tumors to occur in the hilar region are not clear. vations suggest potential common risk mechanisms of tumorigen- Morphologically and genetically, pCCA more closely resemble esis in liver epithelia. extrahepatic dCCA than iCCA. The pathogenesis of pCCA and dCCA is presumed to be similar to that described for iCCA, with an additional contribution of cholestasis. Some of these tumors Molecular Pathogenesis of may originate from progenitor cell populations in the submucous Cholangiocarcinomas glands, and in tumors that have maintained differentiation, mucin production may be prominent. A subtype of iCCA may arise from The mechanism and events responsible for neoplastic transforma- a progenitor cell within the liver that results in tumors with his- tion in the biliary tract are not well understood. It is postulated that tologic and genetic features of mixed hepatocellular carcinoma– chronic inflammation and infection in biliary epithelia and their cholangiocellular carcinoma. interactions with other stromal cells’ active inflammatory signaling A sequence of progression from normal mucosa to adenoma- such as those involving interleukin-6 (IL-6), inducible nitric oxide tous hyperplasia, dysplasia, carcinoma in situ, and then invasive synthase (iNOS), and cyclooxygenase 2 (COX-2).34 These result cancer similar to that described for other mucosal cancers may also in a proliferative stimulus to epithelial cells involving epidermal occur in the biliary tract. Two precursor lesions are identified: bili- growth factor receptor (EGFR), RAS/mitogen-activated protein ary intraepithelial carcinoma neoplasia, which is more common, kinase (MAPK), IL-6, or MET signaling. Malignant transforma- and intraductal papillary neoplasm of the bile duct.38 tion occurs in the setting of genetic alterations and epigenetic changes on this background, and results in the deregulation of sev- Pathology of Cholangiocarcinomas eral signaling pathways that can enhance malignant cell growth, apoptosis, and tumor cell behavior. Tumors may arise from malignant transformation of biliary epithelial cells, progenitor cell Gross Morphology populations, or transdifferentiation of hepatocytes. The gross morphology can be exophytic, (nodular) mass forming, Several genetic and epigenetic alterations and deregulated intraductal, or periductal infiltrating (or sclerosing). Mass-forming 35 signaling pathways have been identified. In PSC, inflammation and periductal infiltrating (or both combined) are the most com- results in the activation of the nuclear factor κB (NF-κB) signaling mon types encountered. iCCAs are more likely to be nodular and and increased tumor necrosis factor alpha (TNF-α) and IL-6. IL-6 mass forming, whereas pCCAs and dCCAs are more likely to be is an important contributor to cholangiocarcinogenesis and has sclerosing, although not exclusively so. The sclerosing type is asso- been associated with several molecular events such as alterations ciated with an intense desmoplastic reaction and often manifest as 34 in EGFR, p38, and p42/44 MAPK and altered let-7 microRNAs. diffuse thickening of the ducts without a defined mass. The nodu- Alterations in hepatocyte growth factor/MET signaling and in lar type tends to result in a mass lesion and usually arises within the EGFR family with overexpression of EGFR and HER-2/neu the liver. Intraductal tumors are less common and can encompass OF ONCOLOGY PRACTICE have been identified. Autocrine growth loops have been identi- a range of lesions from preneoplastic to invasive carcinomas. In fied, involving hepatocellular growth factor HGF( )/MET and some patients, dCCAs may present only as a thickened bile duct 36 IL-6/ glycoprotein 130 (gp130). Alterations in the glycosylation of wall involved in a dense fibrous scar. Polypoid or papillary cancers mucins (MUC proteins) and sialosyl-Tn antigen may be relevant, have the best prognosis. Papillary cancers represent a low-grade 37 although their contribution in not well defined. adenocarcinoma that is represented by a polypoid mass filling the Genetic alterations that have been identified, including acti- lumen of the bile duct, with minimal invasion and no desmoplas- vating mutations of KRAS, loss of TP53, mutations in IDH2 and tic reaction.49 IDH1, and rarely, alterations in BRAF, NRAS, and PI3K.35,38–40 Tis- sue-specific activation of theK-ras G12D mutation in genetically Histology engineered mice results in invasive iCCA, which is augmented by 50 the addition of a loss in p53.41 Mutations of Her-2/neu and c-MET More than 90% of tumors are epithelial adenocarcinomas. Other have also been reported.42 The genetic mutations observed may variants include well-differentiated, pleomorphic, giant cell, ade- vary with type of tumor. Thus, IDH1/2 mutations are not seen with nosquamous, oat cell, and colloid carcinomas. Other types, such as pCCA or dCCA, but may occur in up to 25% of iCCA, whereas squamous cell carcinomas, sarcomas, small cell cancer, and lym- K-ras mutations are more common in the former.43,44 phomas account for less than 5%. Sclerosing tumors are character- Notch signaling is a complex, evolutionarily conserved path- ized by an extensive fibrous stroma with interspersed tumor cells. way that is needed for normal bile duct development. Notch and Papillary tumors may have papillary fronds with extension into the several of its downstream targets SOX9, sex determining region bile duct lumen, and may produce extracellular mucin. Nodular Y-box 9, and hepatocyte nuclear factor 1β, may be involved in mass-forming tumors may vary with appearances akin to sclerosing CCA pathogenesis. SOX9 is strongly expressed in intrahepatic bile type or with tubular pattern. Satellites are common and may result ducts. Loss of SOX9 in CCA is associated with higher tumor grade from spread along the bile ducts or from vascular invasion and in- and stage, and is an independent adverse prognostic factor for sur- trahepatic metastatic spread. Regional lymph node metastases and vival.45 Nuclear colocalization of deltalike ligand 4 (DLL4) with perineural invasion are common with pCCAs and dCCAs. Distant 51 Notch receptor 1 or 3 was associated with nodal metastases, less metastases can occur, but are unusual. histologic differentiation, and worse survival of extrahepatic CCA and gallbladder cancer. Intrahepatic Cholangiocarcinoma In addition to genetic changes, epigenetic changes resulting from alterations in promoter methylation of tumor suppressor Incidence and Etiology genes such as SOCS-3, RASSF1A, p14ARF, and p16INK4A as well as changes in some microRNAs such as miR-21 and miR-200c have iCCAs are cancers of the biliary tract that arise from intrahepatic been described.35 Genomic studies have started to identify distinct bile ducts beyond the second order ductal system within the subgroups of iCCA on patterns of gene expression, but these need to liver. They are the second most common primary epithelial ma- be validated and their clinical applications defined.35,46–48 lignancy of the liver, but are uncommon cancers in the United Although the specific molecular pathogenesis of pCCA tumors States. The incidence and mortality from iCCAs have been re- is unknown, it is postulated that tumorigenesis results from a simi- ported to be increasing in the United States and in many other lar sequence of events to that described previously with the addi- countries.52,53 The incidence of these cancers increases with age, tional contribution of cholestasis. The reasons for the predilection with the majority of patients aged 65 years or older. Patients with 718 Practice of Oncology / Cancers of the Gastrointestinal Tract defined risk factors such as PSC or choledochal cysts tend to de- TABLE 53.1 velop tumors at a younger age. These tumors are slightly more common in men. There are racial and ethnic variations preva- American Joint Committee on Cancer TNM Staging lent, with the highest prevalence among Hispanics in the United for Intrahepatic Cholangiocarcinoma States (1.22 per 100,000) and the lowest among African Americans (0.3 per 100,000).54 Primary Tumor (T) TX Primary tumor cannot be assessed Diagnosis T0 No evidence of primary tumor Patients with iCCAs may be asymptomatic, with the initial pre- Tis Carcinoma in situ (intraductal tumor) sentation being a mass lesion within the liver. When symptoms occur, these may include nonspecific right upper quadrant pain, T1 Solitary tumor without vascular invasion or weight loss. In contrast to pCCAs or dCCAs where obstructive T2a Solitary tumor with vascular invasion jaundice occurs early, jaundice occurs late with iCCAs and usu- T2b Multiple tumors, with or without vascular invasion ally indicates extensive disease.55 Occasionally, a centrally located iCCA may present with jaundice due to extrinsic compression of T3 Tumor perforating the visceral peritoneum or involving the main ducts. Other presentations are rare, and include muco- the local extrahepatic structures by direct invasion bilia or a tumor embolizing into the extrahepatic bile ducts, result- T4 Tumor with periductal invasion; the pathologic 56 ing in pain, jaundice, or even pancreatitis. definition of periductal invasion is the finding of a The diagnosis of iCCA involves demonstrating a mass lesion longitudinal growth pattern along the intrahepatic bile within the liver using abdominal computed tomography (CT) or ducts on both gross and microscopic examination magnetic resonance imaging (MRI).57 On CT scan, the lesion is usually of low attenuation with only mild enhancement seen Regional Lymph Nodes (N) with contrast.58 On a T1-weighted MRI, iCCAs are usually of low NX Regional lymph nodes cannot be assessed intensity, but may have high intensity on T2-weighted images. N0 No regional lymph node metastasis Centripetal filling in after gadolinium administration may be observed on MRI. Ductal dilation is often present peripheral to the N1 Regional lymph node metastasis present tumor. Local vascular invasion is often seen by CT scan, MRI, or Distant Metastasis (M) angiography.59,60 M0 No distant metastasis The differential diagnosis includes hepatocellular cancer (HCC) or metastatic cancer from other primary tumors. Cirrhosis is a risk M1 Distant metastasis present factor for both iCCAs and HCCs. Imaging findings are often used to Anatomic Stage/Prognostic Groups diagnose liver masses as HCCs without obtaining a biopsy. Charac- teristic imaging features of iCCAs that may be helpful in distinguish- Stage 0 Tis N0 M0 ing these tumors from HCCs are slow uptake of contrast, particularly Stage I T1 N0 M0 in highly desmoplastic tumors, and a peripheral rim of enhance- Stage II T2 N0 M0 ment. A liver biopsy should be considered for a diagnosis if the tumor is inoperable due to extensive spread or if other lesions such as focal Stage III T3 N0 M0 nodular hyperplasia are strongly suspected. Otherwise, in potentially Stage IVA T4 N0 M0 resectable cases, further staging studies, including a laparoscopy, would be considered. Any T N1 M0 Grossly, iCCAs may be well or poorly demarcated, single, or Stage IVB Any T Any N M1 multiple. Mucin production, fibrosis between the acini of tumor tissue, and a more overtly glandular pattern are the main differen- Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC tiating characteristics from HCC. Cancer Staging Manual, Seventh Edition (2010) published by Springer Immunohistochemical staining for specific cytokeratins may Science and Business Media LLC, www.springerlink.com, page 203. also be helpful. Unlike HCCs, some cholangiocarcinomas stain positively for CA19-9 or carcinoembryonic antigen (CEA), or α β 61 v 6 integrin, but not for hepatocyte antigen. It may be difficult An algorithm for the management of these cancers is shown in to distinguish iCCA from a liver metastasis of extrahepatic origin Figure 53.1. if a cytological analysis shows adenocarcinoma. Cytokeratin 7 or cytokeratin 20 may be helpful to establish a biliary origin. Cytoker- Surgery. Indications for resectability are not well described. The atin 20 expression is focal and rare in iCCAs in contrast to being 62 goal is to resect the tumor with an adequate margin of normal tissue, diffuse and common in colorectal cancer metastases. If a primary and to obtain microscopically free resection margins, while retain- site cannot be identified, a diagnosis of iCCA should be presumed. ing enough liver tissue behind for the patient to have adequate liver function after surgery. The resection may vary from nonanatomic Staging resections to segmental anatomic resections. Intrahepatic metasta- The tumor-node-metastasis (TNM) system devised by the AJCC ses tend to occur as multiple satellites, and although their presence should be used for staging these cancers.6 The seventh edition impacts prognosis, it should not define resectability. However, for (2010) separated the staging of iCCAs from that of hepatocellular widespread hepatic metastases, curative resection is unlikely, and cancer, as well as from perihilar or distal CCAs. Table 53.1 shows other forms of therapy should be considered. The presence of un- the staging system for iCCAs. derlying advanced cirrhosis with portal hypertension may preclude surgical resection. Extrahepatic spread portends a poor prognosis, Management and carcinomatosis should be considered a contraindication to resection. A staging laparoscopy can help define respectability prior Most treatment information has been derived from small series to a full laparotomy and is recommended.65 gathered over several years, with variable definitions of disease used Outcomes after surgical resection for iCCAs have been reported and, therefore, the best approaches to treatment are not clarified. in small series in the literature. The resectability rate ranges from Consensus guidelines have been proposed for management.63,64 32% to 90%. The mortality of resection is slightly higher than se-

tahir99 - UnitedVRG Chapter 53 Cancer of the Biliary Tree 719

Intrahepatic Cholangiocarcinoma (iCCA)

TNM Stage I TNM Stage II TNM Stage III TNM Stage IV

Intrahepatic disease Extrahepatic Resection only disease

R1, R2 Resection Local–Regional Gemcitabine and R0 Resection N1 Disease Therapy Cisplatin

Adjuvant Therapy/Clinical Studies Figure 53.1 Algorithm for the man- 5-year survival 5-year survival Median survival Median survival agement of intrahepatic cholangio- ~40% ~20% ~15 months ~12 months carcinoma.

ries of hepatic resection for other indications, but is generally less established as the standard of care for patients with biliary can- than 10%. Lymph node metastases, positive margin status, and cers.70 Gemcitabine was dosed at 1000 mg/m2 in combination vascular invasion were reported as significant prognostic factors in with cisplatin at 25 mg/m2, with both agents given intravenously an analysis of 449 patients.66 Other prognostic factors include satel- on days 1 and 8 every 21 days for a maximum of 6 months. The lite metastases, nodal metastases, tumor size, and a CA19-9 level study was conducted using a phase II/III design and enrolled OF ONCOLOGY PRACTICE greater than 1,000. Although rare, intrahepatic intraductal papil- 410 patients across centers in the United Kingdom. Stratifica- lary tumors have an excellent prognosis if completely resected.67,68 tion was done based on the extent of disease (locally advanced The median survival after surgical resection is ∼36 months. versus metastatic), primary tumor site (intrahepatic/extrahepatic The 5-year survival rate with a curative R0 resection is ∼60%, bile ducts, ampullary, gallbladder), performance status (Eastern but curative resections are possible only in about 30% of patients. Cooperative Oncology Group [ECOG] score 0, 1, or 2), prior There is high risk of tumor recurrence both locally with intrahe- therapy (yes/no), and recruiting center. The median overall sur- patic metastases as well as with extrahepatic disease. However, vival in the gemcitabine/cisplatin group was 11.7 months com- there are no established guidelines for surveillance and follow-up pared to 8.1 months in the gemcitabine only group (p <0.001; after surgical resection for iCCAs. As a guide, surveillance could 95% CI, 9.5 to 14.3) with a hazard ratio of 0.64 (95% CI, 0.52 to consist of laboratory tests of liver function and CA19-9 and radio- 0.80). Efficacy was evident across a range of endpoints, including logic evaluations every 3 months for the first 2 years after surgery progression-free survival (8 months versus 5 months; HR, 0.63; and every 6 months thereafter for the first 5 years could be con- p <0.001) and response rate (26.1% versus 15.5%). Prespecified sidered and modified based on the perceived risk. The role and subgroups described earlier all derived clinical benefit. Only utility of surveillance has not been formally established. Surgery is 17.6% (72 of 410) patients went on to receive second-line ther- generally not indicated for recurrent CCAs. apy. The role of subsequent lines of therapy with regard to survival benefit remains to be defined, but fluoropyrimidine-based Liver Transplantation. The outcomes from liver transplanta- regimens have demonstrated preliminary evidence of efficacy in tion for iCCAs, unlike those for hilar CCAs have been disap- studies with small numbers of patients with cholangiocarcinoma/ pointing, with a 5-year survival rate of 29% in data from the gallbladder cancer,71,72 and should be investigated in larger, con- European Liver Transplant Registry.69 As a result of these poor trolled studies. Of patients, 58.8% (241 of 410) had involvement outcomes, liver transplantation is not generally offered for this of the bile ducts in this study; 19.5% (80 of 410) had intrahe- indication. patic disease; 17.8% (73 of 410) had intrahepatic involvement; and 13.9% (57 of 410) had hilar disease. Survival benefit was Local–Regional Therapies. Local–regional therapy for unre- most prominent in the intrahepatic group on a subgroup analysis sectable iCCAs include transarterial chemoembolization (TACE), (HR, 0.57; 95% CI, 0.34 to 0.94). The subgroup analyses were transarterial radioembolization (TARE), radiofrequency ablation not powered to demonstrate benefit within each subgroup and, as (RFA), or microwave ablation. They may be used for palliation and such, should be viewed as hypothesis generating. Response rate local control in persons with a good performance status. A median was 19% versus 11.7% in the subgroup comprising both biliary survival time of 20 months with TACE and 43.7 months with and ampullary cancers. TARE have been reported in case series. For tumors smaller than At a conceptual level, there is support for the consideration 3 cm, RFA resulted in a median survival time of 38.5 months. Most of combined modality chemoradiation therapy for patients with tumors present with a large bulky tumor precluding complete abla- unresectable disease using gemcitabine- or fluoropyrimidine-based tion, and there is a potential risk of biliary complications arising strategies, and efficacy has been observed in smallstudies. 73,74 from bile duct damage. However, definitive data through controlled trials remains unavailable and, as such, this remains an area of active investigation, par- Chemotherapy. Based on pivotal data from the UK-ABC-02 ticularly from the standpoint of patient selection and advantages study, gemcitabine in combination with cisplatin has been over chemotherapy alone. 720 Practice of Oncology / Cancers of the Gastrointestinal Tract

The advent of molecular profiling has uncovered putative CA19-9 and will not manifest an elevation in this marker. Addi- therapeutic targets, which include aberrations in the Akt–PI3K– tional potential markers for CCA include CA242, CA72-4, CA50, mammalian target of rapamycin (mTOR), Fanconi, IDH1/2, CA125, RCAS1, and serum MUC5AC. These have all been evalu- ERBB–MEK, and fibroblast growth factor receptor (FGFR) ated with mixed results.80,83–87 CA19-9 has also been defined as a pathways.43,75,76 Fusions in fused in glioblastoma–repressor of poor prognostic factor in CCA.88 silencing 1 (FIG–ROS1) and various FGFR2 fusions such as A diagnosis is usually based on history, cholangiography and FGFR2–BICC and others have been identified, and more such cytology, or tissue analysis. pCCAs often arise and can progress events will be identified with the increasing use of genomic to obstruction of one of the main bile ducts at the hilum before sequencing studies. The pursuit of these targets may lead to an involving the other main duct. Unilateral obstruction of either eventual individualized and heterogeneous approach to patients the right or left bile duct alone may not lead to jaundice or an with both refractory and untreated disease in lieu of empiric elevated bilirubin because of compensation from the normally approaches such as gemcitabine and cisplatin. draining lobe of the liver. However, the alkaline phosphatase and γ-glutamyltransferase may be elevated. Jaundice may occur Perihilar Cholangiocarcinoma when the tumor extends down the bile ducts to involve the confluence of the right and left ducts. Unilateral obstruction results in atrophy of the affected side of the liver and hypertrophy of the pCCAs are cancers that arise from the extrahepatic biliary tract other side. This atrophy–hypertrophy phenomenon will also occur from the second order ducts to the origin of the cystic duct. These if the portal vein has also been blocked by the tumor. Because cancers are amongst the commonest malignancies of the biliary atrophy– hypertrophy results in an axial rotation of structures in the tract encountered in many parts of the world. hepatoduodenal ligament, its effects need to be considered when pCCAs should be distinguished from nonhilar, distal extracel- interpreting imaging studies or in planning hepatic resections.89 lular tumors because of their distinctive clinical presentations, Any patient who has a perihilar stricture, without evidence of natural history, staging, and management approaches. Although ductal disease elsewhere in the biliary tree suggestive of PSC, and distinctive molecular and pathologic differences have yet to be who has not had previous biliary surgery that might have resulted in determined, and the pathogenesis of these tumors may be similar, stricture, is considered to have pCCA. The diagnosis and evaluation dCCAs are far less common than pCCAs and have better treat- of these tumors depends on the available diagnostic technologies ment outcomes. The reason for the predilection of pCCAs to pre- and expertise. The goals are to (1) ascertain the nature and extent of dominantly arise at the liver hilum is not known. obstruction, (2) obtain tissue for diagnosis if possible, and (3) stage Tumors that cause ductal obstruction at the hilar region are the tumor to determine spread and metastasis to guide therapy. An occasionally referred to as Klatskin tumors. However, the series abdominal ultrasound will confirm the presence of a biliary obstruc- reported in the classical paper by Klatskin included both intra- tion. Additional testing with either a CT or MRI/magnetic reso- hepatic and extrahepatic cancers, and was reported in an era in nance cholangiopancreatography (MRCP) is needed to identify the which the biliary tract was inaccessible to noninvasive preopera- potential and for staging if a malignancy is suspected. The accuracy tive imaging.77 Thus, use of the term Klatskin tumor to describe of CT and MRI/MRCP for the prediction of the extent of ductal pCCAs is inaccurate, confusing, and best avoided. involvement ranges from 84% to 91%; for hepatic arterial invasion, it Diagnosis ranges from 83% to 93%; for portal vein invasion, from 86% to 98%, and for lymph node metastasis, from 74% to 84%.90–92 Patients with early-stage cancers are often asymptomatic. Most Biliary tract imaging (cholangiography) with cytology is used patients present with painless jaundice and its clinical sequelae to establish the diagnosis. Tissue biopsies can be obtained under of dark urine, light stool, and pruritus. Nonspecific gastrointesti- fluoroscopic guidance, or using cholangioscopy during endo- nal symptoms such as anorexia and nausea, as well as mild weight scopic retrograde cholangiopancreatography (ERCP). A cholan- loss and fatigue are not unusual. Most patients will present with gioscopy may allow for direct visualization, but often provides a painless obstructive jaundice, associated with pruritus, abdominal lower amount of tissue for analysis.93–96 In one study, direct visu- pain, weight loss (30% to 50%), and fever in about 20%.78 The alization for biliary strictures using a miniendoscope identified clinical presentation of pCCAs are indistinguishable from other malignancy in 11 of 20 patients and resulted in modification of malignancies causing large bile ductal obstruction such as dCCAs diagnosis of biliary stricture in 20 of 29 patients.97 or pancreatic cancer. Obstruction of the bile duct and biliary stasis Peroral cholangioscopy using the spyglass system may also be may lead to bacterial colonization and cholangitis, particularly in associated with a higher rate of cholangitis. Confocal laser endo- patients with biliary stones. Patients with cholangitis can present microscopy is an emerging technique that may be helpful. Specific with high fever, pain, nausea, vomiting, and rigors. criteria (Miami criteria) for the diagnosis of a malignancy within Serum biochemical tests will reveal the evidence of cho- a stricture using this technique have been proposed, but need to lestasis with elevations in bilirubin, alkaline phosphatase, and be further validated, and the specificity needs to be improved.98 γ-glutamyltransferase. Serum aminotransferase levels may be An endoscopic ultrasound (EUS) with fine-needle aspiration normal or mildly elevated in the early stages. Serum CEA and (FNA) may also be helpful for a diagnosis or to predict unresect- CA19-9 levels are the most commonly elevated serum tumor ability by detecting nodal spread. An intraductal ultrasound per- markers. CA19-9 has limited value because levels can be elevated formed using an ultrasound probe passed into the common bile in benign biliary tract disease, cholangitis, or cholestasis. CA19-9 duct increased the accuracy of ERCP from 58% to 90%.99 levels above 100 U/mL were found to be 89% sensitive and 86% pCCAs are less accessible than other distal CCAs for sampling. specific for the diagnosis of malignancy in patients with PSC.79,80 The highly desmoplastic nature of these tumors further limits the CEA levels also have a low predictive value for cancer and are not amount of cellular material that may be obtained for a cytologic helpful for a diagnosis.79,81 Both CA19-9 and CEA levels may be analysis. As a result, establishing a tissue diagnosis of pCCA is elevated in bile specimens in the presence of cancer.82 A com- extremely difficult. The diagnostic sensitivity of tissue or cytol- bined index of CA19-9 and CEA has been proposed, with studies ogy examination remains poor. Indeed, benign disease has been showing mixed results in predicting cancer. The presence of cho- noted in about 10% of surgical resections performed for presumed langitis or hepatolithiasis can cause elevations of tumor markers, pCCAs.100–102 A positive diagnosis with brush cytology ranges from and these tests should be repeated after symptoms have resolved. 44% to 80%,103–105 with pooled data from over 800 CCA patients CA19-9 is a carbohydrate cell–surface antigen related to Lewis reporting a sensitivity of 42%, a specificity of 98%, and a positive blood group antigens. Patients with a negative Lewis blood group predictive value (PPV) of 98% among patients with confirmed antigen (representing 10% of the population) cannot synthesize cancer.103 A brush cytology is diagnostic and very useful when posi-

tahir99 - UnitedVRG Chapter 53 Cancer of the Biliary Tree 721 tive, but of little value when negative. In a study of 74 patients with TABLE 53.2 pancreaticobiliary strictures, the sensitivity and specificity of brush cytology were 56% and 100%, respectively, and the positive predic- American Joint Committee on Cancer TNM Staging tive value was 100%.106 Intraductal tissue biopsies also have a low System for Perihilar Cholangiocarcinoma diagnostic yield with a pooled sensitivity of 56%, a specificity of 97%, and a PPV of 97%. The use of multiple sampling techniques Primary Tumor (T) should be considered to improve the diagnostic yield of sampling. TX Primary tumor cannot be assessed Mucobilia on ERCP is an uncommon finding that is highly suggestive of a papillary CCA. Papillary tumors could be either T0 No evidence of primary tumor intrahepatic or extrahepatic. FNA is also useful if a mass can be Tis Carcinoma in situ seen on ultrasound examination or on CT scan. T1 Tumor confined to the bile duct, with extension up to the muscle layer or fibrous tissue Staging T2a Tumor invades beyond the wall of the bile duct to Disease staging in pCCA requires an assessment of the extent of surrounding adipose tissue ductal involvement as well as the extent of involvement of the liver parenchyma, lymph nodes, and vasculature and distant metas- T2b Tumor invades adjacent hepatic parenchyma tases.107 The TNM system (Table 53.2) does not help to define T3 Tumor invades unilateral branches of the portal vein or surgical resectability and, therefore, may not adequately predict hepatic artery outcome.51 A classification for hilar tumors was introduced and 108 T4 Tumor invades main portal vein or its branches modified by Bismuth. This classification is based on the level of bilaterally, or the common hepatic artery, or the ductal involvement by the tumor, and provides a guide as to the second-order biliary radicals bilaterally, or unilateral extent of surgical resection that may be required for tumor eradi- second-order biliary radicals with contralateral portal cation. However, it is not a true staging system and has low accu- vein or hepatic artery involvement racy.109 A registry of pCCA has been initiated to collect data that may serve as a resource to guide the development of meaningful Regional Lymph Nodes (N) 110 future staging classifications. NX Regional lymph nodes cannot be assessed Management N0 No regional lymph node metastasis N1 Regional lymph node metastasis (including nodes A suggested approach to the management of pCCA is presented along the cystic duct, common bile duct, hepatic in Figure 53.2. The local extent of the disease along the biliary artery, and portal vein) tree can be determined by direct or imaging-defined cholangi- OF ONCOLOGY PRACTICE ography—either ERCP, magnetic resonance cholangiography N2 Metastasis to periaortic, pericaval, superior mesenteric MRCP or percutaneous transhepatic cholangiography (PTC). artery, and/or celiac artery lymph nodes However, the extent of disease may not be appreciated because Distant Metastasis (M) of tumor spread along the wall of the bile duct without lumenal M0 No distant metastasis compromise. PTC or MRCP may be more useful than ERCP in establishing the upper extent of disease. MRCP is less invasive, M1 Distant metastasis but may need to be supplemented with direct cholangiography at Anatomic Stage/Prognostic Groups times. Vascular invasion has been assessed by MRI/MR angiography, angiography, or Doppler ultrasound. An MRI is useful to Stage 0 Tis N0 M0 assess liver invasion or vascular involvement not clearly identified Stage I T1 N0 M0 on CT scans. CT scans or MR angiography are replacing the need Stage II T2a-b N0 M0 for an invasive angiography to assess vascular involvement. Color- flow Doppler ultrasound is very dependent on the operator, but Stage IIIA T3 N0 M0 can be effective at evaluating portal vein involvement and, in some Stage IIIB T1–3 N1 M0 cases, hepatic artery involvement.111 Positron-emission tomography (PET)/CT scans, intraductal ultrasound (US), and EUS have Stage IVA T4 N0–1 M0 all been used for staging. EUS with FNA may also be helpful for Stage IVB Any T N2 M0 a diagnosis by detecting distal lymph node involvement. A staging Any T Any N M1 laparoscopy with or without ultrasound can identify tumor spread beyond that detected on cholangiography, vascular encasement, or Used with the permission of the American Joint Committee on Cancer lymph node involvement. (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springerlink.com, page 221. Liver Transplantation. Liver transplantation has emerged as a viable option for the treatment of early stage, unresectable pCCA in highly selected patients.112 For patients with tumors that are unresectable, a complete hepatectomy with liver transplantation may pro- ity for pCCA. The use of living donor liver transplantation may vide the only chance for a cure. The presence of extrahepatic nodal overcome some of the limitations of organ availability for this in- disease or metastases is a contraindication to transplant. In carefully dication because 5-year survival after living donor living transplan- selected patients, a multimodality approach combining preopera- tation (LDLT) was 69% compared with 63% after deceased donor tive chemoradiation, staging laparoscopy, and orthotopic liver trans- transplantation. The outcomes are better in patients with pCCAs plantation has resulted in overall 5-year survival rates of up to 82%. arising in the setting of PSC, with a 72% 5-year survival compared A study of the combined experience of several centers showed an with 51% in non-PSC patients. Furthermore, patients with pCCAs overall survival of 53% on an intention-to-treat analysis, with a 65% undergoing neoadjuvant chemoradiation and liver transplantation recurrence-free survival after 5 years.112 It should be noted that these have a quality of life that is similar to those for patients undergoing data reflect results obtained with a highly selected group of patients. transplantation for other indications.113 If liver transplantation is The availability of adequate organs for transplantation has being considered as a treatment option, FNA of the hilar lesion limited the use of liver transplantation as a treatment modal- by EUS should be avoided because of the risk of tumor seeding. 722 Practice of Oncology / Cancers of the Gastrointestinal Tract

Perihilar Cholangiocarcinoma (pCCA)

Early Stage Unresectable/Metastatic

Gemcitabine and Transplant Resection Chemoradiation Cisplatin

R1, R2 Resection R0 Resection N1 Disease

Adjuvant Therapy/Clinical Studies

5-year survival 5-year survival 5-year survival 5-year survival <5% ~53%–82% ~11%–43% ~0% Median survival ~12 months

Figure 53.2 Algorithm for the management of perihilar cholangiocarcinoma.

In early reports, EBRT and bolus fluorouracil (5-FU), followed dysfunction, or pruritus.119 However, preoperative decompression by brachytherapy, 5-FU, and liver transplantation, was used.114,115 can increase complications during or after surgery.120–123 Cholan- Out of 28 patients, 11 were excluded because of metastatic dis- gitis may occur following bacterial colonization of bile and stent- ease found at the time of exploratory surgery. The rest underwent ing may induce fibrosis, making it difficult to delineate the extent liver transplantation with an identifiable tumor noted on ex- of tumor.120 Five randomized trials and a meta-analysis have not plant in 10 patients; 2 patients had recurrence after 40 months demonstrated a benefit, although retrospective studies suggest a and 54 months, respectively; and 2 died of non–cancer-related disadvantage to preoperative stenting.124 It may be appropriate if causes. The median duration of follow-up was 41.8 months (range, a hemihepatectomy for CCA is planned in a jaundiced patient 2.8 to 105.5 months); the 5-year actuarial survival rate for those or if a pancreaticoduodenectomy is to be done in a patient with transplanted was 87%. A follow-up protocol added a intrabiliary long-standing or severe jaundice. Other preoperative preparations brachytherapy using iridium seeds after external beam radiation include correcting a vitamin K deficiency and bowel preparation. therapy (EBRT) and maintenance therapy with capecitabine until The use of MRCP to guide decision making toward surgical resec- transplantation.115 Out of 56 enrolled patients, 28 received a trans- tion may avoid the need for more invasive cholangiography and plant. The actuarial 1- and 5-year survivals were 88% and 82%, stenting. respectively, after transplantation. A similar protocol that com- Excision of the bile ducts may be possible up to the first order bined neoadjuvant brachytherapy and infusional 5-FU followed by branches of the right and left bile ducts. If the tumor extends transplantation was reported, with 5 of 17 patients (29%) achieving beyond this on one side, a partial hepatectomy may be needed, long-term disease-free survival.93 Other small series have demon- and a Roux-en-Y reconstruction performed. The contralateral strated 3-year survival rates from 0% to 53%.116 preserved bile duct should be transected at the level of the first Earlier studies of liver transplantation for patients with all types segmental branch to maximize the chance of a negative margin. If of CCA in unselected patients showed very poor results. Meyer the resection is extended beyond the first order branches, a main et al.117 reported the results of liver transplantation for cholangio- drainage channel may need to be fashioned by suturing the indi- carcinoma in 207 patients collected by the Cincinnati Transplant vidual segmental or sectoral ducts together. A caudate lobe resec- Tumor Registry. Fifty-one percent had recurrence, with a median tion is often routinely performed because invasion of the caudate time of recurrence of 9.7 months, and the median time between ducts may occur. Several early branches of the left hepatic duct recurrence and death being 2 months. In a series of 7 patients drain the caudate lobe and can be involved with the tumor involv- undergoing liver-related transplant for CCA, 6 were alive after a ing the left main hepatic duct. Indeed, 46% of pCCAs microscopi- median follow-up of 20 months. Recurrences were noted in all cally involve the caudate lobe.125,126 patients in this series with iCCA.118 Surgery is indicated in the absence of distant metastases where a preoperative workup suggests that an R0 resection is feasible. Surgery. Surgical resection is complex and associated with mor- Bilateral biliary involvement to the point that all four sectional tality and morbidity. The results of surgical resection for pCCA ducts are involved precludes curative resection.127 Other indicators have been reported in many retrospective single-institution surgi- of unresectability include bilateral intrahepatic bile duct spread, cal series. The goals of surgical resection are to remove the tumor involvement of the main trunk of the portal vein, involvement of with negative resection margins. An en bloc resection of at least both branches of the portal vein or bilateral involvement of the he- one lobe of the liver, the extrahepatic bile duct, and a complete patic artery and portal vein, or a combination of vascular involve- periportal lymphadenectomy may be required. ment on one side of the liver with extensive bile duct involvement The preoperative assessment serves to define the extent of on the other side.89 With vascular replacement, it may be possible resection that may be required. There is a role for preoperative to resect some tumors previously considered unresectable. biliary drainage in some, but not all patients. This could be per- A periportal lymphadenopathy is not a contraindication, and formed either percutaneously or endoscopically with stenting resection with microscopic positive margins (R1) determined after or placement of a nasobiliary tube. Biliary drainage can allevi- resection can provide significant palliation. A lymphadenectomy ate symptoms in patients with severe obstructive jaundice, renal should include all soft tissue in the porta hepatis, excluding the

tahir99 - UnitedVRG Chapter 53 Cancer of the Biliary Tree 723 portal vein and hepatic artery. The common hepatic artery nodes, alone in surgically resected patients has completed enrollment the celiac artery nodes, the peripancreatic nodes, and the interaor- in the United Kingdom and outcomes data are eagerly awaited tocaval lymph nodes should be assessed because dissection may (NCT00363584). The primary endpoint of this study is 2-year be indicated. Adequate staging may require sampling of at least overall survival. An analogous phase III study using gemcitabine seven nodes.128 in combination with oxaliplatin versus observation alone is under- Resectable disease is present in approximately one-third of way in France with disease-free survival as the primary endpoint patients with suspected pCCA. In a series from 2001 to 2008, of (NCT01313377). Data from these two pivotal studies will help de- 118 patients referred for surgery, 51% were resectable and 41% fine the role of adjuvant therapy more definitively. In the interim, underwent R0 resection.129 Operative mortality averaged about the recommendation for patients is to participate in clinical trials 8%130; 5-year survival rates after resection have ranged from 10% to whenever feasible. 35%. The results of surgical resection highly depend on whether negative resection margins are achieved.107,131–135 Frozen sections Palliative Care. For unresectable tumors, palliation may be are used to evaluate tumor margins at the time of surgery and to performed by percutaneous or endoscopic stent placement or by guide the extent of resection. However, the desmoplastic nature of surgical bypass. these tumors and fibroinflammatory changes related to the presence of a biliary stent, often restricts an accurate determination of Stent Placement. The goal is to drain the most functional lobe of the presence of a tumor in frozen sections. the liver with a stent that traverses the malignant obstruction and When negative margins are obtained, median survival of pa- allows for internal drainage. Percutaneous biliary drainage is more tients with a tumor-free margin is ∼3.4 years with a 5-year sur- appropriate for the drainage of intrahepatic ducts and may be re- vival rate from 11% to 43%. However, when margins are positive, quired for access to these ducts. Both internal and external biliary median survival is 1 to 1.2 years and 5-year survival is almost drainage are possible. Both plastic or metallic stents may be used, zero.107,132,135,136 With positive microscopic margins, there were with one study reporting a longer survival and lower complication no 5-year survivors in one study.137 Other negative prognostic vari- rates with the latter.142 Biliary catheters may exit the skin and re- ables include tumor stage, nodal disease, tumor grade, bilirubin main capped. This allows for irrigation and provides easy access for concentration, serum albumin level, postoperative sepsis, and cholangiography and stent changes as needed. However, percuta- absence of mucobilia.119,135,136,138,139 Recurrences most commonly neous draining catheters may decrease quality of life. An attempt occur locally at the resection bed or within the retroperitoneal should be made to enable the drainage of greater than 50% of more lymph nodes. Distant metastases occur in one-third of cases, most of the liver volume, irrespective of whether one or more stents are commonly within the lung, mediastinum, liver, or peritoneum. used or one or more segments are drained. Imaging-based volu- Improved outcomes seen in more recent series may reflect increas- metric assessments may be useful to determine whether drainage ing use of routine liver resections. will be adequate. A guided approach using MRCP may be benefi-

There are no established guidelines for surveillance and follow- cial to routine bilateral stenting. If bilateral stents are placed, they OF ONCOLOGY PRACTICE up after surgical resection. There is high risk of recurrence, with may be used side by side or by contralateral stenting through the peritoneal spread, hepatic metastases, local extrahepatic recur- mesh of the first stent (stent in stent). Plastic stents typically clog rence, and distant metastases (most commonly lung). Laboratory within 2 to 6 months, whereas metal stents last longer, up to 8 to and radiologic evaluations every 3 months for the first 2 years after 10 months. Endoscopic metallic stenting should be performed by surgery and at longer 6-month intervals thereafter could be con- an experienced biliary endoscopist. Catheter tract recurrence is a sidered based on the perceived risk. The role of CA19-9 as a sur- rare complication of PTC-placed stents, and was reported in 6 of veillance indicator is not established, but persistently rising levels 441 patients (2.6%) who underwent percutaneous biliary drain- may precede radiologic evidence of recurrence. The role of CT age for pCCAs.143 Patients with catheter tract recurrence had a scans or MRI for surveillance and detection of tumor recurrence lower survival than those without recurrence (17.5 months versus has not been evaluated in clinical trials. MRIs may be preferable 23.0 months; p = 0.089). to CT scans for surveillance because of the ability to concomitantly visualize the biliary tract. In a recent study, PET/CT scans Surgery. Surgical approaches have not been shown to be supe- demonstrated a higher positive predictive value compared to CT rior to percutaneous or endoscopic biliary drainage. A surgical scans alone (94% versus 78%) for nodal metastases and a higher bypass may avoid the need for long-term biliary tube placement, sensitivity (95% versus 63%) for distant metastases.140 Surgery is and its associated morbidity, such as cholangitis, occlusion, and generally not indicated for recurrent CCA. Close surveillance and need for frequent replacement. The disadvantage of surgical early diagnosis of recurrences may allow for eligibility for clini- bypass for palliation is the morbidity associated with the procedure cal trials. when there is limited overall life expectancy. If advanced unresectable disease is encountered at the time of a laparotomy for Adjuvant Therapy. There is a lack of conclusive data regard- presumed resectable tumors, a bypass could be performed for pal- ing the efficacy of adjuvant radiation therapy or chemoradiation liation to avoid the need for another procedure. A surgical bypass therapy for patients who have a gross residual tumor, a tumor in- for pCCA involving a bypass to intraparenchymal ducts using a volving the resection margins, or regional lymph nodes involved defunctionalized limb of jejunum can be technically challenging with a tumor after undergoing resection with curative intent. The but quite effective for palliation. A surgical biliary enteric bypass reported series have been small with the potential for selection to segment III (Bismuth–Corlette cholangiojejunostomy), where bias, and there are no randomized trials that support any particular the bile duct is accessed through the liver parenchyma anteriorly adjuvant approaches as standard. There is a need to explore and avoids the hilar region that may be involved with the tumor.144 effectively evaluate new regimens for adjuvant therapy in these A bypass to right-sided ducts may be challenging.145,146 The right patients. It is recommended that patients are enrolled in clini- lobe could be drained by a bypass to the anterior sectoral bile duct. cal trials to define the role of adjuvant therapy. Similarly, there Surgical implantation of large-bore tubes through the tumor has is a paucity of data upon which to base decisions on the use of been used in the past but is rarely employed now. adjuvant chemotherapy. In a randomized study, mitomycin C and 5-FU were compared with observation alone in a study of Photodynamic Therapy. Photodynamic therapy with stent- 508 patients with resected pancreaticobiliary cancers that in- ing has shown to improve survival, reduce cholestasis, and im- cluded 139 patients with bile duct cancers.141 No apparent differ- prove quality of life compared to stenting alone in a randomized ences in overall or 5-year disease-free survival were noted. A phase study.147–149 In a small, multicentered, randomized controlled trial III study comparing adjuvant capecitabine versus observation of 39 patients, patients who received photodynamic therapy with 724 Practice of Oncology / Cancers of the Gastrointestinal Tract biliary stenting survived 493 days compared with 98 days for those at the liver hilum or cystic duct. Cancers arising at the hilum are treated with stenting alone.142 In a recently published meta-analysis considered separately as pCCAs, whereas those arising within of 6 studies, 170 patients received photodynamic therapy and were the cystic duct are considered along with other gallbladder compared with 157 who had biliary stenting alone.150 There were cancers. statistical improvements in patient survival and performance status, and a trend in the decline of serum bilirubin was significantly Diagnosis improved and the risk of biliary sepsis was similar (15%). These data also suggest a possible role for photodynamic therapy in these The typical presentation of dCCAs is with obstructive jaundice. In patients. the case of tumors arising below the insertion of the cystic duct, the gallbladder may be palpable. The presentation is similar to that of Radiation Therapy. There are very few data regarding the effi- pCCAs or cancers arising from the head of the pancreas. Patients cacy of the use of radiation therapy either alone or in combination may present with jaundice associated with pruritus, weight loss, with other techniques for advanced stage disease, either unresect- fever, and occasionally, with abdominal pain. Cholangitis may able or resected with gross residual tumor. Most of the reported occur, but is rare as a presenting symptom in the absence of prior series are small and no randomized comparisons exist. Long-term interventions directed toward the biliary tract such as cannulation survivors have been rarely described. or stent placement. Bile is sterile, but can serve as a medium for External-beam irradiation was successful in clearing jaundice bacterial growth and can become contaminated with instrumenta- in 10 of 11 patients in a recent report; no other decompressive tion. Patients with cholangitis may present with fever, abdominal measures were used.151 Brachytherapy has been applied through pain, nausea, vomiting, and rigors. Bacteremia with biliary tract percutaneous tubes, with a median survival of 23 months.152 The flora such asEscherichia coli, Klebsiella, Proteus, Pseudomonas combination of surgery and radiotherapy was reported to provide aeruginosa, Serratia, Streptococcus, and Enterobacter may be a median survival of 14 months in unresectable or recurrent present. disease.153 However, other series have reported no benefit with The presence of obstructive jaundice is an indication for fur- radiation.154 Stereotactic body radiotherapy (SBRT) may have ther diagnostic testing to evaluate for malignant obstruction result- some efficacy but has the potential for severe toxicity. In a study ing from tumors of the bile ducts. of 27 patients (26 with pCCA and 1 with iCCA), of whom 18 Laboratory tests suggest extrahepatic biliary obstruction were treated on a prospective phase II trial and received 45 Gy in with elevations in serum bilirubin, alkaline phosphatase, and γ three fractions over 5 to 8 days,155 the median overall survival was -glutamyltransferase levels. Transaminase levels may be elevated, 10.6 months and the local control at 1 year was 84% with a me- but typically to a lesser level. dian follow-up of 5.4 years. Six patients had severe duodenal or Tumor markers may not be very helpful. CA19-9 has low pyloric ulceration, and three patients developed duodenal steno- accuracy for diagnosis because the levels may be increased in the sis. Interestingly, no such toxicity was observed in another group presence of pancreatic cancer, or in the presence of cholangitis of 13 patients with Klatskin tumors.156 Eight of these received or biliary obstruction from other causes. In patients with PSC, a 48 Gy in four fractions and the others received a range of doses cutoff of 100 IU has a sensitivity of 89% and specificity of 86% for 163 (32 to 56 Gy in 3 to 4 Gy per fraction), and median survival was CCA in PSC. The King’s College group index that incorporates 33.5 months. both CEA and CA19-9 values has attained similar sensitivities for 164 No formal comparative studies have been performed, although cancer arising in patients with PSC. Bile CEA levels are report- the median survival of 1 year observed with radiation therapy ap- edly elevated in CCA, but not in benign diseases, other than intra- 138 pears to be superior to 3 months with chemotherapy or 6 months hepatic stones. with best supportive care alone. Evaluation involves abdominal US, and body imaging with CT scans or MRI, as well as biliary tract imaging with ERCP. US is Other Approaches. Endobiliary radiofrequency ablation may cheap, noninvasive, and is the best initial test for the detection potentially provide benefits that are similar to the use of photody- of biliary stones or for ductal dilation that can occur with long- namic therapy for palliation of malignant ductal obstruction, but standing obstruction. Abdominal imaging with either a CT scan or the experience with this has been limited.157 EUS-guided biliary MRI should be obtained for the patient with painless jaundice in drainage through a transgastric approach is technically feasible, whom malignancy is suspected. The advantage of MRI is that an but has high complication rates, such as bile leakage and peritoni- MRCP could also be performed at the same time. Although a CT tis (20%) even in experienced hands.158–162 scan can identify mass lesions, an ERCP or MRCP may be needed to evaluate for the site and nature of biliary obstruction if no mass Systemic Therapy. As described earlier, based on the UK- lesions are noted. ABC-02 data, gemcitabine and cisplatin should be regarded as the In patients without PSC and with no visible mass lesions, the standard of care for patients with perihilar cholangiocarcinoma presence of a single stricture by ERCP indicates a malignancy. with unresectable disease. Although fluoropyrimidine-based thera- In patients with PSC, a malignancy may be associated with the pies have shown evidence of preliminary efficacy, the role of sub- deterioration of clinical status and liver function tests. However, sequent lines of systemic chemotherapy remains to be definitively dCCAs may also present in these patients without any change in defined. Similarly, molecular profiling of these cancers may even- liver biochemistries. There are no data to determine the efficacy, tually result in a paradigm shift, allowing for the individualized timing, or effectiveness of screening and surveillance for a malignancy in patients with PSC, although this is often done in clinical treatment of patients based on single-agent/combination therapy 164 based on perturbation of aberrant pathways. practice using CT scans or an MRI/MRCP, with CA19-9. The diagnosis of malignancy in patients who have a biliary tract stricture can be very difficult. Because of the dense associated stroma, Distal Cholangiocarcinoma well-differentiated cancers with little invasion are difficult to differentiate from the bile duct that has a fibrotic scar or stricture dCCAs are cancers arising from the extrahepatic common hepatic from PSC or other prior biliary injury. The presence of malignant- duct between the junction of the cystic duct and the papilla, but appearing cells within nerve sheaths (perineural invasion) is an not involving either the cystic duct or the ampulla of Vater. important diagnostic criterion of malignancy that is not present in There is heterogeneity of cancers that arise from the extrahe- a benign stricturing disease such as PSC. patic bile duct. Other cancers that arise from the extrahepatic The differential diagnosis includes any cause of painless obstruc- ducts but are considered separately from dCCAs include tumors tive jaundice such as choledocholithiasis, pCCA, or pancreatic

tahir99 - UnitedVRG Chapter 53 Cancer of the Biliary Tree 725 cancer. As with pCCA, dCCAs must be differentiated from benign TABLE 53.3 fibroinflammatory strictures such as from immunoglobulin (Ig) G4 cholangiopathy or sclerosing cholangitis.165 The former can American Joint Committee on Cancer TNM Staging occur in the extrahepatic and intrahepatic ducts and is diagnosed System for Distal Cholangiocarcinoma by an elevated IgG4 in the serum, or by an increased number of IgG4-positive cells in tissue samples. The failure to consider these Primary Tumor (T) diagnoses may lead to inappropriate therapies, such as long-term TX Primary tumor cannot be assessed stenting or hepatic resection, and these strictures may respond to corticosteroids. T0 No evidence of primary tumor Cancers of the lower bile ducts may not be readily distinguished Tis Carcinoma in situ from ampullary, duodenal, or pancreatic cancers. Although all of T1 Tumor confined to the bile duct histologically these cancers present in a similar manner to dCCA, establishing a diagnosis is helpful because dCCAs are less likely to metastasize T2 Tumor invades beyond the wall of the bile duct widely and may have a more favorable outcome with aggressive T3 Tumor invades the gallbladder, pancreas, duodenum, treatment. or other adjacent organs without involvement of the celiac axis, or the superior mesenteric artery Staging T4 Tumor involves the celiac axis, or the superior The AJCC’s TNM system may be used for staging dCCAs mesenteric artery 6 (Table 53.3). Prior TNM staging systems did not consider separate Regional Lymph Nodes (N) staging systems for extrahepatic bile duct tumors. However, the seventh edition (2010) separated the staging of dCCAs from that NX Regional lymph nodes cannot be assessed of pCCAs. In order to determine resectability of the tumor, staging N0 No regional lymph node metastasis is necessary to identify the extent of tumor spread and the relationship to portal vein and superior mesenteric artery. EUS with N1 Regional lymph node metastasis FNA may be useful in determining the extent of tumor spread and Distant Metastasis (M) 166 involvement of local lymph nodes. Although PET scanning for M0 No distant metastasis staging has been proposed, the benefit has not yet been shown.167 A staging laparoscopy with or without US may enable the direct M1 Distant metastasis visualization of the peritoneal surfaces for metastatic implants, as Anatomic Stage/Prognostic Groups well as detect vascular or nodal invasion, any of which would pre- Stage 0 Tis N0 M0 clude resection for cure.127,168,169 Stage IA T1 N0 M0 OF ONCOLOGY PRACTICE Management Stage IB T2 N0 M0 An approach to the evaluation and management of the patient Stage IIA T3 N0 M0 with suspected dCCA is presented in Figure 53.3. Stage IIB T1 N1 M0 Biliary Decompression. If the distal ducts are dilated and T2 N1 M0 extending into the lower common bile duct, therapeutic decom- T3 N1 M0 pression by ERCP or percutaneous stenting could be performed at the time of the initial evaluation. We recommend obtaining brush- Stage III T4 Any N M0 ings at ERCP even if no masses have been seen on abdominal Stage IV Any T Any N M1 imaging studies. Used with the permission of the American Joint Committee on Cancer Surgery. (AJCC), Chicago, Illinois. The original source for this material is the AJCC Surgical resection can be considered for locally con- Cancer Staging Manual, Seventh Edition (2010) published by Springer fined dCCA without major vascular involvement or distant metas- Science and Business Media LLC, www.springerlink.com, page 229. tases. An intraoperative assessment with the help of the pathologist

Distal Cholangiocarcinoma (dCCA)

Early Stage/Resectable Unresectable/Metastatic

R1, R2 Resection Gemcitabine and R0 Resection Chemoradiation N1 Disease Cisplatin

Adjuvant Therapy/Clinical Trials

5-year survival ~27% 5-year survival <5% Median survival ~25 months Median survival ~12 months Figure 53.3 Algorithm for the management of distal cholangiocarcinoma. 726 Practice of Oncology / Cancers of the Gastrointestinal Tract must dictate the extent of resection. For localized dCCAs, a pan- decompression and jejunal bypass may be performed. A surgical creaticoduodenectomy with resection of the extrahepatic bile duct bypass to the common bile duct does involve the morbidity as- to the level of the confluence may be required. Although dCCAs sociated with laparotomy and bowel anastomosis. A laparoscopic often involve the intrapancreatic portion of the common hepatic bypass of a distal bile duct obstruction can be performed,145 usu- duct, on rare occasions the tumor may be confined to a small really with a cholecystojejunostomy. This will be unsuccessful if the gion of the duct and removed by an extrahepatic bile duct resec- common bile duct at the level of the cystic duct is involved with tion without a pancreaticoduodenectomy. The peripancreatic and the tumor. periportal lymph nodes should be removed and examined, along The efficacy of radiation therapy for advanced unresectable with the interaortocaval lymph nodes, if necessary. disease has never been evaluated in prospective randomized trials. Although the incidence of dCCAs is lower than that of pCCAs, Radiation therapy can result in biliary tract and intestinal compli- the resectability rate of dCCAs is much higher than that of cations. The available data is based on small retrospective reviews pCCAs, which may contribute to improved outcomes. A pancre- with heterogeneous patient populations that have been treated aticoduodenectomy with distal bile duct resection has a reason- with a wide variety of modalities and techniques. As described able chance of providing a margin-negative resection for dCCAs. earlier, based on the UK-ABC-02 data, gemcitabine and cisplatin There is considerable morbidity and a mortality rate from 2% to should be regarded as the standard of care for patients with dCCA. 10%. Morbidity can arise from biliary fistulas in about 2% of pa- Although fluoropyrimidine-based therapies have shown evidence tients or a fistula from the pancreatic–jejunal anastomosis in 5% of preliminary efficacy, the role of subsequent lines of systemic to 10% of patients. Although many patients require pancreatic chemotherapy remains to be definitively defined. Similarly, mo- enzyme replacement after this procedure, few develop diabetes. lecular profiling of these cancers may eventually result in a para- Short-term outcomes and/or quality of life are similar between the digm shift, allowing for individualized treatment of patients based pylorus-preserving and standard types of pancreaticoduodenec- on single-agent/combination therapy predicated on the perturba- tomy.170,171 Extensive en bloc–combined hepatic and pancreatic tion of aberrant pathways. resections could be considered in the rare circumstance that there is extensive involvement of the entire bile duct without any evidence of distant spread. The morbidity of such extensive surgery is GALLBLADDER CANCER very high, and the overall prognosis is poor.126 The 5-year survival rates after an R0 resection is 27%, with a median survival time Incidence and Etiology of 25 months. The expected 5-year survival is between 23% and 50%. Prognostic factors for poor survival include high p53 expres- Gallbladder cancers (GBC) are cancers that arise from the gall- sion, nodal metastases, positive margins, pancreatic invasion, and 172,173 bladder mucosa. GBC is the fifth most common malignancy of perineural invasion. the gastrointestinal tract. The incidence of GBC correlates with There are no established guidelines for surveillance and follow- the prevalence of cholelithiasis. Patients who have gallstones up after surgical resection. Laboratory and radiologic surveillance for longer than 40 years have a significantly higher incidence modalities and intervals will be determined on perceived risk on of GBC than those who have had gallstones for a shorter time. an individual basis. Tumor recurrence may occur locally within It has been postulated that 1% of patients aged 65 years or more the peritoneum or local nodes or with distant metastases. with gallstones would develop GBC, and this may reflect the duration of stone disease.176 GBC affects women three to four Adjuvant Therapy. Postoperative adjuvant radiotherapy can be times more often than men and is more common in Caucasians administered by intraoperative radiotherapy (IORT), EBRT, in- than in African Americans. The incidence of GBC increases trabiliary brachytherapy, or a combination of modalities. EBRT with age, with the greatest incidence in persons aged 65 or more. is widely available, noninvasive, and can deliver a homogeneous However, there have been isolated reports of GBC diagnosed in dose to a large volume. In most series, EBRT has been used to children.177–179 Mortality trends have been variable. Germany deliver a dose of 40 to 50 Gy (at 1.80 Gy per day) to the tumor and the Netherlands have relatively high mortality rates from bed and draining lymph node basin. In some series, a smaller vol- GBC, but have shown declines in most age groups. Sweden, ume (i.e., a boost) was treated with additional EBRT, intraluminal France, and Bulgaria show steady upward trends. In Japan, the brachytherapy, or IORT to a total dose of 60 Gy or more. Most incidence increased through the 1980s but has stabilized in commonly, radiotherapy is administered in a continuous course recent years.180 GBC incidence in the United States, Britain, during 5 to 6 weeks. However, the role of radiotherapy from an ef- and Canada has stabilized or declined. These changes have ficacy standpoint remains to be definitively ascertained. Similarly, occurred coincident with the rise in the number of laparoscopic as described earlier, the role of chemotherapy remains an area of cholecystectomies.181 active investigation in patients with biliary cancers. Geographic Variation Palliative Care. For unresectable dCCA, palliation by stenting for biliary decompression by itself, or in combination with che- The incidence of GBC varies considerably with geographic loca- motherapy may be considered. Plastic or metal stent placement tion.224 In the United States, GBC is the most common cancer can be performed at the time of ERCP or PTC, and an internal or of the biliary tract, but is a rare cancer with an incidence of 1 to external drainage. In general, replaceable plastic stents are used for 2 per 100,000. A study based on data from the Surveillance, Epi- those with a life expectancy of less than 6 months, and metal stents demiology, and End Results (SEER) program reported an inci- are used for those with a longer life expectancy, based on results of dence of 1.2 cases per 100,000 population per year in the United a randomized controlled trial.174 Plastic stents need to be replaced States.182 The highest incidence of GBC occurs in Chileans and every 3 months for best results and to minimize cholangitis. This Bolivians.183 Mortality from GBC in Chile is 5.2%, the highest in requires repeated endoscopy procedures. Metal expandable stents the world.184 GBC is the main cause of death from cancer among remain patent for a longer time and are associated with less chol- women in Chile. The incidence of GBC is also high in Native angitis, but they cannot be readily removed. Tumor advancement American, Hispanic American, Latin American, Japanese, and may lead to a complete stent occlusion. Zimbabwean women,185 and in Americans of Mexican origin.186 A randomized trial of surgical bypass versus endoscopic intu- Lower rates of GBC occur among Nigerians, New Zealand Maoris, bation favored the latter.175 Unresectability can often be deter- and Chinese natives and immigrants.185 Within the United States mined preoperatively, but if unresectability is determined only and the United Kingdom, urban areas show higher incidences at the time of an open exploration, a palliative bypass for biliary than rural regions. It has been suggested that lower socioeconomic

tahir99 - UnitedVRG Chapter 53 Cancer of the Biliary Tree 727 status may lead to delayed access to cholecystectomy, which may associations with gallbladder cancer include previous gastric sur- increase GBC rates.187 gery, inflammatory bowel disease, and polyposis coli.

Ethnicity Pathology There are considerable ethnic differences in the incidence of Sixty percent of GBCs occur in the fundus, 30% occur in the body, GBC. In contrast to the general population, the incidence of GBC and 10% occur in the neck of the gallbladder. Tumors that arise is much higher in Native Americans in the Southwest United in the neck and the Hartman pouch may infiltrate the cystic and States and in Mexican Americans. In Mexico, the highest inci- common bile duct, making them clinically and radiographically dence of GBC is in mestizos (i.e., people of mixed ancestry). The indistinguishable from pCCAs. They may be isolated tumors or incidence of GBC in Spain, Cuba, and Puerto Rico is low, sug- involve the gallbladder through intramural spread analogous to gesting that the geographic and ethnic variations noted in GBC linitis plastica of the stomach. Gallbladder cancer can spread early incidence in North and South America may be related to Native by direct extension into the liver and other adjacent organs. This American rather than Spanish heritage. In Bolivia, differences are 185 cancer also has a propensity to seed and grow in the peritoneal related to tribal origin. cavity, and along needle biopsy sites and in laparoscopic port sites. Risk Factors At autopsy, GBC patients have a 91% to 94% incidence of lymphatic metastasis, 65% to 82% have an incidence of hematogenous Established risk factors include gallstone disease, bile composi- metastasis, and 60% have an incidence of peritoneal spread.206,207 tion, calcification of the gallbladder wall, congenital biliary cysts Hematogenous metastasis tends to be from invasion into small or ductal anatomy, some infections, environmental carcinogens, veins that extend directly from the gallbladder into the portal ve- and drugs. Some of the noted geographic differences may reflect nous system, leading to hepatic metastases in segments IV and V genetic differences. Although gallstone disease is associated with of the liver. There is a high propensity for intra-abdominal recur- GBC, the mechanisms predisposing to this increased risk are not rence after resection, with distant metastasis occurring late in the known. Cholecystolithiasis is present in 70% to 90% of patients course. The only common extra-abdominal site of metastasis is with GBC, and the incidence of GBC in patients with cholecysto- the lung. It is rare, however, to have metastasis to the lung in the lithiasis ranges from 0.5% to 3%.188 The risk of GBC was increased absence of advanced local–regional disease. in a prospective cohort study of patients with gallstones, although GBC can be categorized into infiltrative, nodular, and papil- the incidence (9 per 10,000 per person-years), and the absolute lary forms. The infiltrative tumors are the most common form and number of cases of GBC (5 of 2,583 people) in this population was cause thickening and induration of the gallbladder wall, some- low.189 The duration of gallstone disease, the patient age, the size times extending to involve the entire gallbladder. These tumors of gallstones, and possible carcinogenic effects of gallstones, such spread in a subserosal plane. Tumor seeding into the peritoneal as from the chemical composition or bacteria within the stones, cavity can occur if the subserosal plane is violated during and the PRACTICE OF ONCOLOGY PRACTICE may be important; although, in one study patients with cancers did presence of the tumor is not recognized at the time of cholecys- not have larger stones, nor were their stones of higher cholesterol tectomy. Advanced tumors can invade the liver and can result in content.190,191 a thick wall of tumor encasing the gallbladder. Nodular or mass- Although familial clusters of GBC have been reported, an forming GBCs can show early invasion through the gallbladder inherited predisposition has not been found in large series.192 wall into the liver or neighboring structures. Despite this invasive- A recent cohort study from Sweden found an association among ness, it may be easier to control surgically than the infiltrative form, first-degree relatives, specifically among parents (relative risk [RR], where the margins are less defined. Papillary carcinomas exhibit a 5.1; 95% confidence interval [CI], 2.4 to 9.3) or offspring (RR, 4.1; polypoid or cauliflowerlike appearance and fill the lumen of the 95% CI, 2.0 to 7.6).235 Genetic variants in DNA repair pathways gallbladder with only minimal invasion of the gallbladder wall. may be involved in gallbladder carcinogenesis.193 The prognosis of these tumor is better than other forms of GBC. There is a high incidence of GBC in patients with an anoma- Most malignant neoplasms of the gallbladder are adenocarci- lous pancreatic–biliary duct junction (APBJ), and this risk is nomas. Primary malignant mesenchymal tumors of the gallbladder independent of the presence of gallstones. Studies from Japan have been described, including embryonal rhabdomyosarcoma, have linked APBJ to other biliary tract cancers as well as GBC.194 leiomyosarcoma, malignant fibrous histiocytoma, angiosarcoma, About 2% of Japanese patients examined had APBJ, with about and Kaposi sarcoma. Other primary rare tumors of the gallblad- 75% of these cases associated with a choledochal cyst and duct di- der include carcinosarcomas, carcinoids, lymphomas, and melano- lation. The rest were noted to have normal caliber bile ducts.194,195 mas. In addition, the gallbladder can be involved with metastatic Patients with APBJ get cancer at a younger age than patients with cancers from numerous sites. Many tumors exhibit more than one sporadic GBC. Children with APBJ frequently have epithelial histologic pattern. The only histologic type with clear prognostic hyperplasia of the gallbladder.196 significance is the papillary adenocarcinoma, which has a markedly GBC has been associated with partial or complete calcification improved survival compared with all other histologic types. There of the gallbladder wall (porcelain gallbladder). The association is is also evidence to suggest that oat cell carcinomas, adenosquamous controversial, with some studies reporting an incidence up to 25%, tumors, and carcinosarcomas have a poorer survival rate.208 and other studies disputing the association.197,198 Gallstones are found in more than 75% of all patients with Salmonella typhi carriage has been associated with GBC. GBC. In the presence of gallstones, chronic mucosal irritation Typhoid carriers may also suffer chronic inflammation of the predisposes one to malignant transformation. Cholesterol stones gallbladder and have a sixfold higher risk of gallbladder cancer.199 are the most common type associated with GBC. Bile from high Helicobacter bilis and Helicobacter pylori have been identified in endemic areas is more mutagenic than that from low endemic bile specimens and have been demonstrated to increase the risk of areas.209 Although the chemical composition of stones or bile may carcinoma by about sixfold.200,201 be related to the development of cancer, there are no conclusive Exposure to toxic environmental factors in the automotive, data linking biliary bile acids to GBC. A potential mechanism of rubber, textile, and metal industries have been associated with carcinogenesis may involve the excretion of dietary or chemical GBC.183,190,202 Chemicals implicated in gallbladder carcinogen- metabolites within bile, with bile acids acting as cocarcinogens. esis include methyldopa, oral contraceptives, isoniazid.203–205 Experimentally, GBC was induced by the carcinogen dimethyl- An elevated body mass index has been associated with GBC. nitrosamine in 68% of hamsters with cholesterol pellets inserted Although many cohort studies have identified obesity as a risk fac- into the gallbladder compared to 6% of controls fed the carcino- tor for GBC, this parallels the risk for gallstone disease. Other rare gen alone.210 Calcification is the end stage of a long-standing 728 Practice of Oncology / Cancers of the Gastrointestinal Tract

inflammatory process, and calcification of the gallbladder (porce- for cholecystectomy in the asymptomatic patient, because up to lain gallbladder) is associated with cancer in 10% to 25% of cases. 25% of cases will be associated with gallbladder cancer. Patients Despite this association, the incidence of GBC in patients with with pancreaticobiliary maljunction and a normal-sized bile duct gallstones is only 0.3% to 3%. may benefit from a prophylactic cholecystectomy.225 A study of Cancers arising from gallbladder mucosa behave similar to northern Indian women reported a benefit of prophylactic chole- other adenocarcinomas of the gastrointestinal tract. Premalignant cystectomy.226 A serum CA19-9 evaluation and bile cytology may to invasive malignant changes can be found; metastatic spread be helpful in making a preoperative diagnosis of cancer. A laparo- occurs by lymphatic and vascular routes; the diagnosis is often scopic cholecystectomy could be reserved for those with normal delayed; and survival is related to the stage. Interestingly, at the markers and negative cytology. For those highly suspicious of can- population level, mortality is also inversely related to cholecystec- cer, the laparoscopic approach is not reasonable because of the risk tomy rates.211 GBC originates as mucosal lesions and, as growth for inadvertent seeding of the peritoneal cavity. progresses, the tumor invades the wall of the gallbladder. The lack of a well-defined muscularis leads to early entry of invasive GBC Diagnosis into the perimuscular connective tissue. Lymphatic, neural, and hematogenous invasions occur earlier with GBC than with other Patients with gallbladder cancer are often asymptomatic. When cancers of the gut. symptoms occur, they may be similar to biliary colic or chronic Adenocarcinomas progress from metaplasia–dysplasia to cholecystitis, and are nonspeciifc. In contrast to biliary colic, pa- carcinoma in situ to cancer. Chronic inflammation may play a tients with GBCs may have diffuse abdominal pain of a more con- role in the development of premalignant lesions.212 Two types of stant nature. As a result of the low index of suspicion, patients with metaplasia—intestinal and squamous—have been found in pa- gallbladder cancer present with symptoms at an advanced stage of tients with GBC. The relation of intestinal metaplasia to the subse- disease, or as incidental findings at the time of imaging or chole- quent development of GBC has not been determined. Squamous cystectomy for unrelated reasons. Recent weight loss and persistent metaplasia, in which squamous epithelium replaces the normal right upper quadrant pain should raise the suspicion of GBCs in gallbladder epithelium, is a rare premalignant lesion associated elderly patients over 70 years of age. with squamous cell cancer of the gallbladder. Cholecystitis follicu- In early stage disease, symptoms can mimic those of choleli- laris, a rare type of inflammation, has been reported in a few cases thiasis and cholecystitis or they may be related to associated chole- of GBC, but its premalignant potential is unclear.212 Progression lithiasis. Pain may be dull and aching, colicky, sharp, constant, or from dysplasia to carcinoma in situ to invasive cancer in the gall- intermittent, with radiation to the back and associated with nausea, bladder epithelium can take about 15 years.213 Dysplastic changes vomiting, and anorexia. At more advanced stages, jaundice, weight are found in adjacent mucosa in most GBCs. Gallbladder adeno- loss, hepatomegaly, a palpable mass, or ascites may develop. Jaun- mas are rarely encountered or associated with dysplasia. dice can result from the obstruction of extrahepatic bile ducts by Several mutations have been reported in GBCs. K-ras and p53 direct tumor growth or from metastatic disease. Jaundice is a poor mutations are common.186,214 Mutant p53 is found in 92% of inva- prognostic sign, and 85% of patients with jaundice have unresect- sive carcinomas, 86% of carcinoma in situ, and 28% of dysplastic able tumors.188 Mirizzi syndrome, in which compression of the epithelium, but not in adenomas.215 K-ras mutations are identified common hepatic duct results from an impacted stone in the gall- in 39% of GBCs.216 Data on the expression of ras and myc are bladder neck, can be a presentation of GBC. Rarely, duodenal or conflicting. In one study,b-RAF mutations were evident in 33% of colonic obstruction, cholecystoenteric fistula, or evidence of extra- GBCs.217 The erbB2 oncoprotein is overexpressed in some patients abdominal metastases such as palpable mass, ascites, or paraneo- with GBC, and transgenic mice that express erbB2 in the gallblad- plastic syndromes such as acanthosis nigricans may occur. These der epithelium develop GBC. Activated EGFR and c-MET may indicate an advanced malignancy and unresectable disease. occur.218,219 The fragile histidine triad (FHIT) gene is a candidate Tumor spread can involve the liver and the extrahepatic bili- tumor suppressor gene in GBCs.220 Epigenetic inactivation of ary tree by direct spread. Liver metastases without full-thickness SEMA3B and FHIT occurs in some GBCs.221 invasion of the gallbladder wall occurs in less than 10% of cases. The malignant potential of APBJ is quite high and this ana- Lymph node metastasis to the cystic, pericholedochal, peripan- tomic variant is associated with premalignant histologic changes creatic, and celiac nodes occurs early, and are present at the time of epithelial hyperplasia with a papillary or villous appearance. of diagnosis in more than half of patients. Direct invasion of the The nonmalignant areas of the gallbladder of patients with APBJ- duodenum or colon, intraperitoneal spread, Krukenberg tumors associated GBC show increased hyperplastic changes in the gall- (i.e., ovarian metastases), and hematogenous dissemination can bladder mucosa compared with patients with sporadic GBCs.222 also occur.3 In a cat model, side-to-side biliary–pancreatic anastomosis pro- Laboratory findings lack specificity and are not diagnostic. duced hyperplastic changes in the gallbladder within 6 months.223 Patients may have increased alkaline phosphatase and bilirubin Although K-ras mutations are not commonly observed in lesions levels as a result of ductal obstruction in advanced cases. Serum associated with gallstones, they are frequently identified in dysplas- CEA or CA19-9 may be elevated, but these tumor markers are not tic lesions associated with APBJ. The differences in presentation, diagnostic. A CA19-9 level above 20 U/mL has a 79% sensitivity morphology, and molecular changes indicate that there are at least and a 79% specificity for the diagnosis of GBCs. A CEA greater two distinct pathways to gallbladder carcinogenesis associated with than 4 ng/mL is 93% specific for GBCs, but sensitivity is only 50% either stone disease or with APBJ.224 for detecting cancer. CA125 has also been reported to be a reasonable marker for gallbladder cancer in some small studies.227 Prevention An ultrasound is the usual initial diagnostic study whenever gall bladder or biliary tract disease is suspected. Findings on The low incidence of GBCs in some countries may be related to ultrasonography of the gallbladder that are suggestive, but not di- the rate of cholecystectomy performed for gallstone disease. How- agnostic, of GBCs include thickening of the wall, a lumenal mass, ever, the prevention of GBCs is not considered as a sole indication calcification, or a mass lesion. A comparison between patients to perform cholecystectomy in patients who have asymptomatic with unsuspected GBCs and those with benign gallbladder disease gallstones. The incidence of gallbladder cancer is low compared found that a solitary stone or displaced stone, or an intralumenal or with the incidence of gallstones in the population. invasive mass were more commonly associated with cancer.228 On In certain high-risk conditions involving abnormalities within ultrasonography, a discontinuous gallbladder mucosa, echogenic the gallbladder wall, a prophylactic cholecystectomy could be mucosa, and submucosal echolucency were significantly more considered. A calcified or porcelain gallbladder is an indication common in GBC than in benign gallbladder disease. A polypoid

tahir99 - UnitedVRG Chapter 53 Cancer of the Biliary Tree 729 mass was present in 27% and a gallbladder-replacing or invasive implantation should be considered,237,238 and the gallbladder is mass was present in 50% of cases of GBC examined.228 extracted in a plastic bag. Implantation can arise due to physical Mucosal thickening should be viewed with suspicion. US will contact between the tumor and port site tissues during extraction, detect polyps that may represent nonmalignant lesions such as or can be related to positive-pressure pneumoperitoneum.239 The adenomas, papillomas, or cholesterolosis in addition to GBCs. An tissue surrounding the trocar ports is excised because seeding may invasive cancer is more likely in polyps greater than 1 cm in di- have occurred. Early reoperation may be necessary if the tumor is ameter. The accuracy of US for staging disease extent or spread is discovered on later pathologic examination, or with uncertainty low (38% in one study).229 EUS is useful for a further diagnosis of about residual tumor. Stage I gallbladder carcinomas with clear polyps or gallbladder wall thickening. EUS has a higher sensitivity resection margins may not require further surgical treatment. (92% versus 54%) and specificity (88% versus 54%) for GBC than Gallbladder polyps may be malignant but are rarely so when US. It can also enable FNA of any suspicious masses or aspiration they are smaller than 1 cm in diameter. In a series of patients of bile for cytology. If a tumor is present, EUS can be useful for with gallbladder polyps, none were malignant if less than 1 cm in staging by assessing tumor wall invasion or distant nodal spread. diameter, but 23% of polyps larger than 1 cm were malignant.240 Abdominal CT scans or MRI can identify intraluminal polyps, In another series, 88% of polyps larger than 1 cm in diameter were gallbladder wall thickening, mass lesions, hepatic involvement, malignant, and polyps larger than 1.8 cm were more likely to con- nodal enlargement, or other distant spread. CT scanning will tain a more advanced stage of cancer.241 FNA is an accurate way reveal a mass partially obliterating the gallbladder lumen, a poly- of distinguishing between polyps due to cholesterolosis and neo- poidal mass, or diffuse wall thickening. However, only one-third of plastic polyps,233 especially for polyps that are larger than 1 cm pathologically positive nodes are identified preoperatively by CT in diameter242; however, it is much less accurate in determining scan. The use of MRI for the diagnostic workup of GBC can be whether a neoplastic polyp is an adenoma or carcinoma.242 Dop- helpful. MRCP may provide more detailed information than can pler US imaging of blood flow within a neoplastic polyp may also be provided by US or CT scan.230 MRI may be helpful in deter- be useful in distinguishing these lesions from benign polyps. mining vascular invasion and nodal involvement. There is almost no role for cholangiography using ERCP or PTC, although these Staging may occasionally be needed to plan the extent of surgical resection Several staging systems have been described for GBC. These sys- by determining the extent of ductal involvement or spread.231 tems incorporate clinical and pathologic characteristics with prog- Fluorodeoxyglucose (FDG)-PET scanning has low sensitivity nostic significance. These include the modified Nevin system, the for extrahepatic disease. However, PET scanning may identify a Japanese Biliary Surgical Society system, and the AJCC TNM disease that has not been radiologically apparent and resulted in staging system.6,235,243 The use of these different staging systems a change in stage and treatment in 17% to 23% of cases with pre- makes it difficult to compare the treatment results of different sumed localized resectable disease in one study.65 For suspicious series in the literature. The AJCC TNM staging system should lesions on US, PET scanning has been reported to have a sensitiv- OF ONCOLOGY PRACTICE be used for the standardization of reporting across studies so as to ity of 0.80 and a specificity of 0.82, a positive predictive value of enable a comparison of treatment results. This staging system is 0.67, and a negative predictive value of 0.90.232 shown in Table 53.4. Stage 1 includes tumors that invade the lam- The need for tissue biopsy before definitive exploration and ina propria or muscle layer. Tumors can arise in the Rokitansky– resection of a mass that is suspicious for GBC is controversial be- Aschoff sinuses and are considered stage I in a subserosal position. cause of the risks of the tumor seeding into the peritoneal cavity Tumors with invasion into the perimuscular connective tissue are or abdominal wound. Bile cytology may avoid these and should be considered stage II, and liver invasion is stage III. Extensive nodal performed whenever any patient suspected of having GBC who metastasis to periaortic, pericaval, superior mesenteric artery, or undergoes ERCP or PTC. The diagnostic accuracy of combined celiac artery is now considered stage IVA. Patients with distant me- ERCP and bile cytology is 50% for gallbladder cancers. The sen- tastasis are considered stage IVB. GBCs undergo histopathologic sitivity of bile cytology alone for the diagnosis of GBC has been grading from G1 (well differentiated) to G4 (undifferentiated). reported between 50% and 73%.233 If referral for surgical manage- Although the grade does not factor into staging, it has prognostic ment is being considered, a diagnosis based on bile cytology or significance, with high-grade tumors having a worse prognosis. percutaneous FNA cytology would be preferable to operative or laparoscopic biopsy. Management Percutaneous FNA or core needle biopsy are indicated for unresectable masses. The risk of tumor seeding within the needle Most studies of treatment approaches for GBC are from small case tract is greater with the latter. EUS-directed FNA for gallbladder series or are heterogenous studies that include other biliary tract lesions is associated with a 80% sensitivity and 100% specificity.234 cancers. As a result, the optimal approaches to surgery or pallia- Percutaneous FNA has an 88% accuracy for gallbladder cancers tive therapy with chemoradiation are unknown. The stage of the with a negligible false-positive rate.233 EUS may be useful to distin- disease determines the treatment approach and prognosis.235 The guish between inflammatory nodes and metastatic disease during diagnosis of GBC usually occurs at advanced stages TNM III or an evaluation of periportal and peripancreatic adenopathy. A stag- IV, and most patients in advanced stages are not resectable.244,245 ing laparoscopy to determine the extent of spread may be helpful A suggested management scheme is outlined in Figure 53.4. for some patients.127,169 Survival of patients with GBC is related to stage and histo- Surgery. Surgery is the only potentially curative option for GBCs. logic type of cancer. Lymph node involvement is rare in stage Absolute contraindications to surgery include distant metastases, T1 tumors235,236; that is, lymph node involvement almost never vascular involvement, or nodal spread beyond the hepatoduode- occurs until the muscularis has been penetrated. After that, lymph nal ligament. When GBC is suspected, an open cholecystectomy node involvement is common, occurring in about 50% of stage II is preferable to laparoscopic excision to minimize the potential patients and in 70% to 80% of patients in stage III and IV. There is impact of tumor implantation due to gallbladder perforation and a close correlation between lymph node involvement and progno- bile spillage that are more frequent with the latter. An extraserosal sis. Most long-term survivors are patients with well-differentiated cholecystectomy excises the gallbladder on a deeper plane than a tumors that were minimally invasive. These are usually found inci- standard cholecystectomy, so that the gallbladder and all connec- dentally at or immediately after cholecystectomy. tive tissue down to actual liver tissue are removed. The extent of GBCs may be identified incidentally at the time of chole- resection will depend on the extent of disease spread. For T1 le- cystectomy; the incidence ranges from 0.3% to 1%. If this oc- sions where the tumor has not penetrated the muscularis mucosa curs during a laparoscopic procedure, the potential for port-site and margins are negative, cholecystectomy is sufficient and can 730 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 53.4 American Joint Committee on Cancer TNM Staging of Gallbladder Cancer

Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ T1 Tumor invades lamina propria or muscular layer T1a Tumor invades lamina propria T1b Tumor invades muscular layer T2 Tumor invades perimuscular connective tissue; no extension beyond serosa or into liver T3 Tumor perforates the serosa (visceral peritoneum) and/or directly invades the liver and/or one other adjacent organ or structure, such as the stomach, duodenum, colon, pancreas, omentum, or extrahepatic bile ducts T4 Tumor invades main portal vein or hepatic artery or invades two or more extrahepatic organs or structures Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastases to nodes along the cystic duct, common bile duct, hepatic artery, and/or portal vein N2 Metastases to periaortic, pericaval, superior mesenteric artery, and/or celiac artery lymph nodes Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis Anatomic Stage/Prognostic Groups Stage 0 Tis N0 M0 Stage I T1 N0 M0 Stage II T2 N0 M0 Stage IIIA T3 N0 M0 Stage IIIB T1–3 N1 M0 Stage IVA T4 N0–1 M0 Stage IVB Any T N2 M0 Any T Any N M1

Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springerlink.com, page 213–214.

Gallbladder Cancer (GBC)

Early Stage/Resectable Unresectable/Metastatic

R1, R2 Resection Gemcitabine and R0 Resection Chemoradiation N1 Disease Cisplatin

Adjuvant Therapy/Clinical Trials

5-year survival 5-year survival <5% ~15%–90% Median survival ~12 months

Figure 53.4 Algorithm for the management of gallbladder carcinoma.

tahir99 - UnitedVRG Chapter 53 Cancer of the Biliary Tree 731 be curative. Direct tumor growth into the liver or duodenum or regimens is eagerly awaited. New approaches beyond the currently colon is not a contraindication to surgery, but the extent of spread available chemotherapeutic agents are needed for these cancers will guide the extent of resection for these T2 to T4 lesions. Thus, to achieve any improvements in survival. Understanding the mo- wedge resection of the liver, portal lymph node dissection, and lecular and genomic contributors to this cancer may enable more extrahepatic bile duct resection, or even a pancreaticoduodenec- focused therapy in the future. tomy may be needed in addition to a cholecystectomy. If there is obvious penetration to the serosal layer on the deep surface of the Palliative Care. Advanced GBC has a 1-year survival rate of less gallbladder, or if margins are positive, or the muscularis has been than 5%. Although the resection of gross disease may provide pal- penetrated, resection of at least liver segments IVb and V, and a liation and, in some instances, a chance for cure, it may not always lymph node dissection are performed. If the cystic duct resection be possible. Patients with advanced disease should be considered margin is positive, then, in addition, the extrahepatic bile duct is for clinical trials. The aggressive nature and dismal prognosis of excised to clear margins. A more extensive liver resection may be advanced unresectable cancer should be considered when decid- required if the tumor has penetrated further into the liver. If nega- ing on palliative management. The goals of palliative treatment tive resection margins are achieved, 5-year survival rates range are to prevent biliary and bowel obstruction and to relieve pain. from 90% in stage I disease, 80% in stage II, 40% in stage III, and 15% in stage IV. Lymph node involvement portends a worse prog- Stenting. If biliary obstruction is present, percutaneous stent- nosis than local hepatic invasion alone.243,245 A pancreaticoduode- ing for relief of obstruction can be performed by percutaneous or nectomy may be considered for T2 to T4 disease, but the results endoscopic approaches similar to that for other cancers such as remain poor in advanced stages.246 dCCAs and pCCAs. Randomized studies did not show a benefit of preoperative biliary decompression for jaundiced patients.247–249 However, these Surgery. Surgical bypass is not usually warranted because of the studies were performed in an era in which surgical intervention poor expected survival. The resection of hematogenous metastasis mostly involved palliative bypass of the biliary tree, and the poten- or of distant nodal disease is not justified. tial benefits of preoperative decompression prior to either pancreaticoduodenectomy or liver resection are not defined. Chemotherapy. In the UK-ABC-02 study described earlier, 36.3% (149 of 410) of the patients had advanced gallbladder can- Adjuvant Therapy. GBC has a high risk of systemic spread and cer. The response rate was 37.7% versus 21.4%. Median overall local–regional failure and adjuvant chemotherapy and radiother- survival and progression-free survival differences were not reported apy are recommended by most cancer centers. separately, but the survival benefit did demonstrate significance on As with other biliary tract cancers, published reports on adju- a subgroup analysis in patients with gallbladder cancer (HR, 0.63; vant radiotherapy or chemoradiation therapy after a resection for 95% CI, 0.42 to 0.89). As such, the standard of care in patients

gallbladder cancer consist of retrospective reviews that vary in the with advanced GBC is also regarded to be gemcitabine in com- OF ONCOLOGY PRACTICE type of radiation treatment (e.g., EBRT, brachytherapy, or IORT) bination with cisplatin. As described previously, although fluoro- and the extent of surgical resection (complete or incomplete). As a pyrimidine-based therapies have shown evidence of preliminary result, they cannot provide adequate evidence upon which a stan- efficacy, the role of subsequent lines of systemic chemotherapy dard treatment recommendation could be based. remains to be definitively defined. Akin to CCA, therapeutic strat- A median survival of approximately 2 years has been reported egies based on genomic profiling of tumors will also be an area of for patients receiving adjuvant therapy. critical study to best define approaches that can be more individu- In a study of 21 patients who received postoperative adjunct alized in nature. EBRT with 5-FU, EBRT was applied to a median dose of 54 Gy in fractions of 1.8 to 2.0 Gy per day, with one patient also receiving Regional Therapy. Regional therapy is possible for gallbladder 15 Gy of IORT after EBRT, the median survival rates were 0.6, cancer. In one study, a 48% overall response rate and a prolonga- 1.4, and 15.1 years, and 2-year local control rates were 0%, 80%, tion of median survival from 5 to 14 months compared with histori- and 88% for patients with gross residual tumor, microscopic resid- cal controls was reported with intra-arterial mitomycin C.251 ual tumor, and no residual disease, respectively.250 For six patients who received more than 54 Gy, the 3-year local control rate was Radiation Therapy. EBRT may be considered for symptom- 100% compared with 65% for 15 patients who received less than atic patients. The limited data available suggest that tumor 54 Gy. In a randomized trial comparing mitomycin C and 5-FU control is rarely possible, although some GBCs may be radio- with observation alone that enrolled 140 patients with gallblad- sensitive and spread is mainly by local–regional growth.252,253 der cancers, a significantly better 5-year survival was seen with However, radiation therapy may be considered for palliation of chemotherapy, but these differences were not apparent when an jaundice in some cases, or used in multimodality approaches intent-to-treat analysis was performed.141 combining EBRT with a 5FU-based treatment. The latter approach is supported by consensus guidelines from the European Chemotherapy. Although the role of chemotherapy given in Society of Medical Oncology and the National Comprehensive the adjuvant setting has not been defined definitively, given the Cancer Network.254 Although the benefit of EBRT is minimal, poor outcomes for patients with resected disease, it remains an with a median survival of only 6 to 8 months, it does appear to be area of active investigation. As described earlier, data from pivotal well tolerated and may improve symptoms and prolong survival phase III studies using gemcitabine- or fluoropyrimidine-based in selected patients.

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Ronald S. Chamberlain, Krishnaraj Mahendraraj, and Syed Ammer Shah

SMALL BOWEL CANCER to a clearly defined role for total colectomy or proctocolectomy to prevent cancer development. FAP patients also Although the small intestine comprises 75% of the length and 90% inherit a 4% to 12% lifetime risk of developing adenocar- of the total absorptive surface of the gastrointestinal tract, less than cinoma of the duodenum or periampullary region, which 3% of gastrointestinal malignancies occur in the small bowel.1 is 300 times that of the general population, necessitating Small bowel cancers (SBC) are 40- to 60-times less common than screening esophagogastroduodenoscopy (EGD) as part of colorectal cancer. The rarity of SBCs makes them difficult to di- the work-up.11–18 agnose, especially considering their varied clinical presentation. ■ Hereditary nonpolyposis colon cancer (HNPCC). HNPCC, With an increasing incidence and advanced stage at diagnosis, it also known as Lynch syndrome, is a hereditary condition has become even more important to understand the pathology of that results from a germ-line mutation in DNA mismatch these rare but deadly cancers. repair genes, primarily MSH2 and MLH1. This mutation predisposes one not only to an 80% lifetime risk of colorectal cancer, but also to an increased risk of endometrial, gastric, Epidemiology ovarian, urinary, small bowel, biliary, and skin cancers.19,20 HNPCC patients have a SBC lifetime risk of 1% to 4%, or SBC accounts for ~3% of all the gastrointestinal cancers with a 100-fold greater risk than the general population, which an equal male to female ratio and a median age of 66 years. The also tends to present 10 to 20 years earlier.20 SBC may be the American Cancer Society estimates there will be 9,160 new cases initial presentation of HNPCC in a small cohort of patients, of SBCs in 2014, with 1,210 deaths.2,3 This number represents a and some clinicians recommend small bowel surveillance steady increase in the incidence of SBCs from ~6,100 new cases for this group.20–25 per year in the 1980s based on information derived from the Sur- ■ Peutz-Jeghers syndrome (PJS). PJS is an autosomal-dominant veillance, Epidemiology, and End Results (SEER) database regis- disorder characterized by benign hamartomatous polyps in tries.1–5,8 the intestine along with melanocytic macules on the lips There are more than 40 SBC histologic subtypes, with 93% of and oral mucosa. PJS is due to a mutation in the STK11 them comprised of four major types: carcinoid (37.4%), adeno- (LKB1) tumor suppressor gene, which results in a signifi- carcinoma (36.9%), lymphoma (17.3%), and gastrointestinal stro- cant increased inherited risk for multiple cancer types, with mal tumors (8.4%).6 Historically, adenocarcinoma had a higher the highest risk involving the gastrointestinal tract. By the incidence than carcinoid tumors, but this has changed over the age of 70 years, the cumulative gastrointestinal (GI) cancer ,(of SBC occur in risk is approximately 57% (colon cancer followed by SBC %50ف ,past decade.5–8 In terms of the location the duodenum, where adenocarcinoma predominates, followed which represents a 15-fold increased risk compared to the by the jejunum (30%) and ileum, where lymphoma is more com- general population.27,28 mon proximally, and carcinoid tumors distally. There is an in- ■ MUTYH-associated polyposis (MAP). First described in creased incidence of SBC among colon cancer patients and the 2002, the MUTYH gene encodes for DNA glycosylase, reverse is true also, suggesting a similar causal mechanism rather which is involved in oxidative DNA damage repair and be- than a surveillance bias or the carcinogenic effects treating the longs to the family of DNA mismatch repair genes. Muta- index primary.6,9,10 tions in this gene result in heritable predisposition to GI cancers, including SBC in an autosomal-recessive fashion. Pathogenesis and Risk Factors Mutations of this gene results in G to T transversions, usually involving the APC and KRAS gene, thus predisposing individuals to cancer development.29,30 Proposed risk factors for the predisposition to small bowel neo- ■ Cystic fibrosis. A marginally increased risk of SBC has been plasms are varied, although it is notable that 64% of small bowel documented in cystic fibrosis patients.31 tumors are malignant. Proposed factors that have been associated with SBC include: 3. Inflammatory bowel disease. Although only 2% of Crohn disease (CD) patients will develop a small bowel malignancy (typ- 1. Advanced age: SBCs occur predominantly in the elderly with a ically an adenocarcinoma associated with >10 years of disease .years 66ف mean age of and involving the distal small bowel), this represents a 10- to 2. Specific inheritable syndromes predisposing to SBC11–32: 60-times higher risk than the general population.33–35 Specifi- ■ Familial adenomatosis polyposis (FAP) syndromes. FAP is cally, SBCs in CD occur more commonly in men, in the distal an autosomal-dominant disorder attributable to a mutation ileal location, are more common in small bowel bypass loops in the adenomatosis polyposis coli (APC) gene and char- and in strictures, and in patients with exposure to asbestos or acterized by the development of hundreds or thousands of other carcinogens such as halogenated aromatic compounds.36 polyps throughout the gastrointestinal tract, but predomi- A meta-analysis identified a 33.2 relative risk (95% confidence nately in the large bowel. FAP patients have a 100% life- interval [CI], 15.9 to 60.9) of developing small bowel cancer time risk of developing colorectal cancer, and this has led among CD patients.37–39 734

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4. Celiac disease or sprue (CS). CS is an autoimmune disorder of pallor is seen in ~40% of patients. Up to 77% of SBCs present characterized by villous atrophy, crypt hyperplasia, and in- acutely with either small bowel obstruction or perforation, particu- creased intraepithelial lymphocytes caused by a reaction to the larly adenocarcinomas.47 Patients with familial or genetic predis- wheat protein gliadin in the presence of specific pairs of allelic position to SBCs present, on average, 10 years earlier compared to variants in two HLA DQ2/DQ8 genes. CS is associated with sporadic cases.52–56 an increased risk of enteropathy-associated T-cell lymphoma In comparing different SBC histologies, adenocarcinoma (EATL), which can occur in up to 39% of patients with se- is most often associated with abdominal pain and obstruction, vere or refractory CS (RCS). The overall prevalence of RCS is whereas sarcomas and lymphomas are more often associated with low (0.6% to 1.5%). RCS can be subclassified into RCS type 1, bleeding and perforation, respectively. Adenocarcinomas are fre- which is characterized by increased but nonclonal expansion quently found in the duodenum, carcinoid tumors affect the ileum of intraepithelial lymphocytes (IEL), or RCS type 2, which dis- and sarcomas, and lymphomas are found throughout the entire plays clonal expansion of IELs that evolve into EATL in 60% to small bowel. 80% of such patients within 5 years.40–42 5. Immunosuppression. Iatrogenic (therapeutic) or posttransplant Diagnosis immunosuppression is a generalized dysregulator of homeostasis and predisposes certain patients to both lymphomas and The diagnosis of SBC is often delayed as a result of its rarity and sarcomas. Small bowel lymphomas that develop in these pa- nonspecific presentation. The mean duration of symptoms prior tients are predominantly B-cell as opposed to T-cell lympho- to an accurate SBC diagnosis ranges from 8 to 12 months.48–51 A mas. Posttransplant lymphoproliferative disorders (PTLD) that high index of clinical suspicion is imperative if the diagnosis is to occur develop primarily post–Epstein Barr viral infection and be made early. In many instances, a preoperative diagnosis is not are typically B-cell lymphomas. established because patients present emergently with hemorrhage, 6. Other malignancies. The patient with other primary malignan- perforation, or obstruction. No single diagnostic test has sufficient cies may also be at increased risk for SBCs. This includes pa- sensitivity or specificity to be considered a gold standard.141–167 tients with prior colorectal, pancreas, periampullary, uterine, Conventional abdominal radiographs have a limited, nonspe- ovarian, prostrate, thyroid, skin, and soft tissue tumors.9,10,43 In cific role in the diagnosis of SBCs. Plain abdominal radiographs fact, 30% to 40% of patients with SBCs have a synchronous are helpful when an obstruction exists, but even then accuracy is malignancy, which may be associated with the primary patho- only 50% to 60%. A single or double contrast small bowel follow logic entity or may reflect shared genetic or environmental through (SBFT) is well suited for examination of luminal ab- risk factors. normalities and mucosal abnormalities, but is time consuming 7. Modifiable risk factors. Modifiable risk factors implicated in and associated with an accuracy ranging from 33% to 60%.78–82 SBCs include alcohol use and obesity. In a recent large Asian Small bowel enteroclysis may improve this accuracy to 90%.57 A

study involving over 500,000 patients with a 10.6-year follow- OF ONCOLOGY PRACTICE major limitation of both SBFT and enteroclysis is their inability up, a higher body mass index (>27.5 kg/m2) and alcohol use to evaluate extraluminal pathology, which is circumvented by (>400 g of ethanol per week) were associated with increased cross-sectional imaging, such as computed tomography (CT) SBC risk. Notably, smoking is not associated with an increased scans and magnetic resonance imaging (MRI). CT- and MRI- risk of developing SBC.44–46 Abstinence, weight loss, and di- based enteroclysis has improved the sensitivity and specificity etary modifications (including adhering to a gluten-free diet in of small bowel tumor detection compared to conventional en- those with celiac disease) have been suggested to reduce the teroclysis.58–60 risk of SBCs. In clinical practice, a CT scan of the abdomen with oral and intravenous contrast is the most common diagnostic test utilized Clinical Features in the acute and chronic setting. Pathognomonic CT signs that differentiate between types of small bowel lesions have been well SBC presents in a variety of ways and is more likely to be symp- described. Adenocarcinoma appears as a discrete tumor mass with tomatic early in the disease course compared to benign tumors.47,48 annular narrowing, abrupt concentric or irregular “overhanging The most common presenting symptoms are abdominal pain edges,” or as an ulcerative lesion. Lesions in the duodenum are (45% to 76%), nausea and vomiting (16% to 52%), weight loss typically intraluminal polyps, whereas more distal polypoid lesions (28% to 45%), fatigue and anemia (15% to 30%), and gastrointes- present with intussusception and a characteristic “target sign” tinal bleeding (7% to 23%).49–52 The most common clinical sign (Figs. 54.1 and 54.2).61

A B Figure 54.1 Moderately differentiated primary small bowel adenocarcinoma. (A) The contrast-enhanced axial computed tomography image shows an annular soft tissue lesion (arrows) in the duodenum, resulting in circumferential luminal narrowing and wall thickening. (B) A lateral image from subsequent upper gastrointestinal series shows the annular “apple-core” lesion, resulting in advanced narrowing of the duodenal lumen (arrows). Note the compressed, overhanging edges (arrowhead) of the small bowel at the margin of the mass. 736 Practice of Oncology / Cancers of the Gastrointestinal Tract

A B Figure 54.2 A small bowel intussusception due to primary small bowel adenocarcinoma. (A) A contrast-enhanced axial computed tomography image shows a small bowel target sign consistent with intussusception; the intussusceptum (arrowhead) telescopes into the intussuscipiens (arrow). The lead point for the intussusceptions was a primary small bowel carcinoma. (B) An image from small bowel follow through shows the “coiled spring” appearance of the intussusceptum (arrowhead) as it telescopes into the intussuscipiens (arrow).

Carcinoid tumors appear as hyperintense luminal masses due (GIST).72,74 Fludeoxyglucose (18FDG)-PET has a limited role in to increased vascularity. The tumors typically have intense desmo- the diagnosis and staging of carcinoid tumors because they are not plastic reaction in response to biochemical products produced by 18FDG avid; however, it may play important role in ascertaining the tumor that results in puckering of the adjacent mesentery, giv- treatment response and detecting disease recurrence.72–74 ing a characteristic stellate pattern on the CT scan not necessarily Two notable advances are double-balloon enteroscopy, or reflecting mesenteric invasion (Fig. 54.3). push enteroscopy, and video capsule endoscopy (VCE), which Small bowel lymphomas present as circumferential mural were both introduced in 2001. Double-balloon enteroscopy is a thickening with low homogeneous attenuation and a character- technically challenging procedure that permits the evaluation of istic aneurysmal dilatation in which the involved segment shows the entire small bowel and tissue sampling, which is not possible cavitary dilatation with a nodular, irregular luminal contour and with VCE. Double-balloon enteroscopy most commonly detects peripheral bowel wall thickening (Fig. 54.4).62 Sarcomas appear as symptomatic lesions, including areas of ulceration, stenosis, and homogeneous, well-circumscribed, hypervascular masses on CT GI bleeds, with a sensitivity of 74% to 81%.75–83 VCE is effective at (Fig. 54.5).63–65 identifying 50% of new SBC lesions and 87% of all lesions, with a The MRI has a defined niche in the assessment of early relatively low miss rate of 10%.84–93 small bowel lesions given its improved soft tissue delineation and it may be pivotal in detecting early small bowel pathology (Table 54.1).66–70 Somatostatin receptor scans (octreoscan) and ADENOCARCINOMA metaiodobenzylguanidine (MIBG) scans may be helpful in local- izing and diagnosing of small bowel carcinoid tumors. Octreoscan Adenocarcinoma of the small bowel is the second most common employs a 111In-diethylenetriaminepentaacetic acid analog that histologic SBC subtype, comprising 36.9% of cases.94 The annual targets somatostatin receptors. Over 90% of carcinoid tumors ex- incidence is estimated at 7.3 case per million worldwide. In the press somatostatin receptors, and this test has a sensitivity of 80% United States, 3,050 new cases of SBA are anticipated in 2013.94,95 to 100%. Octreoscans may also provide a functional map of the Patients with SBA usually present between the 6th and 8th decade tumor for anticipated radiolabelled immunotherapy-targeted ther- of life, with earlier presentations in patients with genetic, autoim- apy depending on the stage of the disease.71 mune, or inflammatory conditions (Table 54.2). Positron emission tomography (PET)/CT scans are useful in SBAs display a slight predominance for men, with age-adjusted the initial diagnosis and in disease staging for small bowel adeno- incidence rates highest among African Americans (14.1 per 106) carcinomas (SBA), lymphomas, and gastrointestinal stromal tumor followed by Caucasians (7.7 per 106), Hispanics (6.2 per 106), and

A B Figure 54.3 Primary ileal carcinoid. (A) A contrast-enhanced computed tomography (CT) shows a tethered and thickened segment of ileum (asterisk) containing a small submucosal enhancing lesion (arrow), consistent with primary carcinoid. Note partially imaged metastasis (arrowhead) in the adjacent mesentery. (B) A more inferior CT image shows a stellate mesenteric carcinoid metastasis (arrows) with central calcification and desmoplastic reaction arrowheads( ) in the adjacent fat.

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A B Figure 54.4 Primary small bowel lymphoma. (A) A contrast-enhanced computed tomography (CT) image shows aneurysmal luminal dilatation and extensive wall thickening of a segment of small bowel (arrows). Note enlarged adjacent mesenteric node (arrowhead). (B) A radiograph from the small bowel follow through shows a small bowel segment with luminal dilatation (arrow) and extensive mural thickening and irregularity (arrowheads) corresponding to the diseased segment on the CT.

Asian/Pacific Islanders (5.5 per 106). Adenocarcinoma incidence 35% of SBAs versus 15% of CRCs.77–79 Approximately 50% of the decreases distally in the small bowel, with the highest incidence SBA cases reflect sporadic methylation of theMLH1 gene with a in the duodenum (50% to 5%), followed by the jejunum (16%) relatively high incidence of MSI and MLH1 methylation in CD and ileum (13%). Most SBA patients present at an advanced associated SBA (67% to 73%).106–117 stage (American Joint Committee on Cancer [AJCC] stage III or greater) resulting in a poor overall 5-year disease-free survival (of about 30%) and mean survival (20 months).50 Outcomes are worse Staging and Prognosis for duodenal tumors (28% 5-year survival) compared to jejunal and ileal lesions (38% 5-year survival). The AJCC staging system for SBA is depicted in Table 54.3. Given the nonspecific initial presentation of SBAs, 32% of patients present with stage IV disease, 27% present with stage III, 30% present Etiology 102 with stage II, and 10% present with stage I. Less than 50% of OF ONCOLOGY PRACTICE SBA patients are curative surgical candidates. Survival by stage is SBA shares several etiologic features with colorectal cancers 63% for stage I, 48% for stage II, 32% for stage III, and about 4% (CRC), leading to the adoption of similar treatment strategies, al- for stage IV.102 Multivariate regression analyses identified age over though they are biologically distinct diseases. The most obvious 55 years, males, African Americans, T4 tumor, lymph node in- similarity between SBA and CRC is a common etiopathogenic volvement and ratio, duodenal followed by ileal primary, poor dif- pathways because both cancers are more common in patients with ferentiation, metastatic disease, and positive margins as associated FAP, HNPCC, and inflammatory bowel disease. Available data with a poor prognosis.94,102,120–122 Recent investigations into molec- imply a similar adenoma to carcinoma sequence in both SBA and ular determinants have also identified the CpG island methylator CRC. As with CRC, the risk of progression is associated with the phenotype (CIMP) status, E-cadherin loss, and aberrant β-catenin < size of the adenoma (8.3% for lesions 1 cm and 30% for lesions expression as also associated with a worse prognosis.106,118 >1 cm) and histology (14.3 % for tubular, 23.1% for tubulovillous, and 36% for villous).96–99 A number of molecular similarities and dissimilarities between these two cancers have also been reported. Management In a recent genomic hybridization study looking at GI cancers, SBA was more similar to CRC than to stomach cancer.100 In addi- The site of the disease, the stage at presentation, the available ex- tion, HER2 oncogene amplification is low in SBA similar to CRC pertise, patient comorbidities, and patient performance status are in contrast to gastric cancer.97,98,101,102 Microsatellite instability all important considerations in determining the optimal manage- (MSI) and loss of mismatch repair proteins is present in 18% to ment for individual SBA patients.

A B Figure 54.5 A gastrointestinal stromal tumor of the small bowel. (A) A contrast-enhanced computed tomography image shows a solid, heterogeneously enhancing mass (arrows) arising from the submucosa of the third portion of the duodenum. (B) An image from upper gastrointestinal series shows a filling defect arrow( ) in the third portion of the duodenum due to the submucosal gastrointestinal stromal tumor. 738 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 54.1 Risk Factors and Predisposing Conditions in the Development of Small Bowel Cancer

Risk Factor Lifetime Risk Small Bowel Cancer Type Genetic FAP (2%–5%) 2%–5% Periampullary adenocarcinoma, duodenal/jejunal adenocarcinoma, HNPCC 1%–4% adenocarcinoma, Gardner syndrome, desmoid duodenal adenocarcinoma, Peutz-Jeghers syndrome 15-fold gastrointestinal cancers MUTYH-associated polyposis 4% Cystic fibrosis Autoimmune/Inﬂammatory Crohn disease (>10 yr) 2% Ileal adenocarcinoma, jejunal lymphoma/ adenocarcinoma, celiac disease immunosuppressive lymphoma, posttransplant lymphoproliferative disorder, neurofibromatosis, paragangliomas Malignant Conditions Colorectal, prostate, pancreas, uterine, skin and soft tissue tumors Benign Conditions Cholecystectomy, peptic ulcer disease Other Conditions Male gender, African American, advanced age, high-fat diet, obesity, alcohol

TABLE 54.2 Magnetic Resonance Findings of Common Small Bowel Neoplasms

Type of Lymphatic Secondary and Mesenteric Tumor Type Growth Pattern Margins Intestinal Findings Spread MRI Findings Adenocarcinoma Short annular Irregular margins Stenotic lesion with Local–regional Isointense to muscle lesion with proximal obstruction metastases on T1, heterogeneous intraluminal growth, signal on T2, predominantly in hypovascular after Gd duodenum Lymphoma Long segmental Smooth regular Aneurysmal Bulky retroperitoneal Isointense to muscle infiltrating lesion contours with dilatation without metastases on T1, heterogeneous preservation of the obstruction signal on T2, moderate perivisceral fat plane enhancement after Gd GIST Intramural Smooth lobulated Aneurysmal Peritoneal metastatic Inhomogeneous submucosal mass contours dilatation, stenosis nodules, adenopathy lesions, isointense on with extraserosal or obstruction rare T1, mildly hyperintense extension usually absent on T2, peripheral enhancement in large lesions Carcinoid Focal asymmetric Irregular margins; Intermittent Hypervascular Isointense to muscle predominantly in mesenteric stranding obstruction possible mesenteric on T1, heterogeneous ileum and kinking of the proximal to the metastases with hyperintense on T2, involved segment kinked loop spiculated margins hypervascular on Gd and local adenopathy with calcification

Gd, gadolinium. Adapted from Crusco F, Giovagnoni A, et al. Malignant small bowel neoplasms: spectrum of disease on MR imaging. Radiol Med 2010;115:1279–1291.

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TABLE 54.3 are treated with oncologic-appropriate segmental resection. A right hemicolectomy is the appropriate oncologic approach to tumors American Joint Committee on Cancer near the ileocecal valve. Staging of Small Intestinal Cancer Adjuvant Therapy Primary Tumor Recurrence in SBAs is predominantly distant and rarely local– Tx Primary tumor cannot be assessed regional (86% versus 18%, respectively).50 Although duodenal T0 No evidence of primary tumor SBAs have a higher incidence of local failure, distant recurrence Tis Carcinoma in situ still predominates (59% versus 19%, respectively, and combined, 22%).94,126,127 Most treatment strategies are based on fluoroura- T1a Tumor invades lamina propria cil (5-FU) or, more recently, 5-FU/oxaliplatin–based regimens. 129 T1b Tumor invades submucosaa Overman et al. reported adjuvant therapy improved disease- free survival (hazard ration [HR], 0.23, 95% CI, 0.06 to 0.89, T2 Tumor invades muscularis propria p = 0.03), but not overall survival (HR, 0.48, 95% CI, 0.13 to T3 Tumor invades through the muscularis propria 1.74, p = 0.26) in patients receiving adjuvant chemotherapy into the subserosa or into the nonperitonealized (5-FU or platinum based).129 Multiple retrospective studies have perimuscular tissue (mesentery or demonstrated a mixed response for adjuvant chemotherapy in retroperitoneum) with extension ≤2 cma SBAs.49,50,128–130 T4 Tumor perforates the visceral peritoneum or The role of hyperthermic intraperitoneal chemotherapy directly invades other organs or structures (HIPEC) in the treatment of SBCs has been investigated in four (includes other loops of small intestine, small trials involving a total of 30 patients with peritoneal carci- mesentery, or retroperitoneum >2 cm, and nomatosis. These patients underwent HIPEC followed by adju- abdominal wall by way of serosa; for duodenum vant chemotherapy, with a reported mean overall survival of 22.2 only, invasion of pancreas or bile duct) months compared to 12 months on conventional treatment strategies. The results are encouraging, but the numbers are too small to Regional Lymph Nodes draw any robust conclusions.140 Nx Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis Treatment for Metastatic Disease N1 Metastasis in 1–3 regional lymph nodes Limited randomized controlled trials defining a role for chemo- N2 Metastases in ≥4 regional lymph nodes therapy versus best supportive care (BSC) in patients with advanced OF ONCOLOGY PRACTICE Distant Metastasis SBAs have been performed. Multiple retrospective studies have demonstrated a small survival advantage for palliative chemotherapy M0 No distant metastasis approaches compared to BSC alone (Table 54.4).49,50,131–136 M1 Distant metastasis Although there are no randomized trials comparing different Anatomic Stage/Prognostic Group regimens, a number of SBA clinical trials are currently accruing in an effort to more precisely define the role of chemotherapy in Stage T N M advanced SBA. The role of surgery for all advanced/metastatic 0 Tis N0 M0 SBC is purely palliative. Specific patients might benefit from an IT1N0M0intestinal bypass to maintain an enteral means of nutrition and an improved quality of life.120,137–139 T2 N0 M0 IIA T3 N0 M0 IIB T4 N0 M0 CARCINOID TUMORS IIIA Any T N1 M0 Carcinoid tumors are slow growing neoplasms that arise from the IIIB Any T N2 M0 neuroendocrine cells of Kulchitsky. Of these cells, 75% occur in the gastrointestinal tract (44.7% in the small bowel and 19.6% in IV Any T Any N Any M the rectum), followed by the lung, bronchus, and rarely the liver, a The nonperitonealized perimuscular tissue is, for the jejunum and ileum, pancreas, or gonads. Given the fourfold increase in the incidence part of the mesentery. For the duodenum in areas where serosa is lacking, it of carcinoids that has occurred over the past 2 decades, carcinoids is part of the interface with the pancreas. are now the most common SBC (36.9%) according to the National Used with the permission of the American Joint Committee on Cancer Cancer Database.167,168 (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springerlink.com, page 129. Clinical Presentation and Prognosis

Of small bowel carcinoids, 44.7% occur in the small bowel, 168 Surgery for Local–Regional Disease and over 50% of these are found in the ileum. Carcinoid tumors are most common in the 7th decade of life (mean age, Surgery is the treatment for local–regional confined SBAs.50 The 66 years), in males (52.4%), and in Caucasians (80.4%). Most 5-year survival of resected versus unresected patients is 54% versus carcinoids present in an advanced stage (75%) as a result of 0%.122 The optimal surgical treatment depends on the location of a significant delay and difficulty in diagnosis. Despite the ad- the primary tumor, with duodenal adenocarcinomas managed by vanced stage, most carcinoids follow an indolent course, with either a pancreaticoduodenectomy or segmental resection. Both an overall 5-year survival ranging from 52% to 77%.170–174 Tu- procedures are equivalent with regard to long-term survival, with mors over 10 mm and those with a transmural depth of invasion segmental resection associated with less postoperative morbidity and are the primary risk factors for local–regional progression and length of hospitalization.122–125 Jejunal and ileal adenocarcinomas metastasis.175 740 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 54.4 Current Clinical Trials for Advanced Small Bowel Adenocarcinoma

Identifier Phase Tumor Type N Therapy Line Agent NCT00354887 II Small bowel adenocarcinoma and ampullary 30 1st CAPOX + bevacizumab NCT00433550 II Small bowel adenocarcinoma 33 1st CAPOX + irinotecan NCT01202409 II Small bowel adenocarcinoma and ampullary 20 1st CAPOX + panitumumab (KRAS wild type) NCT00987766 1b Duodenal + ampullary 22 1st GEMOX + erlotinib NCT01730586 II Small bowel adenocarcinoma 10 >2nd Nab-paclitaxel

CAPOX, capecitabine + oxaliplatin, GEMOX, gemcitabine + oxaliplatin, Nab-paclitaxel, nano-article albumin-bound paclitaxel. Adapted from Raghav K, Overman MJ. Small bowel adenocarcinoma—existing evidence and evolving paradigms. Nat Rev Clin Oncol 2013;10:534–544.

Carcinoid Syndrome retrospective series have demonstrated that surgical resection is superior to systemic therapy with regard to both overall survival and Carcinoid syndrome is an array of symptoms that occurs in pa- symptom management.184 tients with carcinoid tumors of the bronchus or metastatic to the liver. Symptoms of carcinoid syndrome include diarrhea, cuta- Hepatic Artery Embolization neous flushing, and wheezing. These symptoms are precipitated Transcatheter hepatic arterial embolization (HAE) with or with- by stress, alcohol intake, and certain physical activities, and are out chemotherapy has been utilized extensively for both symptom secondary to the systemic release of several tumor-derived factors, control and as a definitive treatment for unresectable carcinoid including serotonin, dopamine, tachykinins, histamine, and pros- liver metastasis.185 HAE may be performed with gel foam, poly- taglandins, all of which are metabolized by the liver. Up to 80% of vinyl alcohol, or microspheres. The addition of chemotherapy al- patients with small bowel carcinoids develop carcinoid syndrome, lows for the delivery of much higher intratumoral concentrations and it is the presenting complaint in 10% to 17% of patients. The than can be achieved with systemic therapy. Known complications mainstay of treatment for carcinoid syndrome is somatostatin, include transient or fulminant liver failure, liver abscesses, and which prevents the secretion of hormones by binding to a specific postembolization syndrome (fever, abdominal pain, leukocytosis, receptor on the tumor surface.192,193 Although octreotide is effec- elevations in liver function tests).185 tive in most patients, interferon α (IFN-α) may benefit patients 187 who do not respond to octreotide alone. The antihistamine cy- Systemic Chemotherapy proheptadine has also been used successfully for refractory carcinoid symptoms.188 Several chemotherapeutics have been studied extensively in the management of carcinoid metastases, including 5-FU, streptozoto- Management cin, and doxorubicin. All have yielded modest response rates of ~20%. In addition, IFN-α has been purported to achieve tumor stabilization in 20% to 40% of cases, and octreotide has been shown Surgery for Local–Regional Disease to prevent the progression of metastatic carcinoids in several small An oncologic segmental resection of the tumor is the preferred case series.186–190 Tyrosine–kinase inhibitors like imatinib or suni- treatment for localized small bowel carcinoids.176 Five-year sur- tinib can induce a delay in tumor cell growth in preclinical studies vival after resection of localized disease ranges between 50% and and disease stability in 83% of patients treated over a 1-year period. 85%. Of small bowel carcinoids, 29% are associated with other In a recent phase II study, bevacizumab, a monoclonal antibody noncarcinoid neoplasms, necessitating a thorough inspection of that targets vascular endothelial growth factor (VEGF), was shown the entire bowel at surgery. Appendiceal carcinoids smaller than 2 to stabilize disease in 95% of patients when combined with octreo- cm can be treated with a simple appendectomy, whereas larger tu- tide compared to 68% stabilization when octreotide was combined mors require a right hemicolectomy. Pretreatment with octreotide with IFN-α.191,218,219 prior to anesthetic induction is recommended because surgical intervention/manipulation can precipitate a carcinoid crisis.177–180 Palliative Surgery Surgery for Metastatic Disease The decision to perform palliative resection for disseminated carcinoid tumors should carefully balance the surgical risks and The liver is the most common site of carcinoid metastasis. Liver perceived patient benefits. Orthotopic liver transplantation for pa- resection along with primary tumor resection is recommended for tients with unresectable liver-only disease remains investigational resectable metastatic disease. More radical surgical debulking or and is currently performed by only a small number of transplant cytoreductive surgery has been used for patients with extensive bi- centers. lobar liver disease, liver failure, or extensive metastatic disease to provide prolonged disease-free survival. Several studies have shown that liver resection can improve the 5-year survival rate from 36% SMALL BOWEL LYMPHOMA to 61% compared to historic controls.181–183 Although long-term data are lacking, percutaneous or laparoscopic local ablative Lymphoma is the third most common SBC, comprising 10% to techniques such as radiofrequency, microwave, or cryoablation 20% of cases. Of such cases, 20% to 40% are extranodal lympho- represent alternative cytoreductive modalities for the treatment mas, which arise within a solid organ, and ~50% of extranodal of metastatic carcinoid tumors. Cytoreductive strategies not only lymphomas are GI lymphomas.194–198 Of GI lymphomas, 75% are prolong survival, but are also associated with a decrease in octreo- located in the stomach, followed by the small bowel, colon, and tide doses required to control carcinoid symptoms. A number of other organs such as the pancreas and the liver. GI lymphomas

tahir99 - UnitedVRG Chapter 54 Cancer of the Small Bowel 741 have a peak incidence in the 7th decade of life, with a male to cyte. Tumor cells are CD19, CD20, CD22, and CD79a positive. female ratio of 1.5:1. The incidence of small bowel lymphomas Bcl-2 gene mutation is present in approximately 30% of the cases. has increased in the United States over the last 2 decades, correlat- Immunosuppression is an important risk factor for DLBCL. Sur- ing with an increase in lymphomas among immunocompromised gery is the mainstay of treatment for localized disease, followed by patients. Increased immigration from the Middle East—where pri- adjuvant radiation or chemotherapy.195 Overall 5-year survival is mary intestinal lymphoma constitutes the most common primary between 50% and 70% with multimodality therapy.196 extranodal disease—may also account for some of the increase in small bowel lymphomas. Additional risk factors include Crohn dis- Burkitt Lymphoma ease and prior radiation exposure. Burkitt lymphoma of the small bowel accounts for <5% of all small bowel lymphomas. It can occur endemically or sporadically Staging and Prognosis and is highly aggressive. The endemic subtype is seen predominantly in Central Africa; it affects children with a peak incidence The most important prognostic indicator for intestinal lymphoma at 8 years of age, is associated with Epstein-Barr virus (EBV) in- is tumor spread. Most GI lymphomas are of the non-Hodgkin type fection, and involves the GI tract in only 20% to 30% of cases. and are staged based on the Ann Arbor staging system: stage I dis- Conversely, sporadic Burkitt lymphoma occurs more commonly ease is limited to a single site; stage II tumors are confined to below in Westernized countries, affects a broader age group, is not as- the diaphragm and are separated into two subgroups, namely those sociated with EBV infections and commonly affects the GI tract with regional (stage II 1E) and distant (stage II 2E) lymph node (ileocecal region). Clinically, they can mimic appendicitis by pre- involvement; stage III has involvement of organs on both sides of senting as large masses. Microscopically, cells are monomorphic the diaphragm; and stage IV represents widespread dissemination, medium-sized cells with round nuclei and an abundant basophilic including the liver and the spleen. Primary intestinal lymphomas cytoplasm. It is a rapidly growing tumor with short doubling time; can be differentiated from secondary lymphomas by the absence the high rate of proliferation gives it a starry sky pattern due to the of superficial and mediastinal lymphadenopathies on work-up, if numerous macrophages that have ingested apoptotic tumor cells. there is no evidence of disease on both peripheral blood smears Treatment primarily consists of chemotherapy, usually vincristine, and bone marrow biopsies, if the disease is localized to a specific cyclophosphamide, doxorubicin, and methotrexate.197 small bowel segment and regional draining mesenteric lymph nodes only, and if there is no evidence of hepatic or splenic in- Mantle Cell Lymphoma volvement (except via direct extension from the primary tumor). Mantle cell lymphoma (MCL) is a rare primary GI lymphoma that follows either an indolent or very aggressive course. MCL Variants commonly affects men (ratio, 4:1) in their 6th or 7th decades of life and has a predilection for the small bowel and colon. Macro- PRACTICE OF ONCOLOGY PRACTICE Mucosal-Associated Lymphoid Tissue Lymphoma scopically, MCLs appear as multiple, whitish polypoid lesions that share morphologic features with nodal lymphomas. CD5+ B cells Marginal zone B-cell lymphomas (MALT) are the most common are located within the mantle zone that surrounds the germinal primary gastrointestinal lymphomas. They occur more commonly centers. Four histologic subtypes have been described: nodular, in the stomach, followed by the small bowel (most commonly, the diffuse, mantle zone, and blastic. The blastic type has the worst ileocecal region), the colon, and the esophagus. MALTs occur pre- prognosis, whereas the nodular and diffuse types have the best dominately in men and peak in the 6th decade of life. They present prognosis. MCLs have been associated with t(11:14) (q13; q32) as unifocal, ulcerated overhanging lesions, characterized by cellular chromosomal translocation, causing overexpression of cyclin D1. heterogeneity and bearing close resemblance to normal gut-asso- The vast majority of MCLs present in stage IV disease. ciated lymphoid tissue (Peyer patch and mesenteric nodal tissue). Nonneoplastic reactive lymphoid follicles surrounded by centro- T-Cell Lymphoma cytes are characteristic, with the neoplastic focus occupying the marginal zone or intrafollicular region. These tumor cells express T-cell lymphomas (TCL) of the small bowel are less common than elevated levels of immunoglobulin (Ig)M and B-cell–associated an- their B-cell counterparts, accounting for approximately 15% of all tigens (including CD19, CD20, CD22, and CD79a). Most tumors small bowel lymphomas. TCLs affect men and women equally and are CD5, CD10, and CD23 negative and CD43 variable. MALT most commonly arise in the jejunum or the proximal ileum. TCLs lymphomas are not associated with Bcl-2 or Bcl-1 rearrangements. may remain localized; however, dissemination is common. They typ- MALT lymphomas may be associated with chronic inflamma- ically present as large circumferential ulcers, in the absence of large tory conditions, including autoimmune disorders such as Sjögren masses, with associated mesenteric lymphadenopathy. As with other syndrome and Hashimoto thyroiditis. The majority of patients types of lymphomas, obstruction and perforation are common pre- present with stage I or II disease. Therapy is multimodal and in- sentations. Microscopically, transmural replacement of the intestinal cludes surgical resection and/or chemoradiation therapy, with wall by highly pleomorphic lymphoid cells may be seen. A large num- small bowel lymphomas having a better prognosis than gastric tuber of surrounding intraepithelial lymphocytes may also show cellular mors. Some studies suggest that MALT tumors may be antigen atypia. Tumor cells stain positive for CD3, CD7, CD8, and CD103 driven, especially by Campylobacter jejuni and Helicobacter pylori. and negative for CD4. Small bowel TCLs are known as EATLs due Regression has been reported with eradication of H. pylori infec- to their association with long-standing enteropathies, primarily celiac tion using antibiotics.194 disease. EATL is described in approximately 5% to 10% of all patients with celiac disease, and the relative risk of developing a lymphoma in Diffuse Large B-Cell Lymphoma this setting is 25- to 100-fold higher than normal patients. Prognosis is generally poor, with a 5-year survival rate of 10%.198 The second most common small bowel lymphoma is diffuse large B-cell lymphoma (DLBCL), also known as large cell immuno- blastic, large-cleaved follicular center cell, centroblastic D immu- GASTROINTESTINAL STROMAL TUMORS noblastic cell, or diffuse mixed lymphocytic and histiocytic cell. DLBCL occurs more frequently in men, with a median age of 54 GIST tumors arise from the intestinal cells of Cajal and are char- to 61 years, and primarily involves the ileocecal region. DLBCLs acterized by the presence of a gain-of-function c-kit (CD117) present as unifocal ulcerated lesions, composed of diffuse large B mutation. The c-kit protein codes for a tyrosine–kinase receptor cells with large nuclei that are twice the size of a normal lympho- involved in cellular proliferation, apoptosis, and differentiation. 742 Practice of Oncology / Cancers of the Gastrointestinal Tract

Epidemiology and Genetics compared to a 5-year overall survival rate of 35% for historic controls. Progression-free survival for 1, 3, and 5 years was 96%, 60%, GISTS are the most common mesenchymal tumor of the small and 40%, respectively.214 bowel, despite comprising only 0.5% to 1% of all GI tumors. There In patients in whom the initial complete surgical resection is are between 4,500 to 6,000 GISTs per year in the United States, not possible, the use of imatinib therapy has resulted in a signif- with the stomach being the most common site.199–204 Incidence icant prolongation of survival, with 80% of patients achieving a rates are equal in both genders and peak between 50 and 60 years 5-year overall survival versus 9 months’ survival with no therapy.215 of age. Small bowel GISTs are most commonly found in the je- Neoadjuvant imatinib is also effective at reducing large tumor junum, followed by the ileum, and the duodenum and typically burdens and may facilitate margin-negative, organ-sparing resec- present with pain, intussusception, or bleeding. Approximately tions.216,217 Regorafenib is another novel multitargeted kinase in- 80% to 90% of all GIST tumors contain a c-kit mutation (CD117), hibitor being used in GIST management that inhibits the Ras/Raf/ whereas the remainder have a mutation in another tyrosine–kinase Mek pathways as well as VEGF receptor 2 (VEGFR2) signaling.219 receptor gene or platelet-derived growth factor (PDGF) receptor alpha. It is now recognized that a vast majority of tumors previously identified as leiomyomas and leiomyosarcomas were actually OTHER MESENCHYMAL TUMORS CD117+ GIST. The molecular discoveries have allowed for the development of the specific c-kit tyrosine–kinase inhibitor ima- Leiomyomas and Leiomyosarcomas tinib (Gleevec), a drug initially designed to treat chronic myelog- enous leukemia. Small bowel leiomyomas and leiomyosarcomas arise from the muscularis propria and muscularis mucosa. They have a varied Prognosis and Behavior presentation, primarily involving tumor ulceration and bleeding as the tumor enlarges. Because tumor growth is initially localized All GISTs have the potential for malignancy, and approximately and primarily extraluminal, obstruction does not occur until very 50% of resected patients will have disease recurrence within late in the disease course.223 Leiomyosarcomas stain positive for 5 years. Of GISTs, 30% to 50% are clinically malignant. Most desmin and actin and are negative for CD117 (c-kit and CD34). GISTs have a c-kit gain-of-function mutation, allowing for the pre- Metastasis is via hematologic routes and is mainly to the liver and diction of clinical behavior and recurrence risk stratification.205–208 peritoneum. About one third of patients have metastasis at the Tumors larger than 2 cm have a higher risk of recurrence and me- time of diagnosis, and prognosis is very poor.228–231 tastasis. This risk increases significantly for tumors larger than 3 cm to 5 cm. The mitotic rate has also been studied, and GISTs Desmoid Tumors with five or more mitoses per 50 high-powered field (HPF) have a worse prognosis, whereas mitotic rates higher than 10 per 50 HPF Frequently confused with GISTs, these spindle cell tumors origi- predicts high recurrence and metastatic rates regardless of tumor nate from musculoaponeurotic structures throughout the body size or location, with 5-year survival rates ~25%. The tumor site and are histologically defined by fibroblastic proliferation and the also plays an important role in prognosis, with jejunal and ileal formation of bundles of spindle cells around blood vessels in a GISTs displaying more malignant behavior compared to duode- dense hypocellular fibrous stroma. Desmoids occur with higher fre- nal, rectal, or gastric GISTs. quency in patients with FAP and Gardner syndrome.234 Few mitotic figures are seen, and necrosis is usually absent. Desmoids stain for Management vimentin, smooth muscle actin, and nuclear beta catenin. Although desmoids tumors are benign with no potential for metastasis, they Surgery tend to be locally aggressive and recur even after complete resection.238 Treatment is surgical resection with a wide margin to ensure R0 surgical resection is the mainstay therapy for all GISTs. Ex- negative microscopic margins; however, this may be difficult due tensive resection of the surrounding uninvolved tissue has not to the anatomic location and the involvement of vital structures. been shown to improve outcomes. A routine lymphadenectomy Other treatment modalities include chemotherapy (methotrexate is not indicated because GISTs rarely metastasize to regional and vinblastine, doxorubicin), radiation therapy, nonsteroidal anti- lymph nodes. Intraoperative tumor rupture and spillage has been inflammatory agents, and antiestrogens (tamoxifen).235–237 linked to carcinomatosis, necessitating a meticulous surgical technique. The peritoneum and liver are the main sites of metastasis and recurrence, and both should be inspected during surgical Inflammatory Fibroid Polyps exploration.209–212 These benign lesions are uncommonly seen in the small bowel. Adjuvant Therapy They are typically submucosal and consist of a mixture of small granulation tissue–like vessels, spindle cells, and inflammatory Adjuvant imatinib therapy improves recurrence-free survival after cells. They can stain positively for CD34; however, they do not complete surgical resection of localized disease. The ACOSOG stain for CD117 with the exception of very small areas of stroma Z9001 trial was a randomized phase III double-blinded, placebo- within these tumors.232,233 controlled multicenter trial where 713 patients were assigned to receive either 400 mg of imatinib or placebo daily for 1 year after complete resection of a c-kit–positive, 3 cm (or more) GIST. One- Schwannomas year progression-free survival was 98% in the imatinib arm and 83% in the placebo arm.213 Although relatively rare in the small bowel, schwannomas of the GI Similar results were found in the Z9000 trial, a phase II, in- tract are often found in the stomach, colon, and esophagus. They tergroup trial led by the American College of Surgeons Oncol- are benign lesions, and present as rubbery yellowish trabeculated tu- ogy Group, in which 106 patients who had undergone complete mors characterized by lymph node aggregates around their periph- surgical resection of GIST were prescribed imatinib 400 mg per ery with nuclear palisading Verocay bodies and hyalinized vessels day for 1 year followed by serial radiologic evaluation. At 7.7 years similar to schwannomas found elsewhere in the body. Schwanno- of follow-up, the patients receiving imatinib had 1-, 3-, and mas stain strongly for S100 and glial fibrillary acidic protein, but are 5-year overall survival rates of 99%, 97%, and 83%, respectively, CD117, CD 34, and smooth muscle actin negative.224,225

tahir99 - UnitedVRG Chapter 54 Cancer of the Small Bowel 743

Inflammatory and Myofibroblastic Tumors melanomas of the intestine are extremely rare, with few case reports found in the literature.239 Inflammatory mesenchymal tumors typically present as solid white Clinically, small bowel metastases can present with obstruction, masses with infiltrative margins. Although their precise etiology is perforation, intussusception, malabsorption, and/or GI bleeding. uncertain, several authors have suggested that they are benign re- Obstruction is commonly seen in association with metastatic lobu- actions to infectious processes, although local recurrence has been lar breast carcinoma. A wide array of nonspecific symptoms may reported. These tumors rarely behave in a malignant fashion and also be present, including abdominal discomfort, distension, and are histologically composed of spindle cells admixed with lym- diarrhea. Typical features of intestinal metastases include intestinal phocytes and plasma cells. Unlike GIST, they stain negatively for wall thickening, submucosal spread, and ulcers. Melanomas and CD117 and CD 34, but positive for desmin, muscle-specific actin, sarcomas may appear as nodules or polyps. Metastases are typically and cytokeratin.226,227 located deep within the submucosa or the muscularis propria of the small bowel, with little involvement of the mucosa.221–223 Intestinal metastases usually represent at a late stage of the dis- METASTATIC CANCER TO THE SMALL ease, during which other sites of hematogenous metastases are also BOWEL frequently found. However, the prognosis for patients with small bowel metastasis varies widely according to the primary tumor type Metastatic tumors to the small intestine are 2.5 times more com- and patient-specific factors. Metastatic melanomas or renal carci- mon than are primary SBCs. Metastatic spread to the small intes- nomas with isolated metastasis to the small bowel may be associ- tine from distant primary sites is more frequent than to any other ated with prolonged survival after resection. Other more common site in the GI tract. The main routes by which secondary neo- primary tumors that metastasize to the small bowel are uterus, cer- plasms reach the small bowel is primary dependent and includes vix, colon, lung, and breast tumors. direct extension (for colonic, pancreatic, and gastric cancers), intraperitoneal spread (ovarian cancer), and lympho- or hematog- Management enous embolization (melanoma, and lung and breast cancers). The management of small bowel metastatic disease is defined Epidemiology by the primary tumor of origin. Isolated small bowel metastasis warrants segmental resection to prevent bowel obstruction, to Melanoma is the most common cancer to metastasize to the maintain nutrition, or as part of a debulking procedure (e.g., ovar- small bowel, with up to 4.4% of all melanoma patients demon- ian, appendiceal). Most often, systemic therapy is the modality of strating small bowel metastases. Malignant melanoma is the pri- choice for advanced/diffuse small bowel involvement. A diffuse mary tumor in 50% to 70% of all small bowel metastases, with the disease may rarely warrant debulking or treatment with HIPEC on terminal ileum being the most often affected site.220–223 Primary established protocols. OF ONCOLOGY PRACTICE

SELECTED REFERENCES

The full reference list can be accessed at lwwhealthlibrary.com/oncology. 61. Gore RM, Mehta UK, Newmark GM, et al. Diagnosis and staging of small bowel tumours. Cancer Imaging 2006;6:209–212. 2. Siegel R, Ma J, Zou Z, et al. Cancer statistics, 2014. CA Cancer J Clin 63. Levy AD, Remotti HE, Thompson WM, et al. Gastrointestinal stromal tumors: 2014;64:9–29. radiologic features with pathologic correlation. Radiographics 2003;23:283–304. 8. Chow JS, Chen CC, Ahsan H, et al. A population-based study of the inci- 69. Van Weyenberg SJ, Van Waesberghe JH, Ell C, et al. Enteroscopy and its dence of malignant small bowel tumours: SEER, 1973-1990. Int J Epidemiol relationship to radiological small bowel imaging. Gastrointest Endosc Clin N 1996;25:722–728. Am 2009;19:389–407. 9. Neugut AI, Santos J. The association between cancers of the small and large 74. Cronin CG, Scott J, McDermott, et al. Utility of PET/CT in the evaluation bowel. Cancer Epidemiol Biomarkers Prev 1993;2:551–553. of small bowel pathology. Br J Radiol 2012;85:1211–1221. 10. Scelo G, Anderson A et al. Associations between small intestine cancer and 76. Kita H, Yamamoto H, Yano T, et al. Double balloon endoscopy in two hun- other primary cancers: An international population-based study. Int J Cancer dred fifty cases for the diagnosis and treatment of small intestinal disorders. 2006;118:189–196. Inflammopharmacology 2007;15:74–77. 11. Schiessling S, Kihm M, Ganschow P, et al. Desmoid tumour biology 94. Bilimoria KY, Bentrem DJ, Wayne DJ, et al. Small bowel cancer in United in patients with familial adenomatous polyposis coli. Br J Surg 2013;100: States: changes in epidemiology, treatment and survival over the last 20 years. 694–703. Ann Surg 2009;249:63–71. 27. Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum 97. Pan SY, Morrison H. Epidemiology of cancer of the small intestine. World J of cancers in the Peutz-Jeghers syndrome. Clin Cancer Res 2006;12: Gastrointest Oncol 2011;3:33–42. 3209–3215. 98. Raghav K, Overman MJ. Small bowel adenocarcinomas-existing evidence 29. Yamaguchi S, Ogata H, Katsumata D, et al. MUTYH-associated colorectal and evolving paradigms. Nat Rev Clin Oncol 2013;10:534–544. cancer and adenomatous polyposis. Surg Today 2014;44:593–600. 102. Overman MJ, Hu CY, Kopetz S, et al. A population-based comparison of 31. Maisonneuve P, Marshall BC, Knapp EA, et al. Cancer risk in cystic fibro- adenocarcinoma of large and small intestine: insights into a rare disease. Ann sis: a 20-year nationwide study from the United States. J Natl Cancer Inst Surg Oncol 2012;19:1439–1445. 2013;105:122–129. 106. Lee HJ, Lee OJ, Jang KT, et al. Combined loss of E-cadherin and aberrant 38. Hemminki K, Li X, Sundquist J, et al. Cancer risks in ulcerative colitis β-catenin protein expression correlates with poor prognosis for small intesti- patients. Int J Cancer 2008;123:1417–1421. nal adenocarcinomas. Am J Clin Pathol 2013;139:167–176. 46. Boffetta P, Hazelton WD, Chen Y, et al. Body mass, tobacco smoking, al- 111. Bläker H, Aulmann S, Helmchen B, et al. Loss of SMAD4 function in small cohol drinking and risk of cancer of the small intestine—a pooled analy- intestinal adenocarcinoma: comparison of genetic and immunohistochemi- sis of over 500,000 subjects in the Asia Cohort Consortium. Ann Oncol cal findings. Pathol Res Pract 2004;200:1–7. 2012;23:1894–1898. 118. Fu T, Pappou EP, Guzzetta AA, et al. CpG island methylator phenotype- 47. Neugut AI, Jacobson JS, Suh S, et al. The epidemiology of cancer of the positive tumours in the absence of MLH1 methylation constitute a distinct small bowel. Cancer Epidemiol Biomarkers Prev 1998;7:243–251. subset of duodenal adenocarcinomas and are associated with poor prognosis. 49. Halfdanarson TR, McWilliams RR, Donohue JH, et al. A single-institution Clin Cancer Res 2012;18:4743–4752. experience with 491 cases of small bowel adenocarcinoma. Am J Surg 2010; 120. Howe JR, Karnell LH, Menck HR, et al. American College of Surgeons 199:797–803. Commission on Cancer and the American Cancer Society. Adenocarcinoma 50. Dabaja BS, Suki D, Pro B, et al. Adenocarcinoma of the small bowel: of the small bowel: review of national cancer database 1985-1995. Cancer presentation, prognostic factors, and outcome of 217 patients. Cancer 1999;86:2693–2706. 2004;101:518–526. 130. Kelsey CR, Nelson JW, Willett CG, et al. Duodenal adenocarcinoma: pat- 54. Negri E, Bosetti C, Vecchia C, et al. Risk factors for adenocarcinoma of the terns of failure after resection and the role of chemoradiotherapy. Int J Radiat small intestine. Int J Cancer 1999;82:171–174. Oncol Biol Phys 2007;69:1436–1441. 744 Practice of Oncology / Cancers of the Gastrointestinal Tract

132. Koo DH, Yun SC, Hong YS, et al. Systemic chemotherapy for treatment of 198. Al-Toma A, Verbeek WH, Hadithi M, et al. Survival in refractory coeliac dis- advanced small bowel adenocarcinoma with prognostic factor analysis: retro- ease and enteropathy associated T cell lymphoma: retrospective evaluation of spective study. BMC Cancer 2011;11:205. single centre experience. Gut 2007;56:1373–1378. 136. Zaanan A, Gauthier M, Malka D, et al. Second-line chemotherapy with fluo- 212. Nguyen SQ, Divino CM, Wang JL, et al. Laparoscopic management of rouracil, leucovorin, and irinotecan (FOLFIRI regimen) in patients with ad- gastrointestinal stromal tumors. Surg Endosc 2006;20:713–716. vanced small bowel adenocarcinoma after failure of first-line platinum-based 213. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesy- chemotherapy: a multicentre AGEO study. Cancer 2011;117:1422–1428. late after resection of localised, primary gastrointestinal stromal tumour: 168. Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715 carcinoid tu- a randomised, double-blind, placebo-controlled trial. Lancet 2009;373: mors. Cancer 2003;97:934–959. 1097–1104. 169. Maggard MA, O’Connell JB, Ko CY. Updated population-based review of 214. DeMatteo RP, Ballman KV, Antonescu CR, et al. Long-term results of adju- carcinoid tumors. Ann Surg 2004;240:117–122. vant imatinib mesylate in localized, high-risk, primary gastrointestinal stro- 174. Soga J. Early-stage carcinoids of the gastrointestinal tract: an analysis of 1914 mal tumor: ACOSOG Z9000 (Alliance) Intergroup phase 2 trial. Ann Surg reported cases. Cancer 2005;103:1587–1595. 2013;258:422–429. 184. Osborne DA, Zervos EE, Strosberg J, et al. Improved outcome with cytore- 218. Yao JC, Shah MH, Ito T, et al. Everolimus for advanced pancreatic neuroen- duction versus embolization for symptomatic hepatic metastases of carcinoid docrine tumors. N Engl J Med 2011;364:514–523. and neuroendocrine tumors. Ann Surg Oncol 2006;13:572–581. 219. Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of 185. Gupta S, Yao JC, Ahrar K, et al. Hepatic artery embolization and chemo- pancreatic neuroendocrine tumors. N Engl J Med 2011;364:501–513. embolization for treatment of patients with metastatic carcinoid tumors: the 221. Bender GN, Maglinte DD, McLarney JH, et al. Malignant melanoma: pat- M.D. Anderson experience. Cancer J 2003;9:261–267. terns of metastasis to the small bowel, reliability of imaging studies, and clini- 187. Tiensuu Janson EM, Ahlström H, Andersson T, et al. Octreotide and in- cal relevance. Am J Gastroenterol 2001;96:2392–2400. terferon alfa: a new combination for the treatment of malignant carcinoid 225. Levy AD, Quiles AM, Miettinen M, et al. Gastrointestinal schwannomas: tumours. Eur J Cancer 1992;28:1647–1650. CT features with clinicopathologic correlation. Am J Roentgenol 2005;184: 188. Moertel CG, Kvols LK, Rubin J. A study of cyproheptadine in the treatment 797–802. of metastatic carcinoid tumor and the malignant carcinoid syndrome. Can- 226. Kovach SJ, Fischer AC, Katzman PJ, et al. Inflammatory myofibroblastic tu- cer 1991;67:33–36. mors. J Surg Oncol 2006;94:385–391. 195. Fischbach W, Dragosics B, Kolve-Goebeler ME, et al. Primary gastric B-cell lym- 237. de Camargo VP, Keohan ML, D’Adamo DR, et al. Clinical outcomes of phoma: results of a prospective multicenter study. The German-Austrian Gastro- systemic therapy for patients with deep fibromatosis (desmoid tumor). Cancer intestinal Lymphoma Study Group. Gastroenterology 2000;119:1191–1202. 2010;116:2258–2265. 197. Blum KA, Lozanski G, Byrd JC. Adult Burkitt leukemia and lymphoma. 239. Sachs DL, Lowe L, Chang AE, et al. Do primary small intestinal melanomas Blood 2004;104:3009–3020. exist? Report of a case. J Am Acad Dermatol 1999;41:1042–1044.

tahir99 - UnitedVRG Gastrointestinal Stromal 55 Tumor

Paolo G. Casali, Angelo Paolo Dei Tos, and Alessandro Gronchi

INTRODUCTION much higher than that of clinical cases, which remains low. Preva- lence is low as well, although roughly half of clinical GISTs are Gastrointestinal stromal tumors (GIST) are mesenchymal neo- cured by surgery, and the median survival of advanced GISTs has plasms of the gastrointestinal tract, whose tumor cell’s normal improved with the use of TKIs and is likely still improving. counterpart is the interstitial cell of Cajal. This serves as a pace- GISTs can occur at any age, with a median occurrence at 60 maker of gastrointestinal motility, providing an interface between to 65 years. A small minority of GISTs affect children and adoles- autonomic nerve stimulation and the muscle layer of the gastro- cents: most of them are WT for KIT and PDGFRA and may take intestinal wall.1 GISTs are rare cancers, which were defined as a place within selected syndromes. In general, GISTs are slightly distinct disease in the 1990s, having been classified within smooth more incident in males than females. Succinate dehydrogenase muscle neoplasms for decades from their first description in the (SDH)-deficient WT GISTs typically occur in young females. 1960s.2,3 Coincidentally, in 2000, they became targetable by new No specific causes are known, although the pathogenesis of tyrosine-kinase inhibitors (TKI), given the role played by KIT and KIT- and PDGFRA-mutated GISTs has been elucidated in es- platelet-derived growth factor receptor alpha (PDGFRA) in their sence. There are some predisposing conditions for WT GISTs, pathogenesis.4–7 As of today, GISTs serve as an advanced model which include the Carney triad (marked by GIST, pulmonary displaying both potentials and limits of currently available molecu- chondromas, and extra-adrenal paragangliomas), the hereditary larly targeted agents in medical oncology of solid cancers. Carney-Stratakis syndrome (marked by GIST and familial para- From the clinical point of view, surgery is the mainstay treat- gangliomas), and type 1 neurofibromatosis (NF-1).13–15 Hereditary ment when GISTs are localized, and adjuvant therapy is used de- syndromes driven by germ-line mutations to KIT or PDGFRA are pending on their risk of relapse. Apparently, adjuvant therapy with very rare but well recognized.16,17 OF ONCOLOGY PRACTICE TKIs is mainly able to delay relapse, if due to occur, rather than to avoid it. In the advanced disease, TKIs have substantially improved the prognosis of KIT-mutated GISTs and have become standard ANATOMY AND PATHOLOGY treatment. They face the major limiting factor of secondary resistance, which affects most patients and is marked by genetic het- More than half of GIST cases arise from the stomach, one-fourth erogeneity. A minority of GISTs do not harbor mutations to either from the small bowel, roughly 5% from the rectum, and a small KIT or PDGFRA genes and, therefore, are called wild type (WT). minority from the esophagus.7 Some GISTs have been labeled as They are less amenable to available TKIs, although their natural extragastrointestinal, apparently arising from the mesentery, omen- history tends to be less aggressive. Their variegated nature adds to tum, and retroperitoneum; however, it remains unknown whether the complexity of GISTs as a whole. these are lesions detached from their gastrointestinal origin and/or In brief, GISTs are more complex than initially believed, are metastases from an unknown primary tumor. whereas targeted therapy has substantially improved their progno- Morphologically, GISTs can be made up of spindle cells (in sis but is challenged by its apparent inability to eradicate the disease more than two-thirds of cases), epithelioid cells, or both (Fig. 55.1 (even minimum residual disease), and by the heterogeneity of the A,B).18 Epithelioid-cell GISTs are more common in the stomach secondary resistance it often gives rise to in the advanced setting. and include those that are PDGFRA mutated. Aside from this, Intense translational and clinical research is underway. All this and there are no major clinical implications in the microscopic aspect the rarity of the disease strongly suggest to refer GIST patients to of lesions. Importantly, there are no pathologic clues to make a institutions or networks specializing in their treatment and study. distinction between malignant GISTs and others whose clinical behavior is actually benign. Thus, many GISTs behave as benign diseases as a matter of fact, but this cannot be forecast histologi- INCIDENCE AND ETIOLOGY cally or molecularly. It follows that all GISTs are currently considered malignant neoplasms, although with a highly variable risk GISTs are rare cancers. Their crude incidence is suggested to be of distant relapse, which is negligible in a significant proportion of approximately 1.5 out of 100,000 per year (roughly 5,000 new cases them. This is the reason why risk classification systems are gener- in the United States yearly), with the limitations deriving from the ally used in the clinic as prognosticators, being based today on a fact that only recently were they identified as a clinicopathologic pathologic factor (i.e., the mitotic count) and two clinical variables entity.8,9 However, there are a number of small GISTs that are clini- (tumor size and tumor site).19–24 cally meaningless and generally go undetected. In addition, micro- Immunohistochemically, the hallmark of most GISTs is their scopic GISTs (micro-GIST) might be found incidentally in as many positivity for KIT (CD117) and DOG-1 (Fig. 55.2 A,B).25–27 A low as 10% to 25% of stomachs.10,11 The reasons why the vast majority proportion of GISTs are CD117 negative, which is typical of PDG- do not give rise to clinically overt diseases are not known, especially FRA-mutated GISTs, but immunohistochemical status does not considering the fact that most of them harbor the same mutations to reflect the mutational status with regard to KIT and PDGFRA, per KIT and PDGFRA of fully developed diseases, which implies that se, so that it has no concrete predictive value for sensitivity to TKIs. alterations of these proto-oncogenes are not solely the pathogenetic Thus, CD117 has only a meaning in the pathologic differential drivers of GISTs.12 Thus, the incidence of histologic GISTs may be diagnosis. Given their morphology, GISTs must be differentiated

745 746 Practice of Oncology / Cancers of the Gastrointestinal Tract

A B Figure 55.1 (A) Spindle-cell GIST. (B) Epithelioid-cell GIST. from other soft tissue tumors of the gastrointestinal wall, includ- exon 18 D842V mutation). The latter is known for its wide lack of ing those of smooth muscle and neural origin and desmoid-type sensitivity to available TKIs, along with a few other rare exon 18 fibromatosis, endocrine tumors, melanocytic tumors, lymphomas, mutations, whereas the deletion of codons 842 to 845 is sensitive. etc. Desmin is rarely positive, as opposed to vimentin and CD34. A Possibly because of their similarity with different kinds of normal negative stain for SDHB identifies the subgroup of SDH-deficient interstitial cell of Cajal, some tumor cell mutations correlate with WT GISTs.28,29 elective primary sites of origin. In particular, exon 9 mutations of Molecularly, GIST have become a relatively heterogeneous KIT are preferably found in the small bowel, and PDGFRA muta- and complex group of lesions.30 Gain-of-function mutations of the tions are found in the stomach. oncogenes located on chromosome 4 (4q12) coding for the type Approximately 10% to 15% of GISTs are WT for KIT and III receptor tyrosine kinases KIT and PDGFRA can be found in PDGFRA. They make up a family of tumor subsets with different approximately 80% of GISTs.5,6,31 Pathogenetically, they are the pathogenetic backgrounds and, to some extent, different natural drivers of the disease and, therapeutically, underlie the efficacy of histories (see Fig. 55.3). Their classification is evolving.5,6,31 In es- currently used TKIs. They are mutually exclusive and result in the sence, as of today, one may identify: (1) SDH-deficient GISTs; (2) constitutive activation of either KIT or PDGFRA, which normally neurofibromatosis (NF)-1–related GISTs; or (3) others, including are autoinhibited, being activated by the binding of their respec- those with the BRAF V600E mutation. In fact, half of WT GISTs tive ligands (i.e., stem-cell factor [Steel factor] and platelet-derived are marked by alterations involving the SDH complex, which is growth factor A). The activation of the receptor binds two mol- crucial for the Krebs cycle and mitochondrial respiratory cell func- ecules of KIT or PDGFRA (dimerization), giving rise to down- tion. Immunohistochemically, these GIST are negative to SDHB stream oncogenic signaling, which for both KIT and PDGFRA staining. A group of them includes pediatric GISTs and can be involves the RAS/MAPK and the PI3K/AKT/mammalian target of associated with the Carney triad.13 In fact, these GISTs tend to rapamycin (mTOR) pathways (Fig. 55.3). Mutations can be de- arise in children and young adults of the female sex, are gastric and letions, insertions, and missense mutations. They affect: exon 11 multifocal, can metastasize to lymph nodes, have a rather indolent of the KIT oncogene, encoding for the juxtamembrane domain evolution. When the Carney triad is fully expressed, it includes of the KIT receptor, in slightly less than 70% of GISTs; exon 9 of GISTs, pulmonary chondromas, and paragangliomas. Given the KIT, encoding for the extracellular domain of the receptor, in less absence of mutations to the SDH complex, a posttranscriptional than 10%; exon 13 and 17 of KIT, encoding for the intracellular defect leading to dysfunctions of the SDH complex may be in ATP-binding pocket and activation loop domains, respectively, place. These GISTs are SDHA positive. On the other hand, a in a small minority of GISTs. Approximately 10% of GIST have group of SDH-deficient GISTs carries germ-line mutations of the mutations homologous to these, which affect PDGFRA (i.e., exon SDHA, SDHB, or SDHC units of the SDH complex32,33 and may 12, 14, and 18 of the oncogene, with 70% being represented by the be related to the Carney-Stratakis syndrome.14 This is marked by

A B Figure 55.2 Immunostaining for KIT (CD117) and DOG1.

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KIT or PDGFRA dimer

SDHB SDHA SDHD SDHC

P P NF-1 P P GTP GDP PIP2 Fumarate STAT3 RAS PI3K PTEN PIP3

STAT BRAF RAF1 signalling Cytoplasm AKT MAP2K1/2 Succinate

Transcription MAPK3/1 BAD FRAP1 RPS6KB1 Prolyl hydroxylase

ETV1 mediated Cell Protein synthesis, transcription survival cell growth Cytoplasm HIF1α Nucleus Transcription Transcription PRACTICE OF ONCOLOGY PRACTICE

Angiogenesis VEGF IGF2 HIF1α

Growth signalling

Figure 55.3 Signaling in KIT/PDGFRA-mutated and WT GIST. (From Joensuu H, Hohenberger P, Corless CL. Gastrointestinal stromal tumour. Lancet 2013;382:973–983.)

GIST and paragangliomas. Immunohistochemically, GISTs with Cajal can be found, which may entail altered motility of the gastro- SDHA mutations are negative to SDHA staining. The median intestinal tract. Urticaria pigmentosa and other alterations of skin age of these patients is somewhat higher and the female to male pigmentation may complete the syndrome. predominance is lower, but the course of disease is indolent as It is then clear how important genotyping has become for well. Then, WT SDHB-positive GISTs can occur in the context of GIST patients. In fact, genotyping has an obvious predictive value, NF-1, and their pathogenetic mechanism is supposed to be the ab- which is crucial for all patients who are candidates for medical sence of neurofibromin (i.e., the product of the NF-1 gene), which therapy, whether in the advanced or in the adjuvant setting. In is mutated.34,35 This may lead to increased activity of the RAS path- addition, genotyping has prognostic implications, at least given the way. GISTs related to NF-1 are typically multicentric as well, and peculiar natural history of WT GISTs. Finally, genotyping con- have a rather indolent course, but arise from the small bowel. Of firms the pathologic diagnosis in KIT/PDGFRA-mutated GIST, course, NF-1 may coexist with a non–NF-1-related GISTs. Finally, or leads to further pathologic and molecular assessments in WT the remaining SDHB-positive GISTs are probably a basket of dif- GISTs. Thus, although there are subsets of GISTs with such a ferent conditions: some were reported to have the V600E mutation low risk of relapse as not to make them candidates for any medical of BRAF36,37 or, more rarely, HRAS, NRAS, and PIK3 mutations.5 therapy, a mutational analysis is currently felt as a companion to All this makes the so-called WT GISTs a variegated family of tu- virtually any pathologic diagnosis of GISTs. mors, which can now be identified not only through a negative definition (i.e., by the lack of KIT and PDGFRA mutations), but through immunohistochemical or cytogenetic markers, pointing SCREENING to specific subsets with different natural histories. A very rare subset of familial GISTs does exist, being marked GISTs are rare cancers. Therefore, population-based screening by mutations of KIT or PDGFRA affecting the germ line.16,17 policies are unforeseeable. As for all rare cancers, the clinical They parallel mutations found in sporadic GISTs and lead to the aim should be a timely diagnosis in the individual patient with multicentric and multifocal occurrence of GISTs. The behavior of symptoms and/or signs of disease. A difficulty thereof is the ana- these GISTs is variable (i.e., it is often indolent but some lesions tomical tendency of GIST lesions to grow outwards from the turn out to become aggressive). Hyperplasia of interstitial cells of gastrointestinal wall, so that they may go undetected for long 748 Practice of Oncology / Cancers of the Gastrointestinal Tract

A B Figure 55.4 GIST growing outward of the gastric wall.

periods even when endoscopically explored. However, endoscopic to the gastrointestinal wall is clear, the possibility of a GIST may procedures carried out for other reasons may lead to some risk of be obvious, with a differential diagnosis mainly against epithelial overdiagnosis, even in such a rare disease, when small gastric le- tumors, small bowel endocrine tumors, lymphomas, paraganglio- sions are incidentally detected. Some of them will be benign enti- mas, etc. Otherwise, retroperitoneal sarcomas and desmoid-type ties, and others will be GISTs unlikely to ever grow as to become fibromatosis, germ cell tumors, and lymphomas are the main alter- clinically relevant. Only a minority of them will turn out to be natives. Notably, when this is the clinical presentation, surgery is of clinically aggressive GISTs caught in their making. choice only for some of the possible alternatives within the clinical differential diagnosis. In addition, preoperative treatments may be resorted to even in some of the surgical indications. On top of this, DIAGNOSIS an intraoperative pathologic differential diagnosis is prohibitive. In principle, therefore, a diagnostic core needle biopsy is suggested The outward growth of many GISTs (Fig. 55.4) within the gastroin- by many, allowing pathologic diagnosis and, in the case of GIST, testinal wall is one of the reasons why several are diagnosed relatively a mutational analysis, prior to any surgical exploration. In the case late, either as major abdominal masses or as causes of gastrointestinal of gastric or rectal lesions, a biopsy can be carried out by means bleeding, hemoperitoneum, perforations (Fig. 55.5). Therefore, of endoscopic ultrasound, although, for gastric tumors, the risk of as many as one-fourth of GISTs are diagnosed in a clinical emer- perforation should be factored in depending on the presentation. gency, often leading to surgical explorations resulting in the unex- A CT/ultrasound-guided percutaneous biopsy is the other option, pected finding of the disease. One-fourth of GISTs are discovered apparently with a negligible risk of dissemination if done at a center incidentally during diagnostic assessments (whether an endoscopic of expertise, again factoring in the clinical presentation.38 There procedure, ultrasound, or computed tomography [CT] scan) done may remain some cases in which the difficulty of an endoscopic for other reasons. The remaining are diagnosed because of symp- or percutaneous biopsy and the easiness of a surgical exploration toms of compression from an abdominal mass, or chronic anemia, would suggest the latter. In general, however, a biopsy prior to fatigue, and the like. Therefore, GISTs should be included in the any therapeutic planning can minimize the number of abdominal differential diagnosis of abdominal masses. When their pertinence masses undergoing futile surgery.

A B Figure 55.5 Duodenal GIST with an intratumoral perforation.

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Follow-ups after potentially eradicating surgery is aimed at pick- Current risk classification systems are based on the combination ing up relapses at an early stage. Local relapses are infrequent and of mitotic count, tumor size, and site of origin. Indeed, the mitotic tend to develop outwards from the gastrointestinal wall: therefore, an count is the main prognostic factor, proportionally correlating to endoscopy is generally not used as a routine follow-up procedure. A the risk of relapse. Its downside has turned out to be its possibly low CT scan is the most sensitive exam to pick up peritoneal and liver reproducibility rate, but clearly this can be higher if the patholo- metastases and is recommended. It can be replaced by magnetic gist is aware of its importance in driving treatment choices. Tumor resonance imaging (MRI), while ultrasound is much less sensitive size is the next prognostic factor. On one side, it singles out very on the peritoneum. The maximum risk interval averages 2 to 3 years small gastric lesions (<2 cm), which may undergo watchful sur- after surgery or, if an adjuvant therapy was done, after its comple- veillance if incidentally discovered endoscopically. On the other, it tion. Long-term relapses are unlikely, although they are occasionally highlights lesions in excess of 5 to 10 cm, which have a worse prog- observed, especially in GISTs with a low mitotic rates. All this helps nosis. With regard to the primary site, gastric lesions have a better drive rational follow-up policies for potentially cured patients, though prognosis than small bowel and rectal GISTs. Thus, the combina- there is a lack of any empirical evidence of their effectiveness.39 tion of these three factors allows one to forecast a risk of relapse by using tools such as the Armed Forces Institute of Pathology (AFIP) risk classification, the Memorial Sloan Kettering Cancer Center STAGING (MSKCC) nomogram, or the contour maps. The contour maps have the advantage of treating both the mitotic rate and tumor size Conventional stage classification is seldom used.40 Clinicians as continuous variables as they are, so that the accuracy is increased mainly distinguish localized from metastatic disease and, if the especially for intermediate-risk cases (Fig. 55.6). Also, reproducibil- disease is localized and amenable to complete surgery, quantify ity issues become less crucial by factoring mitotic count as a con- the risk of relapse.20,22,24 tinuous variable. In addition, contour maps segregate the prognosis

ABCGastric, rupture unknown Nongastric, rupture unknown E-GIST, rupture unknown 50 50 50

25 25 25 15 15 15 10 10 10 5 5 5 PRACTICE OF ONCOLOGY PRACTICE 2 2 2

0 0 0

DEFGastric with no rupture Nongastric with no rupture E-GIST with no rupture 50 50 50

25 25 25 15 15 15 10 10 10 5 5 5 2 2 2

0 0 0

GHIGastric with rupture Nongastric with rupture E-GIST with rupture 50 50 50

25 25 25 15 15 15 10 10 10 5 5 5 Mitotic countMitotic count Mitotic count Mitotic 2 2 2

0 0 0 0–1 2 51015 25 0–1 2 5 1015 25 0–1 2 5 1015 25 Tumor size (cm) Tumor size (cm) Tumor size (cm)

0% 10% 20% 40% 60% 80% 90% 100%

Figure 55.6 Contour prognostic maps in localized GISTs. (From Joensuu H, Vehtari A, Riihimäki J, et al. Risk of gastrointestinal stromal tumour recurrence after surgery: an analysis of pooled population-based cohorts. Lancet Oncol 2012;13:265–274.) 750 Practice of Oncology / Cancers of the Gastrointestinal Tract of lesions that underwent tumor rupture, which is a highly adverse index cannot be determined by biopsy or fine-needle aspiration prognostic factor in diseases anatomically facing the peritoneum.41 (FNA), thus preventing the identification of those at higher risk. The natural history of advanced GISTs is marked by their po- Therefore, both observation and resection for GISTs 1 to 2 cm can tential extension to the peritoneum and/or the liver. Thus, a CT be considered, and the risks and benefits of one versus the other scan is the staging procedure of choice to rule out metastatic dis- should be discussed with the patient. The endoscopic resection ease. Lung metastases are rare, with the possible exception of rec- of small gastric GISTs could be an option in these presentations. tal GISTs, although a chest CT scan is generally used to extend Risks of perforation may be low, although the decision is made on a staging workup to lungs and the mediastinum. Bone metastases a case-by-case basis. Regardless of their size, any small GIST that is are possible, but they are usually confined to the very advanced symptomatic (e.g., bleeding from erosions through the mucosa) or stages of disease, so that the skeleton is not routinely assessed in increases in size on serial follow-up should be resected. the lack of symptoms.42 Other sites of distant metastases are ex- A laparotomic or laparoscopic/laparoscopy-assisted resection of ceedingly rare. Lymph node regional metastases are not typical of primary GISTs should be performed following standard oncologic GISTs, as for mesenchymal tumors in general, with the remark- principles. On laparotomy/laparoscopy, the abdomen should be able exception of WT GISTs occurring in children and/or within thoroughly explored to identify and remove any previously unde- syndromes. In addition, all syndromic GISTs may be multifocal tected peritoneal metastatic deposits.48–51 Although primary GISTs and multicentric.43,44 This is not tantamount to metastatic spread, may demonstrate inflammatory adhesions to surrounding organs, being rather a marker of their inherent natural history. All these true invasion is not frequent. The goal of surgery is R0 excision. A features of the natural history of GISTs drive staging procedures, macroscopically complete resection with negative or positive mi- in addition to the potential for other syndromic correlates, depend- croscopic margins (R0 or R1 resection, respectively) is associated ing on the presentation. with a better prognosis than a macroscopically incomplete excision (R2 excision).52,53 Available series have not clearly shown that R1 surgery is associated with a definitely higher risk of local failure, so MANAGEMENT BY STAGE that the decision whether to reexcise a lesion already operated on with microscopically positive margins is doubtful, aside from the Localized GISTs with no evidence of distant metastases are treated fact that sometimes a reexcision may not be technically foreseeable with surgery, followed by adjuvant medical therapy if the risk of re- in the gastrointestinal tract. An exception are GIST of the rectum, lapse is significant. This treatment strategy capitalizes on the con- where microscopically positive margins are clearly associated with solidated curative potential of surgery and prolongs the relapse-free a higher risk of local failure.54 In general, local relapse after R0 interval of patients who are not eradicated. When surgery is unfea- surgery is very unlikely in GISTs. Of course, the margins of a big le- sible or could be made less mutilating or easier through downsiz- sion toward the peritoneum will not be covered by any clean tissue, ing, medical therapy is used if the genotype is sensitive to imatinib, and this may well be the main reason for the high peritoneal relapse possibly followed by surgery and the completion of a medical adju- rate of large tumors even after complete surgery. Tumor rupture or vant treatment if the risk of relapse is significant. When the disease violation of the tumor capsule during surgery are associated with is metastatic, medical therapy with TKIs is standard treatment and a very high risk of recurrence, and therefore should be avoided.41 should be maintained indefinitely. Surgery of metastatic residual Some clinicians approach ruptured GISTs as already metastatic, responding disease can be used when reasonably feasible, but its although there may be different kinds of rupture, possibly leading to added value prognostically is unproven. When imatinib fails and/ different risk levels. A lymphadenectomy is not routinely required, or is ineffective, other available TKIs and judicious use of surgery because lymph nodes are rarely involved (in adult patients) and are of limited progression are resorted to (see Table 55.1 for conven- thus resected only when they are clinically suspect. tionally used agents). This treatment strategy has substantially In general, surgery is a wedge or segmental resection of the improved the prognosis of advanced GIST patients by increasing involved gastric or intestinal tract, with margins that can be less median survival in terms of years if compared to any historical se- wide than for an adenocarcinoma. Sometimes, a more extensive ries, with a proportion of patients, limited though it may be, be- resection (e.g., total gastrectomy for a large proximal gastric GIST, coming long-term progression-free survivors. pancreaticoduodenectomy for a periampullary GIST, or abdomi- When the disease is localized, surgery is the treatment main- noperineal resection for a low rectal GIST) is needed. In the rare stay. Indeed, all GISTs ≥2 cm in size should be resected when syndromic GIST (either SDH deficient or NF-1 related), tumors possible, because none of them can be considered benign. The are often multifocal and confined either to the stomach (SDH- management of GISTs <2 cm in size is more questionable.45–47 deficient GIST) or the small bowel (NF-1–related GIST). The ex- Although the low risk of progression of GISTs <2 cm leads to the tent of surgery should be decided on a case-by-case basis, taking into recommendation of a conservative approach, a reliable mitotic account the risk of recurrence, the lack of benefit from currently available TKIs, and the actual behavior of the underlying disease.55 Adjuvant medical therapy with imatinib was demonstrated to TABLE 55.1 substantially improve relapse-free intervals, although with a trend to lose the benefit in a time span of 1 to 3 years from the end of Standard Medical Agents Currently therapy.56–58 This was shown through randomized trials that com- Used in GIST pared 1 and 2 years of adjuvant therapy with imatinib versus no adjuvant therapy, and 3 years versus 1 year of adjuvant therapy with ■ Imatinib imatinib. As of today, the suggestion from these studies is that adju- – 400 mg by mouth daily vant therapy with TKIs can delay, but probably not avoid, a relapse, – Possibly 800 mg by mouth daily, in case of: if this is due to occur. This correlated with a survival improvement Exon 9 KIT-mutated GIST in one trial57 and with a trend to improvement of a potential sur- Progression on imatinib 400 mg rogate for survival in another,58 where the surrogate was survival free from changing the original tirosine kinase inhibitor (TKI)—in ■ Sunitinib practice, survival without secondary resistance. In fact, secondary – 50 mg by mouth daily for 4 wks every 6 wks resistance is the limiting factor of TKIs in the advanced setting, so – 37.5 mg by mouth daily continuously that an adjuvant therapy will be beneficial as long as it either avoids ■ Regorafenib recurrences or at least prolongs freedom from secondary resistance, – 160 mg by mouth daily for 3 wks every 4 wks but by no means shortens it. Thus, the risk of any detrimental effect was ruled out for adjuvant therapy durations up to 3 years. In this

tahir99 - UnitedVRG Chapter 55 Gastrointestinal Stromal Tumor 751 sense, going beyond 3 years would seem logical, given the tendency are lacking with other TKIs, which may be potentially more active. to lose the benefit after 1 to 3 years from stopping adjuvant therapy, Even more importantly, the natural history of WT GISTs is often but such a policy should be validated by clinical trials ruling out less aggressive. These are the reasons why many clinicians currently any adverse effect on secondary resistance. Results from clinical do not select WT GISTs patients for any adjuvant treatment. studies on longer durations of adjuvant therapy are therefore ex- Given the extensive use of adjuvant therapy with imatinib in pected. Currently, adjuvant therapy is recommended for 3 years the high-risk populations and the activity of the drug, several re- and is reserved for patients with a significant risk of relapse, as long cent multi-institutional retrospective series have questioned the as the benefit in absolute terms will be higher as the risk increases, need for extensive resections such as pancreaticoduodenectomy, as is the case with all adjuvant therapies. In a sense, the lack of abdominal perineal resection, or total/proximal gastrectomy, when a tangible impact on the long-term relapse rate encourages one tumor downsizing can be likely achieved with a preoperative medi- to exclude relatively low-risk patients, which is, to some extent, at cal treatment. In practice, preoperative imatinib can shrink gastric, odds with what is done with adjuvant cytotoxic chemotherapy in periampullary, or rectal GISTs to such an extent as to allow more some solid cancers. This said, the magnitude of risk that is worth limited excisions (wedge gastrectomy, excision of periampullary le- an adjuvant therapy with imatinib for 3 years may well be subject sions, transanal/perineal resection of rectal GISTs, respectively), to a shared decision making with the individual patient, and, as a and imatinib can then be continued postoperatively to complete matter of fact, is generally placed above 30% to 50%. Logically, a the adjuvant treatment (Fig. 55.7). Thus, if extensive surgery is re- benefit can be expected for patients whose genotype is potentially quired for complete tumor removal, preoperative imatinib should sensitive to imatinib.59 In practice, this leads to the selection of all be considered.61–64 In addition to this, there are some big abdomi- patients with a KIT-mutated GIST or a PDGFRA-mutated sensitive nal masses that may be felt by the surgeon as implying a signifi- GIST (with the exception of the D842V exon 18 mutation and the cant risk of tumor rupture during surgery, which can be treated few others which are insensitive in vitro and in vivo to imatinib). with preoperative imatinib. Because downsizing is the clinical end Given the benefit shown with the use of a double dose of imatinib point in these cases, the duration of pre-operative medical therapy (800 mg daily) for advanced GIST patients with an exon 9 KIT- is generally 6 to 12 months, which corresponds to the time interval mutated GIST,60 such a dosage can be selected for them, although when the maximum degree of tumor shrinkage was shown to occur there is a lack of any formal demonstration in the adjuvant setting. in studies on advanced GISTs.65 In addition, mutational status is WT GISTs are much less sensitive to imatinib, and adjuvant studies important in order to select patients likely to respond to imatinib, PRACTICE OF ONCOLOGY PRACTICE

B Figure 55.7 (A) Tumor shrinkage of a gastric primary GIST after 12 months of preoperative imatinib, (B) allowing for a sleeve gastrectomy plus splenectomy and liver resection with preservation of most of the stomach after resection. 752 Practice of Oncology / Cancers of the Gastrointestinal Tract and tumor response should be monitored closely. Positron-emission Clinical wisdom needs to be exercised in order to maintain dose tomography (PET) scans are a resource, because they can demon- intensity vis-à-vis side effects.77 The number of patients truly intol- strate tumor responsiveness in a matter of weeks. erant to imatinib should be exceedingly low. Syndromic GISTs can present with multifocal and/or multicen- Secondary resistance is the limiting factor of imatinib, with tric disease, which may imply delicate surgical decisions. Thus, in a median time to the event averaging 2 years in the frontline ad- WT GISTs, such as those occurring in children and young adults vanced setting. One cannot rule out that current patients, who or in NF-1 patients, one should take into account the indolent are generally put on therapy with lower tumor burdens, may show behavior of many lesions and the possible presence of hyperplasia improved progression-free survival intervals over the earliest series. of the interstitial cells of Cajal on one side, and the possibility that More importantly, the range of time to secondary resistance is single lesions may be aggressive on the other. Surgery should judi- wide, with a limited proportion of patients, averaging 10%, who be- ciously factor in all this. In addition, the relative lack of sensitivity come long-term progression-free survivors. Currently, there are no of WT GISTs to available TKIs may suggest to resort to surgery known prognostic factors for long-term progression-free survivor- more liberally than is currently done with KIT-mutated GISTs. ship, excluding the mutational status, which affects tumor response With regard to the highly rare syndromes of familial GISTs to imatinib, and tumor burden at the onset of imatinib therapy, from germ-line mutations of KIT or PDGFRA, treatment is chal- which affects the duration of response. The group of long-term pro- lenging and may involve resorting to surgery and/or TKIs depend- gression-free survivors may thus represent either just the “tail” of a ing on the behavior and extent of clinically relevant lesions. curve driven by the stochastic mechanisms of secondary resistance, When the disease is metastatic or locally advanced, medical or the result of specific genomic profiles, still to be elucidated. therapy is the best choice and is currently based on imatinib con- In an attempt to download tumor burden, thus potentially pro- tinued indefinitely.66–69 However, given the limiting factor of sec- longing time to secondary resistance, surgery of residual responding ondary resistance, some clinicians prefer to surgically resect some disease has been resorted to in many institutions, and its results were highly localized first distant relapses, thus delaying the start of ima- retrospectively, but not prospectively, evaluated, with the exception tinib to a subsequent relapse. It is unproven whether this approach of an underpowered randomized prospective study in patients who may delay progression, its rationale being to delay the onset of time had only peritoneal disease.78–83 These case series analyses showed a to secondary resistance by delaying the onset of any use of TKIs. better prognosis for patients undergoing surgery, but a selection bias Theoretically, the downside may be starting medical therapy with may well explain the results. Prospective trials have not been success- a higher tumor burden, which was shown to be related to a shorter ful; therefore, the decision whether to surgically excise metastatic time to secondary resistance to imatinib. lesions responding to imatinib is currently left to a shared decision In fact, initial tumor burden is virtually the only prognostic making with the patient in conditions of uncertainty. Of course, clin- factor in the metastatic GIST patient starting imatinib.70 On the ical presentations are manifold, and sometimes the easiness of the other hand, although above 80% overall, the probability of re- surgical resection is the main factor leading to the decision, and vice sponse is strictly correlated with the mutational status, which is, versa. In general, many institutions currently avoid resorting to major therefore, the main predictive factor.71–73 KIT-mutated GIST are surgery for responding metastases. In any case, only patients ame- responsive in most cases, including the most frequent genotype, nable to complete resection of all lesions should be candidates for marked by mutations of exon 11. This applies also to patients who this kind of surgery. In this sense, surgery may be less often indicated underwent adjuvant imatinib and who did not experience tumor in peritoneal compared to liver metastases, because the former are relapse during the adjuvant period, so that these patients are cur- frequently underestimated by available imaging modalities and the rently approached the same way as those who have not been al- selection of completely clearable tumors is less feasible. However, ready exposed to imatinib. The standard daily dosage of imatinib the clinician must be aware that imatinib needs to be continued after is 400 mg. However, there are data derived from retrospective sub- surgery, even if surgery was complete. In fact, some patients enrolled group analyses that suggest progression-free survival is better with in the discontinuation trial of imatinib had had a complete excision doses higher than 400 mg (i.e., 800 mg daily) for exon 9 KIT-mu- of their metastatic lesions.74 In addition, surgery of metastatic GISTs tated GIST patients.60 Thus, many institutions treat these patients was never proved to be eradicating in the pre-imatinib era.84 with 800 mg. PDGFRA-mutated GIST patients can be sensitive Progression during therapy with imatinib is often due to sec- to imatinib as well, with the remarkable exception of the D842V ondary resistance, which essentially is marked by the occurrence mutation, which is the most frequent amongst PDGFRA muta- of new mutations to the same primarily mutated oncogene, or, less tions, and a few others. WT GISTs are less sensitive to imatinib, frequently, oncogene amplifications or alterations of alternative which may, however, be active in some patients. Sunitinib is an pathways.5 It is left to elucidate whether these secondary mutations alternative option, because it was shown to have some activity in should be biologically viewed as developing de novo. Second- WT GISTs.74 Generally, the clinical decision in WT GISTs, and ary mutations entail such consequences as to lower the binding of course PDGFRA D842–mutated patients, takes into account capacity of the KIT or PDGFRA receptor for imatinib and/or to the natural history of these subtypes, which is often less aggressive circumvent its inhibiting action by escape mechanisms.85 It was than in KIT-mutated GISTs. Thus, surgical options, including ab- demonstrated that secondary resistance can be heterogeneous, so lations, may be resorted to when the relapse is limited. However, that more mutations can be detected in different lesions, or even in sensitive genotypes medical therapy is an option even when within the same lesion.86,87 Of course, this is a major limiting fac- surgery is feasible, and any decision on surgery is usually delayed tor for second-line agents targeting KIT or PDGFRA. Secondary to when the tumor response has been established. This allows for mutations in KIT-mutated GISTs are relatively limited in number, the possibility of being certain about a patient’s responsiveness affecting exons 13 and 14, which encode the ATP-binding pocket, to a medical therapy that will need to be prolonged indefinitely or exons 17 and 18, which encode the activation loop. Many re- because the disease is metastatic. sistant PDGFRA-mutated GISTs acquire the D842V mutation, In fact, a discontinuation trial showed that stopping therapy which encodes for the activation loop of the receptor. after 1, 3, or 5 years is followed by progression in a matter of Clinically, the progression may be limited in a substantial pro- months.75 It is true that reestablishing therapy generally leads to a portion of cases. This means that progression is radiologically evi- new response, but its quality may be inferior to the previous one.76 dent only in one or a few lesions, with the others still progressing. In any case, intervals to progression would be remarkably short, A typical clinical pattern is the nodule within the nodule (i.e., a and an untenable stop-and-go treatment policy would be the result. small hyperdensity within a responding hypodense lesion on CT Imatinib is generally well tolerated, with fatigue, edema, mild scan).88 Given the scope of activity of further-line therapies, many diarrhea, and anemia as frequent complaints, along with less fre- clinicians now tend to treat limited progression conservatively quent toxicities, such as neutropenia, skin rash, and others.67–69 from the medical point of view, resorting to selected surgical or

tahir99 - UnitedVRG Chapter 55 Gastrointestinal Stromal Tumor 753 ablative procedures to get rid of the progressing component of the with hand–foot syndrome, hypertension, fatigue, and diarrhea as disease, while continuing imatinib for the remaining. This might main side effects.96 delay the moment when the first TKI is switched to a second-line An observation made in this trial was the persistence of some one. Though this policy is not based on prospective clinical stud- activity when therapy was carried on beyond progression.97 In other ies, it makes sense in the economy of advanced GISTs following words, a subset of patients, although arbitrarily selected by inves- the introduction of TKIs. Clearly this does not apply to generalized tigators on clinical grounds, went on with therapy beyond their progressions. first progression, achieving a second progression-free interval that Radiologic progression should be confirmed, taking into ac- approximated the previous one. This would suggest that a subset count the peculiarities of tumor response patterns in GISTs un- of progressing patients have a disease that might be slowed down dergoing TKIs. Furthermore, before attributing progression on by continuing the TKI in spite of the progression. This observation frontline imatinib to molecular secondary resistance, one should likely applies to all TKIs, at least in selected patients, and is worth rule out any lack of patient compliance with therapy, which may testing prospectively by developing criteria to single out those often go unnoticed and even be underappreciated by the patient. patients who are more likely to benefit. In general, this parallels Another mechanism leading to resistance can lie in changes of the clinical feeling that stopping any kind of TKI may accelerate the pharmacokinetics of the drug. There is evidence that pharma- tumor progression, even when resistance to that TKI has been es- cokinetics can undergo variations with time, in addition to being tablished. Indeed, a criticism that was made to placebo-controlled variable across individuals.89 This has led to the evaluation of the trials on new TKIs in GIST is the lack of any tyrosine kinase in- importance of maintaining target plasma levels of imatinib.90 hibition in the control group, possibly worsening its outcome in There are limitations to the standardization of such assessments, comparison to what could happen by continuing the TKI already and available data pointing to a correlation with progression-free in use or by rechallenging the disease with a TKI used earlier. survival are retrospective in nature. Thus, at the moment, we lack In fact, in anecdotal cases and also in a small randomized clini- any convincing formal demonstration that pharmacokinetics is a cal trial, it was shown that rechallenging a progressing GIST pa- factor able to personalize medical therapy (i.e., to drive changes in tient with TKIs used at an earlier stage can be beneficial, at least drug dosages in the lack of evident progression). However, avail- temporarily.98 In other words, reestablishing imatinib in patients able evidence also suggests that it can well be a variable with many who underwent the drug as frontline therapy and then switched orally administered targeted agents. At least, plasma levels may be to others results in a benefit in terms of progression-free survival assessed in the single patient: in case of clinical progression, to that is not far from what is achievable with further-line agents. rule out that a major pharmacokinetic issue does exist at that stage; One may speculate that there is a process of reexpansion of tumor in case of unexpected side effects; and in case of comedications clones that were sensitive to imatinib and might have been nar- potentially able to interfere with the drug metabolism. rowed by the selective pressure of the drug, as long as resistant In the case of clinical progression with imatinib 400 mg daily, clones were emerging.

an option widely used is to increase the dose to 800 mg daily. Following third-line therapy, there is no standard option at OF ONCOLOGY PRACTICE This proved temporarily successful in a limited proportion of pa- the moment, aside from rechallenge, and clearly patients are eli- tients crossing over to the higher dose in randomized trials that gible for clinical studies on new agents. New drugs investigated compared 400 mg with 800 mg as frontline therapy for advanced in currently ongoing trials include other TKIs targeting KIT and GISTs.91 When valuing this benefit, one should probably discount PDGFRA; agents targeting downstream pathways (e.g., PI3K/ patients who had an exon 9 mutation and who started with 400 AKT); agents targeting heat shock proteins, given their chaperone mg, and possibly some patients failing to comply with therapy, function for KIT and PDGFRA; among others. Clearly, agents whereas other patients may have benefited due to the correction of with a mechanism of action other than imatinib, sunitinib, and pharmacokinetics problems. regorafenib try to address the limiting factor of the heterogeneous Standard second-line therapy is sunitinib, which is a TKI inhib- nature of secondary resistance. Combinations of agents with differ- iting KIT and PDGFRA but also displaying antiangiogenic activ- ent mechanisms of action are tried as well, although their added ity by the inhibition of vascular endothelial growth factor receptor toxicity may be prohibitive even when they are reasonably well (VEGFR)1, 2, and 3. It was shown to be effective at increasing tolerated as single drugs. Future directions might try to exploit mo- progression-free survival by 5 months in a randomized trial versus lecular diagnostics such as the liquid biopsy (i.e., the assessment placebo in patients failing (or intolerant) to imatinib.92 Its molecu- of secondary mutations on circulating DNA shed by tumor cells). lar profile is such as to include activity on exon 9 KIT mutations The sensitivity of this technique for primary and secondary muta- as well as on secondary mutations of regions coding for the ATP- tions of GISTs has been demonstrated.99 Thus, it looks promising binding pocket, thus potentially covering mutations which are, for the future, to allow a degree of molecular personalization of respectively, less affected or not affected by imatinib.93 What lim- therapy, whether following secondary resistance or before it estab- its the potential of molecular prediction in further-line therapies lishes clinically, as a means to avoid or delay its occurrence. Com- of GISTs is basically the heterogeneity that often underlies sec- binations or rotations of TKIs might be tested, rationally driven by ondary resistance, so that the presence of a secondary mutation liquid biopsies. This could exploit the peculiarities of resistance is unlikely to be alone, although potentially sensitive to available seen with TKIs in GISTs. In fact, the efficacy of treatment beyond agents. However, the activity of sunitinib against some secondary progression and of rechallenge suggests that sensitive and resistant mutations and probably its antiangiogenic activity underlie its clin- clones may fluctuate within the tumor load, depending on the ical efficacy after failing to imatinib. Its tolerability profile is less selective pressure they are exposed to. This would be consistent favorable, with fatigue and hand–foot syndrome as its main side with the model of a liquid resistance, which, clinically, could be ex- effects, variable though they may be across patients. Although the ploited by employing new strategies as from the upfront approach clinical trial evaluated a regimen of sunitinib given 50 mg daily for with TKIs. 4 weeks, with a 2-week rest, a continuous regimen with a daily dose A methodologic issue in the medical therapy of GISTs with of 37.5 mg can be used as well.94 all TKIs lies in the peculiar patterns displayed by tumor response Regorafenib, another TKI with activity on KIT and PDGFRA as compared to those observed with standard cytotoxic chemo- as well as VEGFR1, 2, and 3, and thus with antiangiogenic proper- therapy of solid cancers and lymphomas.100,101 These patterns of ties, is standard third-line therapy for advanced GIST patients. In tumor response are marked by the possible lack of tumor shrink- fact, it was shown to be effective as a third-line therapy in patients age in the face of substantial changes in tumor tissue and tumor failing both imatinib and sunitinib, by providing a median advan- metabolic activity. Although most observations derive from ima- tage of 4 months of progression-free survival over placebo in a ran- tinib in frontline therapy, in essence, they regard all TKIs, the domized clinical trial.95 Its tolerability profile is close to sunitinib, main difference being possibly the weakness of tumor response 754 Practice of Oncology / Cancers of the Gastrointestinal Tract to further-line therapies, so that some of these aspects may look less clear cut in the further-line therapy setting as opposed to the frontline. Under these patterns of tumor response, first of all, in the presence of symptoms, a subjective response may take place very early. In a matter of days, if not hours, after starting an effective TKI, a symptomatic patient may well feel a clear degree of subjective improvement. As far as imaging is concerned, this is paralleled by metabolic response as assessed through a fludeoxyglucose (FDG)-PET scan.102 A positive PET scan may turn negative in a few days. Of course, this does not correspond to the disappearance of the tumor lesion, but rather be the consequence of the metabolic switch off that the tumor undergoes when an effective TKI targets its cells. The reverse is true as well, so that any stop of therapy rapidly entails a switch on of functional imaging. Again, this does not correspond to clinical progression, which would follow only for longer interruptions of therapy. This should be taken into account when assessing functional tumor response, because, for instance, any lack of compliance with therapy in the days the exam is made might affect metabolic response as detected through PET scanning. For example, metabolic switch Figure 55.8 Pathologic tumor response of a GIST lesion following on was observed by PET scans performed during the 2 weeks off therapy with imatinib. of therapy with sunitinib. In principle, this adds to the feeling that TKIs need to be maintained in order to preserve tumor response, in the context of a clinically cytostatic effect. It goes with- scan measures the biological effect of a TKI on the tumor cells out saying that when a PET scan has become negative, the tumor very early, but does not necessarily imply any anatomical change lesion will not be visible to functional imaging, so that a CT scan, in the tumor. On the contrary, CT scans and MRI detect actual MRI, or ultrasounds need to be used in order to appreciate the changes in the tumor tissue, which correspond to pathologic evolution of tumor lesions. The radiologic response, as assessed signs of tumor response. These were found to take shape in terms through CT scans and MRI, is marked by tumor shrinkage and/or of a myxoid degeneration widely affecting responding tumor le- changes in tumor tissue. Tumor shrinkage may well appear very sions, with signs of apoptosis (Fig. 55.8). A variable proportion of early, but, in some cases, it is lacking in the early phases of treat- vital cells may be detected, especially to the periphery of lesions ment, or even later on, so that tumor lesions look unchanged di- (pointing in principle to the prospects of regrowth in case of dis- mensionally. Sometimes tumor size may even increase. In these continuation of the TKI). In this sense, a nondimensional tumor cases, however, if a response is in place, the radiologic aspect will response does not mean just absence of progression; indeed, it show substantial changes to the tumor tissue. On a CT scan, this is all about an actual pathologic response, with major changes means a decrease in density of responding lesions, with decreased to the tumor tissue. Of course, all tumor changes one can see contrast enhancement. On an MRI, it entails an hypointense sig- when a tumor response is in place have their counterparts when naling on T1-weighted images and hyperintense on T2-weighted the tumor progresses. Thus, increased tumor density and contrast images, and decreased contrast enhancement. These changes enhancement on a CT scan will mark tumor progression, with or are substantial in GIST patients undergoing frontline therapy without an increase in tumor size. This may well affect just a por- with imatinib, so that recording tumor response is generally un- tion of the tumor lesions, such as its periphery or a small part (as challenging for the clinician, provided tumor shrinkage is not is the case with the nodule within the nodule). In brief, the quality the only criterion. Signs of nondimensional response may prove of the tumor tissue should be observed, in addition to its size, in less obvious when the tumor response is less clear cut, as with order to detect both response and progression in GISTs undergo- further-line therapy with TKIs. Functional imaging may help, ing a TKI. Whatever the response pattern, whether dimensional although it is exposed to the same limitations as well if the re- or not, a tumor response on a CT scan or MRI says that the tumor sponse is less striking. However, when the response is overt, the is undergoing pathologic changes that clearly correlate with the main shortfalls of nondimensional tumor response assessments prognosis. In fact, both dimensional and nondimensional tumor lie in the difficulty to standardize reproducible (i.e., reliable) in- responses have clearly correlated with improved outcome in clin- struments, as is needed in clinical trials. In this sense, Response ical trials, as opposed to progression. Only secondary resistance, Evaluation Criteria in Solid Tumors (RECIST) criteria for tumor or treatment interruption, will terminate a dimensional or nonresponse assessment are based on the measurement on one di- dimensional tumor response, with radiological signs that, as said, ameter of selected target lesions and, thus, have a good record will be dimensional or nondimensional as well. of reproducibility.103 However, their validity is, by definition, un- satisfactory in the presence of a nondimensional response. Choi criteria were worked out in GISTs to accommodate these pat- PALLIATIVE CARE terns of response, by factoring tumor hypodensity on CT scans in addition to a decrease in size.104 Their validity in predicting The natural history of GISTs that are not cured by initial surgery progression-free survival was demonstrated and compared favor- is dominated by abdominal spread involving the liver and the peri- ably with RECIST criteria, while paralleling functional imaging toneum. Liver failure as well as intestinal and urinary obstructions with PET scanning. Then, aside from the need to use easily re- are thus the main palliative challenges. This may well carry the producible instruments in the research setting, for the clinician need of palliative surgery in selected patients. Extra-abdominal the message coming from the GIST model is simple, inasmuch metastases are occasionally seen, mainly to the bone, and can re- as it points to the existence of nondimensional patterns of tumor quire palliative irradiation. A systemic sign such as fatigue may add response, which can be easily highlighted through CT scans and to asthenia induced by anemia as well as directly by TKIs. In fact, MRI on one side and through functional imaging with PET scan the existence of three lines of standard medical therapy, the poten- on the other. One should be aware that the meaning of a radio- tials of rechallenge, and the availability of many agents of interest, logic response through CT scans or MRI is deeply different from either within clinical studies or among TKIs developed for other metabolic response assessed through a PET scan. In fact, a PET diseases, lead to treating many GIST patients with molecularly

tahir99 - UnitedVRG Chapter 55 Gastrointestinal Stromal Tumor 755 targeted therapy even in the very advanced stages of disease. In well as on their current limitations. It also demonstrates how clini- this sense, the usual palliative challenges of abdominal malignan- cal methodology is deeply affected by these agents, not only for cies meet the new palliative challenges posed by the use of TKIs, medical oncologists, but for all members of the multidisciplinary which revolutionized the field of the disease. cancer team, from surgeons to palliative physicians. Interestingly, Indeed, all phases of treatment of GIST are currently a model the model of GISTs shows how a multidisciplinary approach re- for the medical oncology of new molecularly targeted agents. The mains crucial in solid cancers, in all phases of disease, and in the model continues to shed light on their potentials in solid cancers as era of molecularly targeted therapies, too.

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tahir99 - UnitedVRG Molecular Biology of 56 Colorectal Cancer

Ramesh A. Shivdasani

INTRODUCTION with particular histologic features or patient survival and most affect multiple cellular functions. Particular genotypes do, how- The cumulative lifetime risk of developing colorectal cancer (CRC) ever, define CRC subtypes and response to certain therapies. MSI- in the United States is about 6% (www.cancer.gov/statistics) and hi tumors typically arise in the ascending colon and carry a good increases about fourfold in persons with a family history of CRC. prognosis; adjuvant 5-fluorouracil provides little benefit in stage II Fewer than 5% of cases, however, occur in patients with inherited cases of this variety. KRAS or BRAF mutations, together account- predisposition syndromes. Most CRCs are therefore considered ing for about half of all cases, limit response to epidermal growth sporadic, although 20% to 30% of cases might have a familial basis factor receptor (EGFR) antibodies8,9 and are contraindications despite the absence of a known germ-line defect, and genomewide for this treatment. The prognostic and predictive value of other association (GWA) studies reveal at least 20 alleles that elevate the molecular features will become clearer as new therapies enter the risk of developing CRCs. Characteristic somatic mutations, DNA clinic. Meanwhile, specific mutations reveal normal controls on repair defects, chromosomal instability, and epigenetic alterations colonic cells, possibly guiding future prevention strategies and key promote the disease. Predisposing conditions and somatic muta- signaling pathways for rational drug development. tions profoundly inform the molecular understanding of CRCs and serve as a paradigm for the genetic basis of cancer. Global Events in Colorectal Cancer

CRCs acquire genetic instability in stereotypic ways that favor the MULTISTEP MODELS OF COLORECTAL

accumulation of hundreds to thousands of somatic aberrations (see OF ONCOLOGY PRACTICE TUMORIGENESIS Fig. 56.1). About 80% of tumors display widespread chromosomal gains, losses, and translocations—phenomena that lead to gene The genetic basis of CRC is best appreciated in light of the amplifications, rearrangements, and deletions.10 These tumors adenoma–carcinoma sequence. CRCs invariably arise within be- carry, on average, below 100 somatic nonsynonymous point muta- nign precursor polyps that show epithelial overgrowth, dysplasia, tions. Chromosomal segregation defects may account for chromo- abnormal differentiation, and, sometimes, foci of tissue invasion. somal instability (CIN), as the segregation factor Bub1 illustrates Pedunculated polyps are the most significant precursor lesions, in mice,11 but few specific gene defects are implicated confidently. with those larger than 1 cm harboring about a 15% risk of pro- Beyond weak associations with structural changes on chromo- gressing to carcinoma over 10 years; endoscopic removal of these somes 8 and 18,12 specific cytogenetic features barely influence adenomas reduces CRC incidence and mortality.1 The prevalence disease patterns or patient outcomes. of polyps in the United States, estimated at up to 50% by age 70,2 About 15% of CRCs appear globally euploid but carry thousands dwarfs the 6% lifetime risk of CRCs because few adenomas proof point mutations and small deletions or insertions near nucleotide gress to invasive cancer and the successive aberrations that promote repeat tracts—the defect designated as MSI-hi.13 Features and the invasion and malignancy take 1 to 3 decades to accumulate.3 molecular determinants of disease progression in MSI+ adenomas Nonclassical adenomas, such as hyperplastic polyps, were previ- differ from those associated with CIN; for example, BRAF V600E ously thought to have little potential to spawn invasive CRCs, but mutations are more common in MSI+ precursor adenomas than two serrated precursor lesion forms are now recognized.4 Serrated in other types.14 Because hypermutability, whether associated with adenomas with cytologic dysplasia occasionally evolve into common CIN or MSI, results in many changes that are inconsequential or CRCs with chromosomal instability and KRAS mutation, whereas even detrimental to tumors, the mere presence of a mutation does sessile serrated adenomas that lack dysplasia can spawn CRCs with not signify a pathogenic role. Therefore, two features are used to microsatellite instability (MSI-hi), BRAF mutation, and abundant distinguish driver from passenger mutations: appearance in a high CpG island methylation.5,6 About 8% of sporadic CRCs originate in fraction of tumor specimens, and ideally, the experimental demon- such lesions, retain a serrated epithelium with characteristic nuclear stration of its contribution to a malignant property. morphology, and carry a relatively poor prognosis. Epigenetic mechanisms may be as significant as mutations Although cancer progression has both genetic (somatic muta- in cancer but are less well understood. Various covalent histone tions) and epigenetic (unrelated to altered DNA sequence) under- modifications and methylation of cytosine residues in DNA rep- pinnings, we presently know more about the former than the latter. resent prominent modes of gene regulation,15 the latter being far Alterations in several classes of genes drive tumors: oncogenes; better characterized in CRCs than the former. 5′-CpG-3′ dinu- tumor suppressors, including genes that repair damaged DNA; and cleotide pairs are particular targets for methylation in localized those that help control other genes (epigenetic modifiers). Selected areas of high CpG content in promoters, where methylation si- mutations appear at high frequencies in different tumor types and lences adjacent genes. CRCs show 8% to 15% lower total DNA stages, allowing for the assignment of typical sequences (Fig. 56.1), methylation than normal tissue,16 even in colorectal adenomas.17 although mutational order can vary and most tumors do not carry Reduced pericentromeric methylation might decrease the fidel- every alteration. These mutations support the idea of cancer as a ity of chromosomal segregation and altered methylation or loss multifaceted disease that breaches natural checks on cell survival, of imprinting at the IGF2 locus increase CRC risk,18 suggesting growth, and invasion.7 Few specific mutations correlate strongly broad effects of global hypomethylation on cell growth. However, 757 758 Practice of Oncology / Cancers of the Gastrointestinal Tract

Mutation of 18q loss K-Ras DCC,DPC4 Normal Adenoma Carcinoma

Inactivation of CIN defect Inactivation of APC (5q loss) p53 (17p loss) A Familial MSI-H pathway (HNPCC) (p53) MMR mutational Adenoma inactivation Carcinoma APC Mutation of β-catenin K-Ras Axin2 Mutational inactivation of genes Normal with microsatellites: TGFβIIR, BAX

APC Mutation of β-catenin B-Raf MMR Axin2 (>K-Ras) Serrated epigenetic Carcinoma inactivation adenoma (M H1) Sporadic MSI-H Inactivation of tumor suppressor genes pathways by promoter hypermethylation (CIMP) B Figure 56.1 Genetic pathways to colorectal carcinoma. All colorectal cancers (CRCs) arise within benign adenomatous precursors, fueled by mutations that serially enhance malignant behavior. Mutations that activate the Wnt signaling pathway seem to be necessary initiating events, after which two possible courses contribute to the accumulation of additional mutations. (A) Chromosomal instability is a feature of up to 80% of CRCs and is commonly associated with activating KRAS point mutations and loss of regions that encompass P53 and other tumor suppressors on 18q and 17p, often but not necessarily in that order. (B) About 20% of CRCs are euploid but defective in DNA mismatch repair (MMR), resulting in high microsatellite instability (MSI-hi). MMR defects may develop sporadically, associated with CpG island methylation (CIMP), or as a result of familial predisposition in hereditary nonpolyposis colorectal cancer (HNPCC). Mutations accumulate in the KRAS or BRAF oncogenes, p53 tumor suppressor, and in microsatellite-containing genes vulnerable to MMR defects, such as TGFβIIR. Epigenetic inactivation of the MMR gene MLH1 and activating BRAF point mutations are especially common in serrated adenomas, which progress, in part, through the silencing of tumor suppressor genes by promoter hypermethylation. Progression from adenoma to CRC takes years to decades, a process that accelerates in the presence of MMR defects. CIN, chromosomal instability. its precise significance is unclear because some animals show heightened mutation in a setting of ongoing mucosal injury and increased tumor susceptibility with global hypomethylation,19 repair. UC-associated CRCs often arise within flat adenomatous whereas Apc Min mice lacking or overexpressing the de novo DNA plaques and nonadenomatous areas of dysplasia. Compared to methyltransferase DNMT3B show reduced or accelerated progres- sporadic cases, TP53 mutations occur earlier in the cancer se- sion of small adenomas, respectively.20,21 quence,28 APC inactivation is less frequent, and methylation of the Against a backdrop of genomewide hypomethylation, a distinct p16INK4a tumor suppressor gene is more common.29 subset of CRCs shows coordinate hypermethylation of many CpG- rich promoters, conferring the CpG island methylator phenotype (CIMP), with transcriptional attenuation of tumor suppressor genes INHERITED SYNDROMES OF INCREASED such as HIC1 and Wnt-inhibiting SFRPs.22,23 Whole-genome methylation analyses have confirmed the existence of this once contro- CANCER RISK HIGHLIGHT EARLY EVENTS versial entity24 and features that distinguish it from KRAS-mutant AND CRITICAL PATHWAYS IN COLORECTAL CIN disease—origin in sessile serrated adenomas; strong associa- TUMORIGENESIS tion with BRAF-mutant, right-sided MSI-hi tumors with MLH1 gene methylation;25 and distinctive gene expression patterns.26 Two uncommon but highly penetrant Mendelian syndromes, familial Although the features cited previously, especially MMR and adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal CIMP, overlap to some degree, CRCs seem to fall into three gen- cancer (HNPCC), together account for almost 5% of cases. MYH- eral categories: (1) traditional, (2) alternative, and (3) serrated, associated polyposis (MAP), polymerase proofreading-associated which are characterized by CIN, DNA mismatch repair, and polyposis (PPAP), familial juvenile polyposis (FJP), Peutz-Jeghers CIMP, respectively (see Fig. 56.1). The Cancer Genome Atlas syndrome (PJS), and Cowden disease, each occurring in fewer than (TCGA) Network classified CRCs into nonhypermutated (gener- 1 in 200,000 births, also elevate the risk of CRCs (Table 56.1). Knowl- ally CIN+) and hypermutated (encompassing MMR and CIMP) edge about the genes responsible for these inherited disorders allows categories.26 Other variations on the classical adenoma–carcinoma for accurate molecular diagnosis, risk assessment, and targeted pre- sequence are also recognized. A 10-fold elevated risk of CRC in vention in affected families. It also profoundly informs understanding patients with long-standing ulcerative colitis (UC)27 likely reflects of the considerably larger proportion of sporadic cases.

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TABLE 56.1 Genetics of Inherited Colorectal Tumor Syndromes

Syndrome Features Commonly Seen in Affected Individuals Gene Defect Syndromes with Adenomatous Polyps Familial adenomatous Multiple adenomas (>100) and colorectal carcinomas; APC (>90%) polyposis (FAP) duodenal polyps and carcinomas; gastric fundus polyps; congenital hypertrophy of retinal epithelium – Gardner syndrome Same as FAP, with desmoid tumors and mandibular osteomas APC – Turcot syndrome Polyposis and CRC with brain tumors (medulloblastoma, APC, MLH1 glioblastoma) Attenuated adenomatous Less than 100 polyps, although marked variation in polyp APC (5′ mutations) polyposis coli (AAPC) number (from ∼5 to >1,000 polyps) seen in mutation carriers within a single family Hereditary nonpolyposis CRC with modest polyposis; high risk of endometrial cancer; MSH2, MLH1, MSH6 (together colorectal cancer (HNPCC) some risk of ovarian, gastric, urothelial, hepatobiliary, and >90%), PMS2 (about 5%) brain cancers MYH-associated polyposis (MAP) Multiple gastrointestinal polyps, autosomal recessive MYH Polymerase proofreading- Large adenomas, early-onset CRC, elevated risk of POLE or POLD1 associated polyposis (PPAP) endometrial cancer only Syndromes with Atypical Polyps Peutz-Jeghers syndrome (PJS) Hamartomatous polyps throughout the gastrointestinal (GI) STK11 (30%–70%) tract; mucocutaneous pigmentation; estimated 9- to 13-fold increased risk of GI and non-GI cancers Cowden disease Multiple hamartomas involving breast, thyroid, skin, brain, PTEN (85%) and GI tract; increased risk of breast, uterus, thyroid, and some GI cancers PRACTICE OF ONCOLOGY PRACTICE Juvenile polyposis syndrome Multiple hamartomas in youth, predominantly in colon and BMPR1A (25%), SMAD4 stomach; variable increase in colorectal and stomach (15%), ENG cancer risk; facial changes Hereditary mixed polyposis Polyps of highly heterogeneous form and size, a few of GREM1 (imputed) (HMPS) which progress to CRC; confined to rare Ashkenazi Jewish kindreds; only CRC risk is elevated

Familial Adenomatous Polyposis and the barely doubles the lifetime risk of CRC over the background and Central Importance of Wnt Signaling does not affect APC protein function but replaces an (A)3T(A)4 coding sequence with an (A)8 tract that is occasionally targeted FAP is an autosomal-dominant monogenic disorder that underlies for nearby truncating mutations.35 The identification of specific about 0.5% of all CRCs. Individuals develop hundreds to thou- APC mutations in probands allows for a reliable testing of family sands of colonic polyps by their early 20s, and the lifetime risk members. Minimal recommendations for carriers include screen- of CRC approaches 100% at a median age of 39. Extraintestinal ing colonoscopy annually after age 10, gastroduodenoscopy after manifestations include (1) duodenal and gastric adenomas; (2) age 25, and treatment with nonsteroidal anti-inflammatory drugs congenital hypertrophy of the retinal pigmented epithelium; (3) to reduce CRC risk.36 A prophylactic colectomy is highly recom- osteomas and mesenteric desmoid tumors in the Gardner syn- mended, with continued vigilance over the rectal stump and other drome variant30; (4) brain tumors in the Turcot syndrome vari- at-risk tissues. ant31; and rarely, (5) cutaneous cysts, thyroid tumors, or adrenal The larger significance of the APC gene derives from its so- adenomas. Although most of these extraintestinal features are matic inactivation in about 80% of sporadic CRCs and adeno- benign, rare patients develop hepatoblastoma or thyroid cancer. mas,37 including tiny polyps without dysplasia. APC inactivation Reflecting similar homeostatic mechanisms in the small and large is a rate-limiting step in the development of most polyps, and bowel epithelia, a 5% to 10% risk of periampullary adenocarci- knowledge of its cellular functions supports this gatekeeper role. noma mandates endoscopic monitoring of the duodenum after Attesting to the tumor suppressor function, CRCs that arise spo- prophylactic colectomy.32 radically or in FAP show loss of heterozygosity and biallelic APC The gene responsible for FAP, adenomatous polyposis coli inactivation, with one copy usually lost by deletion. Because APC (APC), encodes a 300 kDa protein. Germ-line mutations occur encodes several functional domains, truncated mutant proteins throughout the locus, clustering in the 5′ half and exon 15,33 might interfere with various cellular activities. Disruption of its mostly introducing premature truncations. A few mutations cor- role in chromosome segregation might, for example, contribute relate with phenotypic severity or specific extraintestinal manifes- to CIN.38 However, attention on APC rightly centers on its con- tations, but identical mutations can produce different features. trol of the Wnt signaling pathway. About half the sporadic CRCs Mutations clustered in the extreme 5′ or 3′ ends of APC exons with intact APC function carry activating point mutations in lead to the variant attenuated APC, with few polyps or CRCs devel- CTNNB1,39,40 which encodes β-catenin, a transcriptional effec- oping late in life.34 The I1307K allele, present in Ashkenazi Jews, tor of Wnt signaling; many of the rest carry fusions of genes that 760 Practice of Oncology / Cancers of the Gastrointestinal Tract encode R-spondin cofactors.41 Moreover, acute APC loss in mice CTNNB1 mutations in CRC invariably target residues for produces intestinal defects identical to those observed upon Wnt N-terminal phosphorylation and the mutant protein hence, pathway activation.42 APC mutations are uncommon in sporadic resists degradation. Thus, both alternative gatekeeper lesions cancers outside the intestine. in CRC, inactivating APC or activating CTNNB1 mutations, Wnts are secreted glycoprotein morphogens with diverse de- result in constitutive, Wnt ligand-independent stabilization of velopmental and homeostatic functions, and, especially in the β-catenin. R-SPONDIN genes are translocated in up to 10% intestine, their role is intimately tied to that of R-spondins.43,44 of cases, all with wild-type APC and CTNNB1,41 and the gene In the absence of Wnt ligands, cells use a complex containing fusions are probably pathogenic because they potentiate Wnt APC, AXIN2, and other cytosolic proteins to promote casein ki- signaling. TCF4 (also known as TCF7L2) mutations are surpris- nase I- and glycogen synthase kinase (GSK)-3β-mediated phos- ingly common,26 but their roles and effects are unclear, as is the phorylation of conserved serine and threonine residues at the functional significance of rare AXIN2 mutations in MSI+ cases47 N-terminus of β-catenin; this phosphorylation targets β-catenin and of TCF3 or TCF4 gene fusions in microsatellite stability for ubiquitin-mediated proteasomal degradation. The binding (MSS) cases.48 of Wnt ligands to a surface complex containing a FRIZZLED Normal intestinal crypt stem and progenitor cells require Wnt protein and the obligate coreceptor LRP5/6 inhibits the APC- signaling to proliferate, and APC or CTNNB1 mutation-induced AXIN2 destruction complex and stabilizes a pool of cytosolic loss of this ligand dependence liberates cells from a potent regula- β-catenin (Fig. 56.2), distinct from the abundant cellular stores tory restraint. Accordingly, the Wnt-dependent transcriptional pro- that attach to E-cadherin on the inner cell surface. Accumu- gram in CRC cell lines overlaps significantly with that in intestinal lated β-catenin translocates to the cell nucleus, where it coacti- crypts.49 Cycling crypt base cells that express the surface marker vates genes bound by sequence-specific transcription factors of LGR5 are especially vulnerable to Wnt-induced transformation in the T-cell factor (TCF) family. Of the four proteins in this fam- mice, suggesting that CRC arises from stem cells and not from ily, TCF4 is especially important in normal bowel epithelium mature descendants.50 Laboratory evidence suggests that even and CRCs39,45 and nuclear β-catenin is necessary to activate advanced CRCs remain dependent on constitutive Wnt pathway target genes.46 activity.49 The TCF4–β-catenin complex controls hundreds of candidate genes,49,51 but the individual significance of most target genes is unclear. Apc mutant mice lacking CD44 and selected other Wnt-pathway targets develop fewer adenomas,52 but MYC Wnt seems especially vital because its absence in mouse intestines completely abrogates effects of acute APC loss.53,54

Frizzled Hereditary Nonpolyposis Colorectal Cancer LRP5/6 and the Role of DNA Mismatch Repair Plasma membrane Axin HNPCC, or Lynch syndrome, an autosomal-dominant disorder GSK-3 that confers about 70% lifetime risk of developing CRCs, usually APC before age 50, is estimated to account for 2% to 4% of all cases. Affected individuals do not lack colonic polyps (nearly all CRCs, Proteasomal syndromic or sporadic, arise within benign precursors), but de- ␤-catenin P degradation velop many fewer polyps than patients with FAP, a condition that must be excluded to satisfy diagnostic criteria for HNPCC (Table Nucleus 56.2).55 Cancers tend to develop in the ascending colon and pa- ␤-catenin tients are also predisposed to develop tumors of the endometrium (35% to 50% lifetime risk), ovary and upper urothelium (7% to 8% TCF/LEF risk), stomach, small intestine, biliary tract, and brain—a spectrum reflected in the revised Amsterdam II criteria (see Table 56.2).56 Cancers in HNPCC show pronounced variation in the lengths of microsatellite DNA sequences, and MSI at two or more among Transcription of a panel of five mono- and dinucleotide tracts (BAT26, BAT25, target genes D5S346, D2S123, and D17S250) confers the MSI-hi designation. (e.g., c-myc, cyclin D1) CRCs harboring CIN represent a distinct class and show MSS or, in a small fraction, instability of unclear significance at just one of the five test regions (MSI-lo). Figure 56.2 Outline of Wnt signaling, the key driver pathway in colorectal HNPCC results from germ-line mutations in any of several cancer. Members of the Wnt family of glycoprotein morphogens bind genes that enable DNA mismatch repair (MMR), a proofreading the cell surface coreceptors Frizzled and LRP5/6. In the absence of Wnt binding, normal cells use a complex containing APC, Axin, and other process that corrects base-pair mismatches and short insertions and cytoplasmic proteins to promote GSK-3β–mediated phosphorylation deletions in the normal course of DNA replication. MMR in mam- of the β-catenin N-terminus, which targets β-catenin for proteasomal malian cells is mediated by homologs of bacterial and yeast repair degradation (from Clevers H. Wnt/β-catenin signaling in development proteins, MutS homologs (MSH) 1 through 6, MutL homologs and disease. Cell 2006;127:469). Binding of a Wnt ligand to Frizzled and (MLH) 1 through 3, PMS1, and PMS2. Both MLH1 and PMS2 its obligate coreceptor LRP5/6 antagonizes the APC/Axin destruction are recruited to sites of DNA mismatch as a MutLα complex and complex, stabilizing β-catenin (CTNNB1), which moves into the nucleus in turn recruit MSH2-MSH6 (MutSβ) or MSH2-MSH3 (MutSβ) and coactivates genes through T-cell factor/lymphoid enhancer factor heterodimers to sites of 1-bp or 2- to 4-bp errors, respectively. These (TCF/LEF) transcription factors. Either of the two principal gatekeeper proteins efficiently excise the strand that carries the mismatch and events in colorectal cancer, inactivating APC or activating CTNNB1 mutations, results in constitutive, Wnt-independent stabilization of resynthesize and ligate the repaired DNA. Germ-line mutations β-catenin and unregulated activation of the cognate transcriptional in MSH2, MLH1, MSH6, and PMS2 together explain about 95% 57–59 program. Wnt signaling in the intestine is normally confined to crypt of kindreds, including a subset with germ-line loss of the stop progenitors, and its aberrant activation by APC or CTNNB1 mutations codon of TACSTD1, which results in silencing of its 3′ neighbor confers a permanent cryptlike state that favors cell replication. MSH2 by hypermethylation.60,61

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TABLE 56.2 CASP5 and BAX70; transcription factor genes, including TCF471; and the epidermal growth factor receptor (EGFR)72; but KRAS Criteria for Clinical Diagnosis of Hereditary and, especially, BRAF mutations are rare. CRC pathogenesis re- Nonpolyposis Colorectal Cancer quires deregulated APC–β-catenin gatekeeper function irrespective of MMR status.73 A. Revised Amsterdam Criteria (Clinical Diagnosis) MSI-hi is observed in 12% to 15% of sporadic cases of CRC,74 1. Three or more family members with histologically verified often in older patients with early-stage disease. Such tumors seem HNPCC-related cancers, one of whom is a first-degree to arise from sessile serrated adenomas in the ascending colon and relative of the other two do not reflect unrecognized germ-line mutation or somatic disrup- 2. Two successive affected generations tion of a known MMR gene.75 Rather, most but not all cases reflect 3. One or more of the HNPCC-related cancers (see C, which MLH1 gene inactivation by biallelic promoter hypermethylation follows) diagnosed before age 50 and show activating BRAF mutations and CIMP.76–78 4. Exclusion of familial adenomatous polyposis (FAP) B. Revised Bethesda Guidelines (Criteria to Prompt Microsatellite MYH-Associated Polyposis and Polymerase Instability Testing of Tumors) 1. Diagnosis of CRC before age 50 Proofreading-Associated Polyposis 2. Synchronous or metachronous presence of CRC or other HNPCC-associated cancer Germ-line mutations in MYH, a homolog of the Escherichia coli base excision-repair gene MutY cause MAP, a recessively inherited 3. CRC diagnosed before age 60 with histopathologic features 79 associated with MSI-hi syndrome of multiple adenomas and CRC. CRC develops later 4. CRC in at least one first-degree relative with an HNPCC- in life than in FAP, polyp numbers vary widely, and extracolonic related tumor, with one of the cancers diagnosed before tumors are less frequent than in HNPCC (see Table 56.1). Because age 50 MYH is a DNA glycosylase that helps repair oxidative DNA dam- 5. CRC in two or more first-degree relatives with HNPCC- age, tumors are not associated with MSI but with somatic G:C to related tumors, regardless of age T:A mutations, including in the APC gene. Two alleles, Y165C and G382D, account for most cases, and CRCs develop in ho- C. Spectrum of Sites for HNPCC-related Cancers mozygotes or compound heterozygotes, with no risk elevation Colon and rectum, endometrium, stomach, ovary, pancreas, in monoallelic carriers.80 Surveillance recommendations are the ureter and renal pelvis, biliary tract, small intestine, brain, same as in HNPCC. sebaceous gland adenomas, and keratoacanthomas Rare kindreds with a dominantly inherited high risk of CRC carry particular germ-line defects in POLE and POLD1, which

encode the proofreading exonuclease activities of the leading- and OF ONCOLOGY PRACTICE lagging-strand DNA polymerases ε and δ, respectively.81 Clinical MSI-hi colon cancers typically show exophytic growth, lym- findings of large adenomas and early-onset CRCs resemble those phoid infiltrates, mucinous signet-ring differentiation, and a in HNPCC or MAP, including elevated endometrial cancer risk medullary growth pattern; Bethesda guidelines (see Table 56.2) in women with mutant POLD1. Tumors carry thousands of muta- combine clinical and phenotypic features to facilitate a diagnosis tions, but stable microsatellite tracts reveal a third familial mutator of HNPCC.62 When these criteria are met, tumor DNA should mechanism in CRCs. Hypermutation in the absence of MSI ac- be tested either for MSI in a simple, polymerase chain reaction counts for about 3% of sporadic CRCs, nearly all of which have 26 (PCR)-based assay or by immunohistochemistry for the absence of a somatic POLE exonuclease domain and also APC mutations. the commonly implicated MLH1, MSH2, and MSH6 proteins.63 POLE and POLD1 are nonclassical tumor suppressors because, Because Bethesda guidelines might miss up to a quarter of cases, instead of deletion or truncation, specific missense mutations af- experts now recommend testing all colon cancers arising in pa- fect proofreading function, and the wild-type allele is usually tients under 70 years.64,65 Coupled with thorough personal and retained. Until further characterization of PPAP leads to formal family histories, positive results should prompt DNA testing for surveillance recommendations, it is prudent to adopt those devel- MLH1, MSH2, MSH6, or PMS2 mutations.66 The identification oped for HNPCC. of mutant alleles and carriers allows for the targeting of cost-effective screening and interventions that are proven to reduce mor- Familial Juvenile Polyposis and the Peutz- tality65 (e.g., preventive colonoscopy screening every 1 to 2 years, starting around 30 years of age; family counseling; aspirin therapy). Jeghers, Hereditary Mixed Polyposis, and Carriers should consider prophylactic subtotal colectomy, hyster- Cowden Syndromes ectomy, and oophorectomy; females should at least have an annual endometrial evaluation soon after age 30. Patients with FJP develop premalignant hamartomatous polyps in In incipient cancers, random events first disrupt function of the stomach or the small or large intestine by adolescence82,83 and the wild-type allele of a mutant MMR gene and the resulting may give a revealing family history, although a significant minority mutator phenotype promotes DNA replication errors at rates 102 represent the first case in their families. Germ-line mutations in to 103 times higher than the background.13,57 Consequently, ad- genes encoding the bone morphogenetic protein (BMP) receptor enomas progress into carcinomas over 3 to 5 years instead of 2 BMPR1A, the accessory TGF-β receptor endoglin, ENG, or the or more decades.67 Paradoxically, the prognosis for patients with SMAD4 signal transducer emphasize the role of TGF-β signaling MSI-hi CRCs is better than for those with sporadic MSS disease, in disease pathogenesis (see Table 56.1).84,85 Indeed, sporadic CRCs perhaps because many resulting somatic mutations place tumors are often insensitive to the growth inhibitory effects of TGF-β and at a disadvantage. Both of the most commonly inactivated genes, loss of BMP function in mice expands stem and progenitor cells, ACVR2A and TGFBR2, encode receptors for specific ligands of leading to polyposis or ectopic crypts.86–88 Not all patients carry the transforming growth factor beta (TGF-β) family and contain these mutations, indicating that additional genes remain undiscov- vulnerable mononucleotide tracts in their coding sequences.26,68 ered. Notably, a conditional Smad4 deletion from mouse intestinal TGF-β inhibits the proliferation of intestinal epithelial cells, and cells does not affect growth, whereas selective loss in T lymphocytes biallelic TGFBR2 inactivation is detected in over 90% of MSI- causes intestinal mucosal thickening and polyps.89 These findings hi and 15% of MSS, sporadic CRCs.69 Other genes mutated in confound simple interpretations of TGF-β function and implicate familial MSI-hi colon tumors encode the proapoptotic genes stromal inflammation in intestinal tumorigenesis. 762 Practice of Oncology / Cancers of the Gastrointestinal Tract

Patients with PJS also develop benign tumors that contain these factors converge on insulin signaling, some experts propose differentiated but disorganized cells (hamartomas), mainly in that insulin and insulinlike growth factors play a seminal role in the small intestine but also in the colon or stomach, sometimes CRCs.102 However, three of every four CRCs arise in individuals leading to hemorrhage or intussusception. PJS shows autosomal- lacking a well-defined risk factor, and it is unknown to what extent dominant inheritance and is associated with macular lesions on particular genotypes confer sensitivity to environmental variables. the skin and buccal mucosa; bladder and bronchial polyps; and The cancer spectrum in HNPCC or PPAP and the particular a propensity to develop a range of cancers, including those of the predilection for CRC remain unexplained. Colonic, endometrial, lung, breast, and female reproductive organs (see Table 56.1). The and selected other epithelia may be especially sensitive to the kind lifetime risk for all cancers exceeds 90%, the incidence of small of mutations that occur in the setting of defective DNA mismatch intestine, stomach, and pancreas cancers is 50 to 500 times higher and base-excision repair, loss of wild-type tumor suppressor alleles than the general population, and CRC risk is elevated nearly 100- may occur more readily in these tissues, or they may lack repair fold.90 Serine–threonine kinase 11 (STK11, also known as LKB1), safeguards that protect other cell types. the implicated tumor suppressor gene,91 acts at the nexus of diverse cellular pathways and functions. Its principal activity, exerted through the adenosine monophosphate (AMP)-activated protein Insights from Genomewide Association kinase AMPK, seems to be in linking nutrient and energy utili- Studies zation to controls over cellular structure, particularly cell polarity.92 STK11 also modulates the Rheb-GDP:Rheb-GTP cycle and The quarter or more of sporadic CRC cases with a familial com- downstream activities of the tuberous sclerosis gene TSC2 and the ponent103,104 probably have diverse molecular etiologies, with low mammalian target of rapamycin (mTOR),93 key regulators of pro- risk conferred by some common genetic variants and interaction tein synthesis and cell growth. The roles of STK11 in cell polar- of individual risk alleles with other genes and with environmental ity and metabolism are busy areas of research, likely to hold vital factors. Large multinational GWA studies have interrogated thou- clues into CRC pathogenesis and rational therapy. sands of genomes and, to date, have uncovered statistical associa- Confined to rare Ashkenazi Jewish kindreds descended from tion of CRC risk with at least 20 distinct loci, including those linked a single founder, patients with HMPS develop polyps of several to single nucleotide polymorphisms (SNPs) rs6983267 at 8q24.21, diverse morphologies and CRCs but no other cancers.94 A 40-kb rs4939827 on 18q21, and rs3802842 at 11q23 (Table 56.3). The duplication upstream of GREM1 seems to activate a distant en- frequency of risk alleles ranges from less than 10% to half or more hancer of this BMP antagonist gene, driving ectopic and high ex- of the human population and each one elevates CRC risk no more pression in the colonic epithelium.95 The resulting increased crypt than 7% to 25% above the background in persons with the nonrisk cell turnover likely accelerates the accumulation of oncogenic mu- allele.105,106 Even if homozygosity at some loci and additive effects tations. GREM1 is also the locus of a CRC risk allele identified at compound this risk, allele frequencies are such that the cumula- 15q13.3 in a GWA study.96 tive risk rises no more than 50% to 250% over the background. As Cowden disease encompasses diverse mucosal lesions, specific a result, the total effect of all identified risk variants explains, at cutaneous lesions (facial trichilemmomas and acral verrucous most, 5% to 7% of cases with a family history; it is not presently papules), and breast fibroadenomas, neurofibromas, lipomas, and feasible to predict an individual’s precise risk or modify screening meningiomas.97 The syndrome results from germ-line mutations in recommendations on the basis of known genotypes. Nevertheless, PTEN, a tumor suppressor gene encoding the phosphatase and ten- the identification of risk loci is a crucial advance for an eventually sin homolog deleted on chromosome 10,98 and the second most fre- thorough understanding of disease determinants. quently mutated gene in cancers after TP53. The lipid phosphatase The specific causal significance of most of these DNA sequence PTEN dephosphorylates key phosphoinositide (PI) signaling mol- variants is unclear and many localize far from coding genes, with ecules99 and accordingly regulates intracellular growth signaling growing evidence that they correspond to regulatory regions for negatively through PI-3 kinase and its downstream effectors AKT control of nearby genes. This implies that an altered expression and mTOR. The CRC risk in Cowden syndrome is modest, and of the linked genes either transforms normal colonocytes at low PTEN mutations are rare in sporadic cases, but protein immuno- frequency or, more likely, influences the oncogenic potential of staining is lost in about 40% of CRCs, often as a result of promoter other events. Particularly strong association occurs with the SNP hypermethylation,100 thus highlighting its tumor suppressor role. rs6983267 at 8q24.21, which lies in a gene desert near low-risk susceptibility alleles for breast and prostate cancers. Molecular studies Significance of Inherited Syndromes of indicate that each culpable region acts as a tissue-specific enhancer controlling the nearest gene, CMYC,107–109 thereby modulating Elevated Colorectal Cancer Risk disease risk.110 Attesting to the role of TGF-β signaling in colonic epithelial homeostasis, risk alleles on chromosomes 18q21 and Following a clinical diagnosis of the previous Mendelian syn- 14q22 are linked to SMAD7 and BMP4, respectively.111,112 Some dromes, patients and family members should be tested for perti- genes near risk variants are not expressed in the colonic mucosa, nent germ-line mutations, receive genetic counseling, and enter suggesting a role for extraepithelial genetic effects from stromal or programs for cancer prevention and screening. The corresponding immune cells. In summary, at least 20 common polymorphisms molecular defects profoundly inform an understanding of sporadic elevate CRC risk modestly and with sufficiently low penetrance CRCs, in particular, revealing the seminal role of Wnt signaling that effect detection requires large population-based analyses. The and early, rate-limiting effects of APC inactivation or CTNNB1 ac- pathophysiologic functions of these loci will likely inform future tivation. Similarly, STK11 and PTEN loss in inherited and sporadic prevention and screening strategies and help determine how risk CRCs shed light on crucial molecular pathways, whereas HNPCC alleles interact with environmental factors. and PPAP help classify the disease and reveal the significance of features such as MSI, which is present in 12% to 15% of sporadic cases. Even in the absence of a recognized predisposition syndrome, individuals with a history of CRC in a first-degree relative ONCOGENE AND TUMOR SUPPRESSOR are up to 4 times more likely to develop CRC than those without a GENE MUTATIONS IN COLORECTAL family history. Specific environmental factors that compound the CANCER PROGRESSION risk of developing CRCs are complex and insufficiently characterized, but include obesity, excessive consumption of red meat, Building on the foundation of lost gatekeeper functions in Wnt physical inactivity, and vitamin D deficiency. 101 Because many of signaling, somatic mutations in oncogenes and tumor suppressor

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TABLE 56.3 Single Nucleotide Polymorphisms Conferring Increased Risk of Colorectal Cancer

Chromosomal Imputed SNP Risk Allele Frequency in Location (Risk Allele) Nearest Gene Controls Odds Ratio, 95% CI P Value 18q21.1 rs4939827 (T) SMAD7 0.53 1.16–1.24 8 × 10−28 8q23.3 rs16892766 (C) EIF3H 0.07 1.20–1.34 3 × 10−18 8q24.21 rs6983267 (G) MYC 0.49 1.16–1.39 1 × 10−14 10p14 rs10795668 (A) 0.48 1.10–1.16 3 × 10−13 6p21 rs1321311 (A) CDKN1A 0.25 1.07–1.13 1 × 10−10 20p12.3 rs961253 (A) 0.36 1.08–1.16 2 × 10−10 11q13.4 rs3824999 (C) POLD3 0.51 1.05–1.10 4 × 10−10 11q23.1 rs3802842 (C) C11orf93 0.29 1.08–1.15 6 × 10−10 Xp22.2 rs5934683 (T) SHROOM2 0.38 1.04–1.10 7 × 10−10 14q22.2 rs4444235 (C) BMP4 0.46 1.08–1.15 8 × 10−10 19q13.11 rs10411210 (C) RHPN2 0.90 1.10–1.20 5 × 10−9 16q22.1 rs9929218 (G) CDH1 0.29 1.06–1.12 1 × 10−8 15q13.3 rs4779584 (T) GREM1 0.19 1.14–1.34 5 × 10−7 1q41 rs6691170 (T) 0.35 1.13 20q13.33 rs4925386 (C) LAMA5 0.68 1.11 12q13.3 rs11169552 (C) 0.72 1.12 3q26.2 rs10936599 (C) MYNN 0.76 1.07

CI, confidence interval. PRACTICE OF ONCOLOGY PRACTICE genes cumulatively confer malignant properties. The particular potentially deregulate several effector pathways for cell survival, spectrum of recurring mutations in CRC provides a framework proliferation, invasion, and metastasis (Fig. 56.3). Constitutive to decipher the oncogenic signaling circuits and develop ratio- phosphorylation of ERKs accompanies KRAS mutation, reflect- nal targeted drugs (Table 56.4). The high collective frequency ing the activation of the ERK/MAPK pathway.118 KRAS-mediated of recurrent KRAS, BRAF, and PIK3CA mutations places EGFR growth factor signaling recruits RAF kinases to the plasma mem- and downstream extracellular signal-regulated kinase (ERK, also brane and triggers MEK1 and MEK2 kinases to activate ERK1 known as mitogen-activated protein kinase [MAPK]) signaling at and ERK2, which in turn phosphorylate proteins that control the 119 the center of research and therapeutic efforts. G1–S cell cycle transition, among other substrates. Although other, non–KRAS-mediated growth factor pathways also activate the MAPK cascade, signaling in CRC is most often deregulated The KRAS, BRAF, and PIK3CA Oncogenes through activating mutations in KRAS or BRAF. BRAF is mutated in about 10% of CRCs, especially those associated with MSI Ras-family G-proteins transduce growth factor signals and are aber- and CIMP.120,121 The most common BRAF mutation in CRCs, rantly activated in a wide variety of cancers. KRAS is mutated in melanoma, and selected other cancers, V600E, affects a residue about 40% of CRCs113 and NRAS in another 5% to 8% of cases. within the activation loop of the kinase domain and constitu- Mutations in both genes cluster in codons 12 or 13, and less fre- tively activates kinase function, probably by several hundred-fold quently at codon 61. KRAS mutations appear even in lesions of and acting as a phosphomimetic.122 Like mutant KRAS, acti- low malignant potential, such as aberrant crypt foci lacking dys- vated BRAF also phosphorylates ERKs, lifting intrinsic restraints plasia,114 and certainly in small polyps, although their frequency on cell growth. Indeed, KRAS, NRAS, and BRAF mutations are increases with lesion size.115 A KRAS mutation is not required to mutually exclusive in CRCs,26,120 highlighting their actions in a initiate adenomas, but contributes to disease progression when common cellular pathway and reflecting alternative routes to the combined with other genetic alterations, and specific interfer- same end. ence with mutant KRAS in CRC cells and xenografts impedes Several features of BRAF-mutant CRCs are noteworthy. First, cell growth.116,117 Among the many different growth factor recep- the defect confers a worse prognosis than KRAS mutations in tor signals that KRAS transduces in diverse cells, its activity in the advanced disease,9,123 which indicates distinctive molecular or colonic epithelium and CRC is particularly related to EGFR sig- cellular features. Second, the BRAF mutation is a hallmark of non- naling, which is important for two reasons. First, inasmuch as Wnt familial MSI-hi CRC and occurs early in the natural history of ses- and EGFR signaling drive normal gut epithelial turnover, CRC ile serrated adenomas.121 Third, whereas forced Kras activation in appears to subvert tissue-specific homeostatic circuits. Second, be- the mouse intestine has a modest independent consequence,124,125 cause a KRAS mutation introduces intracellular defects that lock BrafV600E expression rapidly induces persistent generalized EGFR signaling in the “on” state, EGFR antibodies are ineffective hyperplasia with a high penetrance of crypt dysplasia, serrated in this subset of CRCs8 and targeted therapies will need to inter- morphology, and MSI-hi invasive cancers that show Wnt pathway fere further downstream in the signaling pathway. activation.126 Fourth, tumors mutant for either KRAS or BRAF Because KRAS acts early in transducing signals from EGFR intrinsically resist treatment with EGFR antibodies.9,123 Fifth, and other receptor tyrosine kinases, KRAS mutations can BRAFV600E mutant melanomas initially respond to selective, 764 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 56.4 Recurrent Somatic Gene Mutations in Human Colorectal Cancers

Gene Frequency CRC Class Known Cellular or Oncogenic Function Oncogenes KRAS 35%–40% CIN RTK signaling PIK3CA 18%–20% Mostly CIN RTK signaling BRAF 7%–15% MSI-hi, CIMP RTK signaling NRAS 9% CIN RTK signaling ERBB3 ∼8% CIN RTK signaling CTNNB1 ∼5% All Wnt pathway activation Tumor Suppressor Genes APC 85% All Wnt pathway inactivation TP53 50% CIN predominant Stress, hypoxia response; DNA replication SMAD4 10% CIN FBXW7 10% CIN SOX9 5% CIN Wnt-dependent ISC function ACVR2A MSI-hi Wnt pathway activity TGFBR2 MSI-hi TGF-β signaling MSH3 MSI-hi DNA mismatch repair MSH6 MSI-hi DNA mismatch repair POLE Hypermutated (non-MSI) DNA polymerase ε Epigenetic Modiﬁer Genes (Roles Are Emerging) ARID1A MSI-hi Chromatin remodeling SIN3A Transcriptional repression SMARCA5 Chromatin remodeling NCOR1 Transcriptional repression JARID2 Histone modification TET1, 2, 3 DNA demethylation

RTK, receptor tyrosine kinase; ISC, intestinal stem cell.

ATP-competitive BRAF inhibitors such as vemurafenib and take be that mutant KRAS activates PI3K signaling inefficiently.133 months to manifest secondary resistance,127 whereas BRAFV600E More likely, oncogenic signaling pathways are less strictly linear mutant CRCs are intrinsically resistant and barely respond to the than is convenient to depict. Indeed, seemingly parallel streams of same agents. This is because BRAF inhibition in CRC quickly KRAS signaling through RAF–MEK and PI3K (see Fig. 56.3) in- induces feedback EGFR signaling through KRAS and CRAF, re- teract extensively with one another and both streams feed into the storing stimuli for cell replication (melanoma cells hardly express mTOR, which coordinates cell growth with nutrient responses.134 EGFR and therefore avoid this feedback activation).128,129 Because Lastly, insulinlike growth factor 2 (IGF2) is overexpressed in at BRAF inhibition renders cells newly sensitive to direct antagonism least 15% of CRCs as a result of focal gene amplifications, loss of of EGFR, a combined antagonism of BRAF and EGFR signaling imprinting, and other mechanisms.26 Overexpression of IGF2 and may be beneficial. its downstream effector IRS2 is mutually exclusive with PIK3CA KRAS signals are transduced not only through ERKs, but also mutations and PTEN deletions, strongly implying that the under- through phosphatidylinositol (PI) 3-kinase (PI3K),118,130 which lying genetic aberrations represent alternative means to disrupt the phosphorylates the intracellular lipid PI-4,5-bisphosphate at the same signaling circuit. three position, triggering a cascade that promotes cell survival and growth.131 Up to 20% of CRCs carry activating mutations in PIK3CA, the gene encoding the catalytic p110 subunit of PI3K. MYC, CDK8, and Control of Cell Growth and Mutations cluster in exons 9 and 20 and seem to arise late in the Metabolism adenoma–carcinoma sequence, possibly coincident with inva- sion132; many fewer CRCs carry related PIK3R1 mutations. Cel- Although the MYC and CDK8 oncogenes are rarely mutated in lular PI3K activity is countered by the product of the PTEN gene, CRC, considerable gene amplification is seen in at least 10% of which is inactivated (usually by deletion) in another 10% of cases. cases, with moderate increases in copy number and expression in Although both PI3K and BRAF act downstream of KRAS, only up to 25% of cases.26,135 Aberrant MYC gene regulation likely ex- BRAF and KRAS mutations are mutually exclusive; up to one-fifth plains the significant GWA studies risk allele rs6983267 and MYC of KRAS-mutant CRCs also have PIK3CA mutations, implying expression is not only a prominent outcome of Wnt signaling,49 that these oncogenes are not trivially redundant. One reason could but may account for the bulk of the tumor effect in Apc-mutant

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Ligand Receptor tyrosine kinase Cell membrane

P P PIP2 PIP3 IRS P P P

P13K PTEN

Ras AKT

Figure 56.3 Signaling pathways, oncogenic mutations, and therapeutic opportunities in CRC. Raf TSC1 TSC2 It is instructive to consider common genetic alterations in CRC in light of a common canonical outline of signaling through receptor tyrosine kinases, among which the EGFR is a prime MEK Rheb example. KRAS, the oncogene mutated in up to 40% of CRCs, signals receptor activation through RAF proteins (including BRAF, which is mutated in 5% to 8% of CRCs) and phosphatidylinositol 3-kinase (PI3K), whose catalytic PIK3CA subunit MAPK mTOR is mutated in 15% to 20% of CRCs. These transducers in turn activate the intracellular Raptor mitogen-activated protein kinase and AKT or mTOR pathways, respectively. Hence, common mutations confer growth factor independence on cells, resulting in dysregulated proliferation, protein synthesis, and metabolism. They also Cell cycle progression Protein synthesis represent promising targets for therapeutic and proliferation and cell growth interference with aberrantly activated signaling cascades. PRACTICE OF ONCOLOGY PRACTICE mouse intestines.54 CDK8, a cyclin-dependent kinase component colorectal cancer, a receptor for Netrin axonal guidance proteins) of the Mediator complex, couples transcription factors to the basal in the rest. SMAD4/DPC4 and SMAD2 are positive and negative transcriptional machinery and hence resembles MYC in regulat- regulators of TGF-β signaling, respectively, and closely linked on ing thousands of genes, including those necessary for cellular me- 18q. Somatic SMAD4 mutations are present in 10% to 15% of tabolism, proliferation, and self-renewal. CDK8 activity in CRC is CRCs with LOH, and germ-line mutations are noted in some FJP particularly associated with β-catenin.135 Indeed, although APC, kindreds141; SMAD2 and DCC are rarely mutated in CRC,142 but CTNNB1, and probably RSPO mutations kick start colonic ad- DCC mRNA and protein are lost in >50% of cases.143 Together, enomas, additional genetic events in CRC potentiate Wnt activity. these findings suggest a complex, multifactorial basis for the selec- Disrupting this seminally important pathway and/or its downstream tion of 18q LOH in CRC. effector MYC may therefore be imperative in CRC therapy, but FBXW7 (F-box and WD40 repeat domain containing 7), poses formidable challenges, in part because that requires interfer- another gene frequently inactivated in CRCs, encodes a receptor ing with protein–protein interactions downstream of conventional subunit of Skp, Cullin, F-box-containing (SCF)-E3 ubiquitin ligase druggable nodes.136 complexes, which target multiple regulators of cell growth, such as MYC and JUN transcription factors, for degradation. Monoallelic missense mutations tend to cluster in arginine residues within a TP53 and Other Tumor Suppressors β-propeller domain that recognizes specific substrates, including NOTCH, JUN, DEK, and TGIF1 in intestinal cells.144,145 The allelic loss of chromosome 17p is observed in three of every four CRCs but <10% of adenomatous polyps.115 The remaining TP53 allele is inactivated in most tumors with 17p loss of heterozygosity THE MUTATIONAL LANDSCAPE OF (LOH), most often at codons 175, 245, 248, 273, or 282.137 TP53 COLORECTAL CANCER mutations, found in half of all CRCs and LOH of 17p thus appear to arise late in the transition from adenoma to carcinoma, possibly Early analyses of protein-coding genes in a few CRCs produced facilitating progression. Cells with an intact TP53 function undergo average estimates of 81 mutations per tumor and spawned the cell cycle arrest and apoptosis when faced with stress from DNA useful idea that the mutational landscape of CRC contains few damage, hypoxia, reduced nutrient access, or aneuploidy. TP53 loss mountains (genes such as APC, KRAS, TP53, and PIK3CA, with may allow cells to overcome these barriers to tumor survival and frequent mutations) or hills (less frequent but functional muta- progression, but confers no specific disease features in CRCs. tions [e.g., BRAFV600E]).146 Although many additional events are LOH of chromosome 18q, which is rare in small to midsize individually infrequent and may contribute to neoplasia sporadi- adenomas, is observed in >60% of CRCs and nearly all liver cally or represent passenger mutations, they tend to congregate in metastases from MSS tumors.138 This sequence implicates loss genes that control cell adhesion, signaling, DNA topology, and the of resident genes in disease progression, but 18q LOH does not cell cycle.147 In general, CRCs show a genomewide bias toward by itself confer a poor prognosis.139 The minimal common re- C:G to T:A transitions at 5′-CpG-3′ sites and a lower frequency of gion of LOH contains two candidate tumor suppressor genes140: mutations in 5′-TpC-3′ dinucleotides than observed, for example, SMAD4 (DPC4) in about one-third of cases and DCC (deleted in in breast cancer.146 Such findings may eventually link specific 766 Practice of Oncology / Cancers of the Gastrointestinal Tract environmental factors to characteristic mutational spectra. More- Animal Models of Colorectal Cancer Genetics over, an average of 17 genes are deleted or amplified to 12 or more copies per CRC cell,148 and the oncogenes ERBB2, MYC, KRAS, Similar intestinal cell properties and genetics in humans and mice MYB, IGF2, CCND1, and CDK8 are in aggregate amplified or make the laboratory mouse valuable in the investigation of CRCs. overexpressed in most cases, usually together with neighboring The multiple intestinal neoplasia (Min) strain has a truncating genes. Nearly half the copy number alterations—28 amplifications mutation in Apc and phenocopies human FAP with respect to in- and 22 deletions, including 15 recurrent changes encompassing testinal adenomas,157 although tumors form mainly in the small <12 genes—identified in one study149 also appear in other can- bowel. ApcMin mice are a cornerstone for the genetic analysis of cers. CRCs thus reflect the perturbation of selected pathways of intestinal polyps and deregulated Wnt signaling, but other Apc replicative and tissue homeostasis, some in common with most mutants also have value. A D716 allele increases the number of cancers and others restricted to CRCs. adenomas, all with loss of the wild-type copy,158 whereas a larger Detailed data from two genome-scale studies of nearly 300 fraction of Apc1638N adenomas appear in the colon159; ApcPirc rats CRCs and matched normal tissue corroborate these general ob- carry a stop codon at position 1137 and more than half the tu- servations and provide reliable catalogs of genetic alterations.26,41 mors arise in the colon.160 Deletion of the N-terminal degrada- These comprehensive efforts revealed RSPO gene fusions and up tion domain of murine β-catenin also stabilizes the protein and to 10% incidence of monoallelic missense mutations in SOX9, induces widespread intestinal polyposis.161 Expression of activated a transcription factor target of Wnt signaling that is highly ex- Kras alleles in the intestinal epithelium of otherwise intact mice pressed and active in intestinal crypt stem and progenitor cells.150 barely affects cell signaling or proliferation, but similar to human Additionally, MSI-hi tumors showed frequent mutations in the CRCs, expression on Apc mutant backgrounds expands progenitor ARID1A chromatin remodeling factor gene, which may affect a cell numbers and hastens adenoma progression.124,125 In contrast, broad swath of other genes. An updated, partial list of recurrent activated Braf induces crypt hyperplasia, followed by invasive can- genetic alterations in CRC (see Table 56.4) indicates that few new cers with deregulated Wnt and ERK signaling.126 The inactivation mutations fall in genes that appeal to the pharmaceutical industry, of murine genes for DNA MMR162 leads to more lymphomas than such as tyrosine or serine/threonine kinases. intestinal tumors, with some mutants showing neither but revealing roles in meiosis; MMR is nevertheless necessary for protecting Prognostic and Predictive Value of Molecular cells from mutation and malignancy. Properties and Tumor Genotypes Integrated Insights from the Study of Human These specific genetic alterations might confer particular clinical Colorectal Cancers and Mouse Intestinal behaviors, prognoses, or drug responses. Mutational, chromosome Crypts structural, and gene expression profiles are virtually identical in colonic and rectal adenocarcinomas. Aneuploidy and tetraploidy Animal studies strongly suggest that CRCs originate in resident confer a worse prognosis than MSI-hi status in early-stage dis- intestinal epithelial stem cells.50 These cells, characterized mainly ease,151 and the benefits of adjuvant 5-fluorouracil therapy may be 152,153 in the mouse small bowel, replicate frequently and neutral drift restricted to patients with MSS tumors. Because nearly all ensures that each normal crypt contains a monoclonal population CRCs have a constitutive Wnt pathway activity, this element alone of five to eight functional stem cells.163,164 Gatekeeper mutations has limited prognostic value and outcomes seem unaffected by in APC or CTNNB1 in one such cell induce constitutive Wnt whether APC or CTNNB1 mutations stimulate the pathway. The pathway activity; the attendant growth advantage allows this mu- presence of KRAS or BRAF mutations and possibly also PIK3CA tant stem cell to dominate that crypt and eventually take hold as mutation or loss of PTEN expression predicts a lack of response 8,154 a monoclonal population. Notably, the outcome of this stochastic to EGFR monoclonal antibodies. These are important ob- process is not inevitable: Neutral drift permits either wild-type or servations because they direct treatment decisions and because, APC-mutant cells to replace each other quite rapidly, but a selective unlike leukemias or breast cancer, CRCs had previously resisted advantage in the latter gives them a demonstrable edge over their subgrouping on the basis of specific gene alterations. For example, wild-type siblings.165 Once a mutant stem cell clone is established, mutations in the two most frequently affected oncogenes, KRAS with no competing wild-type cells remaining in that crypt, it can or PIK3CA, seem not to impact survival in stage III or stage IV 9,155 flourish indefinitely and accumulate mutations as they occur, by disease treated with chemotherapy, although they will likely chance or by virtue of a hypermutable state, so long as a mutation predict responses to new agents that target MEK or PI3 kinase sig- is not lethal or severely detrimental. Again, the outcome is not in- naling, respectively. Patients with metastatic BRAF-mutant CRC evitable: Few polyps advance into carcinomas and others may even have especially low survival and respond poorly to current chemo- regress. Eventually, various combinations of mutations that co-opt therapy regimens, including adjuvant fluoropyrimidines in stage 9,156 existing signaling circuits confer invasive properties on a fraction III disease. of adenomas. Indeed, the bulk of observed mutations represent alternative means to dysregulate the same few pathways—Wnt, EGFR, TGF-β, IGF2, and PI3K—that control normal colonic cell AN INTEGRATED MODEL FOR turnover. Therefore, although specific genes, such asBRAF and COLORECTAL CANCER INITIATION AND PIK3CA, represent obvious targets for molecular therapy, it may be PROGRESSION more useful in the long run to consider CRCs with broad respect to the pathways in which commonly mutated genes operate. Intensive molecular investigation has informed our understanding of CRC for more than 2 decades, with crucial independent contributions from delineation of the adenoma–carcinoma sequence, SUMMARY uncommon familial syndromes, the Wnt–Rspo–β-catenin pathway, and EGFR signaling through the KRAS–BRAF–ERK and The adenoma–carcinoma sequence represents the overt patho- PIK3CA–AKT–mTOR pathways. Together with whole-genome logic manifestation of sequential genetic alterations that promote analyses of CRC and refined investigation of intestinal crypt biol- cell growth, survival, and invasion. Molecular genetic studies have ogy in animals, a large corpus of knowledge now permits a coher- revealed crucial underlying mutations and the contribution of spe- ent model of disease initiation and advance. cific defects toward CRC pathogenesis. Colonic adenomas begin

tahir99 - UnitedVRG Chapter 56 Molecular Biology of Colorectal Cancer 767 with deregulated Wnt signaling and this pathway’s functions in in- selection of signaling and homeostatic pathways, revealing candi- testinal crypt homeostasis lead us to interpret cancer in relation to date therapeutic targets. Further work on the biologic functions of pools of normal tissue stem cells. MSI-hi distinguishes CRCs that inherited and somatic mutations will help design novel, rational, arise in the setting of HNPCC and about 15% of sporadic cases and targeted therapies. Much also remains unknown about how from the larger fraction of cases with CIN, leading to a molecular environmental factors impinge on the implicated key pathways classification into at least three disease subgroups with distinctive to modulate CRC risk and about specific interventions to prevent features, natural histories, and treatment considerations. Somatic a cancer whose incidence and lethality in developed countries is mutations associated with tumor progression involve a small second only to lung cancer.

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The consensus coding sequences of 1998;58:3455–3460. human breast and colorectal cancers. Science 2006;314:268–274. 79. Sieber OM, Lipton L, Crabtree M, et al. Multiple colorectal adenomas, clas- 157. Moser AR, Pitot HC, Dove WF. A dominant mutation that predisposes to sic adenomatous polyposis, and germ-line mutations in MYH. N Engl J Med multiple intestinal neoplasia in the mouse. Science 1990;247:322–324. 2003;348:791–799. 161. Harada N, Tamai Y, Ishikawa T, et al. Intestinal polyposis in mice with a 81. Palles C, Cazier JB, Howarth KM, et al. Germline mutations affecting the dominant stable mutation of the beta-catenin gene. EMBO J 1999;18: proofreading domains of POLE and POLD1 predispose to colorectal adeno- 5931–5942. mas and carcinomas. Nat Genet 2013;45:136–144. 163. Lopez-Garcia C, Klein AM, Simons BD, et al. Intestinal stem cell replace- 84. Howe JR, Sayed MG, Ahmed AF, et al. The prevalence of MADH4 and ment follows a pattern of neutral drift. Science 2010;330:822–825. BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, 164. Snippert HJ, van der Flier LG, Sato T, et al. Intestinal crypt homeostasis and ACVR1 mutations. J Med Genet 2004;41:484–491. results from neutral competition between symmetrically dividing Lgr5 stem 85. Sweet K, Willis J, Zhou XP, et al. Molecular classification of patients with cells. Cell 2010;143:134–144. unexplained hamartomatous and hyperplastic polyposis. J Am Med Assoc 165. Vermeulen L, Morrissey E, van der Heijden M, et al. Defining stem cell 2005;294:2465–2473. dynamics in models of intestinal tumor initiation. Science 2013;342:995–998. 57 Cancer of the Colon

Steven K. Libutti, Leonard B. Saltz, Christopher G. Willett, and Rebecca A. Levine

INTRODUCTION speaking, CRC incidence and mortality rates are the greatest in developed Western nations.1,7 The reader is referred to the most A more thorough understanding of the molecular basis for this recent detailed incidence and mortality rates in different coun- disease, coupled with the development of new therapeutic ap- tries over time according to gender, ethnicity, and anatomic site proaches, has dramatically altered the way in which patients with as established by the National Cancer Institute on their website. colorectal cancer (CRC) are managed. This chapter and the one As mentioned, there appears to be a recent decrease in age- that follows will provide an up-to-date description of the current standardized CRC incidence and mortality rates within the United state of the science and outline a multidisciplinary approach to the States. From 1999 to 2006, CRC incidence and mortality both patient with colon or rectal cancer. decreased.2 Furthermore, 5-year survival improved. These trends are apparent regardless of gender, race, or ethnic group, except for Native Americans. Although at an initial glance one might invoke EPIDEMIOLOGY alterations in dietary and lifestyle factors, or the utilization of chemopreventive agents, it is clear that enhanced use of colonoscopy with polypectomy represents a significant reason for the improve- Incidence and Mortality ments in trends in some areas.8 Globally, nearly 1,200,000 new CRC cases are believed to occur, which accounts for approximately 10% of all incident cancers, and Emigration Patterns in Population Groups mortality from CRC is estimated at nearly 609,000.1 In 2010, there were an estimated 141,570 new cases of CRC and 51,370 deaths in Seminal studies have revealed that migrants from low-incident the United States.2 As such, CRC accounts for nearly 10% of can- areas to high-incident areas assume the incidence of the host coun- cer mortality in the United States. Prevalence estimates reveal that try within one generation.9–12 For example, for Chinese who immi- in unscreened individuals age 50 years or older, there is a 0.5% to grate to the United States, higher CRC rates have been ascribed to 2.0% chance of harboring an invasive CRC, a 1.0% to 1.6% chance greater meat consumption and diminished physical activity in con- of an in situ carcinoma, a 7% to 10% chance of a large (≥1 cm) trast to controls within their original country.10 These and other adenoma, and a 25% to 40% chance of an adenoma of any size.3 studies underscore the importance of environmental exposure in Age impacts CRC incidence greater than any other demo- CRC incidence and provide a platform for attention to dietary and graphic factor. To that end, sporadic CRC increases dramatically lifestyle modification as preventive measures. above the age of 45 to 50 years for all groups. In almost all countries, age-standardized incidence rates are less for women than for men. Although CRC incidence has been steadily decreasing in the United Race and Ethnicity States and Canada, the incidence is rapidly increasing in Japan, Korea, and China.1 In the United States from 2002 to 2006, the age- Although dietary and lifestyle factors are of paramount importance standardized incidence rates per 100,000 population were 59.0 for in low-incident regions of the world, especially Asia and Africa, men and 43.6 for women when combined for all races.2 Recogniz- nonetheless there are certain trends along racial or ethnic lines. ing that decreases in age-standardized CRC incidence and mortality For example, an inherited adenomatosis polyposis coli (APC) rates are apparent in the United States over the past 10 to 15 years, gene mutation, I1307K, confers a higher risk of CRC within cer- such trends may be counterbalanced by prolonged longevity. tain Ashkenazi Jewish families that is not apparent in other ethnic groups.13,14 Inherited mutations in the DNA mismatch repair While the incidence of CRC in the United States has decreased 15 overall, presumably due to aggressive screening of the population genes may be more common among African Americans, in part accounting for anatomic variation in colon cancers among races in over age 50, there has been a dramatic increase in younger patients. 16,17 A new study using data from the Surveillance Epidemiology and End the United States, an area that is receiving much attention in Results (SEER) program found a rising incidence of CRC over the epidemiology- and biology-based research. last 20 years in patients aged 20 to 49. The most pronounced growth One recent study extracted data from the Adjuvant Colon was in the age group 40 to 44 where colon and rectal cancer increased Cancer ENdpoinTs (ACCENT) collaborative group database 56% and 94%, respectively. Based on these findings and the fact that to analyze time-to-event end points for black and white patients CRC in younger patients tends to be more advanced, the authors participating in 12 randomized controlled adjuvant phase 3 tri- recommend lowering the age for average risk screening by 10 years.4,5 als of resected stage II and III colon cancer. In this cohort of 14,611 patients—controlling for sex, stage, age, and treatment type—both overall 5-year survival rates and 3-year recurrence-free Geographic Variation survival rates were significantly worse for black patients (68.2% versus 72.8% and 68.4% versus 72.1%, respectively). However, The incidence rate for Alaskan Natives exceeds 70 per 100,000,6 recurrence-free interval was similar, arguing against a differential while that for Gambia and Algeria is <2 per 100,000.7 Generally response to the adjuvant therapy itself. The authors concluded that 768

tahir99 - UnitedVRG Chapter 57 Cancer of the Colon 769 poorer outcomes were more likely related to confounding factors relatives of persons with CRC.28,29 The National Polyp Study not measured such as toxicity, comorbid conditions, and racial dis- reveals compelling data; the relative risk (RR) for parents and parities in care for recurrent disease.18 siblings of patients with adenomas compared to spousal controls was 1.8, which increased to 2.6 if the proband was younger than 30 Socioeconomic Factors age 60 at adenoma detection. Provocative assessments of population groups suggest a dominantly inherited susceptibility to colorectal adenomas and cancer, Generally, cancer incidence and mortality rates have been higher which may account for the majority of sporadic CRC, but this may in economically advantaged countries.19,20 This may be related to have variable inheritance based on the degree of exposure to envi- consumption of a high fat and high red meat diet, lack of physical ronmental factors.31 What are these susceptibility factors? The an- activity with resulting obesity, and variations in mortality causes swer has yet to emerge. Nonetheless, genetic polymorphisms may over a longitudinal period of time. be of paramount importance, such as in glutathione-s-transferase,32 ethylene tetrahydrofolate reductase,33,34 and N-acetyltransferases, Anatomic Shift especially NAT1 and NAT2.35 In fact, genetic polymorphisms can vary among different racial and ethnic groups, which may provide Classically, colon cancer was believed to be a disease of the left clues to the geographic variation of CRC as well. or distal colon. However, the incidence of right-sided or proximal colon cancer has been increasing in North America17,21 and Europe.22 Similar trends have been observed in Asian countries.23 Environmental Factors This anatomic shift is likely multifactorial: (1) due to increased longevity; (2) as a response to luminal procarcinogens and carcino- Seminal studies have underscored the importance of environmen- gens, which can vary between different sites of the colon and rectal factors as contributing to the pathogenesis of CRC. One has to tum; and (3) because of genetic factors, which can preferentially take population-based studies into the context of methodologies involve defects in mismatch repair genes with resulting microsatel- employed, lead-time bias, time-lag issues, definition of surrogate lite instability (MSI) in proximal colon cancers and chromosomal and true end points, and the role of susceptibility factors. instability pathway predominant in left-sided colon and rectal One such population-based study recently evaluated risk cancers. These developments in anatomic variation will neces- factors for CRC from the Women’s Health Initiative, a compre- sarily impact considerably on screening procedures, response to hensive prospectively collected database of 150,912 postmeno- chemoprevention, response to chemotherapy, and, ultimately, pausal women, in which 1,210 developed colon cancer and 282 disease-specific survival.24–26 developed rectal cancer. Eleven risk factors were independently associated with colon cancer, some which have little or no previous support in the literature (age, waist girth, use of hormone PRACTICE OF ONCOLOGY ETIOLOGY: GENETIC AND therapy at baseline [protective], years smoked, arthritis [protective ENVIRONMENTAL RISK FACTORS presumably due to medications used], relatives with CRC, lower hematocrit levels, fatigue, diabetes, less use of sleep medication, and cholecystectomy). Three of these factors were also signifi- Inherited Predisposition cantly associated with an increased risk of rectal cancer (age, waist girth, and not taking hormone therapy).36 Family history confers an increased lifetime risk of CRC, but that enhanced risk varies depending on the nature of the family history (Table 57.1). Familial factors contribute importantly to the Diet risk of sporadic CRC, depending upon the involvement of first- or second-degree relatives and the age of onset of CRC. Involvement Total Calories of at least one first-degree relative with CRC serves to double the 27 Obesity and total caloric intake are independent risk factors for risk of CRC. There is further enhancement of the risk if a case is CRC as revealed by cohort and case-control studies.37,38 Increased affected prior to the age of 60. Similarly, the likelihood of harbor- body mass may result in a two-fold increase in CRC risk, with a ing premalignant adenomas or CRC is increased in first-degree strong association in men with colon but not rectal cancer. Weight gains during early to middle adulthood have also recently been linked with increased risk of colon but not rectal cancer. This rela- TABLE 57.1 tionship too seems more prominent in men than women in a large prospective study.39 Etiology of Colon Cancer: Environmental Factors Meat, Fat, and Protein Increased Incidence Decreased Incidence Ingestion of red meat but not white meat is associated with an 40,41 High-caloric diet High-fiber diet?? increased CRC risk, and as such, per capita consumption of red meat is a potent independent risk factor. Whether the total High red meat consumption Antioxidant vitamins abstinence from red meat leads to a decreased CRC incidence Overcooked red meat?? Fresh fruit/vegetables has not been clarified, as there are studies with opposing results.42 Also unclear is whether the type of red meat or the degree of pro- High saturated fats Nonsteroidal anti-inflammatories cessing or cooking method make any difference. While Probst- Excess alcohol consumption Coffee Hensch et al.43 found fried, barbecued, and processed meats to be Cigarette smoking High calcium associated with CRC risk, especially for rectal cancer, with odds ratio (OR) of 6, follow-up reports do not consistently support these Sedentary lifestyle High Magnesium claims. In the population-based Norwegian Women and Cancer Obesity Bisphosphonates cohort including 84,538 participants, highly processed meat Diabetes intake (especially sausage) was associated with increased CRC risk but meat cooking methods and total meat intake were not.44 770 Practice of Oncology / Cancers of the Gastrointestinal Tract

A second study of 53,988 participants reported no difference with Taking this nutritional data a step further, Bamia et al.56 re- processed meat intake either. The authors did find that cancer risk cently evaluated the impact of the Mediterranean diet on CRC was associated with different meat subtypes (i.e., animal of ori- risk in a large European cohort. This diet, introduced in the 1960s gin) which varied by tumor location—specifically, colon cancer as “health-protecting,” includes a high intake of vegetables, fruits, risk was significantly elevated in the setting of high lamb intake nuts, fish, cereals, and legumes with moderate alcohol consump- (incidence rate ratio = 1.07) and rectal cancer risk was affected tion and low consumption of dairy and meat. The authors found by pork (incidence rate ratio = 1.18).45 However, McCullough an 8% to 11% decreased CRC risk when comparing patients et al.46 recently reported a positive association in patients with non- with the highest to lowest diet adherence rates (HR = 0.89). The metastatic CRC between red and processed meat consumption association was strongest for women and colon tumors.56 before cancer diagnosis with higher risk of death after definitive Other dietary factors under recent investigation include cal- surgery. cium, magnesium, and vitamin D. Calcium has been historically implicated as having a protective effect, perhaps due to its ability Coffee to bind injurious bile acids with reduction of colonic epithelial proliferation.57 This is supported through cell culture models. Coffee contains numerous bioactive compounds that may However, population-based studies are not definitive. modulate cancer risk but previous epidemiologic studies inves- A recent meta-analysis evaluating the influence of magnesium tigating its role in CRC have yielded ambiguous results. In a 47 intake demonstrated a modest risk reduction, with pooled RRs of recent meta-analysis of 41 studies (25,965 patients), Li et al. 0.81 for colon cancer and 0.94 for rectal cancer. This association found a significant inverse association from case-control data persisted even after results were adjusted for calcium intake in six = = for CRC (OR 0.85) and colon cancer (OR 0.79), but not of the analyzed studies.58 rectal cancer. This was particularly true among females and in 47 Vitamin D has been shown to inhibit cell proliferation and Europe. Stronger evidence comes from the National Institutes increase apoptosis in vitro, and its deficiency is considered an of Health–AARP Diet and Health Study, a large prospective US important risk factor for many types of solid cancers. In a meta- cohort including 489,706 members. In this report, both caffein- analysis of 18 prospective studies, vitamin D intake and blood ated and decaffeinated coffee drinkers had a decreased risk of 25 (OH)D levels were found to be inversely associated with the colon cancer, particularly of proximal tumors (hazard ratio [HR] risk of CRC as well (RR = 0.79 and 0.62 for colon cancer, re- = for more than six cups a day 0.62), and decaffeinated coffee spectively; RR = 0.78 and 0.61 for rectal cancer, respectively). drinkers also had a decreased risk of rectal cancer. While known While this report offers only preliminary observational data, larger confounders such as smoking and red meat consumption were randomized trials for vitamin D supplementation are warranted59 adjusted for, further investigation is warranted to confirm and 48 and would be needed before routine vitamin D supplementa- clarify this association. tion could be recommended for the purpose of CRC prevention. It is noteworthy that the Institute of Medicine, while supporting Fiber vitamn D supplementation to maintain bone health, found the evidence insufficient to support vitamin D as being protective Classically, a high-fiber diet was associated with a low incidence of 60 CRC in Africa,49 with numerous studies substantiating this prem- against colorectal or any other cancer. ise.50 Protection was believed to be afforded from wheat bran, fruit, and vegetables.41 A high-fiber diet was believed to dilute fecal car- Lifestyle cinogens, decrease colon transit time, and generate a favorable luminal environment. The European Prospective Investigation into Physical inactivity has been associated with CRC risk, for colon Cancer and Nutrition is an ongoing multicenter prospective co- more than rectal cancer. A sedentary lifestyle may account for an hort study, which was one of the largest and most influential studies increased CRC risk, although the mechanism is unclear. Data to initially report an inverse association between dietary fiber and suggest that physical activity after the diagnosis of stages I to III CRC. More long-term data, with a mean follow-up of 11 years and colon cancer may reduce the risk of cancer-related and overall a near three-fold increase in CRC cases, further supports this claim mortality, and that the amount of aerobic exercise correlates with while providing a more precise estimation by fiber food source as a reduced risk of recurrence following resection of stage III colon well. After multivariable adjustments, total dietary fiber was found cancer.61 More recently, positive associations have been estab- to be inversely associated with both colon and rectal cancers (HR lished between increased amounts of recreational physical activity per 10 g/day increased in fiber = 0.87), and this did not differ by before and after CRC diagnosis and lower mortality.62 age, sex, lifestyle, or other dietary factors.51 However, other large, Most studies of alcohol have demonstrated at most a minimally well-controlled studies show no inverse relationship between CRC positive effect. Associations are strongest between alcohol con- and fiber intake.52 In a study of nearly 90,000 women from ages sumption in men and risk of rectal cancer. Perhaps interference 34 to 59 who were followed for 16 years, no protective effect was with folate metabolism through acetaldehyde is responsible.63 noted between fiber and incidence of either adenomatous polyp Prolonged cigarette smoking is associated with the risk of or CRC.52 This was further corroborated by two large randomized CRC.40 Cigarette smoking for >20 pack-years was associated with controlled trials that evaluated high-fiber diets for moderate dura- large adenoma risk and >35 pack-years with cancer risk. To exam- tion and discovered a lack of effect on the number, size, and histol- ine the impact of smoking cessation on the attenuation of this risk, ogy of polyps found on colonoscopy.53,54 At this point, therefore, Gong et al.64 conducted a pooled analysis of eight studies, includ- it is unclear whether dietary fiber plays any substantial role in the ing 6,796 CRC cases and 7,770 controls. The authors found that risk of developing CRC. former smokers also remained at increased risk for up to 25years after quitting. However, this varied substantially by cancer subsite Vegetables and Fruit with risk declining immediately for proximal colon and rectal cases but not until 20 years after smoking cessation for distal colon A protective effect of vegetables and fruits against CRC is generally tumors.64 believed to be true.40 This has been observed with raw, green, and cruciferous vegetables. Whether certain agents such as antioxi- Diabetes dant vitamins (E, C, and A), folate, thioethers, terpenes, and plant phenols may translate into effective chemopreventive strategies Type 2 diabetes has previously been implicated in the development requires further investigation, although the data for folate intake of CRC, but it has been difficult to separate this association from are sound.55 other confounding lifestyle factors such as smoking and obesity.

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Two recent meta-analyses provide further evidence that this con- amyloid A conferred significantly increased risk of colon cancer dition is in fact a significant indepent risk factor. Yuhara et al.65 (OR = 1.50, p = 0.006). This is not surprising given the role identified 14 studies, most of which controlled forsmoking, obesity, inflammation plays in colorectal carcinogenesis as well as the new and physical exercise, and demonstrated that diabetes was associ- promising data surrounding NSAID chemoprevention.74 ated with increased risk of both colon and rectal cancer (RR = 1.38 Leptin, a peptide hormone produced by adipocytes, is also and RR = 1.20, respectively).65 A second report, analyzing 24 stud- thought to contribute to CRC pathogenesis. A recent prospec- ies, found a similar association (RR = 1.26) with even higher risk tive analysis found that soluble leptin receptor levels, which may for those patients on insulin therapy (RR = 1.61).66 regulate leptin function, was strongly inversely associated with both CRC and colon cancer risk (RR = 0.55 and RR = 0.42, Drugs respectively). This finding was independent of leptin levels and other circulating biomarkers.75 Chi et al.76 performed a similar investigation of insulin-like growth factor peptides, also implicated Nonsteroidal Anti-Inflammatory Drugs in CRC carcinogenesis, and found that high levels of insulin-like Population-based studies strongly support inverse associations growth factor I and insulin-like growth factor II significantly in- between use of aspirin and other nonsteroidal anti-inflammatory creased cancer risk (OR = 1.25 and OR = 1.52, respectively).76 drugs (NSAID) and the incidences of both CRC and adenomas. 67–69 Along these lines, high circulating levels of C-peptide, a direct As a result, NSAIDs and selective cyclooxygenase 2 (COX-2) marker of hyperinsulinemia, may also be a predictive factor for inhibitors have been investigated intensively in hereditary and increased CRC risk, as indicated in a recent meta-analysis.77 sporadic CRC. Long-term results have just been reported from the CAPP2 Human Papillomavirus study, the first double-blind randomized controlled trial of aspirin chemoprevention with cancer as the primary end point. In this While human papillomavirus is well-established as the critical study, 861 carriers of Lynch syndrome were randomly assigned to pathogenic force behind cervical and anogenital cancer, its role aspirin or placebo. With a mean follow-up of 55.7 months, the in colorectal malignancy is less clear. An association between the authors report a significantly decreased incidence of CRC in the two was first reported in 1990 and since then, a growing number treatment group as well as a trend toward reduction in extraco- of studies have detected the virus in colon adenocarcinoma speci- lonic Lynch syndrome–associated cancers. Importantly, there was mens. In the first meta-analysis to address this topic (including no significant difference in adverse events such as gastrointestinal 16 articles and 1,436 patients), Damin, Ziegelmann, and Damin78 (GI) bleeding, ulcers, or anemia during the intervention period. not only reported a high prevalence of human papillomavirus These data provide strong rationale for the routine use of aspirin (31.9%) in affected patients, but also found a strong correlation chemoprevention in Lynch syndrome and establish a foundation between human papillomavirus positivity and increased CRC risk for further study in sporadic neoplasia. In a combined analysis of (OR = 10.04; 95% CI = 3.7 to 27.5). These results may indicate OF ONCOLOGY PRACTICE four large randomized trials of lower-dose aspirin (75 to 300 mg/ an alternative pathway of colorectal carcinogenesis that could have day) involving 14,033 patients, aspirin taken for 5 years or more vast implications for treatment and prevention.78 was associated with a reduced 20-year incidence and mortality due to CRC (absolute reduction = 1.76%; 95% confidence interval [CI] = 0.61 to 2.91; p = 0.001). Reduction was largely confined FAMILIAL COLORECTAL CANCER to right-sided tumors.70 In addition to generalized chemoprevention, the question of aspirn and other NSAIDs in patients with a diagnosis of CRC has been addressed. Liao et al.71 have reported Familial Adenomatous Polyposis evidence that suggests that aspirin therapy after CRC diagnosis may be beneficial to those patients whose tumors have a PIK3CA Familial adenomatous polyposis (FAP) constitutes 1% of all CRC mutation, but not in those with wild-type PIK3CA.71 However, incidence (Table 57.2). Hallmark features include hundreds to PIK3CA mutation status had no impact on the influence of the thousands of colonic polyps that develop in patients in their teens COX-2 inhibitor rofecoxib on cancer recurrence.72 to 30s, and if the colon is not surgically removed, 100% of patients progress to CRC. Extracolonic manifestations include benign Bisphosphonates conditions—congenital hypertrophy of the retinal pigment epithelium, mandibular osteomas, supernumerary teeth, epidermal In addition to being one of the most commonly used medications cysts, adrenal cortical adenomas, desmoid tumors (although these for osteoporosis, bisphosphonates have been shown to have various tumors may lead to obstruction)—and malignant conditions— antiproliferative, antiangiogenic, proapoptotic, and antiadhesive thyroid tumors, gastric small intestinal polyps with a 5% to 10% risk effects in preclinical studies. Practical impact on malignant dis- 79 73 of duodenal or ampullary adenocarcinoma, and brain tumors. ease, however, has been inconsistent. Singh et al. performed The brain tumors may be of two types—glioblastoma multiforme a recent meta-analysis demonstrating a statistically significant or medulloblastoma—and the particular association of brain 17% reduction in CRC incidence with bisphosphonate use. This tumors and colonic polyposis is called Turcot syndrome.80 The finding was observed independently for both proximal and distal colonic polyps in Turcot syndrome are fewer and larger than in colon cancers as well as rectal cancers, highlighting another po- 73 classic FAP. An attenuated form of FAP harbors up to 100 colonic tential pathway for chemoprevention. polyps and has a predisposition to colorectal cancer in patients when they are in their 50s or 60s.81 Biomarkers FAP is an autosomally dominant disorder with nearly 100% penetrance. However, about 30% of patients have de novo mu- In an effort to improve screening protocols and advance under- tations and are without an ostensible family history. Based on standing of colorectal carcinogenesis, investigators are focusing on karyotypic analysis that reveals an interstitial deletion on human a variety of biomarkers for increased risk as well. chromosome 5q and subsequent genetic linkage analysis to 5q21, Toriola et al.74 evaluated the role of C-reactive protein and the gene responsible for FAP was identified asAPC . Patients with serum amyloid A, two common inflammatory mediators, in FAP inherit a mutated copy of the APC gene, thereby predisposing the Women’s Health Initiative Observational Study. With over them to early onset polyposis. During life, patients with FAP ac- 900 case-control pairs for each marker, the authors found that quire inactivation of the remaining APC gene copy, which accel- elevated concentrations of both C-reactive protein and serum erates the progression to CRC. Interesting genotypic-phenotypic 772 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 57.2 TABLE 57.3 Familial and Nonfamilial Causes of Criteria for Identifying At-Risk Individuals Colorectal Cancer for Mismatch Repair Deficiency (High Microsatellite Instability) Syndromes with Adenomatous Polyps APC gene mutations (1%): Amsterdam I Criteria ■ Familial adenomatous polyposis At least three relatives with colorectal cancer ■ Attenuated APC One relative should be a first-degree relative of the other two ■ Turcot syndrome (two-thirds of families) At least two successive generations should be affected MMR gene mutations (3%): ■ Hereditary nonpolyposis colorectal cancer types I and II At least one colorectal cancer case before age 50 ■ Muir ‐Torre syndrome FAP should be excluded ■ Turcot syndrome (one-third of families) Tumors should be verified histopathologically Syndromes with hamartomatous polyps (<1%) Amsterdam II Criteria Peutz-Jeghers (LKB1) At least three relatives with HNPCC-associated cancer Juvenile polyposis (SMAD4, PTEN) (colorectal, endometrial, small bowel, ureter, or renal pelvis) Cowden (PTEN) At least two successive generations should be affected Bannayan-Ruvalcaba-Riley At least one case before age 50 Mixed polyposis FAP should be excluded Other Familial Causes (up to 20%–25%) Tumors should be verified histopathologically Family history of adenomatous polyps (MYH) Bethesda Criteria (for Identification of Patients with Family history of colon cancer: Colorectal Tumor who Should Undergo Testing for MSI) ■ Risk more than three times greater if two first-degree Cancer in families that meet Amsterdam criteria relatives or one first-degree relative <50 y with colon Two HNPCC-related cancers, including colorectal or extracolonic cancer ■ Risk two times greater if second-degree relative affected Colorectal cancer and a first degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or colorectal Familial colon-breast cancer adenoma: one cancer before age 45 and adenoma before age 40 Nonfamilial Causes Colorectal cancer or endometrial cancer before age 45 Personal history of adenomatous polyps Right-sided colorectal cancer with an undifferentiated pattern on Personal history of colorectal cancer histopathology before age 45 Inflammatory bowel disease (ulcerative colitis, Crohn’s colitis) Signet-ring cell type colorectal cancer before age 45 ■ Radiation colitis Adenoma before age 40 ■ Ureterosigmoidostomy ■ Acromegaly FAP, familial adenomatous polyposis; HNPCC, hereditary nonpolyposis ■ Cronkhite-Canada syndrome colorectal cancer; MSI, microsatellite instability.

The lifetime risk of CRC in HNPCC is 80%, up to 50% to 60% associations exist between the location of the APC gene mutation for endometrial cancer, and 1% to 13% for all other cancers. 84,85 and certain clinical manifestations, such as congenital hypertrophy Of note, a variant of HNPCC involves skin tumors and is desig- of the retinal pigment epithelium, desmoid tumors, and classic nated as Muir-Torre syndrome. HNPCC is defined classically by FAP versus attenuated FAP. the modified Amsterdam criteria (Table 57.3). The APC gene comprises 15 exons and encodes a protein of HNPCC is an autosomally dominant disorder with about 80% nearly 2,850 amino acids (310 kDa). Nearly all germline muta- penetrance. Genetic and biochemical approaches led to the dis- tions in the APC gene lead to a truncated protein, which can covery of the involvement of human DNA mismatch repair genes be detected through molecular diagnostic assays that can be in- in HNPCC. Recognized as the human orthologues of mismatch re- tegrated into genetic counseling and genetic testing of affected pair genes described in bacteria and yeast, human mismatch repair patients and at-risk family members.82,83 The functions of the APC genes encode enzymes that repair errors during DNA replication protein and the interrelated pathways and regulatory molecules that may occur spontaneously or upon exposure to an exogenous will be discussed later. agent (e.g., ultraviolet light, chemical carcinogen). Mutations in Hereditary Nonpolyposis Colorectal Cancer one of these mismatch repair genes results in MSI, which creates a milieu of somatic mutations of target genes—TGF-β2 receptor, Hereditary nonpolyposis CRC (HNPCC) accounts for about 3% of bax, IGF type I receptor, among others—in HNPCC-associated all CRCs. Salient features include up to 100 colonic polyps (hence tumors.86 About 60% of germline mutations in HNPCC are found the term nonpolyposis), preferentially, albeit not exclusively, in the in either the hMLH1 gene or the hMSH2 gene, but mutations right or proximal colon.84 There is an accelerated rate of progres- in other members of this family—hMSH6, hPMS1, hPMS2—are sion to CRC in these diminutive, at times flat, polyps with mean rare, thereby indicating that other genes are involved but have yet age of onset of CRC being 43 years. This is designated HNPCC to be discovered. Genetic testing is not facile for HNPCC as it is type I. HNPCC type II is distinguished by extracolonic tumors for FAP, but it involves sequencing both the hMLH1 and hMSH2 that originate in the stomach, small bowel, bile duct, renal pelvis, genes (Table 57.4). If a germline mutation is found, then the ureter, bladder, uterus and ovary, skin, and perhaps the pancreas. remaining at-risk family members can be genetically screened.

tahir99 - UnitedVRG Chapter 57 Cancer of the Colon 773

TABLE 57.4 sigmoid colon, and the rectum. The anatomy of the rectum will be discussed in detail in the chapter on rectal cancer. The large Genetic Testing in Inherited Colorectal Cancer bowel has a muscular wall and can be distinguished from the FAP APC protein truncating testing (preferred). If APC small intestine by its increased diameter, the presence of haustra, mutation found, screen for mutation in family. appendices epiploicae, and tenia coli. The tenia consist of con- Less desirable alternatives: gene sequencing, densations of longitudinal muscle fibers starting near the base of linkage testing. the appendix and continuing throughout the abdominal colon to form a continuous longitudinal muscle coat in the upper rectum. HNPCC MSI testing in tumor.a Haustra are outpouchings of bowel wall separated by folds that give If MSI present, proceed to sequencing of both a classic appearance on radiography or barium enema. hMLH1 and hMSH2 genes. The right colon is made up of the cecum (with appendix) If mutation found, screen for mutation in family. and ascending colon. It is anterior to the right kidney and the duodenum. Its vascular supply is from branches of the superior FAP, familial adenomatous polyposis; APC, adenomatosis polyposis coli; HNPCC, hereditary nonpolyposis colorectal cancer; MSI, microsatellite mesenteric artery (SMA). The SMA divides into the middle colic instability. artery and the trunk of the SMA. The middle colic artery immedi- a Immunohistochemistry may be an option. ately forms two to three large arcades in the transverse mesocolon. The SMA ileocolic arterial branches then extend from the SMA. The right colic artery arises as a separate branch from the SMA in 10.7% of cases.88 The ileocolic artery gives off a right colic ar- MSI testing and hMLH1/hMSH2 immunohistochemistry (IHC) tery to the upper ascending colon and forms an anastomosis with can be performed on tumor specimens as a possible prelude to branches from the middle colic artery. The ileal branch of the ileo- genetic testing. colic artery gives off branches to the distal small bowel and cecum, whereas the colic branch supplies the ascending colon. An anastomosis occurs between the distal SMA and the ileal branch of the Hamartomatous Polyposis Syndromes ileocolic artery at the junction of the terminal ileum and cecum. The right colon is a retroperitoneal structure. Hamartomatous polyposis syndromes are rare syndromes, mostly af- The transverse colon is supplied by branches of the middle fecting the pediatric and adolescent population, and represent <1% colic artery. It is the first portion of the colon considered to be in- of CRCs annually. Peutz-Jeghers syndrome involves large but few traperitoneal, and its length can vary. Its boundaries are defined by colonic and small bowel polyps that can manifest by GI bleeding the hepatic flexure on the right and the splenic flexure on the left. or obstruction and an increased risk of CRC. The polyps are distin- Both of these points are fixed. The hepatic flexure abuts the gall- guished by a smooth muscle band in the submucosa. Hallmark clin- bladder fossa, while the splenic flexure lies anterior to the splenic PRACTICE OF ONCOLOGY ical features on physical examination include freckles on the hands, hilum and the tail of the pancreas. The descending colon is where around the lips, in the buccal mucosa, and periorbitally. Associated the colon once again becomes a retroperitoneal structure, and it characteristics include sinus, bronchial, and bladder polyps, and is defined as the segment of colon from the splenic flexure to the about 5% to 10% of patients have sex cord tumors. Patients can also sigmoid colon. The descending colon is the first segment of the develop lung and pancreatic adenocarcinomas. The gene respon- left side of the colon and receives its blood supply from the inferior sible for this syndrome is LKB1, a serine threonine kinase. mesenteric artery. The inferior mesenteric artery arises from the Juvenile polyposis have overlapping clinical manifestations aorta and gives off the left colic artery. It also gives off three to four with Peutz-Jeghers, but the polyps tend to be confined to the sigmoidal arteries, which supply the intraperitoneal sigmoid colon. colon, although cases of gastric and small bowel polyps have been The anastomosis between the vessels of the middle colic artery and described and there is an increased risk of CRC. Extracolonic those of the left colic artery and right colic artery is known as the manifestations are not prevalent. This is a polygenic disease, in- marginal artery of Drummond. The arcade, which effectively con- volving germline mutations in PTEN, SMAD4, BMPR1, or other nects the left and right circulations, is known as the arc of Riolan. genes yet to be identified. The arterial supply to the colon is depicted in Fig. 57.1. Cowden syndrome harbors hamartomatous polyps anywhere in The venous and lymphatic drainage of the colon parallels the the GI tract, and surprisingly, there is no increased risk of CRC. arterial supply, and all three vessels course and divide within the However, about 10% of patients will have thyroid tumors and colonic mesocolon (Fig. 57.2). The mesocolon therefore contains nearly 50% of patients have breast tumors. Germline PTEN muta- the regional lymph nodes (LN) for the segment of colon it supplies tions have been reported. and drains. The efferent lymphatic channels pass from the submu- It is estimated that about 20% to 30% of CRCs are compat- cosa to the intramuscular and subserosal plexus of the bowel to the ible with an inherited predisposition, independent of known syn- first tier of LNs lying adjacent to the large intestine and known as dromes.87 The identification of other responsible genes will have epicolic nodes.89 Paracolic nodes lie on the marginal vessels along great clinical impact. Intensive approaches are being pursued the mesenteric side of the colon and are frequently involved in through sibling-pair studies and other familial studies. As previ- metastases. Intermediate nodes are found along the major arterial ously mentioned, patients may be predisposed to an increased risk branches of the SMA and inferior mesenteric artery in the meso- of adenomatous polyps as well in the context of a family history of colon. The principal nodes are found around the origin of these sporadic adenomatous polyps. vessels from the aorta, and they drain into retroperitoneal nodes. The drainage of the superior and inferior mesenteric veins, which drain the ascending, transverse, descending, and sigmoid colon, is ANATOMY OF THE COLON to the portal vein. The rectum is drained by rectal tributaries to the vena cava. The colon and rectum make up the segment of the digestive The extent of resection of the colon is defined by the vascu- system commonly referred to as the large bowel. Defined as the lar supply and by the need to take the regional draining LNs.90,91 portion of intestine from the ileocecal valve to the anus, the large A careful understanding of the colonic anatomy, structure, loca- bowel is approximately 150 cm in length. It is divided into five tion, and vascular supply is therefore critical in order to perform segments defined by its vascular supply and by its extraperito- a safe and effective cancer operation. The segmental resections neal or retroperitoneal location: the cecum (with appendix) and important for removal of lesions in various locations within the ascending colon, the transverse colon, the descending colon, the colon will be described in greater detail in later sections. 774 Practice of Oncology / Cancers of the Gastrointestinal Tract

Middle colic Transverse colon artery Splenic flexure Hepatic flexure

Right colic artery Inferior mesenteric vein Descending lleocolic colon artery Left colic Ascending artery colon Aorta Inferior mesenteric artery Superior hemorrhoidal artery and vein Sigmoid artery

Cecum Sigmoid Middle colon hemorrhoidal artery Internal pudendal artery Inferior hemorrhoidal Rectum Figure 57.1 The anatomy of the colon with artery particular emphasis on the vascular supply.

DIAGNOSIS OF COLORECTAL CANCER are alarming.92 However, apart from obstructive symptoms, other symptoms do not necessarily correlate with stage of disease or por- Symptoms associated with CRC include lower GI bleeding, tend a particular diagnosis.93 change in bowel habits, abdominal pain, weight loss, change in Physical examination may reveal a palpable mass, bright blood appetite, and weakness, and in particular, obstructive symptoms per rectum (usually left-sided colon cancers or rectal cancer) or melena (right-sided colon cancers), or lesser degrees of bleeding (hemoccult-positive stool). Adenopathy, hepatomegaly, jaundice, or even pulmonary signs may be present with metastatic disease. Obstruction by colon cancer is usually in the sigmoid or left colon, with resulting abdominal distention and constipation, whereas 47 right-sided colon cancers may be more insidious in nature. Complications of CRC include acute GI bleeding, acute obstruc- 20 tion, perforation, and metastasis with impairment of distant organ 59 function. 17 Laboratory values may reflect iron-deficiency anemia, electrolyte derangements, and liver function abnormalities. The carcino- 17 10 embryonic antigen (CEA) may be elevated and is most helpful 12 93 to monitor postoperatively, if reduced to normal as a result of surgery.94 Evaluation should include complete history, family history, 100 physical examination, laboratory tests, colonoscopy, and pan-body computed tomography (CT) scan.95 For rectal cancer, additional 100 imaging techniques, such as magnetic resonance imaging or endoscopic ultrasound, are utilized to further characterize the primary tumor prior to therapy (see Chapter 60). Upon completion of diagnosis and staging for both colon and rectal tumors, it is essential to incorporate the expertise from medical, radiation, and surgical oncologists in order to formulate and implement an optimal treatment plan. With the advent of molecular biologic techniques, attention has been drawn to stool-based tools and new blood-based tests. Technology now exists to extract genomic DNA or protein from stool and assay for evidence of genetic alterations.96,97 Large-scale validation studies are in progress, one of which has just been published, describing an automated multitarget sDNA assay (fecal immunochemical testing) with a 90% specificity and 98% sensitivity for the detection of CRC, as well 83% sensitivity for advanced Figure 57.2 The lymphatic drainage of lesions in various anatomic adenoma with high-grade dysplasia.98 In addition, Epi proColon locations throughout the colon. (Epigenomics AG, Berlin, Germany), a blood-based test, was

tahir99 - UnitedVRG Chapter 57 Cancer of the Colon 775 shown to be noninferior to fecal immunochemical testing in Optical colonoscopy is currently the most sensitive method for preliminary results from a multicenter double blind comparative screening. Advantages include direct visualization, with the ability study (press release from Epigenomics AG, December 4, 2012). to remove polyps (with rate-limiting factors of size and anatomic One particularly attractive pathway for stool-based diagnostics location) and to obtain biopsies. Disadvantages involve the prepa- would be able to stratify patients as high, moderate, or low risk ration, invasive nature of the procedure, and potential side effects for CRC and thus influence screening modalities and frequency that include perforation (although this is <1%). of screening. In a complementary fashion, functional genomics The digital rectal examination should be part of the general are being applied to pair-wise comparisons of normal colon and physical examination. Anorectal masses may be palpated. Flex- CRCs to sample the entire human genome of nearly 30,000 genes ible sigmoidoscopy does not require conscious sedation and to discover those genes, known and novel, that may be upregu- hemodynamic monitoring, and will typically allow visualization lated or downregulated and possibly linked to detection, prognosis, of the rectum, sigmoid colon, and descending colon to the splenic and therapy. flexure. Flexible sigmoidoscopy should not be considered as a single screening measure but requires coupling with barium enema. Barium enema allows visualization of the entire colon, and expe- SCREENING FOR COLORECTAL CANCER rience is necessary to ensure proper visualization of the rectum. Barium enema affords advantages of ease of preparation, lack of Debate is vigorous as to the best approaches for screening, and conscious sedation and hemodynamic monitoring, and ability to multiple factors influence that decision: simplicity and rapidity so visualize polyps and masses. However, small polyps may be missed. as to enhance patient compliance, benefit to risk ratio, sensitivity, Furthermore, if a luminal polyp or mass is identified, then colon- specificity, cost-effectiveness, and other economic factors. To that oscopy will be necessary for polypectomy or biopsies. end, currently, optical colonoscopy likely offers the most effective New noninvasive technologies, such as CT and magnetic reso- approach when one considers all of these factors. nance colonography, are receiving increased attention in clini- The average-risk patient is defined as a man or woman above cal studies, which demonstrate overall feasibility, as well as some the age of 50 without personal or family history of adenomatous advantages.99 polyps or CRC and absence of any occult or acute GI bleeding. Two meta-analyses published in 2011 provide strong support Screening recommendations or guidelines for average-risk and for the implementation of CT colonography as a viable alternative high-risk individuals are presented in Table 57.5. to optical colonoscopy in both average and high-risk populations.

TABLE 57.5

Recommendations for Colorectal Cancer Screening in Average-Risk and Increased-Risk Patients PRACTICE OF ONCOLOGY from the Gastrointestinal Consortium Panel

Average-Risk Patient (Different Options) 1. FOBT: Offer yearly screening with FOBT using a guaiac-based test with dietary restriction or an immunochemical test without dietary restriction. Two samples from each of three consecutive stools should be examined without rehydration. Patients with a positive test on any specimen should be followed up with colonoscopy. 2. Flexible sigmoidoscopy: Offer flexible sigmoidoscopy every 5 y. 3. FOBT plus flexible sigmoidoscopy: Offer screening with FOBT every year combined with flexible sigmoidoscopy every 5 y. When thbo tests are performed, the FOBT should be done first. 4. Colonoscopy: Offer every 10 y. 5. DCBE: Offer every 5 y. Increased Risk for Colorectal Cancer 1. Family history of colorectal cancer or polyps. People with a first-degree relative (parent, sibling, or child) with colon cancer or adenomatous polyp diagnosed at age <60 y or two first-degree relatives diagnosed with colorectal cancer at any age should be advised to have screening colonoscopy starting at age 40 y or 10 y younger than the earliest diagnosis in the family, whichever comes first, and repeated every 5 y. 2. FAP: Flexible sigmoidoscopy to start at ages 10 to 12 y. Genetic testing (for FAP, upper endoscopy with side-viewing scope) should be done every 1 to 3 y. 3. HNPCC: Colonoscopy every 1 to 2 y starting at ages 20 to 25 y or 10 y younger than the earliest case in the family, whichever comes first. Genetic testing (for HNPCC, consideration should be given to screening for uterine and ovarian cancer with hysteroscopy nda transvaginal ultrasound, the frequency of which varies within centers). 4. Personal history of adenomatous polyps A. If one or more polyps that are malignant or large and sessile or colonoscopy is incomplete, then follow-up colonoscopy should be in the short term. B. If three of more polyps, follow-up colonoscopy in 3 y. C. If one or two polyps (<1 cm), follow-up colonoscopy in 5 y (or more). 5. Personal history of colorectal cancer A. Colonoscopy is incomplete at time of diagnosis of colorectal cancer due to obstruction, then repeat colonoscopy 6 mo after surgical resection. B. Colonoscopy is complete at time of diagnosis of colorectal cancer, then repeat colonoscopy in 3 y, and if that is normal, then repeat every 5 y. 6. Inflammatory bowel disease (ulcerative colitis, Crohn’s colitis). Surveillance colonoscopy is recommended.

FOBT, fecal occult blood testing; DCBE, double-contrast barium enema; FAP, familial adenomatous polyposis; HNPCC, hereditary nonpolyposis colorectal cancer. From Rex DK, Johnson DA, Lieberman DA, et al. Colorectal cancer prevention 2000: screening recommendations of the American College of Gastroenterology. American College of Gastroenterology. Am J Gastroenterol 2000;95:868–877; Winawer S, Fletcher R, Rex D, et al. Colorectal cancer screening and surveillance: clinical guidelines and rationale-Update based on new evidence. Gastroenterology 2003;124:544–560. 776 Practice of Oncology / Cancers of the Gastrointestinal Tract

In a review of 4,086 asymptomatic patients, de Haan et al.,100 esti- The Dukes Classification and Its Modifications mates sensitivities of 82.9% and 87.9% and specificities of 91.4% and 97.6% for adenomas ≥6 mm and ≥10mm, respectively. In the 1930s, Cuthbert Dukes, a Scottish pathologist working pre- In a complementary analysis looking exclusively at cancer de- dominantly on a classification scheme for rectal cancer, developed tection, Pickhardt et al.101 concludes that CT colonography is not the classification system that bears his name. The system, and the only clinically equivalent to colonoscopy but perhaps even more several modifications to it made by Dukes and others, is at this time suitable for initial investigation given consistently high sensitivity of historical interest only, and the reader is referred to chapters in (96.1%) without heterogeneity across 49 studies, and 11,151 pa- earlier editions of this book for further details. tients, despite wide variation in technique. Tumor, Node, Metastasis Classification Other reports suggest advantages in long-term costs and patient compliance, although these issues remain controversial.102,103 The current AJCC/UICC staging system for CRC is now the only Lastly, CT colonography may also offer improvements in preop- classification system that should be used.106 The TNM system classi- erative staging as one study found this technique to be highly predic- fies colorectal tumors on the basis of the invasiveness (not size) of the tive of T3-4 tumors. Whether this information will prove as clinically primary (T stage), the number (not size or location) of local-regional relevant in colon cancer as it is for the rectum remains to be seen.104 LNs containing metastatic cancer (N stage), and the presence or absence of distant metastatic disease (M stage) (see Table 57.6). STAGING AND PROGNOSIS OF T Stage. A designation of Tx refers to the inability to describe COLORECTAL CANCER the extent of tumor invasion due to incomplete information. In situ adenocarcinoma (Tis) includes cancers confined to the glan- This discussion will focus primarily on those prognostic and pre- dular basement membrane or lamina propria. The terms high- dictive indicators that are best supported by available data and are grade dysplasia and severe dysplasia are synonymous with in situ appropriate for use and consideration in current practice. The carcinoma and are also classified as Tis. T1 tumors invade into reader should remain aware of the potential for rapid changes and but not through the submucosa. T2 tumors invade into but not advances in this area, however. through the muscularis propria, and T3 tumors invade through the muscularis propria into the subserosa or into nonperitoneal- Staging ized pericolic or perirectal tissue. T4 tumors perforate the visceral peritoneum (T4a) or invade other named organs or structures Although many factors have been identified that have an impact (T4b). Tumors invading other colorectal segments by way of the on recurrence and survival, none exceeds stage in terms of prog- serosa (i.e., carcinoma of the cecum invading the sigmoid) are nostic significance.105 Staging of CRC should be done using the classified as T4b. A tumor that is adherent to other structures or current TNM (tumor, node, metastasis) classification of the Amer- organs macroscopically is classified clinically as T4b; however, if ican Joint Committee on Cancer (AJCC)/International Union the microscopic examination of the adhesions is negative, then the Against Cancer (UICC) staging system (Table 57.6).106 Other sys- pathologic classification is pT3. The V and L substaging should be tems should be regarded as of historical significance only and must used to identify the presence or absence of vascular or lymphatic be comprehended solely for the purposes of understanding the invasion. The “p” prefix denotes pathologic (rather than clinical) studies that were performed and reported in the past using these assessment, and the “y” prefix is attached to those tumors that are older classifications. being reported after neoadjuvant (presurgical) treatment. For example, the pathologic T stage of a tumor showing only penetration into the submucosa after preoperative therapy would be ypT1. TABLE 57.6 Recurrent tumors are reported with an “r” prefix (rpT3). Tumor (T) Node (N) Metastasis (M) Classification N Stage. Because of the prognostic significance associated with of Colorectal Cancer increased numbers of LNs inspected (see the following discussion), the current TNM classification scheme calls for at least Stage T N M 12 LNs to be analyzed, and both the number of nodes that are positive for tumor and the total number of nodes inspected should be 0 Tis N0 M0 reported. The term Nx is applied if no description of LN involve- IT1N0 M0 ment is possible because of incomplete information. A pN0 desig- T2 N0 M0 nation may be made even if fewer than the recommended number IIA T3 N0 M0 of nodes are present; however, the prognostic significance of this pN0 designation is weaker. N0 denotes that all nodes examined IIB T4a N0 M0 are negative. N1a includes tumors with metastasis in one regional IIC T4b N0 M0 LN. N1b refers to involvement of two or three nearby LNs. N1c IIIA T1-T2 N1-N2a M0 defines the presence of cancer cells found in areas of fat near LNs, but not in the LNs themselves. N2a indicates metastasis in four to IIIB T3-T4a N1 M0 six regional LNs. N2b denotes involvement of greater than seven T2-T3 N2a M0 nodes. Metastatic nodules or foci found in the pericolic, perirec- T1-T2 N2b M0 tal, or adjacent mesentery without evidence of residual LN tissue IIIC T4a N2a M0 are regarded as being equivalent to a regional node metastasis and T3-T4a N2b M0 are counted accordingly. T4b N1-N2 M0 Stage I disease is defined as T1-2N0 in a patient without distant metastases (M0). Stage II disease is defined as T3-4N0M0. The IVA T any N any M1a T-stage carries prognostic significance for stage II, and therefore IVB T any N any M1b T3N0 is classified as IIA, and T4a-bN0 is classified as IIB and IIC, respectively. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Node positivity in the absence of M1 disease defines stage III Staging Manual, Seventh Edition (2010) published by Springer Science and CRC. Recently, the prognostic significance of tumor invasive- Business Media LLC, www.springer.com, page 144. ness (T stage) has been reincorporated into the assessment of risk

tahir99 - UnitedVRG Chapter 57 Cancer of the Colon 777 in stage III patients. In an exhaustive review of over 50,000 pa- Prognosis tients, Greene et al.107 demonstrated the prognostic significance of T stage within node-positive patients. Within the N1 category Histologic Grade T stage was found to be highly prognostic, with T1-2 patients fair- ing significantly better than T3-4. Within the N2 population, the Although histologic grade has been shown to have prognostic sig- prognosis was worse than either subgroup of N1 patients, with nificance, there is significant subjectivity involved in scoring of T stage no longer carrying prognostic significance. Thus T stage this variable, and no one set of criteria for determination of grade 105 is prognostic in patients with N0 and N1 but not N2 disease. The are universally accepted. The majority of staging systems divide current TNM staging system takes these findings into account and tumors into grade 1 (well differentiated), grade 2 (moderately dif- now stratifies stage III patients into IIIA (T1-2N1), IIIB (T3-4N1), ferentiated), grade 3 (poorly differentiated), and grade 4 (undif- and IIIC (T any, N2). Stages IIIA, B, and C are highly prognostic ferentiated). Many studies collapse this into low grade (well to for survival. moderately differentiated) and high grade (poorly differentiated or undifferentiated). Greene et al.107 demonstrated that this two- M Stage. Patients are designated M0 if no evidence of distant tiered split has important prognostic significance. metastases is present. Identification of distant metastases denotes a classification of M1. Involvement of the external iliac, com- College of American Pathologists Consensus Statement. mon iliac, para-aortic, supraclavicular, or other nonregional LNs The College of American Pathologists (CAP) has published an is classified as distant metastatic (M1) disease. The M1 category expert panel consensus statement outlining their interpretation of is subdivided into M1a, defined as spread of tumor to one distant the validity and usefulness of a large number of putatively prognos- organ or set of distant LNs, and M1b, where spread has occurred tic and predictive factors in CRC.109 Variables were categorized to more than one distant organ or sets of LNs or spread has oc- as belonging to categories I through IV. Category I was defined as curred to the peritoneum. Although the TNM staging system is those factors proven to be of prognostic import based on evidence regarded as the most comprehensive tool for prognostic and pre- from multiple, statistically robust, published trials and generally dictive purposes, a major criticism of the last two revisions is that used in patient management. Category IIA included factors inten- survival of stage IIIA patients continues to be superior to stage sively studied biologically or clinically and repeatedly shown to IIB. This disparity, which is actually more pronounced in the sev- have prognostic value for outcome or predictive value for therapy enth edition of AJCC manual, has been attributed to inadequate that is of sufficient import to be included in the pathology report, LN assessment and understaging. However, a recent review of but that remains to be validated in statistically robust studies. Cate- SEER data showed this problem persists even in a subset analysis gory IIB included factors shown to be promising in multiple studies of patients with >12 LNs, highlighting the need for additional but lacking sufficient data for inclusion in category I or IIA. Cat- refinement and perhaps the incorporation of nonanatomic prog- egory III included factors felt to be not yet sufficiently studied to 108 nostic factors. determine their prognostic value, and category IV included those OF ONCOLOGY PRACTICE factors that are adequately studied to have convincingly shown no Residual Tumor (R Stage) at Margins of Resection. prognostic significance. A number of these factors are discussed in Tumors that are completely resected with histologically negative further detail in the following. margins are classified as R0. Tumors with a complete gross resec- The T, N, and M categories of the current AJCC/UICC stag- tion but with microscopically positive margins are classified as ing system were all classified as category I. Other category I inclu- R1, the positive margin indicating that at least microscopic tumor sions were blood or lymphatic vessel invasion and residual tumor remains in the patient. Patients who have incomplete resections following surgery with curative intent (the R category). Although with grossly positive margins are classified as having had an R2 not assessed pathologically, an elevation of the preoperative CEA resection. The R0, R1, and R2 designations carry strong prognostic level was also felt to merit category I inclusion. Factors in category implications. IIA included tumor grade, radial margin status (for resection of Identification of the proximal and distal margins of resection is specimens with nonperitonealized surfaces), and residual tumor in relatively straightforward, and definitions of these margins are well the resection specimen following neoadjuvant therapy. Factors in understood. A more complex and often misunderstood (as well as category IIB (many of which are discussed in further detail in the underreported) margin of resection is the circumferential radial following) included histologic type, histologic features associated margin (CRM). All three margins (proximal, distal, and CRM) with MSI (i.e., host lymphoid response to tumor and medullary should be specifically commented upon in the pathology report, or mucinous histologic type), high degree of MSI (MSI-H), loss as all three have prognostic significance. of heterozygosity (LOH) of 18q (DCC [deleted in colon cancer] The CRM is, by definition, a surgically dissected surface. It is gene loss), and tumor border configuration (infiltrating versus defined as the cut retroperitoneal or perineal soft tissue margin pushing border). Factors grouped in category III included DNA closest to the deepest penetration of tumor. It is considered posi- content, all other molecular markers except for LOH of 18q/ tive if tumor is present microscopically (R1) or macroscopically DCC and MSI-H, perineural invasion, microvessel density, tumor (R2) on a cut radial or lateral aspect of the surgical specimen. For cell–associated proteins or carbohydrates, peritumoral fibrosis, the ascending colon, descending colon, and upper rectum, which peritumoral inflammatory response, focal neuroendocrine dif- are incompletely encased by peritoneum, the CRM is created by ferentiation, nuclear organizing regions, and proliferation. Those dissection of the retroperitoneal aspect of the bowel. In the case of factors in category IV (proven to be of no significance) included the lower rectum, which is not encased by peritoneum, the CRM tumor size and gross tumor configuration. is created by sharp dissection of the mesorectum. A tumor simply penetrating into pericolonic or perirectal fat Total Number of Lymph Nodes does not necessarily constitute a positive CRM, but rather is simply a description of a T3 primary. A tumor that involves a peritoneal- It has been well established that an adequate number of LNs must ized surface of the bowel and not a surgically cut surface does not be sampled before a patient can be considered node negative, and constitute a positive CRM, but rather constitutes a T4a primary. If, careful pathologic technique has been demonstrated to be crucial however, the cut surface at the deepest penetration of the tumor to adequate nodal interpretation. Failure to adequately dissect and is positive, then the CRM is positive and the resection is staged display the mesentery will lead to underreporting and understag- R1 (microscopic) or R2 (macroscopic). A positive CRM is highly ing.110,111 It should be noted that an insufficient number of LNs re- predictive of local recurrence and should prompt consideration of ported could be due to a suboptimal nodal dissection at operation, adjuvant treatment. a less than thorough search for nodes by the pathologist, or some 778 Practice of Oncology / Cancers of the Gastrointestinal Tract combination of the two. Additional patient- and tumor-related Microscopic Nodal Metastases factors may also affect LN count independent of pathologist or surgeon. Belt et al.112 found a significant association between The advent of improved pathologic techniques and sensitive meth- MSI phenotype and high LN yield in both stage II and III colon ods such as IHC or polymerase chain reaction may have an impact on the number of positive LNs detected and may have important cancers, with the strongest effect in the latter group. The authors 121,122 postulate that this may be due to a more prominent lymphocytic prognostic significance. However, the prognostic value antitumor response known to be exhibited by MSI-H cancers.112 of these positive LNs, which otherwise would not be detected, remains controversial. In a recent review of 16 studies with survival Another report suggests that low body mass index is associated with 123 increased LN yield, although it did not affect relapse-free or over- data, Sirop et al. found only 8 papers that reported definitely all survival in stage III cancers. Proximal tumor location, well- or poorer outcomes, whereas the remainder were either equivocal in their conclusions or demonstrated no influence on outcome moderately differentiated histology, and stage IIIC cancer were 124 also significant variables for adequate LN recovery.113 Finally, a at all. Jeffers et al. evaluated LNs from 77 patients who were multivariate analysis of two large prospective US cohort databases found to have negative LNs by routine examination with immuno- (121,701 women and 51,529 men) demonstrated that specimen cytochemical staining for cytokeratin AE1:AE3. Nineteen patients length, tumor size, ascending tumor location, T3N0M0 stage, (25%) were found to have immunohistochemical evidence of and year of diagnosis were positively associated with negative node micrometastases; however, there was no difference in survival < between the microscopically positive and negative patients. A count (p 0.002). Mutation of KRAS was borderline significant 125 and requires further study. The authors recommend that these larger trial by Faerden et al., on the other hand, did demon- variables be taken into account when judging adequacy of LN har- strate adverse prognostic impact. In this study, 39 of 126 patients vest and devising individualized treatment plans in the future.114 with stage I/II colon cancer were noted to have micrometastases or isolated tumor cells (MM/ITC+) on IHC staining. Prospective An analysis was reported on outcome versus nodal sampling in + the patients who participated in an Intergroup trial (INT-0089), median 5-year follow-up of MM/ITC compared to MM/ITC- patients revealed recurrence rates of 23% versus 7% (p = 0.010) a large four-arm trial of different 5-fluorouracil (5-FU)–based ad- = 125 juvant chemotherapies in patients with colon cancer. Multivari- and 5-year DFS of 75% versus 93% (p 0.012), respectively. ate analyses were performed on the node-positive (2,768 patients) If micrometastases are reported, the methodology by which they and node-negative (648 patients) groups separately. The median are detected should be specified, as it is likely that differences in number of LNs reported in the assessable patients on this trial was reliability and reproducibility of different techniques will emerge. 11 (range, 1 to 87). Survival (overall, cancer-specific, and disease- Although the actual TNM staging is not altered by the presence of free [DFS]) was found to decrease with an increasing number of micrometastases, many clinicians choose to regard the presence of involved LNs (p = 0.0001 for all three survival end points). How- such a finding as a poor prognostic variable in their consideration ever, after controlling for the number of involved nodes, survival of adjuvant treatment. increased with the total number of nodes (positive plus negative) reported (p = 0.0001 for overall survival, cancer-specific survival, Sentinel Node Analysis and DFS). Even in patients who were node negative, overall sur- Sentinel node analysis is an approach that has received attention in = = vival (p 0.0005) and cancer-specific survival (p 0.007) were the management of cutaneous melanoma and breast cancer.126,127 significantly increased as the number of reported LNs increased. This technique has been proposed as a means of increasing the In a different secondary analysis of the Intergroup trial yield and the diagnostic information for colon cancer.91,92 The (INT-0089), a mathematical model was created to estimate technique for sentinel node mapping and biopsy for colon can- the probability of a true node-negative result on the basis of the cer has been described by Saha et al.128 Unlike sentinel node ap- number of LNs examined in a subset of patients who had at least 115 proaches for melanoma and breast, where the goal is to potentially 10 LNs reported in their resection specimen. A total of 1,585 limit the extent of an unnecessary formal dissection of a node patients with stage III or high-risk stage II colon cancer were evalu- basin, the goal of the sentinel node in colon cancer is to focus the ated. This model concluded that when 18 nodes are examined, pathologic analysis on fewer nodes so a more extensive study can < there is a 25% probability of true node negativity in T1 and T2 be performed. The same extent of node dissection is performed < tumors. However, examination of 10 LNs was needed in T3 regardless of the sentinel node procedure. The initial studies of and T4 tumors to achieve the same probability. The overall con- sentinel node biopsy demonstrated it was technically feasible, with clusions of this analysis were that a very significant proportion of accuracy rates >80% and upstaging in 15.4% of patients according patients are understaged, and that such understaging could have to a recent prospective trial.129–131 In addition, Saha et al.132 suggest important implications for decisions regarding adjuvant therapy that sentinel LN mapping may not just improve staging accuracy and for overall prognosis. but influence the extent of nodal dissection as well. In this study, The CAP consensus statement suggests that a minimum of sentinel LN mapping detected aberrant lymphatic drainage in 12 to 15 LNs should be examined in order to determine node neg- 109 22%, which in turn led to a change in operation (i.e., more exten- ativity. Availability of fewer nodes should therefore be regarded sive resection). In two patients, the aberrant sentinel nodes were as a relative high-risk factor in terms of prognosis and should be the only positive nodes identified.132 However, not all subsequent factored into decisions regarding adjuvant therapy. Further sup- studies have shown positive results. False-negative rates as high as port for this recommendation comes from a newly published 60% have been reported, and some studies have failed to demon- Danish cohort study that indicates that the advantage of larger LN strate any change in the stage determination of the lesion.133 Based harvest extends beyond more accurate staging. In addition to im- on the available data, two conclusions can be reached. First, from proved outcomes for node-negative patients, the authors found a a technical standpoint, sentinel node dissection at the time of a significant increase in overall survival for stage III patients with colon resection can be performed and the sentinel node accurately > < 12 LNs removed as well (58.6% versus 45.2% for 12 LNs), de- identified. Second, the utility of this technique has not yet been spite a higher prevalence of N2 disease in this group. This may established and further large-scale trials are required to establish be related to better surgical technique or an underlying benefit its role in the staging of patients with CRC. of wider lymphadenectomy in general. LN ratio was also shown to be an important independent prognostic indicator and, in fact, Blood or Lymphatic Vessel Invasion superior to N-stage in predicting survival for stage III patients. This finding is consistent with a number of previous reports, many of Although there have been conflicting reports in the literature, the which have advocated for incorporation of this parameter into the CAP consensus statement gave blood and lymphatic vessel invasion AJCC staging system.116–120 category I status, indicating that the preponderance of evidence

tahir99 - UnitedVRG Chapter 57 Cancer of the Colon 779 strongly supports the reliability of these findings as indicators of or MSS colorectal tumors.139,140 MSI-L and MSS tumors tend to poorer prognosis.109 Unfortunately, considerable heterogeneity behave and present similarly. MSI-H tumors are more frequently exists in the methodology for examining and reporting of vessel right-sided, high grade, and mucinous type.24,141 They are char- involvement. The finding of vessel involvement increases with the acteristically associated with increased peritumoral lymphocytic number of sections examined, and differentiation of postcapillary infiltration and are characteristically diploid, whereas MSS tumors venules from lymphatics is often not possible. These aspects can are more likely to be aneuploid.142,143 MSI-H CRCs are more make interpretation of some older data on this topic potentially likely to have a larger primary at the time of diagnosis but are more problematic. Current recommendations are that at least three likely to be node negative. Patients with MSI-H CRCs have a bet- blocks of tumor (optimally five or more) each have a single sec- ter long-term prognosis than stage-matched patients with cancers tion examined using hematoxylin and eosin stain to look for tumor exhibiting MSS.144 invasion of vessels. Vessels not definitively interpreted as venules or Watanabe et al.145 evaluated MSI status as well as allelic loss lymphatics should be reported as angiolymphatic vessels. from chromosomes 18q, 17b, and 8p, as well as cellular levels of p53 and p21waf1/c1p1 proteins as potential prognostic markers. Tu- Histologic Type mors were analyzed from 460 stage III and high-risk stage II patients who had been treated with 5-FU–based adjuvant therapy. Several histologic types of CRC carry specific independent prog- A total of 62 of 298 tumors evaluated for MSI status (21%) were nostic significance. Signet ring carcinomas are characterized by found to be MSI-H. Of the MSI-H tumors, 38 (61%) had a muta- >50% of cells demonstrating the “signet ring” morphology in tion of the gene for type II receptor of transforming growth factor which intracellular mucin accumulation displaces the nuclei and (TGF)-β1. In this analysis, MSI-H was a favorable prognostic indi- cytoplasm toward the cellular periphery. This histology carries an cator for 5-year DFS (p = 0.02) and trended toward being a favor- adverse prognosis.134,135 The prognostic significance of the finding able independent prognostic indicator, but did not reach statistical of mucinous (>50% mucinous) carcinoma remains controversial. significance for overall survival p( = 0.20). However, the 5-year sur- Although some reports list mucinous type as an adverse histology, vival among patients with MSI-H was 74% in the presence of a mu- this has not been consistently demonstrated. Most findings of ad- tated gene for the type II receptor of TGF-β1 and 46% in patients verse prognosis with mucinous histology are based on univariate whose tumors lacked this mutation (RR = 2.90; 95% CI = 1.14 analyses. The one finding in a multivariate analysis of a poor prog- to 7.34; p = 0.04). MSI-H cells are relatively resistant to 5-FU in nostic outcome with mucinous tumors was based on a study of vitro.146 All of the patients in Watanabe et al.’s145 analysis received tumors presenting with obstruction, a presentation that is in itself 5-FU–based chemotherapy. The TGF-β1 pathway inhibits tumor high risk. Some reports have lumped mucinous and signet cell tu- proliferation by causing a late G cell cycle arrest. Therefore, a mors together and found this to be a negative prognostic factor; 1 mutated and presumably nonfunctional TGF-β1 gene could favor however, this may simply reflect the negative impact of the signet increased proliferation, which would be anticipated to confer in- cell tumors, and its meaning regarding the risk of a mucinous his-

creased susceptibility to cytotoxic chemotherapy. A recent evalua- OF ONCOLOGY PRACTICE tology is unclear. Small cell (extrapulmonary oat cell) tumors are tion of the prognostic significance of MSI in the N0147 adjuvant high-grade neuroendocrine tumors with clearly adverse prognos- trial147 demonstrated a more nuanced result. When looking at the tic features. The prognostic significance of focal neuroendocrine colon overall, MSI was not found to be predictive. However, when differentiation is, however, unclear (CAP category III). Most data divided by side, MSI was found to carry a favorable prognosis for indicate that extensive neuroendocrine differentiation is associated right-sided colon lesions, but was a negative prognostic factor in with a poorer prognosis.136 Medullary carcinoma is a subtype char- left-sided colon lesions. The reasons for this difference is not clear; acterized by an absence of glands and distinctive growth pattern however, the different embryologic origins of the left and right that previously would have been classified as undifferentiated. It colon may play a role in these observations. is typically infiltrated with lymphocytes. This histologic subtype is tightly associated with MSI-H and carries a more favorable prog- BRAF nosis.137 Histologic types other than signet ring, small cell, and medullary carcinomas are routinely designated in the pathology BRAF mutation, present in 10% to 20% of CRCs, is linked to a sub- report; however, the majority of these other histologic types carry set of MSI-H tumors that are sporadic and generally have poorer no established independent prognostic significance. prognosis. Ogino et al.148 confirmed this relationship in comparative analysis of 506 stage III patients enrolled in the Cancer and Microsatellite Instability Leukemia Group B (CALGB) 89803 trial. BRAF-mutated patients had significantly worse overall survival (HR= 1.66) compared to As discussed earlier in this chapter, there are two distinct muta- wild-type, a finding that was most pronounced in the setting of tional pathways that can give rise to CRC: the MSI pathway or the MSS.148 In a follow-up study, Lochhead et al.149 also identified chromosomal instability pathway. Microsatellites are sections of combined BRAF/MSI status as a powerful prognosticator and rec- DNA in which a short sequence of nucleotides (most commonly ommends stratification of all patients into poor (MSS/BRAF mu- a dinucleotide) is repeated multiple times.138 MSI is a situation tant), intermediate (MSS/BRAF wild-type), and favorable (MSI-H/ in which a microsatellite has gained or lost repeat units and so BRAF wild-type) groups in order better inform treatment strate- has undergone a change in length, resulting in frame shift mu- gies. Douillard et al.150 confirmed BRAF mutation to be a poor tations or base-pair substitutions. Approximately 15% of CRCs prognostic factor in patients with stage IV disease as well. display these mutations. This form of genetic destabilization is typically associated with defective DNA mismatch repair function. Allelic Loss of 18q (DCC Gene Loss) Studies of HNPCC tumor specimens demonstrated mutations in mismatch repair genes such as MLH1 and MSH2. These genes Allelic LOH that involves chromosome 18q occurs in half or more encode proteins that repair nucleotide mismatches. The pheno- of all CRCs. Allelic loss of 18q typically involves the DCC gene; type of tumors with this defect is termed the MSI-H–instability however, other genes in this region, such as Smad2 and Smad4, may phenotype. also be relevant to CRC development. DCC expression is greatly re- The majority (approximately 85%) of patients with CRC have duced or absent in many colorectal carcinomas, and loss of DCC is cancers characteristic of the chromosomal instability pathway, associated with metastasis and an adverse prognosis.151 The specific typically having genetic alterations involving LOH, chromo- product of the DCC gene has been shown to be the netrin-1 recep- somal amplifications, and chromosomal translocations. These are tor. In the nonpathologic state, this receptor guides the migration of known as the microsatellite-stable (MSS) tumors. MSI-H tumors neuronal axons. DCC induces apoptosis in the absence of netrin-1 have a number of different features relative to low MSI (MSI-L) binding. DCC is cleaved by caspase, and mutation of the site at 780 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 57.7 by the CAP consensus panel.109 Patients in whom the elevated CEA fails to normalize after a potentially curative operation are at Loss of Heterozygosity (Allelic Loss) at 18q particularly high risk. Several authors have presented evidence that and Prognosis in Patients with Stage III indicates that CEA is an independent prognostic factor. In a report Colon Cancer of 572 patients who underwent curative resection for node-negative colon cancer, the preoperative CEA level and the stage of disease Allelic Status No. of Five-Y predicted survival by both univariate and multivariate analyses.155 of 18q Patients Survival (%) P Value Given the prognostic significance of the preoperative CEA, it is No loss 112 69 0.005 reasonable to recommend that all patients who undergo operation Loss 109 50 for CRC have a serum CEA drawn prior to operation. No other serum markers have been demonstrated to be reliably From Watanabe T, Wu TT, Catalano PJ, et al. Molecular predictors of survival prognostic or predictive in CRC. Cancer antigen (CA) 19-9, a fac- after adjuvant chemotherapy for colon cancer. N Engl J Med 2001;344: tor that has become widely used for pancreas cancer, has no role at 1196–1206. this time in the routine management of CRC. Obstruction and Perforation which caspase 3 cleaves DCC suppresses the proapoptotic effect of DCC completely. Binding of netrin-1 to DCC blocks apoptosis.152 Carcinoma of the colon that is complicated by obstruction or per- Loss of DCC as a result of allelic loss in 18q could therefore be an- foration has been recognized as having a poorer prognosis. Data ticipated to impair apoptosis, thereby resulting in greater resistance obtained from 1,021 patients with Dukes stage B and C CRC, who to chemotherapy. This hypothesized mechanism of action of 18q were entered into randomized clinical trials of the National Surgi- LOH is attractive; however, it should be emphasized that it is not at cal Adjuvant Breast and Bowel Project (NSABP) showed that the all clear to what extent DCC is the active moiety in the setting of 18q presence of bowel obstruction strongly influenced the outcome. allelic loss. Watanabe et al.145 evaluated allelic loss from chromo- The effect of bowel obstruction was more pronounced when the some 18q as a potential prognostic indicator in archived specimens obstruction was located in the right colon. The larger-sized tumor of tumors from patients who were treated in one of two national needed to block the ascending colon completely might allow a Intergroup adjuvant trials (INT 0035 or INT 0089). MSI status longer time for these tumors to grow and spread when compared was also evaluated, as were 17p, 8p, and cellular levels of p53 and with tumors located in the descending colon. p21waf1/c1p1 proteins. Tumors were analyzed from 460 stage III and A review of the Massachusetts General Hospital records com- high-risk stage II patients who had been treated with 5-FU–based ad- pared patients who presented with obstruction or perforation with juvant therapy. Allelic loss of 18q was present in 155 of 319 cancers a control group who underwent curative resection. The actuarial (49%). Allelic loss in 18q was highly prognostically significant in this 5-year survival rate seen in patients who presented with obstruction analysis (Table 57.7). In the stage III patients with allelic loss of 18q, was 31%, in contrast to 59% in historical controls. For patients with 5-year overall survival was 50%, while in those with retained 18q al- localized perforation, the 5-year actuarial survival rate was 44%. leles, 5-year survival was 69% (p = 0.005). Other markers evaluated The Gastrointestinal Tumor Study Group (GITSG) multivariate in this analysis were not shown to be prognostically significant. analysis concluded that obstruction was an important indicator of prognosis, independent of Dukes stage. Bowel perforation was a Host Lymphoid Response poor prognostic factor only for DFS. Lymphocytic infiltration has been identified as a favorable prognostic indicator. Whether this is a truly independent predictor of Category III Factors outcome is not clear, however, as this finding is tightly associated with MSI-H, a favorable prognostic factor. Along these lines, the Multiple factors, while of investigational interest, are at this time prognostic value of neutrophil-to-lymphocyte ratio has also been not appropriate for routine clinical use and have so been desig- recently evaluated. Chiang et al.153 found that elevated preopera- nated as category III (defined as not sufficiently studied to prove tive neutrophil-to-lymphocyte ratio (>3) was associated with signif- their prognostic value) by the CAP consensus panel. These include icantly worse DFS in stage I to III colon but not rectal cancers on DNA content, or ploidy, and proliferation indices. Also included multivariate analysis. In another study, neutrophil-to-lymphocyte in category III are all molecular markers other than MSI and 18q ratio (>5) was also found to be an independent risk factor for re- deletions, such as thymidylate synthase (TS), dihydropyrimidine currence. While the direct impact of this parameter is difficult to dehydrogenase (DPD), and p53 mutational status. Perineural inva- explain, the authors of the first study postulate that it may represent sion, microvessel density, tumor cell–associated proteins or carbo- a measure of innate-to-adaptive immunity under stress with rela- hydrates, peritumoral fibrosis, peritumoral inflammatory response, tive lymphopenia, as a marker of depressed cell-mediated immu- and focal neuroendocrine differentiation are also category III. The nity, conferring survival disadvantage.153,154 area of molecular prognostic markers is one of particular activity, however, and it is anticipated that clinical trials that are now ongo- Tumor Border Configuration ing will shed light on these important areas. The configuration of the tumor border (infiltrating versus push- Perineural Invasion ing border) has been shown to have independent prognostic significance. An infiltrating border, characterized by an irregular, The ability of CRCs to invade perineural spaces as far as 10 cm infiltrating pattern at the tumor edge (also known as focal dedif- from the primary tumor has long been described. Early reports ferentiation or tumor budding), has been shown in multivariate suggest an increased disease recurrence rate and worse 5-year analyses to portend a poorer prognosis than tumors with smooth, survival. Multivariate analyses have failed to show the prognostic pushing borders. significance of this finding. The CAP consensus panel classified perineural invasion as category III (insufficient evidence of deter- Carcinoembryonic Antigen mine prognostic significance). An elevated preoperative CEA is a poor prognostic factor for cancer Tumor Size and Configuration recurrence. Although there is variability in the available data regarding the level that denotes a prognostic cutoff, a preoperative CEA Studies have consistently shown that both the size and con- level >5 ng/ml is considered a category I poor prognostic indicator figuration of the primary tumor in CRC do not carry prognostic

tahir99 - UnitedVRG Chapter 57 Cancer of the Colon 781

significance (CAP category IV). In a review of 391 patients, the Diabetes Mellitus mean diameter of Dukes stage B2 tumors was actually greater than the mean diameter of stage C2 tumors (p <0.001) and D tumors The influence of diabetes mellitus on outcome is also unclear. In (p <0.05). The size of the primary tumor showed no relationship the INT-0089 cohort, diabetes conferred a strong disadvantage with to 5-year adjusted survival. These results were confirmed by the affected patients experiencing a significantly worse DFS (48% versus 156 59%; p <0.0001), overall survival (57% versus 66%; p <0.0001), NSABP experience. Tumor configuration is described as exo- = phytic (fungating), endophytic (ulcerative), diffusely infiltrative and recurrence-free survival (56% versus 64%; p 0.012) at 5 years. Median survival for diabetics was 6 years, whereas for nondiabetics (linitis plastica), or annular. The vast majority of studies have failed 158 to show any of these configurations to have consistent independent it was 11.3 years. Other reports, however, have generated less con- prognostic significance. Linitis plastica has been related to a poor sistent results. Among 2,278 subjects from the Cancer Prevention Study-II Nutrition Cohort, patients with CRC and type 2 diabetes prognosis; however, this may be due to the signet cell and other = high-grade features of the tumors that are typically associated with were at higher risk of all-cause mortality (ACM; RR 1.53), but this morphology. only those without insulin use were at higher risk for CRC-specific mortality. These results are in line with previous evidence that hyperinsulinemia (as in poorly controlled diabetes) plays an important Hemorrhage or Rectal Bleeding role in tumorigenesis and metastasis of CRC.161 Another popula- It has been speculated that tumors that present with bleeding might tion-based study did not find any such an association in 6,974 pa- be found earlier and therefore might be associated with a better tients with colon cancer. Disease-specific mortality was only prognosis. This has not been confirmed by data. In the GITSG significantly increased for patients with rectal cancer (n = 3,888, multivariate analysis, the presence of melena or rectal bleeding 10% of whom were diabetic; HR = 1.30). While hyperinsulinemia showed a trend as a prognostic factor for prolonged survival but is again implicated, the authors call for additional study to clarify failed to reach statistical significance p( = 0.08). One large study specific pathways responsible for these rectum-specific findings.162 found bleeding to be a favorable prognostic indicator on univariate analysis; however, this finding disappeared on multivariate analysis. Gender Bleeding at presentation does not appear to carry any significance. Female sex has generally been considered a favorable prognostic factor, but data is limited and inconclusive. In the first study Primary Tumor Location to examine the impact of gender in the era of oxaliplatin-based 163 Large retrospective reviews of data from the NSABP suggest that therapy, Cheung et al. performed a prospectively planned, right-sided colon cancers carry a worse prognosis than left-sided pooled analysis of 33,345 patients participating in the ACCENT ones. However, poorer prognosis for patients with disease in the database of randomized trials. The authors found a significant but left colon has also been reported. Several investigators report no very modest survival advantage for women with early stage disease difference based on the location of the primary tumor. The large that persisted across all ages, stages, and types of adjuvant therapy. OF ONCOLOGY PRACTICE GITSG colon cancer experience showed that tumor location (left, Sex was not a predictive factor for treatment efficacy, however, right, and rectosigmoid or sigmoid) was of low prognostic value. suggesting that chemotherapy regimens should be not be altered 163 A recent analysis of SEER-Medicare data by Weiss et al.157 pro- based on this parameter. vides additionally ambiguous results. Of 53,801 patients, 67% had right-sided colon cancer and were more likely to be older, women, Smoking and diagnosed with more advanced stage and with more poorly As discussed earlier, prolonged cigarette smoking appears to be differentiated tumors. However, on multivariate analysis, there a moderate risk factor for CRC with continued effect even after was no significant difference in mortality for all stages combined smoking cessation. Increasing evidence indicates that this associa- or for stage I. Compared to left-sided lesions, right-sided cancers tion differs not just by tumor site but also by molecular features, were associated with a lower mortality within the stage II subgroup such as the presence of MSI-H and BRAF mutations, which cu- (HR = 0.92; p = 0.001) but higher mortality within stage III = = mulatively seem to confer the strongest risk. Impact on survival (HR 1.12; p 0.001). Critics of this report point out that a less has now also been reported in a recent study analyzing data from aggressive treatment approach was likely employed in this older a large multicenter randomized adjuvant chemotherapy trial study population, as at least 40% of stage III cases did not receive (N0147). The authors found that smokers experienced signifi- adjuvant therapy and nearly half underwent inadequate LN har- cantly shorter 3-year DFS (74% versus 70%; HR = 1.21) that was vest. Regardless, these results further dispel the notion of a straight- most evident in BRAF wild-type and KRAS-mutated tumors.164 forward relationship between tumor location and mortality.157 Blood Transfusions Body Mass Index Considerable controversy has surrounded the question of an While obesity is known to be a risk factor for the development of association between perioperative blood transfusions and the recur- colon cancer, the prognostic impact of body mass index on long- rence rate of CRC. Some investigators have reported worse DFS term outcomes is controversial. In a cohort study conducted within in patients who require transfusions. By multivariate analysis in a a large randomized trial of 3,759 patients with high-risk stage II or large prospective study, however, no negative influence of transfu- III colon cancer (INT-0089), obese women had significantly worse sion on survival could be detected, and it does not appear that overall mortality (HR = 1.34; 95% CI = 1.07 to 1.67); however, this 158 159 perioperative blood transfusions carry negative prognostic value. finding was not apparent in men. Sinicrope et al. found the op- A retrospective analysis evaluating 1,051 patients treated with posite gender correlation using the ACCENT database, a pooled re- curative surgery for stage II or III colorectal adenocarcinoma at the source of 25,291 participants in national and international adjuvant Mayo Clinic demonstrated that the use of blood components prob- chemotherapy trials. On multivariate analysis, with a median follow- ably had no impact on disease recurrence, and the documented up of 7.8 years, obese and underweight men, but not women, had adverse impact of transfusions is more likely due to other variables significantly poorer survival compared to overweight and normal or to the underlying illness necessitating the transfusion.165 weight patients.159 And in another prospective cohort of 913 patients 160 with stage II and III colon cancer, Alipour et al. found no asso- Oncogenes and Molecular Markers ciation between obesity (as measured by either body mass index or body surface area) and oncologic outcomes. Evidently, this topic Oncogenes and molecular markers are discussed extensively in an- warrants further study before any conclusions can be drawn.160 other chapter. At present, none of the markers under investigation 782 Practice of Oncology / Cancers of the Gastrointestinal Tract has achieved adequate validity to permit routine clinical use. colonoscopic biopsy or resection is to, whenever feasible, remove However, the study of molecular markers continues to progress the lesion in its entirety and preserve a tissue architecture in order and continues to advance the understanding of the development to achieve both a therapeutic resection and an accurate pathologic and treatment of CRC. TS continues to be a major area of diagnosis. Various techniques can be employed for the removal of investigation. Data are conflicting on its prognostic significance; lesions in the colon depending on their size and location. Biopsy however, preliminary studies suggest that high TS levels may be forceps and snares are the two most commonly employed instru- predictive for resistance to 5-FU–based therapies.166 At present, ments used during a colonoscopy. These devices are fashioned there is no role for TS determinations in routine clinical practice. from flexible coated wires that can conform to the shape of the The p53 gene located on chromosome 17p is a well-known tumor colonoscope and can also conduct electrical current in order to suppressor gene. The abnormal p53 appears to be a late phenom- achieve coagulation and hemostasis. enon in colorectal carcinogenesis. This mutation may allow the Bleeding and perforation, while uncommon, are seen at an growing tumor with multiple genetic alterations to evade cell increased frequency during a therapeutic as opposed to a di- cycle arrest and apoptosis. In a retrospective review of 141 patients agnostic colonoscopy.171,172 Small polypoid lesions (up to 5 to with resected stage II and III colon carcinoma, a p53 mutation in- 8 mm) that are found during the course of a colonoscopic ex- creased the risk of death by 2.82 times in patients with stage II dis- amination can often be removed in their entirety along with a ease and by 2.39 times in patients with stage III colon carcinoma. small amount of normal mucosa using a biopsy forceps. Bleeding The Southwest Oncology Group assessed the prognostic value of is usually minimal but can be controlled by electrocautery if per- p53 in 66 patients with stage II and 163 stage III colon cancer. p53 sistent. Larger well-pedunculated polyps can often be removed expression was found in 63% of cancers and was associated with using a technique employing a snare and electrocautery. The favorable survival in stage III but not stage II disease. Seven-year snare is placed over the polypoid lesion and cinched down at the survival with stage III disease was 56% with p53 expression versus base of the polyp. Once tightened, an electrical current is applied 43% with nop53 expression (p = 0.012).167 Overall, the data are and the polyp is resected. If the lesions are too large to be re- conflicting on the utility ofp53 as a prognostic variable, and it does trieved through the working port of the colonoscope, they can be not have a use at this time in standard practice. held in place with a snare just beyond the tip of the colonoscope Epidermal growth factor receptor (EGFR) is an important mo- where they can be kept in view and withdrawn with the scope lecular target for antibody-based therapy in various cancer types from the patient. It is important, when sending these specimens and is ubiquitous in colonic tissue. The prognostic impact of this to pathology, to properly orient the polyp so as to indicate the biomarker was recently addressed in a meta-analysis demonstrat- base where the resection took place as well as the other positions ing worse postoperative survival in patients with high compared to of the lesion. This will allow the pathologist to provide important low EGFR expression (HR = 2.34).168 information as to the margin status for the resection. Carcinoma in situ as well as stage I invasive carcinomas found in a well- Genetic Polymorphisms pedunculated polyp can be treated with colonoscopic resection, as described previously, and no further surgical management is Extensive preliminary work is indicating that genetic polymor- > phisms can potentially have important predictive implications needed as long as there is a negative margin 2 mm and the in terms of both efficacy and toxicity with chemotherapy. For tumor is well-differentiated without lymphovascular invasion or extension of malignant cells beyond the stalk (Haggitt levels 1 example, the UGT1A1 polymorphism has been correlated with 173 CPT-11 toxicity, and TS and XRCC1 polymorphisms may predict to 3). If these criteria are not met, further therapy is required. efficacy for oxaliplatin or 5-FU combinations.169 Although a com- It is for this reason that it is often helpful to mark the site of the mercial assay is currently available for measurement of UGT1A1 polyp resection with an agent that will leave a “tattoo” to guide polymorphisms, it is not, at this time, clear how, or if, this assay additional intervention. should be used in routine practice. Currently, there are no specific Larger lesions with a broad base or sessile lesions are best bi- guidelines for dose modifications on the basis of UGT1A1poly- opsied to make a diagnosis rather than resected using the colon- morphism, and the 7/7 mutation, associated with higher toxicity, oscope. The risk of perforation or inadequate resection margins has also been associated with greater antitumor activity. These ap- is greatly increased with broad-based and sessile lesions. Mul- proaches will require considerable more validation and explora- tiple biopsies should be taken in order to determine whether tion before they can be considered for standard management.170 the lesion harbors an invasive cancer, and further resection decisions are made based on the pathologic findings. In cases where there is low suspicion for malignancy, an endoscopic mucosal APPROACHES TO SURGICAL RESECTION or submucosal resection may be attempted, usually by a gastro- enterologist with advanced interventional endoscopic expertise. OF COLON CANCER However, if such a lesion is left behind, it is of critical importance to note the position of the lesion in order that it might be The management of colon cancer is best understood as a multi- more easily found if a subsequent procedure is required. In ad- modality approach tailored to the stage of disease. However, there dition to determining the depth of insertion of the scope, which are certain basic tenets of surgical management for the resection can be highly inaccurate with flexible instruments, other land- of the primary lesion that can be applied across various pathologic marks including the appendiceal orifice or ileocecal valve in the stages. Therefore, in order to provide a clear description of these cecum and the liver/splenic shadows at the flexures should be techniques, they will first be described based on the type of surgi- noted. The most important step however is to properly mark the cal resection. These procedures will then be referred to through- polyp site with 1 ml of tattoo injected submucosally in each of out the discussion of stage-specific treatment. four quadrants for definitive intra- and extraluminal recognition at a later date.174 Colonoscopic Resection of Polyps For lesions that cannot be resected through the scope or are found to be invasive carcinomas that are sessile or broad based, Many lesions of the colon are first detected during endoscopic pro- a variety of surgical resections can be employed depending on cedures. These lesions can range from small hyperplastic polyps the position of the lesion and its T stage. It is important to keep to large fungating invasive carcinomas. The appearance of these in mind, however, that the formal staging of the lesion does not lesions often indicates their relative potential for malignancy. occur until after the resection is completed; therefore, if there is However, the only definitive way to make a diagnosis is through any suspicion of an invasive carcinoma being present, a definitive a pathologic examination of the tissue. Therefore, the goal of a oncologic resection should be performed.175

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Bowel Preparation An important part of the preoperative regimen for a colon resection is the proper cleansing of the bowel in order to reduce the risk of postoperative complications as well as to allow for easier visualization during the procedure, particularly with the laparascopic approach. A variety of regimens have been described, and there are many that have demonstrated efficacy.176,177 Although there are several choices described in the literature, the basic components of a bowel preparation are a mechanical cleansing of the bowel using a cathartic or volume-displacing agent and appropriate anti- biotic prophylaxis.178,179 Recently, some studies have suggested that mechanical bowel preparation may be unnecessary; however, this remains controversial.180,181 For rectal and low sigmoid tumors, a number of surgeons also perform distal rectal washout prior to resection, with the professed AB intention of eliminating exfoliated intraluminal cancer cells that may increase local recurrence risk. There has been little evidence to support this theory, and washout has not been routinely recommended as standard practice. However, a recent meta-analysis of nine studies and 5,395 patients is the first to demonstrate a significant benefit to this maneuver with a nearly two-fold reduction in local recurrence rates (5.79% versus 10.05%; p <0.00001). While the lack of randomized controlled trials limits the strength of this data, the authors conclude that distal washout should be reconsidered in all patients given the minimal cost, time, and risk it entails.182

Anatomic Resection

For invasive carcinomas of the colon, stages I through III, the surgical approach will be dictated by the size and location of lesions 183,184 in the colon. The location will determine what region of OF ONCOLOGY PRACTICE CD bowel is removed, and the extent of its resection is dictated by its vascular and lymphatic supply. Resection of the Right Colon Lesions in the cecum and ascending colon are managed with a right hemicolectomy (Fig. 57.3A,B). The right colon is mobilized from the retroperitoneum by incising its retroperitoneal attachments, taking care to avoid injury to the ureter, inferior vena cava, duodenum, and gonadal vessels. The colon is mobilized from the ileum to the transverse colon, taking care at the hepatic flexure not to injure the gallbladder or duodenum. The ileocolic, right colic, and right branch of middle colic vessels are then ligated and divided. A proximal ligation in order to allow for the removal of colonic mesentery along with LNs is performed for staging purposes. Once the vascular supply is divided and the intervening mesenteric tissue ligated and divided, attention can be addressed to the resection of the colonic tissue. EF There are a variety of techniques for dividing the colon. This Figure 57.3 (A) Surgical resection for a cecal or ascending colon cancer. can be done between clamps using scalpel or using a variety of (B) Surgical resection for a cancer at the hepatic flexure.(C) Surgical stapling devices. One method would be to use a linear GI anastig- resection for a descending colon cancer. (D) Preferred surgical procedure matic stapler. After making a small hole just below the colonic for cancer of the middle and proximal sigmoid colon. In poor-risk patients, wall though the mesentery at the point chosen for resection, the the inferior mesenteric artery and the left colic artery may be preserved. stapler can be positioned across the colon and fired, thus dividing (E) Surgical resection for cancer of the rectosigmoid. (F) A more radical the tissue. This is then repeated across the ileum just proximal to surgical resection for cancer of the rectosigmoid. the ileocecal valve. Once divided, all remaining mesenteric tissue is carefully ligated and divided, and the colonic specimen can be removed. Although a no-touch “technique” has been advocated in near the hepatic flexure can be resected with an extended right the past, studies have demonstrated that this has no influence on re- hemicolectomy. This extension should encompass up to and in- currence or seeding of distant disease.185 Once the right colon has clude the middle colic vessel. The advantage of such a resection been removed, intestinal continuity can be re-established by creat- over a true transverse colectomy is that the anastomosis performed ing an anastomosis between the terminal ileum and the remaining to restore intestinal continuity involves an anastomosis between transverse colon using either a hand-sewn or stapled technique. the ileum and the remaining colon. Due to the improved blood Resection of the Transverse Colon supply delivered by the small bowel mesentery, there is a decreased risk of an anastomotic leak in an ileocolic as opposed to a For lesions located in the transverse colon, a variety of ap- colocolic anastomosis.175 Likewise, a lesion in the distal transverse proaches can be undertaken. Those lesions that are proximal and colon can be resected with an extended left hemicolectomy, which 784 Practice of Oncology / Cancers of the Gastrointestinal Tract will be described in more detail in the following section. For those procedures provide very good control of continence and a rela- lesions that are in the midportion of the transverse colon, however, tively normal lifestyle.188 a transverse colectomy can be performed. This procedure requires mobilization of the right colon in order to allow this tissue to be brought over for an anastomosis following the resection. SURGICAL MANAGEMENT OF The omentum is divided from the greater curvature of the stomach up to and including its attachments at the splenic helium. COMPLICATIONS FROM PRIMARY COLON The omentum can often be a source of micrometastatic disease CANCER and therefore its resection at the time a transverse colectomy is indicated. After dividing the omentum and mobilizing the right Patients with primary lesions of the colon can present with ob- and transverse colon up to and including the splenic flexure, the struction, bleeding, and perforation. The surgical management of middle colic artery is ligated at its trunk and smaller vessels from these patients can be complex, requiring intraoperative decisions the right and left colic artery branches can be ligated and divided tailored to the situation encountered. Blood per rectum can be as required. A linear stapler can once again be used to divide the one of the most frightening experiences for patient and physician colonic tissue, and then the mobilized right colon can be anasto- alike. Bleeding from a CRC can occur anywhere from the cecum mosed to the descending colon in an end-to-end fashion using a to the distal rectum. Although bleeding can be temporized with hand-sewn anastomosis or using a side-to-side stapled technique. endoscopic fulguration and the patient supported with transfu- Depending on the size of the transverse colon, however, it is often sion, definitive management of the lesion with either surgery or safer and easier to resect the right and transverse colon and con- radiation therapy will ultimately be required. Other maneuvers nect the ileum to the descending colon. This allows enough co- such as angiographic embolization may provide only a temporary lonic reserve for water absorption and normal bowel movements. solution. Fortunately, life-threatening hemorrhage due to a colon cancer primary is a rare occurrence. More often, these lesions lead to a chronic blood loss, resulting in anemia. Resection of the Descending and Sigmoid Colon Colonic obstruction due to a primary tumor is not uncommon. For lesions in the proximal descending colon, the splenic flexure is Obstructing colon lesions present several important issues. First, mobilized and the left colic artery can be ligated and divided with the acute obstruction must be managed. Ideally, an exploration the portion of colon removed by mobilizing the splenic flexure with resection of the tumor and primary anastomosis with or with- and dividing the omentum (Fig. 57.3C,D). The transverse colon out a diversion is ideal. However, given the fact that the operation can be brought over to the region of the sigmoid colon for anas- will be performed on unprepared bowel and the patient’s physical tomosis. For lesions in the midportion of the descending colon, condition may be less than optimal, resection without an anasto- a left hemicolectomy can be performed, taking care to ligate the mosis and an end colostomy should be considered. In some in- left colic vessel along with some sigmoidal branches and taking an stances, the obstructing lesion may present significant technical adequate portion of mesentery for staging purposes. hurdles for resection in the setting of an acutely dehydrated and ill For lesions that involve the sigmoid colon, a sigmoid colectomy patient. In these circumstances, a decompression maneuver that can be performed with margins of resection on either side of the lesion. can be performed rapidly and with minimal morbidity such as a The descending colon is mobilized (together with the splenic flexure transverse loop colostomy or a colostomy and mucous fistula can as needed) and connected to the rectum using either a hand-sewn be performed to temporize the situation and allow the patient to anastomosis or stapling device. The mesentery can be divided either be prepared and resuscitated adequately for a definitive resection at the level of the sigmoidal branches with preservation of the left colic at a second exploration. artery or at the origin of the inferior mesenteric pedicle (Fig. 57.3E,F). Bypass operations should be reserved only for the most extreme While the latter approach is preferred by some to achieve greater mo- circumstances as complications following these procedures due bilization and higher lymph node counts, neither this nor a more ex- to repeat obstructions and leakage with abdominal sepsis are not tensive left hemicolectomy has resulted in improved survival. insignificant. The approaches to the resection of lesions below the peritoneal Another option is to place an endoscopic stent either for tem- reflection will be discussed in the chapter on rectal cancer. porary decompression or for definitive palliation of unresectable lesions. Multiple studies over the past 10 years have demonstrated the feasibility and safety of this maneuver in selected patients.189–194 Total Abdominal Colectomy As a bridge to surgery, stenting can provide a minimally invasive means for converting an emergency situation into an elective one, For patients with ulcerative colitis or familial polyposis syndrome allowing time for resuscitation, bowel prep, and adjuvant thera- who either have evidence of invasive carcinoma or are at significant pies. In a small randomized, controlled trial from 2009, Cheung risk for the development of invasive carcinoma, a total abdominal et al.195 reported additional advantages including significantly re- colectomy may be required. This can be performed by mobiliza- duced rates of perioperative morbidity and stoma creation. tion of the right colon, transverse colon along the omentum, tak- While short-term data seem to support the use of self-expand- ing the omentum as part of the resection, the hepatic and splenic ing metallic stents (SEMS) as a bridge to surgery, other reports as flexures, as well as the complete mobilization of the descending well long-term results from a recent comparative trial do not.196,197 colon down to the peritoneal reflection. Ligation of the ileo colic, Sabbagh et al.198 performed a head-to-head, intention-to-treat anal- right colic, middle colic, left colic, and sigmoid branches will ysis of 87 patients undergoing either stenting or emergency surgery, allow for removal of the colon down to the peritoneal reflection. using a propensity score to correct for selection bias. Overall sur- For ulcerative colitis and familial polyposis syndromes without vival at 3 and 5 years was significantly better in the surgery group evidence of carcinoma below the peritoneal reflection, the opera- (66% versus 44%, p = 0.015, and 62% versus 25%, p = 0.0003, tion can be terminated at this point with ileorectal anastomoses respectively) and remained superior even when patients with per- and careful surveillance of the remaining rectum via proctoscopy. foration and metastatic disease were excluded (74% versus 51%, However, in order to remove all tissue at risk for further lesions, a p = 0.02, and 67% versus 30%, p = 0.001, respectively). Five-year total protocolectomy is often advocated.186,187 Although this pro- cancer-specific mortality was significantly higher in the SEMS cedure can be performed as an abdominal perineal resection with group (48% versus 21%, p = 0.02) and there were trends toward a permanent end ileostomy, most surgeons now advocate one of worse 5-year DFS and increased recurrence as well as mean time many continent pull-through procedures in order to preserve fecal to recurrence. Based on these findings, the authors have markedly continence in a patient population that is often very young. Such changed their management of left-sided malignant obstruction,

tahir99 - UnitedVRG Chapter 57 Cancer of the Colon 785 now reserving SEMS strictly for palliative indications and patients on an intention-to-treat model. The study measured oncologic with high postoperative mortality risk.198 outcomes and compared them with a computerized case-matched open resection group, using case-matching variables consisting of age, gender, site of primary tumor (colon versus rectum), and TNM Laparoscopic Colon Resection stage. The group who received laparoscopic resection was followed prospectively and the data were updated on a regular basis. Follow- Since its introduction to the field of general surgery for gallblad- up of these patients consisted of a combination of office visits, tele- der resection, the use of laparoscopic surgery has found increasing phone calls, and a review of the US Social Security Death Index 199 applications. Laparoscopic surgery has become a particularly Database. There were 172 patients in each group, and the groups important addition to the armamentarium of the surgical oncolo- were well matched for age, TMM stage, prior chemo- or radiation gist. The use of laparoscopy for the staging of the extent of disease therapy, and site of the primary tumor (colon versus rectum). for peritoneal malignancies, pancreatic cancer, colon cancer, and Thirty-day mortality was 1.2% in the laparoscopic resection 200–202 gastric cancer is now widely accepted. Laparoscopic resec- group and 2.4% in the open resection group; however, this differ- tion has also found a niche for the removal of adrenal tumors, ence was not statistically significant. The local recurrence rate of the 203,204 the spleen, and distal pancreas. The use of laparoscopic ap- laparoscopic group was 3.5% compared to a local recurrence rate in proaches for the resection of malignant lesions in the colon is now the open group of 2.9%. The stage-for-stage overall 5-year survival becoming more common. rate between the two groups was similar, and the conclusion of the With the increasing application of laparoscopic techniques to authors, while acknowledging drawbacks based on the nonrandom- colon cancer surgery, concerns ranging from inadequacy of resec- ized nature of the study, was that there was no significant differ- tion margins, inadequacy of LN sampling, and the potential seeding ence in outcomes between using laparoscopic approaches versus an 205–207 of port sites with malignant cells have been raised. Although open approach in the management of primary colon and rectal tu- these concerns are important, there are several potential advan- mors. There was, however, no formal cost analysis in this study, and, tages for laparoscopic approaches to the surgical management of therefore, although oncologic outcomes were no different between colon cancer. Issues regarding length of incision, patient recovery the two groups, it is impossible to determine whether one group was time, and return to bowel function are often cited as justification superior to the other with respect to other outcomes. for a laparoscopic approach. However, just as important are the A case-matched comparison of clinical and financial outcomes technical advantages of surgery utilizing laparoscopic systems. The following laparoscopic and open colorectal surgery has been per- improved visualization due to magnification provided by video lap- formed.206 The group at the Cleveland Clinic studied patients from aroscopy allows much more intricate and careful dissections in the a prospective database who had undergone laparoscopic or open deep pelvis, which could potentially reduce postoperative morbid- colectomy and were matched for age, gender, and disease- related ity from low anterior resections that utilize a mesorectal excision groupings. A group of 150 patients undergoing laparoscopic co-

technique. The ability to carefully trace vessels in the mesentery lectomy was compared to a matched group of patients undergoing OF ONCOLOGY PRACTICE under magnification could improve the ability to perform high li- open colectomy. There was no difference found between the two gations in order to retrieve a greater number of LNs for sampling. groups for diagnosis, complications, or 30-day readmission rate. The technical difficulties faced during laparoscopic resection Although operating room costs were significantly higher after lapa- of the colon relate, in general, to the size of the specimen being re- roscopic colectomy, this was offset by a decrease in the length of moved and the need to perform an anastomosis. Each of these can hospital stay with an overall significant reduction in total costs. be overcome through careful placement of incisions for specimen This is attributed mainly to a lower cost for pharmacy, laboratory, removal as well as a judicious use of stapling devices in order to per- and ward nursing expenses. form both intracorporeal as well as a combination of intracorporeal The ultimate role of laparoscopic resection in the manage- and extracorporeal anastomotic techniques. A number of studies ment of CRC has yet to be determined. The studies discussed have have examined the relative risks and benefits of the laparoscopic shed some light on the relative risks and benefits as well as costs 205,208–210 resection of colon cancer. A prospective random assign- of these two procedures. The questions will remain, however, if ment trial conducted by Clinical Outcomes of Surgical Therapy the procedures are equivalent and whether deviating from the Study Group examined both the oncologic outcomes with respect accepted gold standard of open resection for the management of to DFS and overall survival as well as the impact of laparoscopic CRC will be warranted. Longer follow-up will hopefully assist in versus open surgery on patient recovery, pain management, and this assessment. time to return of bowel function. An initial report on quality of life In the meantime, exploration of other minimally invasive ap- showed only a modest short-term benefit for laparoscopic resection proaches to resection is ongoing. Early studies report the feasibility 211 versus a conventional open procedure, but the overall results of and safety of single port surgery, or “SILC” (single-incision lapa- the trial with respect to oncologic outcomes demonstrated equiva- roscopic colectomy), as well as equivalent oncologic outcomes at 212 lence between the laparoscopic and open approach. 2 years, and robotic colectomy has also been performed although Long-term follow-up from the corresponding UK randomized its greatest potential is thought to lie with rectal dissection.215–221 study (CLASICC Trial Group), which was similarly designed to Natural orifice surgery is another area of interest with data accu- compare laparoscopic to conventional surgery for colon and rectal mulating on transvaginal specimen extraction as well as a pure cancer, and that initially reported noninferiority results in 2007, transrectal approach.222–224 Whether any of these novel modalities lends further support to the laparoscopic approach. With a median will offer real advantages (other than cosmesis) to offset the signifi- follow-up of 62.9 (range, 22.9 to 92.8) months, the authors found cant drawbacks of increased technical difficulty, operating time, no statistically significant differences in overall survival (82.7% and cost remains to be seen. versus 78.3%), DFS (77% versus 89.5%), or local recurrence.213,214 Over a period of 10 years, the group from the Colon and Rectal Clinic of Orlando, Florida, performed a prospective nonrandom- POLYPS AND STAGE I COLON CANCER ized study comparing laparoscopic to open resection for colorectal carcinoma. Laparoscopic resection was offered selectively in the ab- The management of polyps and stage I colon cancer is through sur- sence of a large mass, invasion into the abdominal wall or adjacent gical resection. Most cancer in polyps is not diagnosed until after organs, or if the patient did not have multiple prior operations.205 the polypectomy is performed. Therefore, with respect to pedun- All laparoscopic resections were performed with curative intent, culated lesions, care should be taken to resect the stalk completely, and 20% of the patients whose procedures were converted to open down to its base. Invasive early stage I cancers found in a polyp resection were included in the laparoscopic resection group based managed by polypectomy do not require further resection if there 786 Practice of Oncology / Cancers of the Gastrointestinal Tract is a negative margin >2 mm and the tumor is well- differentiated these agents have now been studied in the adjuvant setting in without lymphovascular invasion or extension of malignant cells comparison to the now defunct Mayo Clinic 5-FU schedule. In a beyond the stalk (Haggitt levels 1 to 3).173,225 Sessile lesions that study designed to assess for noninferiority in 3-year DFS, Twelves are biopsied and shown to harbor an invasive cancer should be et al.235 randomly assigned 1,987 patients with resected stage III managed with a segmental colon resection. Large polypoid lesions colon cancer to receive either oral capecitabine (1,004 patients) may also require a segmental resection. or Mayo Clinic bolus 5-FU plus leucovorin (983 patients). Each Because the stage of the lesion will not be determined until treatment was planned for 24 weeks. DFS in the capecitabine after the resection, all colon cancer lesions managed with a seg- group was at least equivalent to that in the 5-FU/leucovorin group mental resection should be approached the same way. The type of (in the intention-to-treat analysis [p <0.001] for the comparison of resection will be dictated by the location of the lesion, as has been the upper limit of the HR with the noninferiority margin of 1.20), described. Following a complete resection of a stage I lesion, no and capecitabine resulted in significantly fewer adverse events further adjuvant therapy is required. Patients managed in this way than Mayo Clinic bolus 5-FU/leucovorin (p <0.001). Overall, can expect a 5-year survival of over 95%.225 Those that recur are this trial demonstrates that capecitabine is a reasonable alternative most likely improperly classified stage II or III lesions. to intravenous 5-FU/leucovorin in the adjuvant treatment of colon cancer in reliable, motivated patients who are able to comply with a complex schedule of oral medication. However, as discussed STAGE II AND STAGE III COLON CANCER in the following, while possibly appropriate for some stage II patients, 5-FU/leucovorin alone is no longer the standard postsurgical adjuvant treatment for stage III colon cancer. As such, the Adjuvant Chemotherapy Considerations role of single-agent capecitabine in the adjuvant management of resected colon cancer remains limited at this time. Data support- The earliest clinical trials of adjuvant chemotherapy in colon can- ing its use with concurrent intravenous oxaliplatin are discussed cer were conducted in the 1950s, utilizing the limited arsenal of subsequently. anticancer agents that were available at that time. Many of these The NSABP C-06 trial assessed the use of oral UFT plus oral agents are now known to have no meaningful activity in metastatic leucovorin in the treatment of stage II and III colon cancer.236 A CRC, and thus would not be studied in the adjuvant setting today. total of 1,608 patients with stage II (47%) and stage III (53%) colon The adjuvant trials of the 1950s through the mid-1980s tended cancer were randomly assigned to receive either oral UFT with to be small by current standards. Based perhaps on an unrealisti- leucovorin or intravenous 5-FU with leucovorin. With a median cally optimistic expectation of what magnitude of benefit might follow-up of 62.3 months, there were no significant differences be achieved from the use of available chemotherapies, the size of in DFS or overall survival between the treatment groups. Toxic- the trials did not allow evaluation of more modest clinical benefits. ity and primary quality of life end points were similar in the two A large meta-analysis of controlled randomized trials of adjuvant groups. As such, similar to the situation with capecitabine, the therapy published through 1986 indicated a nonsignificant trend combination of oral UFT with leucovorin is an acceptable alterna- toward an overall survival benefit, with a mortality OR of 0.83 in tive to parenteral 5-FU/leucovorin; however, use of fluoropyrimi- 226 favor of therapy (95% CI = 0.70 to 0.98). This sobering analysis dine plus leucovorin alone is no longer routine standard practice suggested that substantially larger trials would be needed to detect (see the following) in the adjuvant treatment of at least stage III the modest advantages that available chemotherapies might afford. disease. Furthermore, UFT is not commercially available in the United States. Large-Scale Randomized Trials Combination Adjuvant Therapies The large-scale 5-FU trials have been well summarized previously, and the reader who is interested in the details is referred to sub- Clinical trials in the metastatic setting have established the an- ject-relevant chapters in the previous edition of this book.227 The titumor activity of combinations of agents, including irinotecan, outcome of numerous trials performed largely in the 1990s can be oxaliplatin, bevacizumab, cetuximab, and panitumumab (see briefly summarized as follows. Trials comparing 5-FU–based ther- discussion of treatment of metastatic disease for more details). apy to surgery only demonstrated a clear benefit in terms of 5-year Although it had been assumed that activity in the metastatic set- DFS (essentially, an increased cure rate) for stage III patients ting would translate into an increased cure rate in the adjuvant who received chemotherapy.228,229 Six months of chemotherapy setting, this assumption has turned out to be overly simplistic and was sufficient, and no further benefit was provided by extending often untrue. Of the agents listed previously, only the addition treatment to either nine or twelve months. Levamisole, an agent of oxaliplatin to fluoropyrimidines has resulted in benefit in the initially thought to be active, was, in fact inactive, and high-dose adjuvant setting. leucovorin did not confer superior efficacy over low-dose leucovorin, so comparisons of various 5-FU/leucovorin schedules did Oxaliplatin not demonstrate clear superiority of one schedule over the other in terms of efficacy. However, the Mayo Clinic daily times five Oxaliplatin plus biweekly infusional 5-FU/leucovorin was first schedule was substantially more toxic than either weekly bolus of evaluated in the adjuvant setting in the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant biweekly infusion schedules. Alfa interferon conferred substantial 237 toxicity and provided no benefit.230–234 Treatment of Colon Cancer (MOSAIC) trial. The results of this trial are summarized in Table 57.8. A total of 2,246 stage II and III patients were randomized to the LV5FU2 regimen, a bi- Oral Fluoropyrimidine Therapies weekly infusional and bolus 5-FU/leucovorin regimen that has been demonstrated to have comparable efficacy to the Mayo Oral administration of 5-FU proved to be problematic second- Clinic daily times five bolus schedule in the adjuvant setting, or ary to erratic bioavailability. This was likely due in large part to to the FOLFOX-4 regimen, which is LV5FU2 plus oxaliplatin on variable effects of DPD, the rate-limiting enzyme in catabolism day 1.230 For the combined stage II and III study population, the of 5-FU, on the first pass clearance of oral 5-FU by the liver. Two 5-year DFS rates were 73.3% and 67.4% in the FOLFOX-4 and oral 5-FU prodrugs, capecitabine and uracil/tegafur (UFT), have LV5FU2 groups, respectively (HR = 0.80; 95% CI = 0.68 to 0.93; demonstrated efficacy in metastatic disease that is comparable to p = 0.003).237 Six-year overall survival rates were statistically signif- the Mayo Clinic schedule of parenteral 5-FU/leucovorin. Both of icantly improved by 2.5% (78.5% versus 76.0% in the FOLFOX-4

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TABLE 57.8 Results of The Mosaic Trial: Biweekly Infusional Fluorouracil/ Leucovorin Versus 5-Fluorouracil/Leucovorin Plus Oxaliplatin in Patients with Stage II and III Colon Cancer

FOLFOX (%) 5FULV2 (%) P Value Five-y disease-free survival (stage II+III) 73.3 67.4 0.003 Six-y overall survival (stage II+III) 78.5 76.0 0.046 Six-y overall survival (stage III only) 72.9 68.7 0.023 Six-y overall survival (stage II only) 85 83.3 0.65 Grade 3–4 neutropenia 41 5 Grade 3–4 diarrhea 11 7 Grade 3 neuropathy 12 0 Grade 2 neuropathy 32 0

FOLFOX, fluorouracil/leucovorin plus oxaliplatin; 5FULV2, fluorouracil/leucovorin.

and LV5FU2 groups, respectively; HR = 0.84; 95% CI = 0.71 to tingling in the hands and feet did remain substantially elevated 1.00; p = 0.046). For the stage III population, the 6-year overall over time.239 survival rates were improved by 4.2% (72.9% versus 68.7%, respec- Another recent study examined the effect of diabetes and other tively; HR = 0.80; 95% CI = 0.65 to 0.97; p = 0.023), whereas comorbidities on oxaliplatin-induced neuropathy. With symptoms for the stage II population, the addition of oxaliplatin conferred identified in 65% of patients, hypertension, smoking, and diabetes no survival benefit (6-year survival 85.0% and 83.3%, respectively; were associated with higher trends although not statistically sig- p = 0.65). A more recent update showed that even amongst the nificant differences in severe neuropathy. Additionally, patients stage II patients with high-risk factors, an improved outcome with with diabetes developed oxaliplatin-induced neuropathy at a sig- the addition of oxaliplatin was not evident. While toxicity was nificantly lower cumulative dose, highlighting the importance of 240 regarded as manageable, the FOLFOX-4 regimen resulted in tailoring patient-specific regimens to minimize toxicity. PRACTICE OF ONCOLOGY 41% grade 3 or 4 neutropenia versus 5% in the control arm, and In an exploratory analysis, however, the authors noted sig- 11% grade 3 or 4 diarrhea versus 7%. All-cause mortality in the nificant age-related differences in response to oxaliplatin, finding first 60 days was 0.5% in each arm. Peripheral sensory neuropathy, statistically improved overall survival in patients <70 years old, a toxicity not present in the LV5FU2 control arm, was a frequent whereas older patients actually fared worse with increased grade occurrence on the FOLFOX-4 arm. Grade 2 neuropathy was re- 4-5 toxicity (OR = 1.59) and a 4.7% decrease in 5-year overall ported in 32% of the patients, and grade 3 occurred in 12%. In survival. some cases, the duration of the neuropathy was substantial. One This age-treatment interaction has also been supported by a year after completion of therapy, 30% of patients still experienced 2012 pooled analysis of 5,489 patients >75 years old from four some grade of neuropathy (0.8% grade 2 and 1.3% grade 3). Four large data sets that demonstrated minimal benefit of oxaliplatin years after completion of therapy, 15.4% still had some degree of in this group.241 Moreover, post hoc analysis of MOSAIC data as neuropathy, and 0.7% still had grade 3 neuropathy. It is reasonable well as revised findings from the ACCENT study (which initially to assume that the toxicity still present at 4 years out from the last showed no age-related difference) further indicate the limited treatment is essentially permanent. clinical utility of this agent in older patients.241,242 Taking all this Oxaliplatin has also been combined with a weekly bolus 5-FU into account, the 2013 National Comprehensive Cancer Network regimen in an adjuvant trial. The NSABP C-07 trial studied the (NCCN) guidelines now recommend individualizing the decision FLOX regimen of oxaliplatin given on weeks 1, 3, and 5 plus to add oxaliplatin to adjuvant regimens in the elderly.243 weekly bolus 5-FU/leucovorin on weeks 1 through 6, repeated at More recently, a 1,866-patient study comparing capecitabine 8-week cycles, versus the standard weekly Roswell Park regimen plus oxaliplatin (Cape/Ox) with bolus 5-FU/leucovorin in the ad- of 5-FU/leucovorin.238 A total of 2,409 patients were randomized juvant treatment of stage III colon cancer has been reported.244 to FLOX or to 5-FU/leucovorin. A total of 29% of patients had The Cape/Ox regimen had a statistically significant DFS ad- stage II disease and 71% had stage III. With a median follow-up of vantage over 5-FU/leucovorin, with 66.1% of patients alive and 8 years, FLOX showed a superior DFS, with 69.4% versus 64.2% disease-free at 5 years with Cape/Ox versus 59.8% with 5-FU/leu- alive and free of disease at five years (HR= 0.82; 95% CI = 0.72 covorin. The difference between arms in overall survival at 5 years to 0.93; p = 0.002). However, the overall survival difference favored the Cape/Ox arm by 3.4%; however, this difference did not was not statistically significantly different between the two arms. reach statistical significance at the time of this analysis p( = 0.15). Treatment-related deaths were 1.3% versus 1.1% in the FLOX and The efficacy results of the FOLFOX and Cape/Ox studies appear 5-FU/leucovorin arms, respectively. Grade 2 or higher neurotox- more similar than different at this point in time and appear to jus- icity was reported in 30.4% of patients on the FLOX arm versus tify interchangeability of these regimens in the adjuvant setting. 3.6% on 5-FU/leucovorin. Grade 3 diarrhea was 38.1% and 32.4% Data for FLOX regimens appear to show higher rates of serious or in the two arms, respectively, reflecting the higher incidence of life-threatening diarrhea, and the lack of a statistically significant serious diarrhea with the weekly bolus 5-FU regimen. Kidwell et survival benefit at 6 years is notable. The higher degree of severe al.239 published long-term data regarding the persistent neurotoxic and life-threatening diarrhea seen with FLOX would appear to be side effects of oxaliplatin beyond 4 years from this same NSABP a potential reason for favoring FOLFOX or Cape/Ox over FLOX, C-07 trial, and found that there was a statistically but not clinically although in the absence of a head-to-head comparison, the relative significant increase in total neurotoxicity for those who received safety and efficacy when comparing one or these regimens to the the agent, with initial differences between the two groups dissi- other is impossible to know with certainty. The Cape/Ox regimen pating by 7 years. However specific symptoms of numbness and is a reasonable consideration only in highly reliable, motivated 788 Practice of Oncology / Cancers of the Gastrointestinal Tract

patients who can be expected to comply with taking multiple pills stage III patients. Five-year overall survival was 82.5% versus 80.7% of capecitabine orally (typically three to five pills, twice daily) for (p = 0.56) for the entire study, and 78.7% versus 77.6% for the stage 2 weeks on, 1 week off, in the setting of concurrent emetogenic III patients. There was a separation between the curves at the 1-year intravenous chemotherapy. mark; however, this began to diminish a few months later and was all but absent by year 3. This finding suggests that bevacizumab Irinotecan did delay progression of micrometastases in some patients, but only for as long as it was continued. Bevacizumab did not contribute to Based on improved overall survival in the first- and second-line the eradication of micrometastases and thus did not improve the metastatic settings, it was widely assumed that irinotecan would be cure rate in the adjuvant setting. Although some might choose to beneficial to patients in the adjuvant setting.245–247 This assump- interpret these data to suggest that if bevacizumab were continued tion has turned out to be incorrect, however, and the results of the indefinitely, an improved survivalmight be seen, the long-term con- adjuvant trials with this agent underscore the importance of both sequences of lifelong suppression of vascular endothelial growth performing trials in the adjuvant setting and waiting for the results factor (VEGF), as well as the psychological, social, and economic of those trials before adopting changes in practice. considerations involved, render such an approach inappropriate, es- The CALGB studied the weekly schedule of irinotecan plus pecially considering that only a very small percentage of patients so bolus 5-FU and leucovorin (IFL). Early safety analysis of this trial treated would actually have the potential to benefit, if there is a ben- identified an alarming elevation in early mortality for the experi- efit. Another trial, termed the AVANT trial, also explored the use of mental arm on this trial, with 18 deaths within the first 4 months bevacizumab in the adjuvant treatment of stage III colon cancer, of treatment on the IFL arm versus 6 deaths within the same time and also found no benefit.255 This study randomized 3,451 patients, period on the control arm (p = 0.008).248 At a median follow-up of 2,876 of whom had stage III disease, to FOLFOX4, FOLFOX4 plus 2.1 years in each arm, futility boundaries for both DFS and overall bevacizumab, or Cape/Ox plus bevacizumab. The bevacizumab- survival had been crossed; thus, the final result of this trial is that containing arms did not achieve a statistically significant improve- the addition of irinotecan provided no benefit, while increasing ment in DFS. After a minimum of 60 months follow-up, overall toxicity, including lethal toxicity.249 survival data suggested a possible detriment with the addition of Results of adding irinotecan to biweekly infusional 5-FU/leu- bevacizumab, as the survival in the two bevacizumab-containing covorin (LV5FU2 versus FOLFIRI) were also negative. In the arms trended toward inferior to the FOLFOX-alone control arm; ACCORD 02 trial, 400 patients with high-risk stage III disease however, these differences did not reach statistical significance. (defined as four or more positive nodes or perforated or obstructed Thus, the available evidence suggests that bevacizumab is not primary tumors) were randomly assigned to LV5FU2 versus FOL- beneficial in the treatment of colon cancer in the adjuvant set- FIRI. In this high-risk population, there was no benefit seen in the ting, and might, in fact, be harmful. Until and unless data to the FOLFIRI group, and in fact the study trended insignificantly in contrary emerge, bevacizumab should not be used in the adjuvant favor of the nonirinotecan-containing arm (3-year DFS 60% for treatment of stage II and III colon cancer. LV5FU2 versus 51% for FOLFIRI).250 A second, larger trial of LV5FU2 versus FOLFIRI was con- Cetuximab ducted by the PETACC-3 investigators.251 The prespecified primary efficacy analysis of this trial was based on 2,094 patients with As outlined in detail in the following, cetuximab has demonstrated stage III disease. At a median follow-up of 6.5 years, there was no clinical activity in metastatic CRC, prompting investigation of its statistically significant difference in the 5-year DFS (56.7% ver- usefulness in the adjuvant setting. Intergroup trial N0147 random- sus 54.3% for FOLFIRI versus LV5FU2, respectively; p = 0.1) ized patients with stage III colon cancer to modified FOLFOX-6 or in 5-year overall survival (73.6% versus 71.3%, respectively; with or without cetuximab.256 Once investigators became aware p = 0.94). FOLFIRI was associated with an increased incidence of that the study included only patients whose tumors lacked muta- grade 3 or 4 GI events and neutropenia. tions in the KRAS gene (see the following), the study was modi- Taken together, the results of these three trials to evaluate iri- fied to obtain KRAS genotyping on all patients and to only enroll notecan in the adjuvant setting clearly establish that despite hav- those with wild-type KRAS. Despite this selection, this large, ad- ing substantial activity in the metastatic setting, irinotecan has no equately powered, randomized phase 3 trial showed no benefit meaningful activity, and no role, in the adjuvant treatment of colon for the addition of cetuximab to FOLFOX in the adjuvant treat- cancer. Of interest, an analysis from the CALGB trial suggested that ment of patients with KRAS–wild-type stage III colon cancer. DFS patients with MSI-H showed a benefit from inclusion of irinotecan and overall survival curves trended insignificantly in favor of the in their adjuvant treatment; however, a similar, substantially larger FOLFOX-alone control arm, and the addition of cetuximab was analysis from the PETACC-3 trial contradicted this and showed no overtly harmful in patients >70 years of age. Cetuximab should benefit from adding irinotecan in patients with MSI-H.252,253 therefore not be used in the treatment of stage III colon cancer. Bevacizumab Panitumumab As detailed subsequently, bevacizumab has demonstrated the abil- Panitumumab, like cetuximab, is a monoclonal antibody that ity to favorably augment standard chemotherapy for metastatic blocks ligand binding to the EGFR. Although no investigations disease and has become a part of standard management in that have been reported to evaluate panitumumab in the adjuvant set- arena. This led to evaluation of this agent in the adjuvant setting. ting, results in the metastatic setting suggest that panitumumab In the NSABP C-08 trial, 2,672 patients, 25% with stage II and 755 and cetuximab are extremely similar in terms of target, mecha- with stage III colon cancer, were randomized to receive modified nism of action, mechanisms of resistance, and clinical activity. It FOLFOX-6, either alone or with bevacizumab.254 A design imbal- is therefore extremely unlikely that these agents would differ in ance that could have been problematic had this been a positive the adjuvant setting, and statements regarding cetuximab in this trial, the FOLFOX was given for 6 months in each arm, while the setting may be reasonably applied to panitumumab. bevacizumab was given both with the FOLFOX and then for an additional 6 months, for a total of 1 year of bevacizumab. This was, however, a fully negative trial, so the issues regarding the design of TREATMENT OF STAGE II PATIENTS the trial are moot. With a median follow-up of 5 years, the addition of bevacizumab to FOLFOX did not improve either the DFS or the The optimal management of patients with stage II colon cancer overall survival. DFS was 77.9% versus 75.1% (p = 0.35) for the remains undefined. Although the role of adjuvant therapy in pa- study overall, and DFS was 73.5% versus 71.7% (p = 0.55) for the tients with stage II colon cancer has not been firmly established,

tahir99 - UnitedVRG Chapter 57 Cancer of the Colon 789 it is interesting to see what practice patterns have been emerging. patients remains a matter of conjecture, and in the absence of de- Using the SEER-Medicare linked database, Schrag et al.257 identi- finitive data, definitive recommendations on this topic cannot be fied 3,151 patients age 65 to 75 with resected stage II colon cancer made at this time. In fully informed high-risk stage II patients, it and no adverse prognostic features. Using Medicare billing rec- is reasonable to consider adjuvant treatment. All reports form the ords, they identified those patients who did or did not receive che- MOSAIC trial have shown no benefit for the addition of oxali- motherapy within 3 months of operation. Their review identified platin to 5-FU/leuvocorin in terms of overall survival of stage II that 27% of patients received chemotherapy during the 3-month patients. Uniquivocally, stage II patients lacking high-risk factors postoperative period. Younger age, white race, unfavorable tumor have not been shown to benefit from oxliplatin, and considering grade, and low comorbidity were associated with a greater likeli- the short- and long-term toxicities of this agent, oxaliplatin should hood of receiving treatment. The 5-year survival was 75% for un- not be used in the management of good-risk stage II patients. A re- treated patients and 78% for those patients who received therapy cent update of the outcomes for stage II patients on the MOSAIC in this nonrandomized comparison. After adjusting for known be- trial demonstrates no benefit to use of oxaliplatin, even in patients tween-group differences, the HR for survival associated with adju- on the trial with one or more high-risk factors.242 Whereas patients vant treatment was 0.91 (95% CI = 0.77 to 1.09). Thus, despite the with exceptionally poor risk stage II tumors may still seem reason- lack of proven benefit, a substantial percentage of Medicare ben- able for consideration of oxaliplatin-containing regimens, these eficiaries have received adjuvant chemotherapy for stage II disease. negative data suggest that routine use of oxaliplatin in most pa- Because stage II patients as a group have a relatively favorable tients with stage II colon cancer is unlikely to be appropriate. prognosis, benefits from treatment could only be expected if either a highly efficacious therapy were used or if extremely large trials were done to detect very subtle differences. The International Mul- Impact of Microsatellite Instability on ticentre Pooled Analysis of B2 Colon Cancer Trials meta-analysis Treatment in Stage II and III Colon Cancer provides one of the largest samples of stage II patients.258 A total of 1,016 stage II patients were randomized between 5-FU/leucovorin Ribic et al.267 investigated the usefulness of MSI status as a predictor and surgery alone. The surgery-only arm had a long-term overall of benefit from 5-FU–based adjuvant chemotherapy in 570 stage II survival rate of 81% versus 83% for those stage II patients who re- and III patients from five randomized trials in which no treatment ceived adjuvant 5-FU/leucovorin. This absolute difference of 2% control arm was used. MSI-H was exhibited in 95 patients (16.7%), closely approached, but did not reach, statistical significance. MSI-L in 60 patients (10.5%), and MSS in 415 patients (72.8%). More recently, published studies have not generated any con- In the 287 patients who did not receive adjuvant chemotherapy, sensus on this topic. In a large retrospective, population-based those with tumors exhibiting MSI-H had superior 5-year survival analysis of 3,716 patients undergoing surgery for stage II disease compared to patients with MSI-L or MSS tumors (HR = 0.31; with or without adjuvant chemotherapy, there was a statistically p = 0.004). In the population of patients who received adjuvant

significant survival advantage for the adjuvant group (12 years ver- chemotherapy, there was no difference in survival between the pa- PRACTICE OF ONCOLOGY sus 9.2 years). However, this is not a randomized trial, and patients tients with MSI-H and patients without MSI-H (p = 0.8). In the receiving chemotherapy were more likely to be younger, with left- patients with MSI-L or MSS tumors, chemotherapy resulted in sided lesions and a higher LN yield, all of which are now known improved survival versus no chemotherapy (HR = 0.72; p = 0.04). to be favorable prognostic factors. As such, it is difficult to draw However, 5-FU/leuvocorin did not improve survival in the patients conclusions from this study.259 Another study that evaluated data with MSI-H tumors (Table 57.9). from 24,847 patients, 75% of whom had one or more prognostic 5-FU/leuvocorin was associated with improved outcome in features, found no survival benefit from an adjuvant regimen.260 both stage II and III patients with MSS or MSI-L, with an HR of Finally, Wu et al.261 performed a systematic review of 12 random- 0.67 (95% CI = 0.39 to 1.15) in stage II patients and 0.69 (95% ized controlled trials including both colon and rectal cancers that CI = 0.47 to 1.01) in patients with stage III cancer. In contrast, in suggested some improvement in 5-year overall survival and DFS patients with MSI-H tumors, treatment did not improve survival, for both tumor sites as well as a significant reduction in recurrence risk for stage II colon cancers. While the review has substantial flaws that limit interpretation of these results, it does indicate that TABLE 57.9 larger, higher-quality trials are warranted.261 One such study underway is the SACURA trial, a multicenter, randomized phase 3 Microsatellite Instability Versus Outcome with study designed to evaluate the superiority of a 1-year adjuvant regi- 5-Fluorouracil-Based Adjuvant Chemotherapy men compared to observation in stage II colon cancer. Investiga- tors will seek to identify “high-risk factors of recurrence/death” as Five-Y well as predictors of efficacy and toxicity in the adjuvant arm. End No. of Disease-Free points include DFS, overall survival, and recurrence-free survival Patients Survival (%) P Value as well as the incidence and severity of adverse events. Results from All Patients this trial will hopefully facilitate a definitive therapeutic strategy Adjuvant chemotherapy 285 70 0.06 for stage II colon cancers moving forward.262 Several prognostic indicators have been identified that corre- No adjuvant chemotherapy 287 62 late with a higher risk for subsequent failure in stage II patients. Patients with MSI-L/MSS These include obstruction or perforation of the bowel wall as well as other less-established risk factors, such as elevated preop- Adjuvant chemotherapy 230 70 0.01 erative or postoperative CEA, poorly differentiated histology, and No adjuvant chemotherapy 245 59 tumors not demonstrating high levels of MSI, or an 18q deletion Patients with MSI-H in colorectal tumors, which may correlate with a poor prognosis.145,263–265 Additionally cited poor prognostic factors include Adjuvant chemotherapy 53 69 0.11 macroscopically infiltrating-type tumors, high serum CA 19-9 lev- No adjuvant chemotherapy 42 83 els, extensive venous invasion, male gender, age >50 years old, and <12 dissected LNs.266 It appears that stage II patients with one MSI-L, low level of microsatellite instability; MSS, microsatellite stable; MSI-H, high level of microsatellite instability. or more of these risk factors have a poorer prognosis, one closer to From Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite- patients with stage III disease. Whether adjuvant chemotherapy instability status as a predictor of benefit from fluorouracil-based adjuvant can provide similar benefits in these patients as it does in stage III chemotherapy for colon cancer. N Engl J Med 2003;349:247–257. 790 Practice of Oncology / Cancers of the Gastrointestinal Tract and in fact was associated with a trend toward worse outcome for individuals, but it provided no guidance on whom to treat. Thus, both stage II (HR for death = 3.28; 95% CI = 0.86 to 12.48) and despite the interesting data outlined in the following, it would ap- stage III cancers (HR = 1.42; 95% CI = 0.36 to 5.56). Of note, an pear to be of little value in decision making at this time. analysis of MSI status from the NSABP failed to corroborate the Despite this limitation, research efforts have been increasingly results of the Ribic et al.267 study, and the authors concluded that focused on developing and refining such gene signatures over the in their trial there was no interaction between MSI status and treat- past few years, with three that stand out presently, promising to ment effect, and that their data do not support the use of MSI-H improve and possibly replace current risk stratification models.275 as a predictive marker for chemotherapy benefit.268 However, an Unfortunately, none of these approaches are able to predict who updated expansion on the data from the Ribic et al.267 report ap- will or will not benefit from adjuvant chemotherapy. While these pears to corroborate the original findings, leading the authors of prognostic scores may be of scientific interest, at present they are not that study to suggest that MSI determinations should be performed recommended for routine clinical use in NCCN guidelines, as they on all stage II patients, and that stage II patients with MSI-H appear to offer little if any guidance in terms of treatment decisions. should not be treated with fluoropyrimidines alone.269 The Eastern The Oncotype DX Recurrence Score, which is the only exter- Cooperative Oncology Group I is leading a trial (ECOG 5202) in nally validated assay available for commercial use, is based on a which patients with MSI-H and absence of LOH in chromosome 12-gene signature that separates 3-year recurrence risk into low, 18q are being selected for observation, on the hypothesis that these intermediate, and high (12%, 18%, 22%, respectively), indepen- patients will have a highly favorable prognosis with observation dent of clinicopathologic features, and with enhanced accuracy. It alone, whereas others are being assigned to FOLFOX chemother- has been shown to be highly prognostic in stage II and III patients apy and randomized to with or without bevacizumab. This trial has receiving 5-FU/leucovorin, and enables better discrimination of accrued and data are pending at the time of this writing. absolute oxaliplatin benefit as a function of risk. A recent analysis An analysis of data indicate that patients with MSI-H stage III of long-term costs and outcomes in “average-risk” stage II colon tumors, while having a more favorable prognosis than MSS tu- cancers (T3, MSS) concluded that this signature, when applied mors, do nevertheless achieve benefit from, and in the absence of appropriately, could potentially reduce adjuvant chemotherapy contraindications, should receive, 5-FU–based adjuvant therapy.270 use by 17% with increased quality-adjusted life expectancy of This recommendation is further supported when considering 0.035 years and cost-savings of $2,971 per patient.276 oxaliplatin-based chemotherapy in stage III disease. This would be Another interesting signature, ColoPrint (Agendia Inc. USA, reasonable to expect, as platinum-DNA adducts are not removed Irvine, CA), is an 18-gene prognostic classifier developed on fresh- by the mismatch repair enzymes that are deficient in MSI tumors. frozen tumor tissue to identify 5-year metastasis-free survival. A more recent analysis of MSI impact in stage III disease in the Separating patients into two risk categories, this assay is particularly N0147 trial suggested a more complex and nuanced impact, with precise in identifying low-risk stage II cases that be managed with- MSI-H tumors having a favorable prognostic impact when arising out chemotherapy irrespective of MSI status. It also appears to bet- in the right side of the colon, but actually having a negative prog- ter classify high-risk patients than clinicopathologic factors alone. nostic impact when occurring in the left colon.147 The reasons for While the signature has been validated twice in retrospective trials, this difference remain unclear; however, the different embryo- it is not yet available for commercial use. A large prospective clini- logic origins of the left and right colon, and the resultant different cal validation study is under way (PARSC: Prospective Analysis of venous drainges, may contribute to this. Risk Stratification by ColoPrint) that may better clarify the role of The incidence of MSI has more recently been shown to vary ColoPrint specifically in the management of stage II disease.277 with stage of disease presentation, with 22% of stage II patients, Colorectal Cancer DSA (Almac Diagnostics, Craigavon, 12% of stage III, and only 3.5% of stage IV patients found to ex- Unite Kingdom) is the most recently reported signature, based on hibit MSI, consistent with the data that MSI-H is a favorable prog- 634 genes, developed to identify stage II patients at higher risk of nostic factor. Data from the PETACC-3 trial suggest that it is a recurrence (HR = 2.53) and cancer-related death (HR = 2.21) strong prognostic factor in stage II disease; however, it was less so at 5 years. It has been shown to perform independently of known in stage III.271–273 prognostic factors. While this assay is also not available for commercial use at the time of this writing, a prospective validation trial in stage II patients is being planned.278 Other Molecular Markers The lack of clear direction on the matter of treatment of good- risk stage II patients is reflected in a current consensus statement, As the majority of stage II, and even stage III, patients do not ben- which, while not recommending therapy for all stage II patients, does efit from adjuvant therapy, it would be highly desirable to be able recommend a medical oncology consultation for the purpose of dis- to identify those patients who are both at risk for recurrent disease cussing the pros and cons of chemotherapy for all stage II patients.279 (i.e., harbor micrometastases) and those whose micrometastases are sensitive to, and will be eradicated by, a particular chemotherapy. At present there are no such validated markers, with the pos- TREATMENT OPTIONS FOR sible exception of MSI, as discussed previously. KRAS mutations STAGE III PATIENTS have no prognostic value in the adjuvant setting, and as there is no role for use of anti-EGFR agents in the adjuvant setting, the It is clear that in the absence of medical or psychiatric contraindica- expense of genotyping patients with less than stage IV disease is tions, patients with node-positive colon cancer should receive post- difficult to justify.273,274 BRAF mutations appear to be prognostic of operative chemotherapy. At the very least, a 5-FU–based regimen poorer overall survival in stage II disease that is not MSI-H; how- would appear to be appropriate, and approximately 6 months of ever, this appears to be regardless of therapy, and so again it pro- therapy would be supported by the majority of trials. The daily times vides no information to inform treatment decision making.273 At five Mayo Clinic schedule or a variant has been shown to be more present, no molecular test has been validated as useful for making toxic than other 5-FU/leucovorin schedules; therefore, daily times adjuvant treatment decisions, and none should be utilized outside five schedules should not be used. Oral capecitabine or oral UFT/ of a clinical trial. More recently, a genetic profiling assay utiliz- leucovorin are acceptable alternatives if a fluoropyrimidine-only ap- ing 21-gene signature analysis has become available.271 This assay proach is selected. At this time, the data for incorporation of oxali- has been shown to provide risk stratification with stage II patients platin into the routine adjuvant treatment of colon cancer appears who are classified as having from 8% to 22% chance of recurrence. compelling, and the FOLFOX schedule is now the most widely However, there was no interaction with treatment, meaning that used adjuvant therapy. FLOX is an acceptable alternative; however, the test is prognostic, identifying relatively lower or higher risk nonrandomized comparisons suggest that FLOX may carry a higher

tahir99 - UnitedVRG Chapter 57 Cancer of the Colon 791 risk of serious diarrhea than FOLFOX. Cape/Ox is also an accept- systemic 5-FU and levamisole.285 A randomized trial of 241 stage able alternative in appropriately motivated and reliable patients. II and III patients compared intraperitoneal plus systemic 5-FU/ Although the pivotal adjuvant study was done with FOLFOX-4, in leucovorin to systemic 5-FU/levamisole.286 With 4 years’ median practice this regimen is rarely used, and the modified FOLFOX-6 follow-up, no benefit was seen for the stage II patients. Among regimen, which has been the basis for all FOLFOX-based National the 196 eligible patients with stage III disease, however, a 43% Cancer Institute Intergroup adjuvant and metastatic trials, is rou- reduction in mortality was seen. This small trial is encouraging tinely used due to its greater convenience. The risk of peripheral but would require further corroboration before being accepted neuropathy and the possibility of long-term neuropathy must be into standard practice. considered in the selection of therapy. At the time of this writing, Hyperthermic intraperitoneal chemotherapy has been explored FOLFOX or Cape/Ox are the regimens of choice in treatment of all as a possible means of providing a benefit in patients at high risk for patients with stage III colon cancer in the absense of specific con- developing peritoneal metastases. Sammartino et al.287 explored traindications. The long-term morbidity of oxaliplatin treatment has this hypothesis in a small case control study of patients with T3/4 become more appreciated; however, it is anticipated that risk stratifi- lesions and mucinous or signet ring cell histology who underwent cation strategies may become available in the near future to identify either standard resection or extended surgery (including omentec- those patients who are likely to benefit from oxaliplatin treatment. tomy, bilateral adnexectomy, hepatic round ligament resection, Irinotecan-based regimens should not be used in the adjuvant and appendectomy) followed by hyperthermic intraperitoneal setting, as randomized data have shown increased toxicity and no chemotherapy. The experimental group experienced statistically long-term benefit. Bevacizumab, cetuximab, and panitumumab significantly decreased rates of peritoneal recurrence (4% versus should also not be used in the adjuvant setting, as they add toxicity 22%) as well as improved DFS (36.8 months versus 21.9 months; and expense, and do not add benefit. p <0.01). Large randomized trials would be necessary, however, before nonresearch use of this highly aggressive and potentially 287 Timing of Treatment toxic treatment strategy could be considered. Vaccines Traditionally, adjuvant chemotherapy is commenced within 8 weeks of surgery. However, this time frame is somewhat arbitrary, based Vaccination strategies endeavor to stimulate the patient’s immune largely on what has been mandated in clinical trials. A 2010 meta- system to recognize and eradicate the patient’s tumor cells. An analysis pooled data from 13,158 patients with stage II or III disease ideal immunologic target molecule would be a highly antigenic and concluded that delaying treatment beyond this interval was as- epitope that is always expressed on the tumor and never expressed sociated with interior survival (RR = 1.20).280 However, these data on normal tissue. Such an ideal target has yet to be identified; are retrospective, nonrandomized, and fail to adequately consider however, a number of approaches have been explored. the collateral implications of whatever medical and surgical condi- CEA is a commonly expressed antigen in colorectal carcino- tions might have contributed to the delay in start of therapy. As such, mas. Unfortunately, CEA does not appear to be particularly immu- OF ONCOLOGY PRACTICE these findings should be regarded as hypothesis-generating only, nogenic. Several approaches have been pursued in an attempt to and certainly not definitive. Another study that included only stage increase immune recognition of CEA. Thus, a number of avenues III cancers found no such clear correlation. Secondary analysis did of investigation are being pursued; however, at this time the use demonstrate a trend toward poorer outcomes after 8 weeks, particu- of vaccine therapy for treatment of resected colon cancer remains larly in younger patients (<66 years) as well as significantly inferior highly investigational. survival for patients beginning chemotherapy after 9 and 10 weeks One tumor-associated antigen that may be a more promising (HR of death = 1.68 and 1.67, respectively).281 candidate is the MUC1 glycoprotein, which is abnormally expressed on neoplastic cells in a hypoglycosylated form that induces Investigational Adjuvant Approaches humoral and cellular response. A vaccine based on this antigen was found to be highly immunogenic in the premalignant setting, inducing long-term memory responses and no significant toxicity Portal Vein Infusion when administered to patients with advanced colonic adenomas. The NSABP C-02 trial randomized 1,158 patients with Dukes Subsequent studies will determine whether these results translate 288 A, B, or C colon cancers to either a 7-day portal vein infusion of into meaningful clinical outcomes. 2 282 5-FU (600 mg/m per day) or to surgery alone. A modest, albeit Active Specific Immunotherapy statistically significant, advantage in DFS (74% versus 64% at 4 years) was demonstrated for the group who received intraportal Irradiated cancer cells maintain their immunogenicity; however, chemotherapy; however, no difference was seen in the incidence they are unable to proliferate. Active specific immunotherapy is a of hepatic recurrences. maneuver in which patients are immunized with a preparation of Similar findings were reported from a 533 patient trial per- their own irradiated tumor cells plus an immunostimulant such as formed by the Swiss Group for Clinical Cancer Research.283,284 In bacillus Calmette-Guérin. This technique has been explored for this trial, intraportal chemotherapy included 10 mg/m2 mitomycin some time now as a potential adjuvant immunotherapy for CRC. C by 2-hour infusion followed by a 7-day infusion of 5-FU at a dose Overall, trials have failed to show a benefit for the use of active of 500 mg/m2 per day. The 5-year DFS and overall survival were specific immunotherapy in the management of colon cancer, and modestly improved in the intraportal treatment versus surgery-only its use should remain limited to investigational settings. groups (57% versus 48%, and 66% versus 55%, respectively). Subsequently, a large meta-analysis of intraportal chemother- Preoperative Chemotherapy apy trials involving over 4,000 patients in 10 randomized studies Investigators are currently exploring the role of preoperative che- revealed only a 4% improvement in 5-year overall survival for motherapy in the management of nonmetastatic disease. A pilot the patients who received portal infusion. At present, intraportal phase of the first randomized trial to address this topic (FOx- adjuvant chemotherapy has not been accepted as routine practice TROT) has recently been completed, demonstrating the feasibil- and remains limited to clinical investigations. ity and safety of this approach in locally advanced, operable colon Intraperitoneal Chemotherapy cancer. The 150 patients who underwent meticulous radiologic staging were randomly assigned to receive 6 weeks of preoperative A small, single-arm study explored the feasibility of immediate oxaliplatin/5-FU/I-folinic acid followed by surgery and 18 weeks postoperative intraperitoneal floxuridine and leucovorin plus of postoperative chemotherapy or upfront resection followed by 792 Practice of Oncology / Cancers of the Gastrointestinal Tract

24 weeks of treatment. There were no significant differences in and CEA monitoring should not be continued beyond 5 years. postoperative morbidity between the two groups. While a small Of note, older studies advocating routine monitoring of complete proportion of the patients receiving preoperative therapy had ap- blood count, liver function studies, lactate dehydrogenase, chest parent progression during the time between staging and surgery, X-rays, and fecal occult blood monitoring have not been supported there were no tumor-related complications during this interval. by subsequent data, and none of these are recommended for rou- Overall, preoperative therapy resulted in significant downstaging, tine monitoring of patients at this time. The role of CEA mea- including reductions in apical node involvement and incomplete surement in patients following definitive management of CRC has resections as well as two pathologic complete responses. Whether been controversial.94,297,298 ASCO carefully reviewed its utility in these results will translate into improved survival and potentially an additional panel guided in 1996.299 Their recommendation for change the accepted pathway for management of nonmetastatic CEA monitoring then, which was confirmed in the surveillance disease remains to be seen. A larger phase 3 trial now under way guideline panel review, was postoperative serum CEA testing to be will hopefully shed light on this issue in the near future.289 performed every 3 months in patients with stage II or III disease for up to 3 years after diagnosis. An elevated CEA level, if confirmed by retesting, warranted further evaluation for metastatic disease. FOLLOW-UP AFTER MANAGEMENT OF This further workup of an elevated CEA typically consists of a COLON CANCER WITH CURATIVE INTENT colonoscopy and a CT scan of the chest, abdomen, and pelvis. If these studies are negative, the clinician is faced with a dilemma. The Follow-up after definitive management has two primary goals. First, question of what to do in the face of a rising serum CEA level in the patients with a history of CRC are at higher risk than the general absence of imageable disease by conventional imaging modalities population for a second colon cancer primary.290,291 A colonoscopic is one that has been addressed in clinical trials.300–305 Strategies to screening may benefit in the early detection of a second primary ma- image CEA expression might improve upon the detection capability lignancy or detection of a benign polyp, which can then be resected, of standard imaging studies. Several studies were performed using im- potentially preventing the development of an invasive cancer. munoscintigraphy with an antibody directed against CEA or Tag72, Second, surveillance may increase the chance of identifying a CEA-like glycoprotein (CEA scan and OncoScint [Cytogen Corp, local regional or distant recurrence that is potentially curable by Lonza Biologics, Princeton, NJ] scan, respectively).306–308 The results surgery. It should be noted that it is this detection of potentially of these studies using antibody-directed immunoscintigraphy were curable recurrent or second primary disease that justifies routine variable, and at this time, CEA scintigraphy is no longer considered postoperative surveillance. To date, there are no compelling data in standard care. In an older study, in order to more directly address that indicate that early detection of unresectable asymptomatic this clinical dilemma, a prospective study was performed compar- metastatic disease is of benefit to the patient. In other words, if ing CEA immunoscintigraphy to PET using 18-fluorodeoxyglucose recurrent disease is unresectable and therefore incurable, there (FDG) and blind “second look” laparotomy.303 is no urgency to identify it; there is no compelling evidence that In this study patients with a rising CEA level without image- the early initiation of palliative chemotherapy is of benefit in the able disease by CT scan of the chest, abdomen, and pelvis as well asymptomatic, incurable patient. Although the choice of follow-up as colonoscopy and abdominal ultrasound were enrolled along routine and which studies to include in that follow-up have been with patients with a single site of otherwise resectable disease. All the subject of much debate in the colon cancer literature,292–295 patients had a CEA scan performed as well as a PET scan with subsequent analyses have shown that most interventions that have FDG. All patients who failed to demonstrate evidence of disease been considered are not value-added and not appropriate for rou- outside of the abdominal cavity went on to have an exploratory tine use. The American Society of Clinical Oncology (ASCO) laparotomy by a surgeon who had no knowledge of the CEA or the has recently updated its guidelines for postsurgical follow-up.296 FDG scan results. A second surgeon participated in the remainder These recommendations are for physical examination and blood of the exploration after thoroughly reviewing all studies including CEA monitoring every 3 to 6 months for the first 3 years, and every the nuclear medicine scans. Twenty-eight patients were studied in 6 months for years 4 and 5. CT scans of the chest and abdomen this fashion, and the trial demonstrated that PET scan with FDG are recommended once a year for the first 3 years. Positron emis- was far superior to CEA scans in detecting recurrence; roughly sion tomography (PET) scans are specifically not recommended 30% of the patients on the study potentially benefited by having for routine screening and surveillance. NCCN guidelines differ recurrent disease treated at the time of surgery (Fig. 57.4). only slightly in that they recommend annual CT scanning for Based on these findings, it appears that serum CEA surveil- up to 5 years and include CT scans of the pelvis. Colonsocopy lance following definitive management of a primary CRC is a is recommended at 1 year after resection (or 3 to 6 months after reasonable surveillance technique. If the CEA level is elevated on resection if a complete colonoscopy was not performed prior to repeat testing, imaging studies should be performed consisting of surgery) and then 3 years later, and then every 5 years. CT scans CT scans and a through evaluation of the colon with colonoscopy

Figure 57.4 From left to right, the ﬁrst panel depicts a contrast-enhanced computed tomography scan image of a patient with a rising carcinoembryonic antigen following a definitive resection of a right colon cancer. Themiddle and far panels show the same region imaged with fluorodeoxyglucose position emission tomography. (From Libutti SK, Alexander HR Jr, Choyke P, et al. A prospective study of 2-[18F] fluoro-2-deoxy-D-glucose/positron emission tomography scan, 99mTc-labeled arcitumomab [CEA-scan], and blind second-look laparotomy for detecting colon cancer recurrence in patients with increasing carcinoembryonic antigen levels. Ann Surg Oncol 2001;8:779.)

tahir99 - UnitedVRG Chapter 57 Cancer of the Colon 793 performed as well. If no recurrence or second primary is detected, ranging from no specific follow-up to interval laboratory tests and watchful waiting and repeat of CT imaging at approximately plain X-rays or ultrasound. They found that there was an absolute 3-month intervals versus a PET scan with FDG can be consid- reduction in mortality of 9% to 13% by employing an aggressive ered. If disease is discovered, it should be managed as indicated. follow-up regimen, consisting of serum CEA measurements and If no disease is detected, then continued surveillance is warranted CT scans. Two studies in particular showed the greatest impact with repeat CEA levels and CT or magnetic resonance imaging at on survival. intervals.303,309 In summary, a rational postoperative surveillance program The role of physical examination has also been evaluated.310 would include CEA measurements every 3 to 6 months and a The ASCO panel noted that no formal examination of the contri- yearly CT scan of the chest, abdomen, and pelvis (for rectal can- bution of physician’s history and physical examination to help out- cer) for the first 3 years. Colonoscopy can be performed every 3 to comes of CRC has been performed. However, data from the larger 5 years following the resection. At the time of CEA measurements, studies of surveillance showed that 80% of recurrences were found a physician encounter should be scheduled where a discussion of by CEA testing, whereas only 20% were found by routine history patient symptoms and a physical examination can be performed. If and physical examination done at the same time.311 This has been a rising serum CEA is detected on two consecutive measurements confirmed by other studies.312,313 Although no direct effects were in the absence of imageable disease by CT scan, a PET scan with shown on history or physical examination about the impact and FDG can be considered. Lesions found on colonoscopy should detection or outcome in the surveillance period, a physician– be managed appropriately either with colonoscopic resection or patient encounter provides a vital link for other studies that may surgical management. These surveillance guidelines should allow influence outcome. Therefore, while not in itself substantiated by for the early detection of either resectable recurrence or second the data in the literature, it is felt that routine postresection visits primary lesions and therefore the potential to impact patient be performed every 3 to 6 months for the first 3 years following outcome. resection and every 6 months during years 4 and 5. The role of liver function tests as a means for detecting colorectal recurrence has also been carefully evaluated. No studies that SURGICAL MANAGEMENT OF were reviewed by the ASCO panel demonstrated any benefit for STAGE IV DISEASE the routine use of liver function test measurements in the post- surveillance period.310,314 In fact, studies suggest that other routine For a select group of patients with metastatic CRC, complete blood tests such as CEA detected recurrence far earlier than liver surgical resection of stage IV disease (discussed in detail in function test abnormalities.94 Therefore, the 2005 ASCO consen- Chapter 60) may be an option and may provide a long-term sur- sus panel did not recommend the routine use of liver function test vival advantage. This is especially true with respect to metastatic measurements in the postresection surveillance period. sites in the liver and lung. Resection of locoregional recurrence

Routine fecal occult blood testing, routine complete blood OF ONCOLOGY PRACTICE can also benefit the patient with respect to local control and counts, and routine chest X-rays were all not thought to be of ben- overall outcome. Numerous regional approaches have also been efit in postoperative surveillance. Although the panel was not in explored for the treatment of stage IV colon cancer depending uniform agreement with respect to chest X-ray, it was thought that on the organ or body cavity involved. Organ-specific infusional all three of these modalities should be reserved for the evaluation therapy, isolated or continuous perfusion therapy, radiofrequency of the patient with evidence of recurrence such as a rising CEA ablation or cryotherapy, surgical debulking, and radiation are all level or a positive endoscopy. Each of these modalities in and of technical approaches that have been performed. Many of these itself was not found to be useful. regional strategies as well as surgical metastasectomy will be dis- The panel recommended that annual CT of the chest and cussed in separate chapters and therefore will not be specifically abdomen (with pelvis for rectal cancer) be performed for 3 years addressed here. in those patients at higher risk for recurrence who could be candidates for curative-intent surgery of a recurrence. With respect to colonoscopy and flexible proctosigmoidoscopy, the panel, after reviewing the literature, recommended that all patients have a MANAGEMENT OF UNRESECTABLE colonoscopy for the pre- or perioperative documentation of the METASTATIC DISEASE cancer and to ascertain that the remainder of the colon is free from polyps. Further, the panel agreed that the data were sufficient to Unresectable metastatic CRC is generally not curable with current recommend colonoscopy at 3 years to detect new cancers and pol- technology. Management centers around palliation and control yps and then every 5 years if normal. However, they did not recom- of symptoms, control of tumor growth, and attempts to lengthen mend routine annual colonoscopy as follow-up following definitive progression-free and overall survival. Given the palliative nature of management of patients with CRC. Further, the panel concluded such treatments, extreme care must be taken to adequately assess that colonoscopy was superior to flexible proctosigmoidoscopy and each individual’s potential for both benefit and harm from che- therefore should be performed as previously discussed for patients motherapy. Care must also be taken with surgical interventions following both colon and rectal cancer surgery. Other studies have as well. Quality-of-life issues must be frankly and objectively dis- also supported the routine use of colonoscopic examination fol- cussed with patients and their caregivers so that informed deci- lowing definitive management of CRC.315,316 sions can be made and expectations can be contained within a A meta-analysis and systematic review of randomized trials to realistic framework. The issue of whether patients presenting with address the impact of close postoperative surveillance on over- unresectable stage IV disease should have their primary tumors all survival following definitive management of CRC was also resected has been the matter of some debate. Although such re- performed by Renehan et al.317 A total of five randomized trials sections had been routinely performed in the past, more recent that met their inclusion criteria were reviewed, representing data suggest that such interventions are not required, and may in 1,342 patients. For four of the studies, intensive follow-up con- fact be counterproductive. Temple et al.318 reviewed the linked sisted of blood work including serum CEA, colonoscopy, physical SEER-Medicare databases and found that of 9,011 elderly patients examination, abdominal ultrasound, and CT scans. In one study, presenting with synchronous stage IV disease, that 72% had un- no CEA measurements or CT scans were performed. Follow-up in dergone resection of the primary, and that the 30-day mortality the intensive arm was performed every 3 months for 2 years and for these resections was 10%. In a retrospective review, Poultsides then every 6 months thereafter up to 5 years, with yearly CT scans et al.319 demonstrated that 93% of 233 pateints never required and endoscopy. All five studies had a control arm subjected to a surgical intervention on their primary tumors. More recently, the less aggressive follow-up regimen, which varied from study to study NSABP C-10 trial prospectively addressed this question, treating 794 Practice of Oncology / Cancers of the Gastrointestinal Tract

90 patients with unresectable stage IV disease and intact, asymp- Thus, chemotherapy for patients with incurable metastatic tomatic primary tumors with initial medical management with disease should be approached with appropriate caution. Good FOLFOX-6 plus bevacizumab. Twelve patients (14%) experienced performance status in well-motivated patients with good bone major morbidity due to the intact primary tumor. This study met marrow reserve and good organ function portend a significant its prespecified end points for acceptability of intial nonoperative potential for substantial benefits from chemotherapy and should management, and the investigators concluded that good perfor- be strongly considered for aggressive therapy. Patients with poor mance status patients with asymptomatic primaries can be spared performance status and significant comorbidities should be initial noncurative resection of their primaries.320 considered for either less aggressive therapies or for supportive Surgical intervention can be a very effective method of pallia- care only. tion and is often indicated in cases of impending obstruction, perforation, bleeding, or pain. However, it can also be associated with high postoperative morbidity and mortality. Stillwell et al.321 iden- Fluorouracil tifies several adverse prognostic factors that can guide clinicians considering surgical palliation versus other less aggressive maneu- Virtually the entire history of chemotherapy for CRC has revolved vers. In a retrospective analysis of 379 patients who underwent pal- around the use of 5-FU. Developed by Heidelberger et al.322 and liative resection, elderly (≥70 years) patients with advanced local patented in 1957, it is a source of frustration and humility for disease or extrahepatic metastases were at greatest risk for postop- investigators working to move beyond it that over 50 years later erative mortality. Other independently associated factors included this agent remains at the very core of most chemotherapeutic ap- emergency operation and medical complications. Advanced nodal proaches to CRC. disease (N2) and poor tumor differentiation were significant pre- 5-FU must be metabolized before it can exert cytotoxic ac- dictors of decreased long-term survival.321 tivity. The details of 5-FU metabolism are covered in a separate The chemotherapy options available and the developmental chapter. The history of investigations of 5-FU in CRC treatment work that supports their utility are outlined subsequently. It is of has been well summarized in previous editions of this book.227 paramount importance to keep in mind that virtually all of the 5-FU remained the only drug available to treat CRC for almost clinical trials done in patients with metastatic disease were per- four decades, during which time numerous agents were studied formed by design on patients who were in good overall general for their ability to “biomodulate” 5-FU. Of these, only leucovorin medical condition. Entry criteria for most trials require a favor- remains in use today, and it is debatable whether this reduced able performance status and acceptable bone marrow, renal, and folate truly contributes to the efficacy of 5-FU. Most studies that hepatic function, and they often specify evidence of reasonable evaluate the same dose of 5-FU with or without leucovorin find nutritional intake. that both activity and toxicity are increased in the leucovorin It is not reasonable to extrapolate the results of these trials to arm, whereas studies that evaluate single-agent 5-FU versus an patients who do not conform to these entry criteria. The likeli- equitoxic schedule of a lower dose of 5-FU plus leucovorin find hood of benefit in a poor performance status patient is substan- equivalent activity. Nevertheless, use of leucovorin persists in tially diminished, and the likelihood of a serious adverse event is most standard regimens today. Data comparing bolus versus in- greatly increased. Patients with hepatic or renal dysfunction may fusional schedules of 5-FU show a slight benefit for infusions. be particularly prone to additional toxicity if the drug is cleared These infusional schedules achieved widespread acceptance in or metabolized by these organs. Patients with marginal nutritional Europe sooner than in the United States. It was not until the ad- intake may have their nutritional deficiencies further exacerbated vent of combination schedules of 5-FU plus other active agents by drugs that produce nausea or anorexia, and patients with partial that the benefits of infusional schedules, especially in terms of or complete bowel obstruction or other causes of prolonged GI improved toxicity, asserted themselves in North American prac- transit time may have increased toxicity from those drugs that un- tice. A selection of commonly used 5-FU regimens is outlined in dergo an enterohepatic recirculation. Table 57.10.323–325

TABLE 57.10 Commonly Used 5-Fluorouracil Regimensa

Name of Regimen Author (Ref.) Schedule (All Agents Administered Intravenously) Roswell Park Haller et al., 1998231 LV 500 mg/m2 over 2 hr; 5-FU 500 mg/m2 by bolus 1 hr into LV infusion. Treatments given weekly for 6 consecutive wk, repeated every 8 wk. Low-dose weekly LV Jager et al., 1996323 LV 20 mg/m2 over 5–15 min, followed by bolus 5-FU 500 mg/m2; treatments given weekly for 6 consecutive wk, repeated every 8 wk. Protracted venous Lokich et al., 1989324 5-FU 300 mg/m2/d by continuous infusion. infusion AIO (weekly Kohne et al., 1998325 LV 500 mg/m2 over 2 hr, followed by 5-FU 2,600 mg/m2 over 24 hr, repeated 24-hr infusion) weekly. LV5FU2 de Gramont et al., 1997341 LV 200 mg/m2 over 2 hr days 1 and 2, followed by bolus 5-FU 400 mg/m2/day 1 and 2, followed by 5-FU 600 mg/m2 over 22 hr days 1 and 2; cycle repeated every 14 d. Simplified LV5FU2 Adapted from Andre et al., 1999333 LV 400 mg/m2 over 2 hr, followed by bolus 5-FU 400 mg/m2, followed by 5-FU 1,200 mg/m2/d times 2 d (2,400 mg/m2 over 46–48 hr); cycles repeated every 14 d.

LV, leucovorin; 5-FU, 5-fluorouracil; AIO, Arbeitsgemeinschaft Internistische Onkologie (Oncology Working Group, Germany). a Doses listed are recommended starting doses for good performance status patients with normal renal, hepatic, and bone marrow function. Individual dose adjustments may be required.

tahir99 - UnitedVRG Chapter 57 Cancer of the Colon 795

Capecitabine inhibiting topoisomerase I than irinotecan and is thus the predominant active form of the drug. CPT-11 is often considered to Capecitabine is a 5-FU precursor that is administered orally. It is be a prodrug for SN-38; however, this concept may be a bit too absorbed intact through the gut and then activated by a series of simplistic, as achieved CPT-11 concentrations may be several logs enzymatic alterations. Some data suggest that thymidine phosphor- higher than those of SN-38. ylase levels are higher in tumor than in normal tissue. This could, Camptothecin, CPT-11, and SN-38 function as inhibitors of in theory, provide a degree of preferential intratumoral activation; topoisomerase I (topo I). Topo I is a nuclear enzyme that aids in however, clinical trials do not appear to support a substantially bet- DNA uncoiling for replication and transcription. When topo I ter therapeutic index than 5-FU.326 Phase 2 studies demonstrate binds to DNA, it causes a reversible single-stranded break in the that this agent has substantial activity in CRC, with an acceptable DNA, allowing the intact strand to pass through the break to re- toxicity profile.327 Because the addition of leucovorin did not ap- lieve torsional stress on the coiled helix, and then reseals the break. pear to show any benefit, clinical development went forward with- CPT-11 and SN-38 stabilize these single-stranded breaks. Although out additional biomodulation. Phase 3 randomized clinical trials, the stabilized breaks do not cause irreversible damage, the colli- performed both in the United States and Europe, have now shown sion of replication forks with open single-stranded breaks results that this orally administered agent is at least as effective as intrave- in double-stranded breaks, leading to lethal DNA fragmentation. nous 5-FU/leucovorin, and the side effect profile of capecitabine The early development of irinotecan and its single-agent schedules is superior to the daily times five Mayo Clinic schedule of 5-FU/ have been well documented in earlier editions of this textbook.227 leucovorin.328,329 However, as this bolus daily times five schedule is now known to be unnaceptably toxic and is not used anymore, the CPT-11 in First-Line Combination Regimens relevance of the toxicity comparison is questionable. Head-to-head studies of modern infusional 5-FU/leucovorin regimens versus Numerous phase 1 combinations of 5-FU, usually with leucovo- capecitabine have never been done; however, a reasonable extrapo- rin, plus CPT-11, were tried. Saltz et al.332 reported a phase 1 trial lation from available data would suggest that these two approaches built on the weekly CPT-11 schedule that had been selected for are extremely similar in efficacy and tolerability. The dose used in phase 1 development in North America. A low dose of weekly these pivotal trials was 1,250 mg/m2 given twice daily for 14 days leucovorin was utilized in order to reduce the potential for 5-FU/ followed by a 7-day rest. The major side effects of capecitabine leucovorin–induced diarrhea. The phase 1 trial showed that the appear to be palmar-plantar erythrodysesthesia, commonly called full single-agent dose of 125 mg/m2 of CPT-11 could be given with hand-foot syndrome, and to a lesser extent diarrhea. The hand- 500 mg/m2 of 5-FU and 20 mg/m2 leucovorin, with all drugs given foot toxicity is frequently a dose-limiting side effect, and although weekly for 4 consecutive weeks followed by a 2-week break. This the approved starting dose is 1,250 mg/m2 twice daily, this dose is and other CPT-11/5-FU/leucovorin regimens are summarized in based on trials conducted mainly in Europe. For unclear reasons, Table 57.11. This combination of IFL was compared to the Mayo possibly related to higher serum folate levels, American patients PRACTICE OF ONCOLOGY Clinic schedule of 5-FU/leucovorin in a multicenter, multina- tolerate capecitabine less well than European patients, and cli- tional phase 3 trial.247 For regulatory reasons, a single-agent CPT- nicians in the United States often choose to initiate therapy at a 11 arm was included as well. The IFL arm was found to be superior lower dose and escalate if little or no toxicity is seen. to Mayo Clinic 5-FU/leucovorin in terms of response rate, time to tumor progression, and overall survival. The CPT-11–alone arm Irinotecan appeared to be comparable in efficacy to the 5-FU/leucovorin arm. The overall incidence of severe toxicity was similar in all arms of Irinotecan (CPT-11) is a semisynthetic derivative of camptothecin, this trial. More serious diarrhea and vomiting were seen with IFL, a plant alkaloid extracted from the wood of the Asian tree while more neutropenia, neutropenic fever, and stomatitis were Camptotheca acuminate.330 CPT-11 possesses a bulky dipiperidino seen with 5-FU/leucovorin. Treatment-related deaths occurred in side chain linked to the camptothecin molecule via a carboxyl-ester 1% of patients in each arm of this trial. Although this IFL schedule bond. This side chain provides solubility but greatly decreases an- represented a step forward over the Mayo Clinic 5-FU/leucovorin ticancer activity. Carboxylesterase, a ubiquitous enzyme with pri- schedule, neither of these are recommended for current use. As mary activity in the liver and gut, cleaves the carboxyl-ester bond to outlined in the following, the infusional 5-FU schedules have a form the more active metabolite 7-ethyl-10-hydroxycamptothecin superior safety and efficacy profile and are preferred for use, espe- (SN-38).331 SN-38 is as much as 1,000-fold more potent in cially in combination regimens.

TABLE 57.11 Commonly Used Irinotecan/5-Fluorouracil Combination Regimensa

Name of Regimen Author (Ref.) Schedule (All Agents Administered Intravenously) FOLFIRI Douillard et al., 2000246 Irinotecan 180 mg/m2 over 2 hr; LV 200 mg/m2 concurrently with irinotecan (can be given in same line through “Y” connector); followed by 5-FU bolus 400 mg/m2, followed by 5-FU 600 mg/m2 infusion over 22 hr. Irinotecan given day 1 only. All other meds given days 1 and 2. Cycle repeated every 14 d. FOLFIRI (simplified) Andre et al., 1999333 Irinotecan 180 mg/m2 over 90 min; LV 400 mg/m2 concurrently with irinotecan (can be given in same line through “Y” connector); followed by 5-FU bolus 400 mg/m2, followed by 5-FU 1,200 mg/m2/d times 2 d (2,400 mg/m2 infusion over 46–48 hr). Cycle repeated every 14 d. FUFIRI Douillard et al., 2000246 Irinotecan 80 mg/m2, then LV 500 mg/m2, followed by 5-FU 2,300 mg/m2; all drugs given weekly for 6 wk, repeated every 7 wk.

FOLFIRI, irinotecan, 5-FU, LV; LV, leucovorin; 5-FU, 5-fluorouracil; FUFIRI, 5-FU, LV. a Doses listed are recommended starting doses for good performance status patients with normal renal, hepatic, and bone marrow function. Individual dose adjustments may be required. 796 Practice of Oncology / Cancers of the Gastrointestinal Tract

In Europe, a parallel study to investigate the benefit of add- 5-FU/leucovorin alone or with oxaliplatin.338–340 Two hundred ing irinotecan to a 5-FU–based schedule was undertaken.246 Two patients were randomly assigned to receive a 5-day course every high-dose intermittent infusional schedules were developed. In 3 weeks of chronomodulated 5-FU and leucovorin (700 and France, a biweekly treatment for 2 consecutive days was explored, 300 mg/m2 per day, respectively; peak delivery rate at 4 a.m.) with while German investigators, building on their experience with or without oxaliplatin on the first day of each course (125 mg/m2, weekly 24-hour high-dose infusions of 5-FU, combined CPT-11 as a 6-hour infusion). The group who received oxaliplatin had a su- with this schedule. A randomized phase 3 trial was performed in perior response rate (53% versus 16%; p <0.001). Progression-free which a participating center chose which of these two schedules survival was also superior, just reaching statistical significance would be used, and then the patients were randomized to that (8.7 months versus 7.4 months; p = 0.048). There were no differ- 5-FU/leucovorin schedule plus or minus CPT-11. Again, response ences in median overall survival (19.4 months and 19.9 months, rate, progression-free survival, and overall survival were superior in respectively). Survival outcomes in this trial are somewhat difficult the CPT-11– containing arm of the trial. Of note, only the cohort to interpret as extensive use of resection of metastatic disease was treated with the biweekly schedule demonstrated a statistically applied in both arms. superior survival over the 5-FU/leucovorin control arm, and the Most of the combination 5-FU/leucovorin/oxaliplatin trials biweekly combination schedule is the only one registered for use have used flat (nonchronomodulated) administration of agents in the United States. and have centered on variants of the FOLFOX regimen. The acro- More recently, the biweekly schedule of LV5FU2 plus iri- nym FOLFOX (FOL for folinic acid [leucovorin], F for fluoroura- notecan has been studied with a simplified LV5FU2 infusion cil, OX for oxaliplatin) refers to a series of combinations of these schedule.333 This schedule, known as FOLFIRI (FOL for folinic agents. These are biweekly (every other week) regimens using acid, F for 5-FU, and IRI for irinotecan), was initially studied as a 2 days of infusional 5-FU on a 14-day cycle (LV5FU2).341 The salvage regimen; however, this has now gained widespread accep- FOLFOX-1, -2, and -3 regimens employed various alterations in tance as a first-line treatment option, based on the data discussed dosing of each oxaliplatin, 5-FU, and leucovorin.342,343 They are of subsequently. historical interest, but were never evaluated in randomized trials. The BICC-C (Bolus, Infusional, or Capecitabine with Camp- FOLFOX-3 and FOLFOX-4 were reported in a combined series tosar-Celecoxib) trial is the only trial to directly compare weekly to have a response rate of 21% in a population of patients who bolus IFL to FOLFIRI.334 This trial utilized a modified bolus IFL had progressed on the same 5-FU/leucovorin schedule without schedule, giving treatment on days 1 and 8, repeated on a 3-week oxaliplatin.342 The FOLFOX-4 regimen had a modestly higher cycle. This modified IFL was compared to FOLFIRI as well as to response rate and lower toxicity than FOLFOX-3 (which used capecitabine/irinotecan. The first phase of this trial (430 patients) higher doses of 5-FU and leucovorin), and FOLFOX-4 appeared confirmed the superior safety and efficacy of FOLFIRI over IFL to be better tolerated. The more commonly used oxaliplatin/5-FU/ (median progression-free survival 7.6 months for FOLFIRI ver- leucovorin combinations are outlined in Table 57.12.344,345 sus 5.8 months; p = 0.007) and over capecitabine/irinotecan A randomized phase 3 trial was undertaken to evaluate (progression-free survival 5.7 months; p = 0.003). The trial was FOLFOX-4 versus the LV5FU2 schedule in patients with previ- halted when bevacizumab (see the following) became commer- ously untreated metastatic CRC (essentially a trial of LV5FU2 with cially available, and a second phase randomized 117 patients to or without oxaliplatin).346 Patients treated with FOLFOX-4 had a modified IFL plus bevacizumab versus FOLFIRI plus bevaci- statistically significantly superior outcome in terms of response zumab (capecitabine/irinotecan was dropped from the second rate (51% versus 22%; p = 0.001) and progression-free survival phase of this trial). This second phase showed a significant over- (9 months versus 6.2 months; p = 0.0003). The FOLFOX arm all survival advantage for FOLFIRI/bevacizumab over modified had a 1.5-month improvement in median overall survival; how- IFL/ bevacizumab (p = 0.002). The BICC-C trial also had a ever, this did not reach statistical significance (16.2 months ver- second randomization of all patients to celecoxib versus placebo. sus 14.7 months; p = 0.12). The number of patients experiencing Celecoxib was found to provide no benefit in terms of either safety grade 3 or 4 neutropenia was increased with FOLFOX-4 over 340 or efficacy and does not appear to have a role as part of standard (42% versus 5% of patients). Grade 3 or 4 diarrhea (12% versus 5%) chemotherapy of this disease. was also increased in the FOLFOX arm. Neurotoxicity, virtually absent in the LV5FU2 arm, was frequent in the FOLFOX arm, with 18% of patients experiencing grade 3 neurosensory toxicity. Oxaliplatin The FOLFOX-4 regimen has also been evaluated in a multicenter randomized trial in second-line therapy following failure Oxaliplatin (1,2-diaminocyclohexane (trans-l) oxalatoplatinum) is of first-line IFL chemotherapy.347 Patients were randomly as- a third-generation platinum compound of the diaminocyclohex- signed to one of three arms: FOLFOX-4, LV5FU2, or single-agent ane family. Initial single-agent phase 1 studies established that oxaliplatin. Response rates were 10% for FOLFOX, 0% for oxaliplatin could be safely administered, with evidence of clini- LV5FU2, and 1% for oxaliplatin alone (p <0.0001 for FOLFOX cal activity.335,336 No significant nephrotoxicity was seen. Nausea versus LV5FU2). Time to tumor progression was also superior for and vomiting, minimal leucopenia, and rare thrombocytopenia FOLFOX-4 (4.6 months) versus LV5FU2 (2.7 months) and ox- were observed. Extra et al.335 were the first to describe in detail aliplatin alone (1.6 months). These data confirm initial clinical the most notable toxicity encountered with oxaliplatin: neurotoxic- impressions that oxaliplatin/5-FU combinations have superior ac- ity. This neurotoxicity manifested as paresthesias and dysesthesias tivity to single-agent oxaliplatin, even in 5-FU–refractory disease. of the hands, feet, perioral region, and throat. Pharyngolaryngeal FOLFOX-4 has activity in IFL-refractory disease; however, single- dysesthesia, a sensation of choking without overt airway blockage, agent oxaliplatin essentially does not. was described as well. These neurologic toxicities were induced Further modifications have been made to the FOLFOX sched- or worsened by exposure to cold. Early single-agent explorations ule. FOLFOX-5 was designed with an increased dose of oxaliplatin with oxaliplatin have been well outlined in the prior edition of this to 100 mg/m2 every 14 days; however, this regimen was never tested textbook.337 in clinical trials. FOLFOX-6 utilized this 100 mg/m2 oxaliplatin dose with a simplified 5-FU/leucovorin schedule.348 Oxaliplatin Oxaliplatin/5-Fluorouracil/Leucovorin 100 mg/m2 is given over 2 hours, with leucovorin 400 mg/m2 given Combination Trials concurrently via a “T” connector. These are then followed by a 400 mg/m2 bolus of 5-FU, and then a 46-hour infusion of 5-FU Based on a series of phase 2 trials by Levi et al., Giachetti et al.338 at 2,400 to 3,000 mg/m2. More recently, the FOLFOX-7 regi- from the same group reported a phase 3 trial of chronomodulated men has been reported, utilizing a 130 mg/m2 dose of oxaliplatin

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TABLE 57.12 Selected Commonly Used Oxaliplatin/5-Fluorouracil Combination Regimensa

Name of Regimen Author (Ref.) Schedule (All Agents Administered Intravenously) FOLFOX-4 de Gramont et al., 2000346 Oxaliplatin 85 mg/m2 over 2 hr; LV 200 mg/m2 concurrently with oxaliplatin (can be given in same line through “Y” connector); followed by 5-FU bolus 400 mg/m2, followed by 5-FU 600 mg/m2 infusion over 22 hr. Oxaliplatin given day 1 only. All other meds given days 1 and 2. Cycle repeated every 14 d. FOLFOX-6 Tournigand et al., 2004349 Oxaliplatin 100 mg/m2 over 2 hr; LV 400 mg/m2 concurrently with oxaliplatin (can be given in same line through “Y” connector); followed by 5-FU bolus 400 mg/m2, followed by 5-FU 1,200 mg/m2/d times 2 d (2,400 mg/m2 infusion over 46–48 hr). Cycle repeated every 14 d. Modified FOLFOX-6 Widely used in current phase 3 Oxaliplatin 85 mg/m2 over 2 hr; LV 400 mg/m2 concurrently with oxaliplatin trials, Wolmark et al. 2009344 (can be given in same line through “Y” connector); followed by 5-FU bolus 400 mg/m2, followed by 5-FU 1,200 mg/m2/d times 2 d (2,400 mg/m2 infusion over 46–48 hr). Cycle repeated every 14 d. FUFOX Grothey et al., 2002345 Oxaliplatin 50 mg/m2 over 2 hr, followed by LV 500 mg/m2, followed by 5-FU 2,000 mg/m2 over 24 hr, weekly for 5 wk, repeated every 6 wk.

FOLFOX, folinic acid, 5-FU, oxaliplatin; LV, leucovorin; 5-FU, 5-fluorouracil; FUFOX, 5-FU, folinic acid. a Doses listed are recommended starting doses for good performance status patients with normal renal, hepatic, and bone marrow function. Individual dose adjustments may be required. every 14 days. The simplified leucovorin/5-FU administration oxaliplatin would be protective against neurotoxicity, but a defini- of FOLFOX-6 is maintained, with deletion of the bolus 5-FU. tive trial has now demonstrated that this is not the case.350 Oxaliplatin is discontinued after 3 months, with planned reintroduction after 12 weeks or sooner if clinical progression occurrs.349 Comparisons of Oxaliplatin- and Irinotecan-Based This rationale appears promising, both for treatment of metastatic Combinations disease and for potential use in the adjuvant setting. Given the similar response rates after 12 weeks, it would appear that the increased With both oxaliplatin- and irinotecan-based regimens show- PRACTICE OF ONCOLOGY dose of oxaliplatin in FOLFOX-7 is unnecessary. A reasonable ing encouraging activity, the question of which agent to use first approach to standard use of FOLFOX in the metastatic setting is was addressed by a number of investigators. Tournigand et al.349 to use a modified FOLFOX-6, with 85 mg/m2 of oxaliplatin and reported a phase 3 trial of FOLFOX-6 versus FOLFIRI. This trial simplified LV5FU2 at a dose of 2,400 mg/m2 over 46 to 48 hours utilized identical simplified LV5FU2 schedules, with the only (1,200 mg/m2 per day for 2 consecutive days). As discussed in the variable being oxaliplatin or irinotecan. All patients were planned following, the OPTIMOX trial data support cessation of oxaliplatin to crossover to the other regimen at time of progression, and the after 12 weeks and reintroduction of the oxaliplatin at a later date primary end point was time to tumor progression after both che- upon disease progression. It had been previously hypothesized motherapy regimens. Results are shown in Table 57.13. Although that administration of high doses of calcium and magnesium with the study is somewhat underpowered at a total of 226 patients, the

TABLE 57.13 Comparison of First-Line Use of Irinotecan Versus Oxaliplatin in Conjunction with the Same Simplified Biweekly Infusional 5-Fluorouracil/Leucovorin Schedule

FOLFIRI FOLFOX-6 (n = 109 Patients Treated) (n = 111 Patients Treated) P Value Major objective response rate (partial plus 56% 54% 0.68 complete responses) Time to tumor progression (on first-line regimen) 8.5 mo 8.1 mo 0.65 Time to tumor progression (after first- and 14.4 mo 11.5 mo 0.65 second-line regimen) Overall survival (from initial randomization) 20.4 mo 21.5 mo 0.9 Two-yr overall survival 41% 45% Grade 3–4 neutropenia 25% 44% Neutropenic fever 6% 1% Grade 3–4 diarrhea 14% 11% Neuropathy (grade 3) 0% 34% Alopecia (grade 2) 24% 9%

FOLFIRI, irinotecan, 5-fluorouracil, leucovorin; FOLFOX, folinic acid, 5- fluorouracil, oxaliplatin. From Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004;22:229–237. 798 Practice of Oncology / Cancers of the Gastrointestinal Tract results show a striking consistency between regimens, suggesting to be 4.5%. Because this was a new metric, however, there were that use of either FOLFOX-6 or FOLFIRI in first-line treatment no readily available historical controls; no one had ready access to is acceptable. A somewhat larger trial of 360 patients randomized data to say what the 60-day ACM had been in previous trials, either to FOLFOX-4 versus the equivalent FOLFIRI schedule, utilizing with IFL or with 5-FU/leucovorin regimens. The 4.5% ACM was the same LV5FU2 dose and schedule in each arm, again shows therefore compared to the previously reported death rate for the comparable efficacy data, with differing and predictable toxicity IFL regimen, which was 0.9%. However, the previously reported profiles.351 death rate was the treatment-related death rate, the percentage of The North Central Cancer Treatment Group–led US Inter- deaths judged by the investigators to have been caused by treat- group study N9741, a complex and important trial that underwent ment, not all deaths within 60 days of starting therapy. Of further many iterations before its completion, initially opened as a four- concern to the safety monitoring committee, however, the experi- arm trial comparing the Mayo Clinic 5-FU/leucovorin control mental arms (FOLFOX-4 and IROX) each showed 60-day ACMs arm to three different CPT-11/5-FU/leucovorin regimens: weekly of 1.8% (compared to 4.5% for the IFL control arm). This informa- bolus IFL as reported by Saltz et al.,247 a “Mayo II” schedule of tion was difficult to put into context, however, because the efficacy CPT-11 on day 1 and bolus 5-FU/low-dose leucovorin on days 2 of the two experimental arms had not yet been established. to 5, or the biweekly infusional schedule of LV5FU2 plus CPT-11 In fact, the 60-day ACM on the original phase 3 trial of IFL as reported by Douillard et al.246 and Goldberg.352 After accruing a (subsequently calculated after N9741 was halted) was 6.7%, and small number of patients, the trial was closed to incorporate three the 60-day ACM for the Mayo Clinic control arm of that trial oxaliplatin-containing arms: FOLFOX-4, IROX (a once every was found to be 7.3%. Although the 7.3% 60-day ACM appeared 3 weeks combination of irinotecan and oxaliplatin, without 5-FU), subjectively to be unusually high, no historical baseline data on and a modified Mayo Clinic schedule of bolus 5-FU plus low-dose 60-day ACM in 5-FU–based regimens were readily available. To leucovorin days 1 through 5, with oxaliplatin given on day 1. The help interpret these data, an analysis was undertaken to determine infusional LV5FU2 plus CPT-11 arm was dropped. This created a the 60-day ACM in multiple large-scale randomized trials that six-arm trial. In March 2000, the trial was again halted, based on had used 5-FU/leucovorin schedules over the prior decade. This presentation of evidence that the combination of CPT-11/5-FU/ analysis confirmed that 60-day ACM regularly was encountered leucovorin, using either bolus or infusional schedules, was supe- at a rate of 5% to 8% in the treatment of metastatic CRC.353 Thus rior to 5-FU/leucovorin. The Mayo Clinic control arm of N9741 the 60-day ACM for the IFL regimen was actually lower on N9741 was now dropped, and weekly bolus IFL became the control arm. than in previous trials and was lower than what had been seen con- At the same time, ongoing real-time monitoring of fatal toxicities sistently with 5-FU/leucovorin regimens alone. In the final analy- identified unacceptably high rates of treatment-related mortality sis of N9741, the 60-day ACM seen in the IFL, FOLFOX-4, and in the oxaliplatin plus Mayo Clinic 5-FU/leucovorin and in the IROX arms were 4.5%, 2.6%, and 2.7%, respectively, and these CPT-11 plus 5-FU/leucovorin arms. These schedules were also differences were not statistically significant. dropped from the trial and from further development, leaving a The efficacy results of N9741, however, were statistically sig- three-arm trial of CPT-11 plus bolus 5-FU/leucovorin (IFL), oxali- nificant and showed superior outcome for the patients randomized platin plus infusional LV5FU2 (FOLFOX-4), and oxaliplatin plus to FOLFOX-4, as compared to those randomized to either IFL or CPT-11 (IROX). IROX, in terms of response rate, time to tumor progression, and The trial was stopped a third time in April 2001, when mon- overall survival (Table 57.14).354 Toxicity for FOLFOX-4 was also itoring of the trial indicated what appeared to be a higher than superior for virtually all parameters, except of course neurotoxicity. expected early mortality in the IFL control arm.248 This observa- The results of the IROX arm did not statistically significantly differ tion, however, was based on utilization of a new metric, the 60-day from those of the IFL arm in terms of toxicity, response, or time ACM. This metric records death from any cause within 60 days of to tumor progression; however, survival was borderline statistically initial therapy. The 60-day ACM of the IFL arm was initially noted significantly better in the IROX arm than the IFL arm p( = 0.04).

TABLE 57.14 Results of Intergroup Trial N9741: Irinitecan Plus Bolus 5-Fluorouracil/Leucovorin, Oxaliplatin Plus Infusional 5-Fluorouracil/Leucovorin, and Irinotecan Plus Oxaliplatin in First-Line Treatment of Patients with Metastatic Colorectal Cancer

IFL (n = 264) FOLFOX-4 (n = 267) IROX (n = 264) P Value (IFL vs. FOLFOX) Major objective response rate (partial 31% 45% 35% 0.03 plus complete responses) Time to tumor progression 6.9 mo 8.7 mo 6.5 mo 0.001 Overall survival 15.0 mo 19.5 mo 17.4 mo 0.0001 Received second-line therapy with active 24% (oxaliplatin) 60% (irinotecan) 50% (fluorouracil) Not given drug not included in first-line regimen Grade 3–4 neutropenia 40% 50% 36% 0.35 Neutropenic fever 15% 4% 11% 0.001 Grade 3–4 diarrhea 28% 12% 24% 0.001 Grade 3–4 nausea 16% 6% 19% 0.001 Grade 3 neuropathy 3% 18% 7% 0.001 60-d all cause mortality 4.5% 2.6% 2.7% Not significant

IFL, 5-fluorouracil, leucovorin; FOLFOX4, oxaliplatin plus infusional 5-fluorouracil/leucovorin; IROX, irinotecan plus oxaliplatin From Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and xaliplatino combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004;22:23–30.

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Taken together, where do these trials leave us in terms of first- Although a regimen of oxaliplatin, weekly bolus 5-FU, and low- line use of oxaliplatin- and irinotecan-based regimens? Data from dose weekly leucovorin (bFOL) appeared promising in an initial trial N9741 indicate that FOLFOX-4 is superior to IFL in both phase 2 trial, two sequential randomized phase 2 trials, known response rate and time to tumor progression. Overall survival as TREE-1 and TREE-2, suggest modestly inferior activity for was superior in the FOLFOX-4 arm versus IFL as well; however, the bFOL schedule compared with FOLFOX or Cape/Ox.357,358 interpretation of the survival results of N9741 is somewhat com- Thus, in the metastatic setting, oxaliplatin with bolus 5-FU sched- plicated due to imbalances between arms in availability of effec- ules is therefore not recommended for routine use. tive second-line therapy. Second-line CPT-11 was available to Use of planned sequential administration of FOLFOX and all patients who had received FOLFOX-4. Oxaliplatin, however, FOLFIRI has also been proposed, both in terms of pretreatment was not commercially available in the United States during the for potentially resectable patients with liver metastases and in course of N9741. To what degree this imbalance in second-line terms of adjuvant treatment of earlier stage disease. Several groups therapy may have influenced the survival result is unknown. Also, are also exploring the use of “triple therapy” with oxaliplatin, CPT- as IFL contains bolus 5-FU, while FOLFOX-4 contains infusional 11, and 5-FU/leucovorin (FOLFOXIRI). A randomized phase 3 leucovorin/ 5-FU2, it is difficult to isolate the irinotecan versus ox- trial conducted in Italy reported that FOLFOXIRI is tolerable aliplatin component from the 5-FU bolus versus 5-FU infusion and offers a modest survival benefit over FOLFIRI. These trials component. utilized higher doses of 5-FU than are likely to be tolerable by Two other trials indicate that the FOLFOX and FOLFIRI American patients, and use of this combination has not gained regimens have similar safety and efficacy, with differing toxic- widespread acceptance.359 ity profiles.349,351 Thus, FOLFOX has comparable efficacy to As discussed previously, a trial comparing FOLFIRI to capecita- FOLFIRI, whereas FOLFOX has a superior response rate, time bine/irinotecan suggested inferior outcome for the capecitabine- to tumor progression, and possibly some degree of survival benefit containing regimen.334 However, a large randomized trial has over IFL. Toxicity with irinotecan-based regimens shows a higher now compared Cape/Ox versus FOLFOX. The study also had a degree of alopecia. Diarrhea and neutropenia are increased on two-by-two randomization to with or without bevacizumab (dis- the bolus 5-FU schedule but are similar between FOLFOX and cussed subsequently). This trial demonstrated the Cape/Ox regi- FOLFIRI. Oxaliplatin-based regimens, however, have neurotox- men to be noninferior to FOLFOX, and each had acceptable icity, absent from the irinotecan-based regimens, which can be toxicity, indicating that Cape/Ox is an acceptable alternative problematic in some patients. It would therefore seem reasonable to FOLFOX.360 It should be noted that the Cape/Ox regimen at this time to favor the use of a high-dose intermittent infusional requires a motivated, reliable patient who will be able to take mul- 5-FU/leucovorin schedule plus either oxaliplatin (i.e., FOLFOX) tiple pills of oral medication on a complex schedule, even in the or CPT-11 (i.e., FOLFIRI). Data do not support continued routine setting of potentially emetogenic oxaliplatin. use of the bolus IFL schedule, nor are there randomized data to

support the routine use of a bolus 5-FU/leucovorin schedule with OF ONCOLOGY PRACTICE oxaliplatin in the metastatic setting. Routine use of IROX is also Duration of Therapy not supported by the currently available body of data. Whether to use an irinotecan-based or oxaliplatin-based com- Controversy continues to exist regarding the optimal duration bination in first-line treatment of good performance status patients of chemotherapy for palliation of metastatic disease. Traditional can be considered a matter of patient preference, and discussion practice for many years had been to continue chemotherapy until of the differing toxicity profiles is appropriate to help individuals either unacceptable toxicity, clinical deterioration, or disease pro- decide. It is hoped that in the near-term future molecular prognos- gression. When efficacy of treatment was more limited, with the tic indicators and pharmacogenomics will provide useful guidance duration of therapy typically limited to a small number of months, for the individualization of therapies, but such approaches remain the issue of treatment breaks did not seem relevant. Now, with pa- investigational at this time. tients typically living multiple years with metastatic CRC and with The only oxaliplatin schedule registered for use in the United some treatments maintaining control for more extended periods of States is FOLFOX-4; however, the modified FOLFOX-6 would time, the need for patients to have breaks (often referred to as “treat- appear at this time to be a very reasonable schedule for routine ment holidays” or “chemotherapy-free intervals” [CFI]) is greater, clinical use when the decision is made to use an oxaliplatin/5-FU and there is considerable interest in using these approaches. Both combination. physically and psychologically, many patients appear to both need The recognition of neurotoxicity as a major limitation of the and derive benefit from these treatment interruptions. FOLFOX regimens led to the investigation of optimization of The concept of noncontinuous chemotherapy has been in- oxaliplatin (the OPTIMOX study).355 In this trial, patients were vestigated for some time now. Maughan et al.361 conducted a randomly assigned to receive either standard FOLFOX-4 until randomized trial of continuous versus interrupted treatment in progression or 12 weeks of FOLFOX-7, followed by planned cessa- 354 patients who were responding or who had stable disease after tion of oxaliplatin and continuation of the LV5FU2. As designed, receiving 12 weeks of either 5-FU– or raltitrexed-based chemother- the study called for a reintroduction of oxaliplatin after 6 months apy. Patients were randomized to either continue chemotherapy of LV5FU2, although this actually occurred in the minority of until progression or to stop chemotherapy after the first 12 weeks, patients and outcomes were superior in those patients in whom followed by a planned restarting on the same chemotherapy at reintroduction of oxaliplatin occurred.356 The primary end point the time of progression. At randomization, 41% of patients had was duration of disease control, the time from initiation of treat- achieved a major objective response and 59% had stable disease. ment until either progression through all agents (including fail- There was no evidence of a difference in overall survival, the ure after reintroduction of oxaliplatin if this was done), or death. primary end point, between the two groups, with an HR of 0.87 Duration of disease control as well as progression-free survival and (p = 0.23, favoring the intermittent arm). overall survival were not statistically significantly different between More recently, the idea of planned early cessation of all chemo- the two arms. As anticipated, toxicity, including neurotoxicity, was therapy was investigated in the OPTIMOX-2 trial.362 A total of 202 substantially reduced in the OPTIMOX arm. This OPTIMOX patients with previously untreated metastatic CRC were treated. strategy of planned interruption of oxaliplatin can be considered All patients received six cycles of modified FOLFOX-7 followed a standard care option in metastatic disease. It is important to by either continued LV5FU2 until progression, or a complete ces- discuss plans for such planned interruptions with patients at the sation of all chemotherapy (a CFI). Patients on both arms were beginning of therapy so that they will not be surprised or alarmed planned to receive retreatment with FOLFOX following tumor at the removal of one of the drugs. progression. The results of this study did not support the use of this 800 Practice of Oncology / Cancers of the Gastrointestinal Tract planned, early interruption in therapy, as the median duration of arms in progression-free survival or overall survival, nor were there disease control, progression-free survival, and overall survival were differences in quality-of-life scores. all inferior in the arm with the early planned CFI. This should not Overall, there appears to be no compelling evidence that con- be misconstrued as evidence that CFIs are contraindicated, but tinuation of chemotherapy indefinitely is necessary for optimal rather that early planned CFIs for all patients is not an appropriate control of metastatic disease. The option of discontinuation of strategy. The authors suggest that this study indicates there are no therapy after a reasonable period of time appears to be an appro- pretreatment parameters that can identify a priori those patients priate consideration in standard practice. who can successfully benefit from a CFI. Thus, specific decisions regarding use and timing of CFIs cannot be made in advance of starting treatment; rather, clinical judgment must be exercised in Combination versus Single-Agent deciding on treatment interruptions for CFIs in responding pa- Chemotherapy tients after a favorable response. In a retrospective review of 822 patients in the two OPTIMOX studies, after excluding those patients Given that combination regimens are invariably associated with who had early progression within the first 3 months of treatment more toxicity than single agents, the question of the need for as well as those who underwent complete gross resection of meta- universal upfront use of these combinations was investigated. static disease within 3 months of stopping chemotherapy, Perez- The CAIRO (CApecitabine, IRinotecan, Oxaliplatin) trial ran- Staub et al.363 noted that there was no indication of a detriment domized 820 patients to sequential versus concurrent therapies in survival when comparing those patients who took a CFI versus (Table 57.15).366 In the sequential arm, first-line therapy was those who did not. In fact, in this retrospective, nonrandomized single-agent capecitabine. Upon failure, single-agent irinotecan analysis, the median survival was 37.5 months in patients who had was used, and then third-line therapy was Cape/Ox (since single- a CFI versus 21.2 months in matched patients who did not have a agent oxaliplatin is essentially inactive in 5-FU–refractory CRC). CFI. Of note, median overall survival of patients who stopped che- The combination arm used Cape/Ox as first-line therapy and motherapy earlier than 3 months was 24 months, whereas it was capecitabine and irinotecan as second-line therapy. The primary 42 months when a CFI was taken between 3 and 9 months into end point, median overall survival, was not statistically significantly therapy, and 44 months when a CFI was taken later than 9 months different between the two arms (17.4 months for combination ver- into chemotherapy. These studies were accomplished prior to the sus 16.3 months for the sequential arm; p = 0.33). Dose-limiting use of bevacizumab. Some clinicians have advocated the continu- toxicity (grade 3 or 4) was not significantly different between the ation of bevacizumab during CFIs. Such an approach is not sup- two groups; in fact, grade 3 hand-foot syndrome was somewhat ported by data, and given the absence of activity of single-agent more common in the sequential arm (13% versus 7%; p = 0.004). bevacizumab in CRC, use of single-agent bevacizumab during Similar findings were reported in the FOCUS study.367 In this otherwise CFIs is not recommended at this time. trial, a total of 2,135 patients were randomized to one of three Other investigators specifically addressed the question of arms. Arm A was sequential therapy, with initial treatment given whether rechallenge with 5-FU after a planned treatment interrup- with 5-FU on the leucovorin/5-FU2 (biweekly infusional) sched- tion could produce a response. A pooled analysis was conducted ule until progression, at which point second-line therapy was given on 613 patients involved in three randomized trials of first-line with single-agent irinotecan. Arm B also gave biweekly LV5FU2 5-FU–based therapy.364 All patients had a planned maximum treat- until failure, and then LV5FU2 was continued with the addition ment period of 6 months. Patients with responding or stable disease of either oxaliplatin or irinotecan (this was a second randomization at the end of that period were observed off treatment with a plan within this arm). Thus, second-line therapy was a change from for retreatment at the time of disease progression. Median time to biweekly LV5FU2 to either FOLFOX or FOLFIRI in this arm. rechallenge was 11.7 months. Seventeen percent of patients had In arm C, patients began with combination chemotherapy, and an objective response to rechallenging. Median survival for the within this arm were randomized to either FOLFOX or FOLFIRI. group was 14.8 months. These nonrandomized data indicate that The primary end point, median overall survival, for arm A was 13.9 patients have a meaningful response rate at time of reinstitution of months. For arm B, survival was 15.0 months for irinotecan and chemotherapy. 15.2 months for oxaliplatin. Arm C had a median overall survival A similar approach was explored in patients who received sec- of 16.7 months for the FOLFIRI patients and 15.4 months for ond-line irinotecan therapy.365 A total of 333 patients entered into those treated with FOLFOX. Only the difference between arm A a trial to receive 24 weeks of irinotecan. Patients who remained in and the irinotecan arm of arm C reached statistical significance the study at the end of that time were to be randomized to either (p = 0.01). Arm B (initial LV5FU2 followed by FOLFOX or continue treatment or to stop therapy. Of the 333 patients, most FOLIRI) was noninferior to arm C (initial FOLFOX or FOLIRI) came off the study due to progression or toxicity before reaching (HR = 1.06; 90% CI = 0.97 to 1.17). the 24-week mark. Fifty-five patients with responding or stable Taken together, the CAIRO and FOCUS trials provide a strong disease agreed to randomization. Although the numbers available argument that not all patients with unresectable metastatic dis- for comparison were small, there were no differences between the ease require exposure to the toxicity of combination therapy, and

TABLE 57.15 Sequential Versus Combination Chemotherapy with Capecitabine, Irinotecan, and Oxaliplatin in Advanced Colorectal Cancer: Efficacy End Points

Progression-Free Overall Survival One-Yr Survival Survival (First Line) Response Rate Sequential Cape, then Iri, then Cape/Ox (n = 401) 16.3 mo 64% 5.8 m 20% Combination Cape/Iri, then Cape/Ox (n = 402) 17.4 mo 67% 7.8 m 41% P value 0.33 0.38 0.0002 0.0001

Cape, capecitabine; Iri, irinotecan; Ox, oxaliplatin. From Koopman M, Antonini NF, Douma J, et al. Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial. Lancet 2007;370:135–142.

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TABLE 57.16A Efficacy Outcomes, First-Line Treatment of Metastatic Colorectal Cancer: Irinotecan Plus Bolus 5-Fluorouracil/Leucovorin Plus Placebo Versus 5-Fluorouracil/Leucovorin Plus Bevacizumab

Regimen No. of Patients Response Rate Progression-Free Survival Overall Survival IFL + placebo 411 34.8% 6.2 mo 15.6 mo IFL + bevacizumab 402 44.8% 10.6 mo 20.3 mo p = 0.004 p < 0.001 p < 0.001

IFL, 5-fluorouracil, leucovorin.

that initial use of fluorinated pyrimidine alone in patients with It should be noted that no crossover to second-line bevacizumab in previously untreated metastatic CRC is a treatment alternative the IFL/placebo control arm was allowed in this trial. that needs to be carefully considered. In order to better understand the effects of bevacizumab in 372 Bevacizumab conjunction with 5-FU/leucovorin, Kabbinavar et al. combined the data from three separate modest-sized trials to create a more Bevacizumab is a humanized monoclonal antibody that binds to robust data set. In this combined analysis of 5-FU/leucovorin with VEGF, thereby substantially reducing the amount of circulating or without bevacizumab, there was a statistically significant survival ligand and thus preventing receptor activation.368,369 The first trial advantage for the patients who received bevacizumab. Given the of bevacizumab in CRC was a modest-sized, three-arm, random- favorable aspects of the biweekly infusional LV5FU2 schedule used ized phase 2 trial in which a total of 104 patients were randomly in the FOCUS trial, the LV5FU2 schedule would seem most ap- assigned to either one of two different doses levels of bevacizumab propriate for combination with bevacizumab.373 At the same time as (5 mg/kg or 10 mg/kg) plus weekly 5-FU/leucovorin or to 5-FU/ the pivotal front-line study was accruing, the Eastern Cooperative leucovorin alone.370 The response rate, time to tumor progression, Oncology Group (ECOG) also performed a trial (ECOG-3200) to and overall survival were superior in the 5-FU/leucovorin with evaluate the use of bevacizumab in the second-line setting.374 This 5 mg/kg bevacizumab arm. Despite the small size and limited sta- trial randomized patients who had failed irinotecan and 5-FU but tistical power of this study, this result would served as the basis for were naive to bevacizumab, to one of three arms: bevacizumab/ design of the pivotal phase 3 trial of bevacizumab in CRC. FOLFOX, FOLFOX alone, or bevacizumab. The investigators

The initial design of the phase 3 pivotal trial was a comparison chose to investigate a 10 mg/kg bevacizumab dose. Overall, a mod- PRACTICE OF ONCOLOGY between 5-FU/leucovorin plus placebo to 5-FU/leucovorin plus 5 est but statistically significant improvement in median overall sur- mg/kg of bevacizumab. However, as the randomized phase 2 trial, vival was demonstrated for FOLFOX-4 with bevacizumab versus discussed previously, was nearing completion, the randomized FOLFOX-4 alone (12.5 months versus 10.7 months; p = 0.0024), phase 3 trial was reported, which demonstrated a modest but statisti- and grade 3 or 4 toxicities were not increased. The bevacizumab- cally significant survival advantage for the IFL regimen (irinotecan alone arm had substantially inferior progression-free survival and plus weekly bolus 5-FU/leucovorin) compared with 5-FU/leucovo- an investigator-adjudicated response rate of 3%, suggesting that sin- rin alone.247 As a result of this trial, the IFL regimen was then felt to gle-agent bevacizumab does not have meaningful activity in CRC be the appropriate control arm for subsequent phase 3 trials. There and should not be used. It is important to note that this trial was per- were no safety data at the time, however, on the combination of bev- formed exclusively in patients who had not received bevacizumab acizumab plus IFL. As a result of this, a three-arm trial was designed in the first-line setting. This trial provides no data on whether use that contained (1) 5-FU/leucovorin/bevacizumab, (2) IFL/bevaci- of bevacizumab with a second-line regimen after progression on a zumab, and (3) IFL/placebo (the control arm).371 The design in- first-line bevacizumab-containing regimen is efficacious. cluded a preplanned analysis of safety on all arms when enrollment Although it was performed in second-line patients, the ECOG- reached 100 patients per arm, with a further plan to close the 5-FU/ 3200 trial was the first trial to provide safety data for the combi- leucovorin/bevacizumab arm at that time if the safety data indicated nation of bevacizumab plus FOLFOX. As a result of this, even acceptable tolerability and safety of the IFL/bevacizumab arm. before front-line data were available, bevacizumab plus FOLFOX In the final efficacy analysis, the IFL/bevacizumab cohort expe- had become widely accepted as a front-line option in the United rienced superior outcome compared to the IFL/placebo group in States for metastatic CRC. More recently, the NO16966 trial response rate (45% versus 35%; p <0.003), progression-free survival directly addressed the question of front-line bevacizumab plus (10.6 months versus 6.2 months; p <0.00001), and overall survival oxaliplatin-based therapy (Table 57.16B).375 In this trial, 1,400 pa- (20.3 months versus 15.6 months; p = 0.00003) (Table 57.16A). tients with previously untreated CRC were randomly assigned to

TABLE 57.16B Efficacy Outcomes, First-Line Treatment of Metastatic Colorectal Cancer: Capeox/Folfox Plus Placebo Versus Capeox/Folfox Plus Bevacizumab

Progression-Free Regimen No. of Patients Response Rate Survival Overall Survival CapeOx/FOLFOX + placebo 701 49% 8.0 mo 19.9 mo CapeOx/FOLFOX + bevacizumab 699 47% 9.4 mo 21.3 mo p = 0.31 p = 0.0023 p = 0.078

CapeOx, capecitabine, oxaliplatin; FOLFOX, fluorouracil, leucovorin, oxaliplatin. From Saltz LB, Clarke S, Diaz-Rubio E, et al. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 2008;26:2013–2019. 802 Practice of Oncology / Cancers of the Gastrointestinal Tract either FOLFOX-4 or Cape/Ox and then to either placebo or beva- analysis of these events suggested that the risk was essentially linear cizumab, in a two-by-two randomization. Although the study did over time, indicating that the risk of a new arterial thrombotic show a statistically significant progression-free survival advantage event was the same in earlier versus later months of exposure.376 for the addition of bevacizumab (9.4 months versus 8.0 months for Another complication of bevacizumab that has been rarely chemotherapy with bevacizumab versus chemotherapy with pla- described in the literature is fistula formation. Ganapathi et al.377 cebo, respectively; HR = 0.83; p = 0.003), this difference was more reports a 4.1% incidence of this problem in a review of 222 patients modest than the 4.4-month progression-free survival difference seen with metastatic CRC. Two-thirds were perineal or anal with the re- in the initial bevacizumab with IFL front-line trial. Overall survival mainder colovesicular, occuring an average of 3.9 months after ini- improvement with bevacizumab approached, but did not reach, tiation of treatment. Cessation of bevacizumab led to fistula healing statistical significance (21.3 months versus 19.9 months; HR= in nearly all cases; however, three patients required fecal diversion. 0.89; p = 0.077) Also, in the NO16966 trial, the addition of bevaci- The authors suggest that this complication has been underreported zumab to front-line oxaliplatin-based chemotherapy did not confer thus far and stress the importance of early recognition.377 any response benefit. It is noteworthy that the majority of patients on this trial discontinued treatment, presumably due to nonbeva- Bevacizumab Beyond Progression cizumab-related toxicity issues, before progression. This may have diminished the impact of bevacizumab on survival and progression- Prior studies had demonstrated the activity of bevacizumab when free survival but would not have impacted the response rate. added to first-line chemotherapy, and the ECOG 3200 trial had shown that bevacizumab added to second-line chemotherapy in Toxicity bevacizumab-naïve patients. Until recently, however, data were lacking regarding the question of continuation of bevacizumab with second-line therapy after progression of disease through a In terms of toxicity, grade 3 hypertension was higher in the first-line, bevacizumab-containing regimen. This question has bevacizumab/IFL arm than in the placebo/IFL arm (11% versus now been addressed by the TML trial.378 In this trial, 820 patients 2%) in the IFL/bevacizumab study.371 Hypertension is now widely who had progressed through a first-line, bevacizumab-containing recognized as a common side effect of bevacizumab, and monitor- regimen were assigned to a noncross-resistant chemotherapy regi- ing for and treatment of hypertension with antihypertensive medi- men (irinotecan plus fluoropirymidine if previously treated with cations is a routine part of bevacizumab management. Incidences oxliplatin or oxaliplatin-fluoropyrimidine if previously treated with of overall thromboembolic events and proteinuria were not sta- irinotecan) and then randomized to receive bevacizumab with tistically different between the two arms. However, two rare but this second-line chemotherapy or not. The arm receiving bevaci- extremely serious toxicities were encountered with increased fre- zumab showed a modest but statistically significant survival benefit quency in the bevacizumab-containing arm: GI perforations and of 1.4 months (overall survival of 11.2 months versus 9.8 months; arterial thrombotic events. HR = 0.81; 95% CI = 0.69 to 0.94; p = 0.0062). Grade 3 to 5 The GI perforations were a group of events that included bleeding or hemorrhage (8 [2%] versus 1 [1%]), GI perforation a perforated gastric ulcer, small bowel perforations, and free air (7 [2%] versus 3 [1%]), and venous thromboembolisms (19 [5%] under the diaphragm without identified sources. Although these versus 12 [3%]) were more common in the bevacizumab plus che- were somewhat heterogeneous in nature, it was noted that six such motherapy group than in the chemotherapy-alone group. events occurred on the bevacizumab-containing arm (one fatal) compared with none on the chemotherapy-alone arm. No clear risk factors for these perforations could be identified from this Aflibercept trial. Interestingly, GI perforations were not frequent occurrences in large cooperative group trials in patients with lung cancer or Aflibercept is a fusion molecule containing the binding domains breast cancer; however, an unusually high GI perforation rate has of VEGF receptors 1 and 2 bound to the human immunoglobulin recently halted accrual on a trial of bevacizumab in patients with (Ig) G Fc fragment, forming a VEGF trap molecule. Aflibercept ovarian cancer. These ovarian observations illustrate an important binds all human VEGF A isoforms, VEGF B, and placental growth aspect about GI perforations in association with bevacizumab: factor with greater affinity than the native receptors for these li- there is not an association between the presence of an intact pri- gands. Aflibercept has been evaluated in the large scale phase 3 mary tumor in the colon and a GI perforation. Concerns have VELOUR trial, in which 1,226 patients who had progressed on been expressed by some clinicians about the possibility of needing a first-line oxaliplatin-containing regimen were randomized to to remove an asymptomatic primary colorectal tumor in a patient receive second-line FOLFIRI plus aflibercept 4 mg/kg versus with synchronous stage IV disease before using bevacizumab out of FOLFIRI plus placebo. All treatments were given every 2 weeks. an unsubstantiated fear that the primary will put the patient at risk Thirty percent of patients had received prior bevacizumab with for perforation. At present, there are no data to support this assump- their first-line treatment regimen, while the remainder were naïve tion, and surgery for an asymptomatic primary tumor in a stage IV to anti-VEGF therapy. The group receiving aflibercept achieved patient is not routinely indicated, regardless of whether there are a modest, but statistically significant overall survival benefit of plans to use a bevacizumab-containing chemotherapy regimen.319 1.4 months (13.50 months versus 12.06 months; HR = 0.817; 95% The other rare but very serious identified increased risk with CI = 0.713 to 0.937; p = 0.0032).379 PFS was also statistically bevacizumab-containing treatment was that of arterial thrombotic significantly improved from 4.67 months to 6.9 months with the events. Initially, no clear indication of this risk was detected in the addition of aflibercept p( <0.0001). Reponse rate was improved pivotal phase 3 trial. However, in a combined analysis of several from 11.1% to 19.8%. trials, an important observation was made. Here again, multiple The findings of the VELOUR and TML trials show striking events were combined into one metric. Thus, cerebral vascular similarities to one another. Each utilized an anti-VEGF strategy accidents, myocardial infarctions, transient ischemic attacks, and in second-line treatment in conjunction with active chemother- angina were combined to create the metric of arterial thrombotic apy, and each shows a 1.4-month survival benefit. Given these events. The observed incidence of these events was 2.5% in the findings, use of either with second-line FOLFIRI (if second- nonbevacizumab-containing control arms versus 5.0% in the line FOLFIRI is deemed appropriate) would seem reasonable. bevacizumab-containing experimental arms. It was noted that Aflibercept has not demonstrated benefit in conjunction with patients who had histories of cardiovascular or atherosclerotic oxaliplatin-based regimens at the time of this writing, and so use disease appeared to be at greater risk for increased bevacizumab- of aflibercept with oxaliplatin-based chemotherapy is not recom- related arterial thrombotic complications. In addition, a further mended. Furthermore, a change from FOLFIRI-aflibercept to

tahir99 - UnitedVRG Chapter 57 Cancer of the Colon 803

FOLFIRI-bevacizumab (or vice versa) is not supported by current form only, was conducted in patients who were determined by data, nor is use of either aflibercept or bevacizumab as a single their treating investigator to have progressed on irinotecan.385 Pa- agent. As such, aflibercept presents an option for second-line ther- tients were treated with cetuximab at a dose of 400 mg/m2 load- apy in conjunction with FOLFIRI, but does not create a new line ing dose week 1 over 2 hours, followed by weekly 250 mg/m2 over of therapy in the continuum of treatment. 1 hour. Irinotecan was given on the same dose and schedule as had previously failed. Irinotecan dose reductions made previously, Regorafenib prior to study entry, were maintained upon initiation of the study treatment. One hundred twenty patients with irinotecan-refractory CRC Regorafenib is a small molecule multitargeted tyrosine kinase in- were identified and enrolled. In addition, in a parallel portion of hibitor. It is closely related to its parent compound, sorafenib, and the trial, 28 patients with clinically and radiographically stable dis- differs only by the addition of a fluorine atom. After phase 1 trials ease after receiving a minimum of 3 months of irinotecan therapy identified preliminary evidence of activity in patients with refrac- were also enrolled and treated by the addition of cetuximab to their tory CRC, a large phase 3 trial of regorafenib versus placebo was ongoing irinotecan therapy. The response outcome of this “stable undertaken.380 A total of 760 patients, all with ECOG grade 0 or disease cohort” was not reported; only those patients who were 1 performance status, who had progressed through all standard felt to be irinotecan refractory were included in the initial report. therapies, were randomized 2:1 to received regorafenib 160 mg As reported by an independent response assessment committee, orally daily versus placebo. The regorafenib group achieved a mod- 22.5% of irinotecan-refractory patients achieved a major objective est but statistically significant overall survival benefit of 1.4 months response. The irinotecan-related toxicity was relatively mild in this (6.4 months versus 5.0 months; HR = 0.77; 95% CI = 0.64 to population, at least in part because many patients had already had 0.94; p = 0.0052). Response was essentially nonevident, with a irinotecan dose modifications made prior to starting on this trial. response rate of 1% in the regorafenib arm. Grade 3 hand-foot Of the side effects specifically attributable to cetuximab, 3% of syndrome (17%) and grade 3 fatigue (10%) were the most com- patients developed an allergic, anaphylactoid reaction requiring mon toxicities encountered on the regorafenib arm. Regorafenib discontinuation of cetuximab therapy, and 75% of patients experi- monotherapy can be considered as a standard care option for good enced a skin rash (12% grade 3), a rash now recognized to be char- performance status patients who have progressed through standard acteristic of all EGFR inhibitors. This rash superficially resembles therapies. Studies assessing the use of regorafenib in earlier lines of acne, leading to its initial description as an acneiform rash. How- therapy and in combination with cytotoxic agents are in progress at ever, microscopically this is not acne, and topical acne medica- the time of this writing. tions are ineffective in its management. An interesting observation Cetuximab and Panitumumab from this trial, which has since been corroborated in multiple trials, is that the presence and severity of the rash appeared to be

The EGFR, also called HER-1, is a transmembrane glycoprotein associated with response in this study. PRACTICE OF ONCOLOGY receptor. When the external binding domain of the EGFR binds The results seen in the phase 2 cetuximab plus irinotecan com- specific ligands, such as epidermal growth factor or TGF-α, recep- bination trial raised the question, both from a scientific and from tor dimerization occurs (either homodimerization with another a regulatory perspective, of the activity of single-agent cetuximab EGFR or heterodimerization with another member of the EGFR in irinotecan-refractory CRC. A small phase 2 trial was therefore family). This in turn stimulates phosphorylation of the tyrosine quickly designed and accrued. In this trial, 5 of 57 patients (9%) kinases on the intracellular domain of the receptor, which initiates achieved a partial response confirmed by an independent radio- a signaling cascade, which ultimately regulates cell proliferation, logic review.386 migration, adhesion, differentiation, and survival.381–383 Cetuximab Based on the preliminary results of the initial phase 2 cetuximab (c-mab), is a chimeric IgG1 monoclonal antibody that recognizes plus irinotecan study, described previously, a subsequent larger and binds to the extracellular domain of the EGFR. Panitumumab trial, ultimately reported by Cunningham et al.,245 was designed (p-mab) is a fully human IgG2 monoclonal antibody that also tar- to provide confirmatory evidence of the activity ofcetuximab gets the EGFR. Binding of either c-mab or p-mab to this receptor in CRC (Table 57.17). This large, randomized phase 2 trial in does not cause receptor activation, but rather results in a steric patients with irinotecan-refractory CRC, which has become interference with the ligand binding site.384 known as the BOND trial, compared cetuximab plus irinotecan to Preclinical models of cetuximab, or its murine precursor, dem- cetuximab monotherapy. A total of 329 patients were randomized onstrated more substantial activity when given in combination in a two-to-one schema. The response rates of 22.9% for cetuximab with cytotoxic chemotherapy. Based on these observations, and on plus irinotecan and 10.8% for cetuximab alone were virtually iden- a single anecdotal report of a major response to cetuximab plus iri- tical to the response rates that had been reported previously in the notecan in a young woman with irinotecan-refractory CRC, a mul- two US phase 2 trials, confirming the activity of this agent in CRC. ticenter phase 2 trial was initiated. This trial, reported in abstract Time to tumor progression in the Cunningham et al.245 study was

TABLE 57.17 Efficacy Outcomes: Cetuximab Plus Irinotecan Versus Cetuximab Alone in Irinotecan-Refractory Colorectal Cancer

Response Rate Disease Control Median Median OS No. of Patients (95% CI) (95% CI) TTP (mo) (mo) (95% CI) Cetuximab 111 11% (6%–18%) 32% (24%–42%) 1.5 6.9 (5.6–9.1) Cetuximab + irinotecan 218 23% (18%–29)a 56% (49%–62%)b 4.1c 8.6 (7.6–9.6)

CI, confidence interval; TTP, time to progression; OS, overall survival. a p = 0.0074. b p = 0.0001. c p < 0.0001. From Cunningham D, Humblet Y, Siena S, et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004;351:337–345. 804 Practice of Oncology / Cancers of the Gastrointestinal Tract

4.1 months for the combination versus 1.5 months for single-agent mutation. The progression-free survival in the patients with KRAS cetuximab. Survival in the two arms was not significantly different; wild-type tumor who received panitumumab was 12.3 weeks versus however, the study was neither designed nor powered to address 7.3 weeks for best supportive care. In patients with KRAS-mutated the issue of a survival advantage for cetuximab, and cetuximab was tumors, there was no difference in progression-free survival with given to all patients on both arms of the study. panitumumab versus best supportive care. Again, overall survival A National Cancer Institute Canada phase 3 trial compared in this trial could not be interpreted due to extensive postprogres- cetuximab plus best supportive care to best supportive care alone sion crossover. in 572 patients who had exhausted standard treatment options.387 Similarly, analysis of the National Cancer Institute Canada The median overall survival was improved by 1.5 months (from study, discussed previously, demonstrated that activity of cetuximab 4.6 months to 6.1 months) in the cetuximab group compared to as a single agent in chemotherapy-refractory disease was limited to supportive care alone. Partial responses occurred in 23 patients the KRAS wild-type patients only (Table 57.18).394 Approximately (8.0%) in the cetuximab group versus none in the supportive care 70% of patients in this trial had tissue available for KRAS geno- group (p <0.001). typing, and 42% were found to have mutated KRAS. Those with Similar results were reported with panitumumab. As seen with mutated KRAS showed no evidence of clinical benefit from cetux- single-agent cetuximab, phase 2 evaluations of panitumumab in imab, while patients whose tumors had wild-type K-ras showed a patients with CRC indicate approximately a 10% response rate, 4.7-month improvement in median overall survival with cetuximab with over 90% of patients experiencing some degree of acneiform- versus best supportive care (9.5 months versus 4.8 months; HR for like rash.388,389 The fully human nature of this antibody appears death = 0.55; 95% CI = 0.41 to 0.74; p <0.001). In the control to reduce the likelihood of anaphylactoid infusion reactions, group who received best supportive care, KRAS mutation status with only 1 of the 148 patients treated after experiencing a dose- had no impact on median overall survival (p = 0.97). Although limiting allergic reaction. A randomized trial of panitumumab some data have suggested that tumors with KRAS exon 2, codon versus best supportive care in the salvage setting demonstrated 13 mutatuions might still garner some benefit from first-line treat- a modest (8 weeks versus 7.3 weeks) but highly statistically sig- ment with cetuximab or panitumumab,395 subsequent data have nificant improvement in median progression-free survival for refuted this, and any KRAS exon 2 mutation remains a firm contra- single-agent panitumumab over best supportive care (HR = 0.54; indication to treatment with an EGFR inhibitor. (More recently, p <0.000000001). Response rate to p-mab was 10%. There was no a retrospective analysis suggested that in addition to exon 2 KRAS difference in overall survival; however, there was extensive postpro- mutations, tumors with mutated BRAF, NRAS, or PIK3CA were gression crossover, which obscures this end point.390 significantly associated with a low response rate to cetuximab or panitumumab.396) The question of the impact of other KRAS mu- KRAS and Other Determinants of tations outside of exon 2 has been further addressed, as has the impact of NRAS mutations. Data strongly suggest that the presence Anti–Epidermal Growth Factor of any KRAS or NRAS mutation confers resistance to cetuximab Receptor Resistance and panitumumab, and that these agents should not be used in patients whose tumors harbor any of these mutations.150 The role of Perhaps the most important development in the use of anti-EGFR BRAF genotyping remians less definitive. While an unpreplanned agents over the past several years has been the recognition that these retrospective subset analysis of a combination of two first-line trials agents only have the potential to be beneficial to patients whose suggests some possible contribution of cetuximab in patients with tumors have nonmutated, or wild-type, KRAS gene. KRAS is a sig- BRAF-mutated tumors, most published datasets of patients treated nal transduction protein that is a critical intermediate in transmis- in the nonfirst-line setting show essentially no activity for cetux- sion of growth and survival signals from the EGFR to the nucleus. imab or panaitumumab in patients with BRAF-mutated tumors. Mutations in exon 2 of the gene that encodes for the KRAS protein Genotyping for KRAS mutation status should now be regarded lead to constitutive activation of this signaling pathway, which ren- as standard practice in all patients with stage IV disease, and cetux- ders blocking of the EGFR-binding site on the surface useless. Sev- imab and panitumumab should only be considered in patients with eral small retrospective series identified KRAS mutations as being nonmutated KRAS.397 Importantly, using a matched set of resected incompatible with responses to cetuximab.391,392 Subsequently, metastases and primary tumors from 84 patients, Vakiani et al.398 Amado et al.393 demonstrated that the activity of panitumumab in demonstrated near-complete concordance between primary and me- the registration study referenced previously was limited to those tastasis for RAS, BRAF, and PIK3CA. Therefore, genotyping of the patients with wild-type KRAS. In this trial, 92% of patients had tis- primary tumor is sufficient and patients do not need to be subjected sue available for KRAS genotyping, and 43% of tumors were found to a biopsy of a metastatic site for the purposes of tissue genotyping. to harbor a mutation in codons 12 or 13 in exon 2 of KRAS. The It is prudent to obtain KRAS genotyping at the time that stage objective response rate to single-agent panitumumab was 17% in IV disease is diagnosed, not necessarily because the information is KRAS wild-type tumors and 0% in those tumors that had a KRAS needed for first-line therapy, as only a minority of patients will be

TABLE 57.18 Cetuximab Versus Best Supportive Care in Metastatic Chemotherapy-Refractory Colorectal Cancer

Overall Survival Progression-Free Survival Response Rate KRAS Wt KRAS Mut KRAS Wt KRAS Mut KRAS Wt KRAS Mut Cetux 9.5 mo 4.5 mo 3.7 mo 1.8 mo 12.8% 1.2% BSC 4.8 mo 4.6 mo 1.9 mo 1.8 mo 0% 0% P value 0.001 0.89 0.001 0.96 NR NR

Wt, wild type; Mut, mutant; Cetux, cetuximab; BSC, best supportive care; NR, not reported. From Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med 2008;359: 1757–1765.

tahir99 - UnitedVRG Chapter 57 Cancer of the Colon 805 appropriate for first-line anti-EGFR therapy, but because whether Patients were randomized to one of three arms: Nordic FLOX a patient can consider the use of cetuximab or panitumumab in given continuously, cetuximab plus Nordic FLOX given continu- the course of multiple lines of therapy is easier to both determine ously, or cetuximab plus Nordic FLOX given intermittently. There and to deal with early on when there are multiple options, rather were no statistically significant differences in the median progres- than waiting until all other options are exhausted. At present, there sion-free survival between the three arms (7.9 months, 8.3 months, is no role for determining KRAS status in stage I, II, or III disease, and 7.3 months, respectively). Overall survival also showed no dif- as there is no basis for use of EGFR agents in other than stage IV. ference between the three arms (20.4 months, 19.7 months, and Preliminary data suggests that KRAS status might play a role 20.3 months, respectively). Even in patients with KRAS wild-type in oxaliplatin sensitivity as well. In vitro analysis, published by Lin tumors, cetuximab did not provide demonstrable benefit. et al.399 demonstrated that this mutation caused downregulation of Taken in the aggregate, the data do not lend substantial sup- ERCC1 (excision repair cross-complementation group 1), which port to the use of cetuximab with oxaliplatin-based chemotherapy. led to enhanced oxaliplatin sensitivity. Overexpression of ERCC1 Curiously, however, the results with panitumumab are somewhat has been shown previously to be associated with resistance to plati- different. In a phase 3 trial of FOLFOX with or without panitu- num-based therapy in a number of cancers. Improved understand- mumab (6 mg/kg every 14 days), 1,183 patients were randomized, ing of this pathway may prove critical toward defining new targets of whom 60% had wild-type KRAS.405 Progression-free survival for KRAS-mutant CRC treatment.399 was modestly but statistically significantly improved with panitumumab in the KRAS wild-type patients (9.6 months versus = Cetuximab or Panitumumab in First-Line Therapy 8 months; p 0.02), and response rate was increased from 48% to 55%. However, as was seen with cetuximab, in the patients with A 1,200-patient study of FOLFIRI with or without cetuximab, known KRAS-mutated tumors, the addition of panitumumab resulted in at the CRYSTAL trial, has been reported.400 The primary end point a statistically significantworsening of median progression-free sur- of the trial, progression-free survival, was statistically significantly im- vival from 8.8 months in the control arm to 7.3 months in the proved with the addition of cetuximab, albeit by only 0.9 month, or panitumumab-containing arm. In an updated analysis focusing 27 days. When the study was analyzed in terms of KRAS genotype, on KRAS wild-type patients only, as statistically significant sur- those patients with mutated KRAS showed no benefit, while those vival benefit was seen with the addition of panitumumab in this with wild-type KRAS showed a progression-free survival improve- cohort.150 The addition of panitumumab resulted in increased skin ment of 1.2 months, or 37 days, but also a median overall survival rash, diarrhea, and hypomagnesemia. improvement from 20.0 months to 23.5 months (HR = 0.796; p = Also reported in abstract form is a phase 3 trial of second-line 0.0093).401 Response rates were also statistically significantly higher FOLFIRI with or without panitumumab.406 Despite this being a (57.3% versus 39.7%) in the cetuximab arm for the KRAS wild-type second-line study, patients had an excellent performance status tumors. Skin rash and diarrhea were increased in the cetuximab (ECOG 0 or 1 in 94% of patients). KRAS mutations were pres-

arm. As has been noted in virtually all trials of anti-EGFR agents, ent in 45% of patients. For the patients with KRAS wild-type OF ONCOLOGY PRACTICE there was a strong correlation between severity of skin rash and clini- tumors, the progression-free survival was statistically significantly cal benefit, with progression-free survival advantage being limited improved in the panitumumab-containing arm (5.9 months ver- to those patients with grade 2 or 3 skin rash. BRAF was confirmed sus 3.9 months; p = 0.004), and response rate was improved as as a poor prognostic factor but was not predictive of response to ce- well (35% versus 10%). Overall survival differences in favor of tuximab in this trial. The numbers of BRAF-mutated tumors limit the panitumumab arm (14.5 months versus 12.5 months) did not the power to detect a predictive role of BRAF in this trial, however. reach statistical significance p( = 0.1). There were no differences FOLFOX with or without cetuximab had been initially investi- in efficacy outcomes with the addition of panitumumab in the gated in a randomized phase 2 trial in which the primary end point patients with KRAS-mutated tumors. Again, skin rash, diarrhea, was response rate.402 A total of 337 patients were treated. The overall and hypomagnesemia were increased in the panitumumab arm. response rate was improved by the addition of cetuximab from 36% More recently the long-awaited initial results of the NCI coop- to 46%, a result that did not achieve statistical significance p( = 0.64). erative group 80405 study have been reported in abstract form. In For the KRAS wild-type patients, however, the result was more robust, this trial, patients with previously untreated metastatic colorectal with an improvement from 37% to 61% (p = 0.011). Progression-free cancer with wild-type KRAS were enrolled. Patients were assigned survival was very modestly, albeit statistically significantly improved to receive either FOLFOX or FOLFIRI per physician prefer- in the KRAS wild-type patients by a median of 15 days; however, ence, and then randomized to receive either cetuximab or beva- progression-free survival was statistically significantlyworse in the cizumab. There was no difference in overall survival, the primary cetuximab arm in those patients whose tumors had mutated KRAS. study endpoint, between the cetuximab and bevacizumab arms However, several larger phase 3 trials have cast considerable (29.0 months vs 29.9 months, p = 0.34).407 doubt on the role of cetuximab in conjunction with oxaliplatin- based therapy. In the Medical Research Council COIN trial, 1,603 patients with previously untreated metastatic CRC were Toxicities of Anti–Epidermal Growth Factor treated with oxaliplatin plus a fluoropyrimidine (either the Receptor Monoclonal Antibodies FOLFOX or Cape/Ox regimen) and randomized to receive cetuximab in addition or not. In the patients with KRAS wild-type The primary toxicity of cetuximab and panitumumab is an acne- tumors (367 with cetuximab plus oxaliplatin-containing chemo- like rash, which is seen to some degree in from 75% to 100% of pa- therapy and 362 with oxaliplatin-containing chemotherapy alone), tients treated. This rash is not acne, and it is accompanied by skin there was no improvement in overall survival (17.9 months versus dryness and paronychial cracking. Other than moisturizers, which 17 months; HR = 1.04; p= 0 .67) or in progression-free survival are recommended, no topical agents have been shown to be of (8.6 months versus 8.6 months in the two arms). Overall response benefit in the treatment of this rash. Drying agents and retinoids, rate increased from 57% to 64% with the additon of cetuximab such as are used in the treatment of acne, are contraindicated. An- (p = 0.049). The data from this trial do not support use of cetux- ecdotal reports of benefit for topical steroids or antibiotics do not imab with front-line oxaliplatin-based chemotherapy. Outcomes have supportive randomized data, and as the natural history of the were worse with the addtion of cetuximab to capecitabine plus rash is to wax and wane, interpretation of these anecdotal reports oxaliplatin, and the use of that combination is specifically not is problematic. There are data suggesting that prophylactic use of recommended.403 In addition, the Nordic VII trial investigated the oral antibiotics may somewhat mitigate the severity of the rash.408 addition of cetuximab to the Nordic FLOX regimen of oxalipla- Importantly, it has been well established that there is a clear cor- tin, bolus 5-FU and leucovorin in a 571-patient phase 3 trial.404 relation between severity of skin rash and favorable outcome with 806 Practice of Oncology / Cancers of the Gastrointestinal Tract

EGFR agents.409 The mechanism of this correlation has not yet would not be excluded from standard off-protocol treatment with been determined; however, it is clear that benefit from these agents cetuximab simply on the basis of EGFR status. Subsequently, is virtually confined to those patients who experience a grade 2 or a retrospective review was conducted using the computerized 3 skin rash. A severe rash does not guarantee a response or clinical pharmacy records to identify all patients who had received non- benefit; however, absence of a rash after the first month of therapy research cetuximab-based therapy at Memorial Sloan Kettering is virtually incompatible with clinical benefit from these agents. Cancer Center in the first 3 months of cetuximab’s commercial This is an important point to consider, especially in consideration availability. This review identified 16 patients with irinotecan- of front-line use; only those patients with a very substantial rash refractory, EGFR-negative CRC who had been treated. Fourteen stand a chance of benefit. of these patients had received cetuximab in combination with Hypersensitivity reactions, which are anaphylactoid in nature irinotecan and two had received cetuximab alone. Of the 16, and are completely separate and distinct from the skin rash tox- four patients experienced major objective (response rate = 25%; icity discussed previously, occur in approximately 3% of patients 95% CI = 4% to 46%), demonstrating that the hypothesis that a with cetuximab and <1% of patients with panitumumab. Almost negative EGFR stain would preclude the possibility of response all of these reactions are first-dose events. Dramatic regional dif- to cetuximab is false.414 A similar lack of correlation of EGFR ferences in the frequency of these reactions have been noted, with staining and activity with panitumumab has also more recently serious hypersensitivity reactions to cetuximab noted in up to 20% been reported.415 of patients in North Carolina and Tennessee, while the serious Because current EGFR IHC techniques have no predictive hypersensitivity reaction rate in the northeastern United States value, these techniques have no role in current management of is <1%.410 Subsequently, it has been demonstrated that there is CRC. The exclusion of a patient from cetuximab-based or panitu- a high prevalence of cetuximab-specific IgE in Tennessee, sug- mumab-based therapy solely on the basis of EGFR IHC is not ap- gesting cross-reactivity with an environmental allergen.411 Panitu- propriate. Likewise, no patient, with CRC or otherwise, should be mumab does not appear to exhibit this marked regional variation given an anti-EGFR treatment solely on the basis of a high EGFR in incidence of hypersensitivity reaction, and would be the clearly IHC expression. preferred agent over cetuximab in these areas of high incidence of cetuximab hypersensitivity. Bevacizumab Plus Anti–Epidermal Growth Factor It should be noted that the incidence of skin rash appears to be Receptor Agents quite similar between cetuximab and panitumumab, as does the degree of clinical activity. Thus, outside of the areas that see high Given the reported activity of both bevacizumab and cetuximab, frequency of cetuximab hypersensitivity reactions, there appears to investigators logically became interested in the idea of concurrent be little reason to favor one agent over the other. Case reports and use of these agents. Both some limited preclinical data, as well as anecdotal evidence suggest that patients who experience hyper- mechanistic understandings of potential interaction between anti- sensitivity to cetuximab do typically tolerate panitumumab. There EGFR and anti-VEGF pathways, supported the concept. As will is no basis, however, for using one of these agents after clinical be discussed subsequently, this concept serves as yet another ex- failure on the other. ample of perfectly logical, well-thought out assumptions supported Another more recently recognized toxicity of anti-EGFR ther- by preliminary clinical evidence that turned out to be incorrect apy is hypomagnesemia.412 This result is due to hypermagnesemia, when subjected to the appropriately rigorous test of an adequately presumably promoted by EGFR antagonism in the loop of Henle. powered clinical trial. Regular monitoring of serum magnesium levels, and intravenous The first study to attempt to administer bevacizumab and magnesium supplementation, when indicated, should be prac- cetuximab concurrently was a small randomized phase 2 study ticed routinely with anti-EGFR therapies. Oral magnesium is un- of bevacizumab added to cetuximab alone or to cetuximab plus likely to provide adequate supplementation, as diarrhea from this irinotecan in patients with irinotecan-refractory CRC.416 This is often dose-limiting. was a feasibility trial to assess the safety of concurrent administration of these agents and to look for preliminary evidence of Cetuximab and Panitumumab in Epidermal efficacy. The study concluded that coadministration of these two Growth Factor Receptor–Negative Patients monoclonal antibodies together was feasible, and that the preliminary data were encouraging. It should be noted, however, From the outset of clinical development, the assumption was that this was a small feasibility trial with 41 and 40 patients, re- made that quantitative EGFR expression would be predictive of spectively, reported in each arm. Furthermore, this study was the activity, or lack thereof, of an anti-EGFR antibody, and that conducted in patients who were naive to both cetuximab and an absence of demonstrable EGFR expression would therefore bevacizumab. As most patients now receive bevacizumab with preclude clinical activity of cetuximab or panitumumab. For this their first-line regimen, the results in the bevacizumab-naive reason, all early trials with these agents required that the patient’s population might not necessarily have a bearing on current prac- tumor shows EGFR positivity by IHC as a criterion for study eli- tice today. A small follow-up trial in patients with prior progres- gibility. This assumption, that EGFR expression would be pre- sion on a front-line bevacizumab-containing regimen showed far dictive, has never been supported by clinical or preclinical data less activity, with 3 of 33 patients (9%) achieving a partial re- and has been refuted by all clinical data that have addressed the sponse and a median time to tumor progression of 3.9 months.417 issue. All of the reported cetuximab trials to date, the earlier ones These small trials were designed to serve as the safety pilots for of which excluded EGFR-negative patients altogether, have dem- large-scale front-line studies that combined bevacizumab plus onstrated absolutely no correlation between the intensity of the cetuximab with front-line chemotherapy. Two such studies have EGFR expression and clinical response.245,385 Additionally, the re- now been reported, with alarming results, which highlights the sults of a small cohort of nine patients who were EGFR-negative dangers of jumping to conclusions prior to the availability of ma- and treated with cetuximab were reported in abstract form.413 Two ture, definitive data. major objective responses were reported by the investigators, one The CAIRO-2 study randomized 755 patients with previously of which was confirmed as a major response by third-party review untreated metastatic CRC to Cape/Ox-bevacizumab with or and one of which was not. without concurrent cetuximab (Table 57.19A).418 Not only was On the basis of the lack of correlation between EGFR staining there not a benefit to the addition of cetuximab, but the group intensity and response, as well as the small data set outlined pre- receiving cetuximab actually had a worse median progression-free viously, a decision was made at Memorial Sloan Kettering Can- survival of 9.4 months, compared to 10.7 months in the Cape/Ox- cer Center in New York that patients with EGFR-negative CRC bevacizumab–alone arm (p = 0.01). Response rates were identical

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TABLE 57.19A Capecitabine, Oxaliplatin, and Bevacizumab with or without Cetuximab in Metastatic Colorectal Cancer

Median Progression-Free Median Objective Survival Overall Survival Response Rates COB (n = 332) 20.3 mo 10.7 mo 50% COB plus cetux (n = 317) 19.4 mo 9.4 mo 52.7% P value 0.16 0.01 0.49

COB, capecitabine, oxaliplatin, bevacizumab; cetux, cetuximab. From Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009;360:563–572.

(44%) in the two arms. Furthermore, quality-of-life scores were Oral Epidermal Growth Factor Receptor, Vascular lower in the cetuximab-containing arm. Overall survival was not Endothelial Growth Factor, and Cyclooxygenase-2 statistically significantly different between the two groups. Even Inhibitors for the wild-type KRAS patients, there was no benefit in progression-free survival with the addition of cetuximab. As might now The limited experiences with the oral EGFR tyrosine kinase in- be anticipated (Table 57.19B), within the cetuximab-containing hibitors gefitinib (ZD1839) and erlotinib (OSI-774) in CRC have arm, patients whose tumors had mutated KRAS had statistically been essentially negative, and at present there is no role for these significantly decreased progression-free survival compared to those agents in this disease.420,421 This is consistent with the findings with wild-type KRAS tumors (8.1 months versus 10.5 months; that the activating mutation seen in lung cancer required for anti- p = 0.04). However, for the patients with KRAS mutations, those EGFR tyrosine kinase activity does not appear to occur in CRC. who received cetuximab also had a worse outcome than those on Oral VEGF tyrosine kinase inhibitors, with the exception of the noncetuximab-containing control arm (progression-free sur- regorafenib noted previously, have been similarly disappointing. vival 8.1 months versus 12.5 months, p = 0.003; overall survival Sunitinib showed essentially no activity as a single agent in che- 17.2 months versus 24.9 months, p = 0.03). motherapy-refractory disease, and front-line trials of chemotherapy Another study that investigated the use of combined beva- with or without sunitinib, as well as chemotherapy with or with- cizumab plus anti-EGFR monoclonal antibody was the Pani- out sorafenib, have now been closed early by their respective data PRACTICE OF ONCOLOGY tumumab in Advanced Colon Cancer Evaluation (PACCE) monitoring committees for futility.422 Two large, randomized trials trial.419 This trial used FOLFOX-bevacizumab (823 patients) of FOLFOX with or without the investigational VEGF tyrosine ki- or FOLFIRI-bevacizumab (230 patients) and randomized nase inhibitor PTK-787 have also been reported as negative trials. them with or without concurrent panitumumab. Again, the result of adding the anti-EGFR to chemotherapy plus bevaci- Cyclooxygenase-2 Inhibitors. Cyclooxygenase-2 (COX-2) cat- zumab was not only not beneficial, but was actually detrimental. alyzes the synthesis of prostaglandins in the inflammatory response The median progression-free survival for the overall study was process. COX-2 has been frequently shown to be upregulated in 10.0 months versus 11.4 months for the panitumumab-contain- malignant and premalignant tissues. COX-2 expression has been ing versus chemotherapy-bevacizumab–alone arm. The median correlated with increased invasiveness, resistance to apoptosis, and overall survival was decreased by 5.1 months, from 24.5 months increased angiogenesis.423 The science behind COX-2 inhibition ap- in the control arm to 19.4 months in the panitumumab arm. peared so compelling that many clinicians had chosen to add drugs Toxicity, including not only skin rash but also diarrhea, infec- such as celecoxib or rofecoxib (now withdrawn from the market for tions, and pulmonary embolisms, was more frequent in the pa- safety reasons) in the absence of efficacy data with the assumption nitumumab-containing arm, and worse outcomes were seen in that “it couldn’t hurt.” Evidence that use of either NSAIDs or selec- the panitumumab-containing arm regardless of KRAS mutation tive COX-2 inhibitors has a beneficial role in the treatment of CRC status. is lacking. The large randomized BICC-C trial showed no benefit Clearly, the concurrent use of anti-EGFR monoclonal antibod- whatsoever for the use of celecoxib in terms of either safety or effi- ies, bevacizumab, and cytotoxic chemotherapy, despite supportive cacy.334 In the absence of any emerging data to the contrary, routine encouraging preliminary data, is not an acceptable treatment use of COX-2 inhibitors with chemotherapy is not recommended. strategy. The reasons for this unanticipated negative interaction The role of aspirin as an adjuvant agent is also of particular remain unknown at this time. interest, especially after a recent case-control study suggested that

TABLE 57.19B Impact of KRAS Mutation Status on Addition of Cetuximab to Capecitabine, Oxaliplatin, and Bevacizumab

Progression-Free Survival COB + Overall Survival COB + COB cetux COB cetux KRAS wild-type 22.4 mo 21.8 mo (p = 0.64) 10.6 mo 10.5 mo (p = 0.30) KRAS mutated 24.9 mo 17.2 mo (p = 0.03) 12.5 mo 8.1 mo (p = 0.003)

COB, capecitabine, oxaliplatin-bevacizumab; cetux, cetuximab. From Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetuximab in metastatic colorectal cancer. N Engl J Med 2009;360:563–572. 808 Practice of Oncology / Cancers of the Gastrointestinal Tract initiation of this medication after diagnosis reduced overall CRC that would have an increased likelihood of efficacy or a decreased specific mortality (HR= 0.53; 95% CI = 0.33 to 0.86).424 The likelihood of toxicity would be clinically useful. Such means of ASCOLT study is the first randomized, placebo-controlled trial de- rational selection do not yet exist. signed to investigate this question in patients with stage III-IV and One avenue of investigation has been the elucidation of mark- high-risk stage II disease. End points will include DFS and overall ers of resistance to 5-FU based on knowledge of its metabolic path- survival with anticipated follow-up of 5 years.425 ways. Studies have indicated that high levels of either TS, DPD,427 In the meantime, a large observational study of 4,481 patients or thymidine phosphorylase, as measured in a tumor specimen lends further support to the potential therapeutic benefits of aspi- by reverse transcription–polymerase chain reaction, predict for rin in CRC. The authors report a 23% decrease in disease-specific failure to respond to an infusional 5-FU regimen.166,428,429 These mortality for patients who took aspirin for any length of time after observations are intriguing but are insufficient to exclude the use diagnosis compared to nonaspirin users as well as a 30% lower dis- of 5-FU in a particular patient, and they need to be validated in ease-specific mortality for those who took aspirin for 9 months after large-scale prospective trials before being applied to routine prac- diagnosis. A survival benefit was also found for prediagnosis users, tice. There is, at this time, no role for the use of these markers in although this was less pronounced at 12%.426 standard practice. Others have investigated genomic analysis as an indicator of response or toxicity.170,430 Although these approaches Other Novel Agents appear promising, they are not yet validated and should not be considered as part of standard care. A recently reported mechanism of resistance thought to be The number of agents that are undergoing early evaluation in independent of other mutations or MSI involves the tumor sup- CRC is too large to allow a complete discussion of these in this pressor gene TFAP2E (transcription factor AP-2 epsilon) and chapter. Many are variations on the currently available agents and its downstream target DKK4(dickkopf homolog 4 protein). In are unlikely to substantially move the field if successful in gaining an analysis of 220 patients with CRC, Ebert et al.431 approval. At present, no new agent with a unique mechanism of found that action has been identified as having meaningful activity in CRC. hypermethylation of TFAP2E led to decreased protein expres- Furthermore, all of these at this point are of research interest only sion and was significantly associated with nonresponse to 5-FU– and do not have a role in standard treatment of CRC at this time. based chemotherapy, whereas hypomethylation yielded a six-fold higher likelihood of response. Moreover, TFAP2E hypermethylation in vitro led to overexpression of DKK4, which was in turn MOLECULAR PREDICTIVE MARKERS associated with increased chemoresistance to 5-FU but not irinotecan and oxaliplatin. The authors suggest that future studies With the availability now of a number of active agents, the abil- focus on specific targeting of DKK4 to overcome this pathway of ity to prospectively select a particular drug or drug combination chemoresistance.431

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Fuchs CS, Marshall J, Mitchell E, et al. Randomized, controlled trial of ing the epidermal growth factor receptor. Clin Cancer Res 2001;7:2958–2970. irinotecan plus infusional, bolus, or oral fluoropyrimidines in first-line treat- 384. Thomas SM, Grandis JR. Pharmacokinetic and pharmacodynamic prop- ment of metastatic colorectal cancer: results from the BICC-C Study. J Clin erties of EGFR inhibitors under clinical investigation. Cancer Treat Rev Oncol 2007;25:4779–4786. 2004;30:255–268. 335. Extra JM, Espie M, Calvo F, et al. Phase I study of oxaliplatin in patients with 386. Saltz LB, Meropol NJ, Poehrer PJ Sr, et al. Phase II trial of cetuximab in advanced cancer. Cancer Chemother Pharmacol 1990;25:299–303. patients with refractory colorectal cancer that expresses the epidermal growth 336. Raymond E, Chaney SG, Taamma A, et al. Oxaliplatin: a review of preclini- factor receptor. J Clin Oncol 2004;22:1201–1208. cal and clinical studies. Ann Oncol 1998;9:1053–1071. 387. Jonker DJ, O’Callaghan CJ, Karapetis CS, et al. Cetuximab for the treatment 338. Giacchetti S, Perpoint B, Zidani R, et al. Phase III multicenter randomized of colorectal cancer. N Engl J Med 2007;357:2040–2048. trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first- 390. Van Cutsem E, Peeters M, Siena S, et al. Open-label phase III trial of panitu- line treatment of metastatic colorectal cancer. J Clin Oncol 2000;18:136–147. mumab plus best supportive care compared with best supportive care alone 342. Andre T, Bensmaine MA, Louvet C, et al. Multicenter phase II study of in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin bimonthly high-dose leucovorin, fluorouracil infusion, and oxaliplatin for Oncol 2007;25:1658–1664. metastatic colorectal cancer resistant to the same leucovorin and fluorouracil 393. Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for pani- regimen. J Clin Oncol 1999;17:3560–3568. tumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol 344. Wolmark N, Yothers G, O’Connell MJ, et al. A phase III trial comparing 2008;26:1626–1634. mFOLFOX6 to mFOLFOX6 plus bevacizumab in stage II or III carcinoma of 394. Karapetis CS, Khambata-Ford S, Jonker DJ, et al. K-ras mutations and the colon: Results of NSABP Protocol C-08. J Clin Oncol 2009;27:Abstr LBA4. benefit from cetuximab in advanced colorectal cancer. N Engl J Med 347. Rothenberg ML, Oza AM, Bigelow RH, et al. Superiority of oxaliplatin and 2008;359:1757–1765. fluorouracil-leucovorin compared with either therapy alone in patients with 397. Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: Oncology provisional clinical opinion: testing for KRAS gene mutations in interim results of a phase III trial. J Clin Oncol 2003;21:2059–2069. patients with metastatic colorectal carcinoma to predict response to anti- 349. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol or the reverse sequence in advanced colorectal cancer: a randomized 2009;27:2091–2096. GERCOR study. J Clin Oncol 2004;22:229–237. 398. Vakiani E, Janakiraman M, Shen R, et al. Comparative genomic analysis of pri- 352. Goldberg RM. N9741: a phase III study comparing irinotecan to oxaliplatin- mary versus metastatic colorectal carcinomas. J Clin Oncol 2012;30:2956–2962. containing regimens in advanced colorectal cancer. Clin Colorectal Cancer 399. Lin YL, Liau JY, Yu SC, et al. KRAS mutation is a predictor of oxaliplatin 2002;2:81. sensitivity in colon cancer cells. PLoS One 2012;7:e50701. 354. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial 400. Van Cutsem E, Kohne CH, Hitre E, et al. Cetuximab and chemother- of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in apy as initial treatment for metastatic colorectal cancer. N Engl J Med patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2009;360:1408–1417. 2004;22:23–30. 401. Van Cutsem E, Kohne CH, Lang I, et al. Cetuximab plus irinotecan, fluoro- 355. Tournigand C, Cervantes A, Figer A, et al. OPTIMOX1: a randomized study uracil, and leucovorin as first-line treatment for metastatic colorectal cancer: of FOLFOX4 or FOLFOX7 with oxaliplatin in a stop-and-Go fashion in ad- updated analysis of overall survival according to tumor KRAS and BRAF mu- vanced colorectal cancer—a GERCOR study. J Clin Oncol 2006;24:394–400. tation status. J Clin Oncol 2011;29:2011–2019. 360. Cassidy J, Clarke S, Diaz-Rubio E, et al. Randomized phase III study of 403. Maughan TS, Adams RA, Smith CG, et al. Addition of cetuximab to oxali- capecitabine plus oxaliplatin compared with fluorouracil/folinic acid plus platin-based first-line combination chemotherapy for treatment of advanced oxaliplatin as first-line therapy for metastatic colorectal cancer. J Clin Oncol colorectal cancer: results of the randomised phase 3 MRC COIN trial. 2008;26:2006–2012. Lancet 2011;377:2103–2114. 812 Practice of Oncology / Cancers of the Gastrointestinal Tract

404. Tveit KM, Guren T, Glimelius B, et al. Phase III trial of cetuximab with 418. Tol J, Koopman M, Cats A, et al. Chemotherapy, bevacizumab, and cetux- continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic imab in metastatic colorectal cancer. N Engl J Med 2009;360:563–572. FLOX) versus FLOX alone in first-line treatment of metastatic colorectal 419. Hecht JR, Mitchell E, Chidiac T, et al. A randomized phase IIIB trial of cancer: the NORDIC-VII study. J Clin Oncol 2012;30:1755–1762. chemotherapy, bevacizumab, and panitumumab compared with chemother- 405. Douillard JY, Siena S, Cassidy J, et al. Randomized, phase III trial of pa- apy and bevacizumab alone for metastatic colorectal cancer. J Clin Oncol nitumumab with infusional fluorouracil, leucovorin, and oxaliplatin 2009;27:672–680. (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with 423. Blanke CD. Celecoxib with chemotherapy in colorectal cancer. Oncology previously untreated metastatic colorectal cancer: the PRIME study. J Clin (Huntingt) 2002;16:17–21. Oncol 2010;28:4697–4705. 424. Chan AT, Ogino S, Fuchs CS. Aspirin use and survival after diagnosis of 409. Perez-Soler R, Saltz L. Cutaneous adverse effects with HER1/EGFR-targeted colorectal cancer. JAMA 2009;302:649–658. agents: is there a silver lining? J Clin Oncol 2005;23:5235–5246. 425. Ali R, Toh HC, Chia WK, et al. The utility of Aspirin in Dukes C and High 411. Chung CH, Mirakhur B, Chan E, et al. Cetuximab-induced anaphylaxis Risk Dukes B Colorectal cancer—the ASCOLT study: study protocol for a and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med 2008;358: randomized controlled trial. Trials 2011;12:261. 1109–1117. 426. Bastiaannet E, Sampieri K, Dekkers OM, et al. Use of aspirin postdiagnosis 412. Schrag D, Chung KY, Flombaum C, et al. Cetuximab therapy and symptom- improves survival for colon cancer patients. Br J Cancer 2012;106:1564–1570. atic hypomagnesemia. J Natl Cancer Inst 2005;97:1221–1224. 430. Iqbal S, Lenz HJ. Targeted therapy and pharmacogenomic programs. Cancer 414. Chung KY, Shia J, Kemeny NE, et al. Cetuximab shows activity in colorectal 2003;97:2076–2082. cancer patients with tumors that do not express the epidermal growth factor 431. Ebert MP, Tanzer M, Balluff B, et al. TFAP2E-DKK4 and chemoresistance receptor by immunohistochemistry. J Clin Oncol 2005;23:1803–1810. in colorectal cancer. N Engl J Med 2012;366:44–53.

tahir99 - UnitedVRG Genetic Testing in 58 Colon Cancer (Polyposis Syndromes)

Kory W. Jasperson

INTRODUCTION In AFAP, the lifetime risk of CRC is approximately 70% with an average age at onset in the 50s.4 The colonic phenotype of AFAP Hereditary colonic polyposis conditions account for less than 1% of is quite variable, even within the same family. Colonoscopies in all colorectal cancers (CRC). Accurate classification of these condi- 120 mutation-positive individuals within the same family revealed tions is imperative, given their distinct cancer risks, management that 37% had less than 10 adenomatous colon polyps (average age, strategies, and consequent risk to relatives. However, overlapping 36 years; range, 16 to 67 years), 28% had 10 to 50 polyps (average features and atypical or attenuated presentations make diagnosis dif- age, 39 years; range, 21 to 76 years), and 35% had greater than 50 ficult in some cases. Determining the histologic types of colorectal polyps (average age, 48 years; range, 27 to 49 years).4 In addition, polyps identified is especially useful in guiding diagnostic strategies. the total number of polyps per individual ranged from zero to 470.4 Adenomatous polyps are the predominant lesion in familial adenomatous polyposis (FAP), attenuated FAP (AFAP), and MUTYH Extracolonic Features (MutY human homolog)–associated polyposis (MAP), whereas hamartomatous polyps are the primary gastrointestinal lesion in The most common extracolonic finding in individuals with FAP Peutz–Jeghers syndrome (PJS), juvenile polyposis syndrome (JPS), and AFAP is upper gastrointestinal tract polyps. Although the co- and Cowden syndrome (CS). Extracolonic features, which are high- lonic phenotype in AFAP is less severe than in FAP, the upper gas- lighted for each syndrome in Tables 58.1 to 58.3 are also important trointestinal phenotype is comparable. Adenomatous polyps of the clues in the diagnostic workup. Genetic testing is now available for duodenum (20% to 100%) and the periampullary region (at least OF ONCOLOGY PRACTICE these conditions and, in most cases, allows for a precise diagnosis. 50%) are common.5,6 The relative risk of duodenal or periampullary carcinoma in FAP is estimated to be 100 to 330 times greater ADENOMATOUS POLYPOSIS than the general population, although the absolute risk is only around 5%.5 The majority of FAP- and AFAP-associated small- bowel carcinomas arise in the duodenum. Familial Adenomatous Polyposis and Fundic gland polyps are found in most cases of FAP/AFAP and Attenuated Familial Adenomatous Polyposis often number in the hundreds.7 Unlike polyps in the colon or small bowel, fundic gland polyps are a type of hamartoma. They are typi- Of all of the colonic polyposis conditions, FAP is both the most cally small (1 to 5 mm), sessile, and usually asymptomatic and are 7 common and the best characterized. FAP is caused by germ-line located in the fundus and body of the stomach. Adenomatous pol- 8 mutations in the adenomatous polyposis coli (APC) gene and is yps of the stomach are occasionally found in FAP and AFAP. Gas- estimated to occur in about 1 in 10,000 individuals. With the clas- tric cancers arising from fundic gland polyps have been reported in 8 sic presentation of FAP, hundreds to thousands of adenomatous FAP, although most are believed to arise from adenomatous polyps. polyps occur by the age of 20 to 40 years.1 The attenuated or less se- Individuals with FAP have an 800-fold increased risk for desmoid vere colonic phenotype associated with AFAP may mimic sporadic tumors (aggressive fibromatoses), with a lifetime risk of 10% to 9–11 colon polyps and cancer, or other known syndromes, such as MAP. 30%. Risk factors for desmoid tumors in FAP include a family This creates diagnostic difficulties when evaluating an individual history of desmoid tumors, APC mutations 3′ to codon 1,399 (geno- with moderate adenomatous polyposis. Other conditions linked type–phenotype correlation), female sex, and previous abdominal 10 to germ-line APC mutations include Gardner syndrome (with surgery. Although desmoid tumors do not metastasize, they can be association of colonic polyposis and osteomas, epidermoid cysts, locally invasive, aggressive, and difficult to treat, resulting in signifi- 12 fibromas, and/or desmoid tumors) and Turcot syndrome (with as- cant morbidity and the second leading cause of mortality in FAP. sociation of colonic polyposis and medulloblastomas).2 However, The phenotypic spectrum of germ-line APC mutations also in- it is now believed that the features associated with Gardner syn- cludes other benign findings such as osteomas, epidermoid cysts, drome and Turcot syndrome are the result of variable expressivity fibromas, dental abnormalities, and congenital hypertrophy of of APC mutations as opposed to being distinct clinical entities. the retinal pigment epithelium (CHRPE). In addition, there are increased risks for other cancers, including those of the pancreas, thyroid, bile duct, brain (typically medulloblastoma), and liver Colon Phenotype (specifically hepatoblastoma).6 Although adenomatous polyps associated with FAP have a similar malignancy rate as those that develop in the general population, Management the sheer number of polyps present in FAP results in nearly a 100% lifetime risk of CRC in untreated individuals. In FAP, colorectal Without treatment, CRC is inevitable in FAP. However, with early polyps begin to develop on average around the age of 16 years.1 screening and polypectomies, in addition to prophylactic colecto- The mean age at CRC onset is 39 years, with 7% developing CRC mies after polyps become too difficult to manage endoscopically, by 21 years and 95% before the age of 50 years.3 most CRCs can be prevented in AFAP and FAP. In FAP, annual 813 814 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 58.1 Characteristic Features and Recommendations: Adenomatous Polyposis Conditions

Lifetime Cancer Risks Management Recommendations Nonmalignant Features FAP (APC ) Colorectum (100%) Annual colonoscopy/sigmoidoscopy by 10–12 y until 100–1,000s of colorectal adenomas colectomy Duodenum (5%) Upper endoscopy every 1–4 y by 25–30 y Fundic gland polyposis Stomach (≤1%) Duodenal polyposis Thyroid (1%–2%) Annual physical examination CHRPE, epidermoid cysts, osteomas Pancreas (1%–2%) Dental abnormalities Hepatoblastoma (1%–2%) Desmoid tumors Medulloblastoma (<1%) AFAP (APC ) Colorectum (70%) Colonoscopy every 1–2 y by 18–20 y 10–100 colonic adenomas (range, 0–100s) Duodenum (5%) Upper endoscopy every 1–4 y by 25–30 y Fundic gland polyposis Stomach (≤1%) Duodenal polyposis Thyroid (1%–2%) Annual physical examination Other nonmalignant features are uncommon Pancreas (1%–2%) MAP (biallelic MUTYH ) Colorectum (80%) Colonoscopy every 3 y by 25–30 y 10–100 colonic adenomas (range, 0–100s) Duodenum (4%) Upper endoscopy every 3–5 y by 30–35 y Multiple hyperplastic and sessile serrated polyps possible Duodenal adenomatous polyposis

Data derived from National Comprehensive Cancer Network. NCCN Guidelines and Clinical Resources Web site. Colorectal Cancer Screening, Version 1.2012. 2012. http://www.nccn.org. Accessed April 3, 2012.

colonoscopies or flexible sigmoidoscopies are recommended start- Genetic testing has also been shown to be cost-effective,16 although ing around the age of 10 years.13 In AFAP, screening begins in the it is unlikely to change colon management for cases with extensive late teenage years, and colonoscopies, rather than sigmoidoscopies, adenomatous polyposis. are necessary because of proximally located polyps.13 Colectomies Given the phenotypic variability, a consensus as to what constitutes can sometimes be avoided in AFAP, which is not the case for in- a diagnosis of AFAP has not been reached. The NCCN currently rec- dividuals with FAP. After polyps become too numerous (usually ommends that individuals with greater than 10 cumulative colorectal >20 to 30 polyps) to manage endoscopically or when adenomas adenomas be referred for genetic counseling and the consideration of with advanced histology are identified, a prophylactic colectomy is genetic testing.13 The identification of anAPC mutation in these less advised.13 A proctocolectomy with an ileal pouch anal anastomosis severe polyp cases confirms a diagnosis of AFAP. It is also noteworthy is the standard surgery in FAP, whereas a total colectomy with ileo- that individuals with 100 or more adenomatous polyps may have AFAP rectal anastomosis is often the preferred approach with AFAP or in if polyp development occurs at a later age (typically after 40 years). FAP cases with limited rectal involvement.13,14 Continued screen- Differentiating among FAP, AFAP, and other colonic polyposis ing of the remaining rectum or ileal pouch is still necessary.13 conditions is not always straightforward. Family history, which is Recently, it has been shown that duodenal cancer detected consistent with an autosomal-dominant mode of inheritance, is sug- through surveillance improves survival compared with individu- gestive of FAP/AFAP and increases the likelihood of finding anAPC als presenting because of symptoms.15 The National Compre- mutation.6 However, 10% to 30% of probands with germ-line APC hensive Cancer Network (NCCN) currently recommends the mutations are de novo (new mutation) cases, and consequently, consideration of an esophagogastroduodenoscopy (EGD) with a their parents are unaffected.6,17 In addition, it is not uncommon for side-viewing examination beginning around the age of 25 years for individuals with AFAP to have less than 10 cumulative adenoma- duodenal cancer surveillance.13 The extent of duodenal polyps, tous polyps.4 In patients with fewer polyps, it is not clear whether as defined by the Spigelman staging criteria, is used to determine genetic testing should be performed.13 However, it is important that the EGD follow-up interval.13 Additional considerations for the these individuals be closely followed up, and if multiple adenomas management in individuals with germ-line APC mutations are continue to develop, genetic testing should be reconsidered. outlined and updated annually by the NCCN (www.nccn.org). Unlike what is found in some of the other conditions described in this review, hyperplastic or hamartomatous colon polyps are not known to be associated with FAP/AFAP. Therefore, if multiple Genetic Testing and Counseling hyperplastic or hamartomatous colon polyps are found in an individual, a genetic testing of APC is unlikely to be informative. A clinical diagnosis of FAP is considered when at least 100 colorec- Other features associated with APC mutations that may assist with tal adenomatous polyps are detected by the 2nd or 3rd decade of making a diagnosis of AFAP or FAP include fundic gland polypo- life.6 Genetic testing of APC is still recommended to clarify extra- sis, duodenal adenomatous polyps, osteomas, CHRPE, desmoid colonic cancer risks and to help determine FAP status in relatives. tumors, and hepatoblastoma.6

tahir99 - UnitedVRG Chapter 58 Genetic Testing in Colon Cancer (Polyposis Syndromes) 815

MUTYH-Associated Polyposis Extracolonic Features

As the name implies, MAP is a colonic polyposis condition caused A number of extracolonic findings have been reported in individu- by germ-line mutations in the MUTYH gene. Contrary to the als with MAP.23 However, it is still unclear whether most of these other conditions described in this review, MAP is inherited in an manifestations are chance occurrences or due to an underlying autosomal-recessive pattern. In 2002, Al-Tassan et al.18 were the defective MUTYH. In a study of 276 individuals with MAP, only first to describe a family with biallelic (homozygous or compound two developed duodenal cancer.22 However, compared with the heterozygous) mutations in MUTYH, which is part of the base ex- general population, the risk of duodenal cancer was significantly cision repair system. In this family, three siblings had CRC and/ elevated, with a standard incidence ratio of 129 and an estimated or multiple colorectal adenomas, but no detectable mutations in lifetime risk of 4%.22 Although the lifetime risk of duodenal cancer APC.18 All three of the affected siblings were found to have com- is similar between MAP and FAP/AFAP (4% and 5%), gastric and pound heterozygous mutations in MUTYH, whereas the other duodenal polyps are far less common in MAP. Of 150 individu- four unaffected siblings did not.18 als with MAP who underwent an EGD, 11% had gastric polyps, It is now widely accepted that MAP is associated with a signifi- whereas 17% had duodenal polyps.22 cant increased risk for multiple colorectal adenomas and cancer. Extraintestinal malignancies have also been reported in MAP,22 Whether monoallelic MUTYH carriers have a modest increase in although the data supporting an association are conflicting.28,29 risk of CRC is debatable.19 Monoallelic mutations in MUTYH are Desmoid tumors, thyroid and brain cancer, CHRPE, osteomas, found in 1% to 2% of the general population, whereas biallelic and epidermoid cysts are rarely seen in MAP.23 mutations account for less than 1% of all CRCs.20 Genetic Counseling and Testing Colonic Phenotype Since the first reported family with biallelicMUTYH mutations There are a number of similarities between the colonic phenotype of was described in 2002, more than 500 individuals with MAP MAP and AFAP, including the average number, proximal distribu- have been confirmed.23 As was the case with this first MAP fam- tion, and young age at onset of adenomas and cancers.4,19 MUTYH- ily, genetic testing strategies to evaluate for MUTYH are typically associated polyposis is associated with a 28-fold increased risk of CRC, targeted toward individuals with multiple colorectal adenomas. with a penetrance of 19% by the age of 50 years, 43% by 60 years, and However, there are many other factors that can influence genetic 80% by 70 years.19,21 Although the risk of CRC has been reported to testing approaches for MUTYH and APC mutations. Family his- be as high as 100%,22 the actual penetrance is likely to be incomplete tory; age at polyp onset; types, location, and total number of pol- and similar to that of AFAP. The total number of polyps in MAP is yps; CRC history (including age at onset and location); ethnicity; also highly variable, with some individuals developing CRC without and extracolonic features are just some of the factors that influence OF ONCOLOGY PRACTICE polyps, whereas others have more than 500 colorectal polyps.23 Typi- genetic testing strategies and detection rates. The purpose of this cally, affected individuals have between 10 and 100 polyps.23 review was not to present every scenario and strategy for MUTYH Adenomas are the predominant polyp type seen not only in and APC genetic testing, but instead to outline some key concepts AFAP and FAP, but also in MAP. Unlike individuals with germ- and considerations when multiple adenomas are detected. line APC mutations, serrated polyps are common in MAP. Serrated Given the inheritance pattern of MAP, it is uncommon for more polyps include hyperplastic polyps, sessile serrated polyps (also re- than one generation to be affected; however, a family history of CRC ferred to as sessile serrated adenomas), and traditional serrated ad- in more than one generation does not exclude MAP. Consanguinity enomas.24 Boparai et al.25 evaluated 17 individuals with MAP and (sharing a common ancestor) is seen in some MAP families and is an found that almost one-half (47%) had hyperplastic and/or sessile important element to evaluate for when taking a history. Siblings of serrated polyps. In addition, three met the criteria for hyperplas- affected individuals have a one in four chance (25%) of having MAP, tic polyposis, now known as serrated polyposis. The World Health whereas parents and children are obligate carriers. Therefore, when Organization diagnostic criteria for serrated polyposis include an there is clear evidence of recessive inheritance in a family (more individual with any of the following: (1) at least five serrated pol- than one sibling affected in a family, but no one else), genetic testing yps proximal to the sigmoid colon with at least two larger than 10 should start with MUTYH. APC should still be evaluated in these mm; (2) greater than 20 serrated polyps of any size, but distributed families if no MUTYH mutations are identified, because germ-line through the colon; and (3) any number of serrated polyps proximal mosaicism can result in more than one affected sibling with FAP to the sigmoid colon in an individual with a first-degree relative with and unaffected parents.30 To clarify risk to offspring, spouses of in- serrated polyposis.24 Interestingly, Chow et al.26 also identified bial- dividuals with MAP should also be offered MUTYH genetic testing. lelic MUTYH mutations in 1 (∼3%) of 38 cases meeting hyperplas- This strategy has been shown to be cost-effective.31 tic polyposis/serrated polyposis criteria. Another family involving Generally, germ-line APC mutations are more common than bi- three brothers with biallelic MUTYH mutations has recently been allelic MUTYH mutations; therefore, unless there is clear evidence reported, further highlighting this variability in phenotype. Their for recessive inheritance in a family, APC genetic testing typically history included one with CRC at the age of 48 years but had no ad- precedes MUTYH analysis. There are two common mutations ditional polyps, another was 38 years old and reportedly met criteria in MUTYH that are found in the majority of affected individuals: for serrated polyposis but had only two confirmed adenomas, and Y179C and G396D (previously known as Y165C and G382D). the other brother was 46 years old and had four hyperplastic polyps These hotspot mutations were found in the original MAP family.18 removed.27 Currently, the etiology of serrated polyposis is largely According to Nielsen et al.,23 a review up to 2009 revealed more unknown; however, there is growing evidence that the base excision than 100 distinct MUTYH mutations. In individuals with Northern repair pathway may be involved in a minority of these cases. European ancestry and MAP, at least one of the two hotspot mu- Boparai et al.25 also compared the frequency of KRAS mutations are found in 90% of cases.23,32 Testing specifically for the tations and G:C to T:A transversions in hyperplastic or sessile hotspot mutations, followed by full MUTYH sequencing only if one serrated polyps in individuals with MAP to controls. In MAP, 51 of these mutations is found, is often performed. In other populations, (70%) of 73 serrated polyps had KRAS mutations, and 48 (94%) the scope of MUTYH mutations is less well understood, and thereof these 51 had G:C to T:A transversions, whereas in the control fore, full gene sequencing of MUTYH is often performed in individ- group, only 7 (17%) of 41 serrated polyps had KRAS mutations, uals of non–Northern European ancestry. Similar to APC, genetic and 2 (29%) of 7 had G:C to T:A transversions.25 These findings testing of MUTYH is considered when greater than 10 adenomas are support an association between MAP and serrated polyps. documented.13,23 The detection rates of biallelic MUTYH mutations 816 Practice of Oncology / Cancers of the Gastrointestinal Tract in individuals with 10 to 100 and 100 to 1,000 polyps are 28% and TABLE 58.2 14%, respectively.23 Given the growing evidence that hyperplastic and sessile serrated polyps are associated with MAP, these polyps Testing and Diagnostic Criteria for Peutz–Jeghers should also be included in the total polyp count when considering Syndrome, Juvenile Polyposis Syndrome, and when to test someone for MUTYH mutations. Individuals with FAP/ Cowden Syndrome AFAP are not known to develop numerous serrated polyps; therefore, genetic testing of APC in someone with multiple serrated polyps is PJS unlikely to be informative. The NCCN guidelines do not currently A clinical diagnosis of PJS is considered when any of the recommend genetic testing of MUTYH in individuals with multiple following are met: 13 serrated polyps and no adenomas. (1) ≥3 histologically confirmed Peutz–Jeghers polyps It is not unusual for individuals with MAP or AFAP to present (2) Any number of Peutz–Jeghers polyps and a family history of 4,33 with early-onset CRC and few to no polyps. However, a con- PJS sensus as to whether genetic testing of APC or MUTYH should be (3) Characteristic, prominent, mucocutaneous pigmentation and 13,23 performed in these cases has not yet been reached. a family history of PJS (4) ≥1 Peutz–Jeghers polyp and characteristic, prominent, Management mucocutaneous pigmentation JPS Colonoscopy screening starting at around the age of 25 years is rec- 13 A clinical diagnosis of JPS is considered when any of the ommended for individuals with MAP. The frequency of screen- following are met: ing depends on polyp burden. As is the case with AFAP and FAP, (1) 3–5 juvenile polyps of the colorectum colectomy is advised when polyps become endoscopically uncon- (2) Juvenile polyps throughout the gastrointestinal tract trollable. EGDs should be considered in the 30s and, if duodenal (3) ≥1 juvenile polyp in an individual with a family history of JPS adenomas are found, managed the same as in AFAP and FAP.13 a Currently, the evidence does not support increased CRC screen- CS ing in monoallelic MUTYH carriers. Genetic testing for CS is considered in individuals meeting any of the following criteria: (1) Adult onset Lhermitte–Duclos disease HAMARTOMATOUS POLYPOSIS (2) Autism spectrum disorder and macrocephaly (3) ≥2 major criteria (one must be macrocephaly) ≥ Peutz–Jeghers Syndrome (4) 3 major criteria without macrocephaly (5) Bannayan–Riley–Ruvalcaba syndrome (6) One major and ≥3 minor criteria PJS is an autosomal dominant condition caused by mutations in (7) ≥2 biopsy-proven trichilemmomas the STK11/LKB1 gene. It is estimated to occur in 1 in 50,000 to (8) ≥4 minor criteria 200,000 births.34 The two most characteristic manifestations of PJS are the distinct gastrointestinal-type hamartomas, called Peutz– Major Criteria Minor Criteria Jeghers polyps, and the mucocutaneous melanin pigmentation. Multiple gastrointestinal A single GI hamartoma/ Both of these features are included in the diagnostic criteria for (GI) hamartomas/ ganglioneuroma PJS (Table 58.2). Although it is not 100% penetrant and can fade ganglioneuromas with time, mucocutaneous hyperpigmentation in PJS typically presents in childhood. By the age of 20 years, 50% of individu- Nonmedullary thyroid cancer Thyroid adenoma or multinodular als present with small-bowel obstruction, intussusception, and/or goiter bleeding due to small-bowel polyps.35 The polyps in PJS can also Breast cancer Fibrocystic disease of the breast number in the hundreds and are most often found in the small Endometrial cancer Mental retardation (i.e., IQ ≤75) intestine, followed by the colon and the stomach.34 The cancer risks associated with PJS are more significant after Mucocutaneous lesions Autism spectrum disorder the age of 30 years, although earlier-onset malignancies do occur. One biopsy proven Fibromas In the largest study to date of 419 individuals with PJS, the risk trichilemmoma of developing any cancer was 2% by the age of 20 years, 5% by Multiple palmoplantar Renal cell carcinoma 30 years, 17% by 40 years, 31% by 50 years, 60% by 60 years, and keratoses 85% by 70 years.36 Gastrointestinal tract cancers had the highest cumulative risk. The specific cancer risks associated with PJS are Multiple cutaneous facial Uterine fibroids outlined in Table 58.3. papules Macular pigmentation of Lipomas Juvenile Polyposis Syndrome glans penis Multifocal/extensive oral JPS is an autosomal-dominant condition caused by germ-line mu- mucosal papillomatosis tations in SMAD4 or BMPR1A genes, with an incidence of 0.6 to Macrocephaly 1 in 100,000 and a de novo rate of 25% to 50%.37,38 Juvenile polyps 38 (megalocephaly) (at least are the hallmark lesion in JPS. They are most commonly found 97th percentile) in the colorectum and can number in the hundreds, although the carpeting of polyps is not usually seen in JPS like it is in FAP.38 Of IQ, intelligence quotient. note, solitary juvenile polyps can occur in children without JPS a Data derived from: National Comprehensive Cancer Network. NCCN (see Table 58.2). Hematochezia is the most common presenting Guidelines and Clinical Resources Web site. Colorectal Cancer Screening, Version 1.2012. 2012. http://www.nccn.org. Accessed April 3, 2012. symptom and, similar to PJS, intussusception and obstruction are common. The highest risk of cancer (see Table 58.3) in JPS is CRC. Gastric cancers typically occur only in the setting of gastric polyposis, which is more commonly present in individuals with

tahir99 - UnitedVRG Chapter 58 Genetic Testing in Colon Cancer (Polyposis Syndromes) 817

TABLE 58.3 Characteristic Features and Recommendations: Peutz–Jeghers Syndrome and Juvenile Polyposis Syndrome

Lifetime Cancer Risks Management Recommendations Nonmalignant Features PJS (STK11) Breast (54%) Annual mammogram and breast magnetic resonance Mucocutaneous pigmentation imaging by age 25 y Colon (39%) Colonoscopy every 2–3 y by age 25 y Pancreas (11%–36%) CA19-9 and magnetic resonance cholangiopancreatography Peutz–Jeghers polyps and/or endoscopic ultrasound every 1–2 y Stomach (29%) Upper endoscopy by 25–30 y; consider small-bowel visualization (computed tomography [CT] enterography, small-bowel enteroclysis) by 8–10 y Small bowel (13%) Ovarya (21%) Annual pelvic examination and Pap smear Uterine/cervixb (11%) Lung (15%) No specific recommendations Testiclec (<1%) Annual testicular examination JPS (SMAD4 and BMPR1A) Colon (40%–50%) Colonoscopy by age 15 y repeating annually if polyps are Juvenile polyps present and every 2–3 y if no polyps Features of hereditary hemorrhagic telangiectasia Stomach (21% if gastric polyps are present) Upper endoscopy by age 15 y repeating annually if polyps Congenital defects are present and every 2–3 y if no polyps a Sex cord tumor with annular tubules. b Adenoma malignum. OF ONCOLOGY PRACTICE c Sertoli cell tumor. Data derived from: National Comprehensive Cancer Network. NCCN Guidelines and Clinical Resources Web site. Colorectal Cancer Screening, Version 1.2012. 2012. http://www.nccn.org. Accessed April 3, 2012.

37 mutations in SMAD4 than in BMPR1A. JPS occurring in infancy at least 1 colonoscopy, 62 (∼93%) had colonic polyps, and 16 met (also known as juvenile polyposis of infancy) is often fatal, but rare. criteria for hyperplastic polyposis.41 Although hamartomas pre- Hereditary hemorrhagic telangiectasia symptoms, such as arterio- dominate, a variety of other colon polyps also develop, including venous malformations, telangiectasia, and epistaxis, occur in some adenomatous, hyperplastic, sessile serrated, ganglioneuromatous, 37 individuals with mutations in SMAD4, but not BMPR1A. inflammatory, lymphoid, and lipomatous. Of all of the mutation carriers in this large study, nine (7%) were diagnosed with CRC.41 Cowden Syndrome Peutz–Jeghers Syndrome, Juvenile Polyposis CS, which is part of the phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome, occurs in about 1 in 200,000 to 1 Syndrome, and Cowden Syndrome: Genetic in 250,000 individuals and is caused by germ-line mutations in Counseling and Testing the PTEN gene.39 It is a multisystem disorder associated with characteristic mucocutaneous features, macrocephaly, and a variety Hamartomatous polyps consist of an overgrowth of cells native to of cancers and gastrointestinal manifestations.39 Although other the tissue in which they occur. They are rare, account for a mi- malignancies may be seen in CS, the primary cancers associated nority of all colon polyps, and can be a red flag for an underlying with CS include breast (25% to 50%), nonmedullary thyroid (3% cancer predisposition syndrome. When hamartomatous polyps are to 10%), and endometrial (5% to 10%).39 A recent study estimated found in an individual, the differential diagnosis depends, in part, that the lifetime risk for these cancers in PTEN mutation carriers on the histologic type, total number, and age at onset of the polyps. was 85%, 35%, and 28%, respectively.40 However, these risks are Hamartomas can often be misdiagnosed as other polyp types, and likely overestimates, because Tan et al.40 failed to accurately ac- therefore, review by a gastrointestinal pathologist should be consid- count for ascertainment bias in their study. ered.42 When hamartomatous colonic polyps are identified, EGD Gastrointestinal polyps are one of the most common features and a thorough physical examination may identify extracolonic in CS.41 Polyps develop throughout the gastrointestinal tract, from manifestations leading to a precise diagnosis. A detailed family the esophagus to the rectum, and numerous polyps or diffuse pol- history is also imperative. Diagnostic criteria for JPS and PJS are yposis can be seen.41 Multiple, white flat plaques in the esophagus, summarized in Table 58.2. Guidelines for genetic testing of CS, called glycogenic acanthosis, also occur in the setting of CS. In which are quite extensive and include a number of extraintestinal a large study of 127 individuals with PTEN mutations, 39 under- features, are also included in Table 58.2. Given the complexity of went at least 1 EGD, and 8 (∼23%) had glycogenic acanthosis, genetic testing for CS, the NCCN updates their guidelines annu- 26 (∼67%) had duodenal and/or gastric polyps, and only 2 (5%) ally.13 Management considerations are reviewed for PJS and JPS in had fundic gland polyps.41 Of the 67 individuals who underwent Table 58.3 and are also updated annually by the NCCN.13 818 Practice of Oncology / Cancers of the Gastrointestinal Tract

CONCLUSIONS genetic testing to a specific condition. Once the genetic cause has been identified in an affected individual, predictive testing in at-risk There are numerous presentations that may warrant genetic testing relatives is critical. Family members who test negative can be spared for hereditary colonic polyposis conditions. Simplified guidelines the increased surveillance and risk-reducing procedures that are for referral for genetic counseling include individuals with any warranted for family members who test positive. It is important that of the following: (1) greater than 10 colonic adenomas, (2) three health-care providers involved in the care of patients with heredi- or more hamartomatous polyps, or (3) at least one Peutz–Jeghers tary colonic polyposis conditions stay updated with management polyp. Other manifestations in these individuals may help target guidelines because recommendations are constantly evolving.

REFERENCES

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WHO Classification of Tumours of the Digestive System. 4th ed. Lyon, large kindred with attenuated familial adenomatous polyposis. Gastroenterol- France: IARC; 2010:160–165. ogy 2004;127:444–451. 25. Boparai KS, Dekker E, Van Eeden S, et al. Hyperplastic polyps and sessile 5. Gallagher MC, Phillips RK, Bulow S. Surveillance and management of up- serrated adenomas as a phenotypic expression of MYH-associated polyposis. per gastrointestinal disease in familial adenomatous polyposis. Fam Cancer Gastroenterology 2008;135:2014–2018. 2006;5:263–273. 26. Chow E, Lipton L, Lynch E, et al. Hyperplastic polyposis syndrome: Phe- 6. Jasperson KW, Burt RW. APC-associated polyposis conditions. In: Pagon notypic presentations and the role of MBD4 and MYH. Gastroenterology RA, Bird TD, Dolan CR, et al., eds. Gene Reviews. Seattle: University of 2006;131:30–39. Washington; 1993. 27. Zorcolo L, Fantola G, Balestrino L, et al. MUTYH-associated colon disease: 7. Burt RW. Gastric fundic gland polyps. Gastroenterology 2003;125:1462–1469. Adenomatous polyposis is only one of the possible phenotypes. A family re- 8. Garrean S, Hering J, Saied A, et al. Gastric adenocarcinoma arising from fun- port and literature review. Tumori 2011;97:676–680. dic gland polyps in a patient with familial adenomatous polyposis syndrome. 28. Out AA, Wasielewski M, Huijts PE, et al. MUTYH gene variants and breast Am Surg 2008;74:79–83. cancer in a Dutch case-control study. Breast Cancer Res Treat 2012;134: 9. Nieuwenhuis MH, Casparie M, Mathus-Vliegen LM, et al. A nation-wide 219–227. study comparing sporadic and familial adenomatous polyposis-related 29. Santonocito C, Paradisi A, Capizzi R, et al. Common genetic variants of desmoid-type fibromatoses. Int J Cancer 2011;129:256–261. MUTYH are not associated with cutaneous malignant melanoma: Applica- 10. Nieuwenhuis MH, Lefevre JH, Bulow S, et al. Family history, surgery, and APC tion of molecular screening by means of high-resolution melting technique mutation are risk factors for desmoid tumors in familial adenomatous polyposis: in a pilot case-control study. Int J Biol Markers 2011;26:37–42. an international cohort study. Dis Colon Rectum 2011;54:1229–1234. 30. Schwab AL, Tuohy TM, Condie M, et al. Gonadal mosaicism and familial 11. Sinha A, Tekkis PP, Gibbons DC, et al. Risk factors predicting desmoid oc- adenomatous polyposis. Fam Cancer 2008;7:173–177. currence in patients with familial adenomatous polyposis: a meta-analysis. 31. Nielsen M, Hes FJ, Vasen HF, et al. Cost-utility analysis of genetic screening Colorectal Dis 2011;13:1222–1229. in families of patients with germline MUTYH mutations. BMC Med Genet 12. Nieuwenhuis MH, Mathus-Vliegen EM, Baeten CG, et al. Evaluation of 2007;8:42. management of desmoid tumours associated with familial adenomatous 32. Goodenberger M, Lindor NM. Lynch syndrome and MYH-associated pol- polyposis in Dutch patients. Br J Cancer 2011;104:37–42. yposis: Review and testing strategy. J Clin Gastroenterol 2011;45:488–500. 13. Colon Cancer, Version 1.2015. Clinical Practice Guidelines in Oncology 33. Wang L, Baudhuin LM, Boardman LA, et al. MYH mutations in patients (NCCN Guidelines). National Comprehensive Cancer Network. http:// with attenuated and classic polyposis and with young-onset colorectal cancer www.nccn.org. Accessed September 3, 2014. without polyps. Gastroenterology 2004; 127:9–16. 14. Guillem JG, Wood WC, Moley JF, et al. ASCO/SSO review of current role 34. Offerhaus GJA, Billaud M, Gruber SB. Peutz–Jeghers syndrome. In: Bosman of risk-reducing surgery in common hereditary cancer syndromes. J Clin On- FT, Carneiro F, Hruban RH, et al., eds. WHO Classification of Tumours of col 2006;24:4642–4660. the Digestive System. 4th ed. Lyon, France: IARC; 2010:168–170. 15. Bulow S, Christensen IJ, Hojen H, et al. Duodenal surveillance improves the 35. Latchford AR, Phillips RK. Gastrointestinal polyps and cancer in Peutz– prognosis after duodenal cancer in familial adenomatous polyposis. Colorec- Jeghers syndrome: clinical aspects. Fam Cancer 2011;10:455–461. tal Dis 2011;14:947–952. 36. Hearle N, Schumacher V, Menko FH, et al. Frequency and spectrum 16. Cromwell DM, Moore RD, Brensinger JD, et al. Cost analysis of alternative of cancers in the Peutz–Jeghers syndrome. Clin Cancer Res 2006;12: approaches to colorectal screening in familial adenomatous polyposis. Gas- 3209–3215. troenterology 1998;114:893–901. 37. Gammon A, Jasperson K, Kohlmann W, et al. Hamartomatous polyposis syn- 17. Hes FJ, Nielsen M, Bik EC, et al. Somatic APC mosaicism: An underesti- dromes. Best Pract Res Clin Gastroenterol 2009;23:219–231. mated cause of polyposis coli. Gut 2008;57:71–76. 38. Offerhaus GJ, Howe JR. Juvenile polyposis. In: Bosman FT, Carneiro F, 18. Al-Tassan N, Chmiel NH, Maynard J, et al. Inherited variants of MYH as- Hruban RH, et al., eds. WHO Classification of Tumours of the Digestive Sys- sociated with somatic G:C–>T:A mutations in colorectal tumors. Nat Genet tem. 4th ed. Lyon, France: IARC; 2010:166–167. 2002;30:227–232. 39. Pilarski R. Cowden syndrome: a critical review of the clinical literature. 19. Lubbe SJ, Di Bernardo MC, Chandler IP, et al. Clinical implications of J Genet Couns 2009;18:13–27. the colorectal cancer risk associated with MUTYH mutation. J Clin Oncol 40. Tan MH, Mester JL, Ngeow J, et al. Lifetime cancer risks in individuals with 2009;27:3975–3980. germline PTEN mutations. Clin Cancer Res 2012;18:400–407. 20. Cleary SP, Cotterchio M, Jenkins MA, et al. Germline MutY human homo- 41. Heald B, Mester J, Rybicki L, et al. Frequent gastrointestinal polyps and logue mutations and colorectal cancer: a multisite case-control study. Gastro- colorectal adenocarcinomas in a prospective series of PTEN mutation carri- enterology 2009;136:1251–1260. ers. Gastroenterology 2010;139:1927–1933. 21. Jenkins MA, Croitoru ME, Monga N, et al. Risk of colorectal cancer in 42. Sweet K, Willis J, Zhou XP, et al. Molecular classification of patients with monoallelic and biallelic carriers of MYH mutations: a population-based unexplained hamartomatous and hyperplastic polyposis. JAMA 2005;294: case-family study. Cancer Epidemiol Biomarkers Prev 2006;15:312–314. 2465–2473.

tahir99 - UnitedVRG Genetic Testing in 59 Colon Cancer (Nonpolyposis Syndromes)

Leigha Senter-Jamieson

INTRODUCTION Malignancies of the ovary, stomach, small bowel, urothelium, and biliary tract are also seen with greater frequency in individuals Approximately 5% to 10% of colorectal cancers (CRC) are heredi- with LS when compared with the general population. Although tary and are often categorized by the presence or absence of polypo- cumulative risk estimates of these less common tumor types have sis as a predominant feature. Lynch syndrome (LS), also sometimes been published, they are usually based on fewer cases than studies referred to as hereditary nonpolyposis CRC, is the most common focused on CRCs and ECs, and have typically shown a lifetime form of hereditary CRC, accounting for approximately 2.2%1 of cancer risk of less than 10%.3 There have also been reports of LS- population-based CRCs diagnosed in the United States. LS also ac- associated pancreatic and breast cancers, but the data have been counts for 2.3%2 of all newly diagnosed endometrial cancers (EC), inconsistent. A recent prospective study showed an increased risk and individuals with LS also have an increased risk of developing of developing both tumor types when comparing carriers of MMR other cancers, including cancers of the ovary, stomach, small bowel, gene mutations to their unaffected relatives.12 Additional data are urothelium, and biliary tract.3 Given these increased cancer risks, necessary, however, to determine whether screening recommen- cancer screening recommendations for individuals with LS differ sig- dations should change based on these reported risks. Some indi- nificantly from general population screening recommendations with viduals with LS also have a predisposition to developing sebaceous a goal of reducing the cancer risk and burden to the extent possible. lesions and keratoacanthomas of the skin. When an individual has Mutations in one of four mismatch repair genes (MLH1, one of these lesions in addition to a visceral organ malignancy, they have a variant of LS called Muir–Torre syndrome.13 Some recent

MSH2, MSH6, and PMS2) cause LS, and clinical genetic testing OF ONCOLOGY PRACTICE is available for all of them. Unlike most other hereditary cancer studies suggest that these skin lesions are more common in LS than syndromes, however, clinical testing for LS typically begins with originally thought and that sebaceous tumors of the skin should microsatellite instability (MSI) testing and/or immunohistochemi- be considered part of the typical LS spectrum.14 Another variant of cal (IHC) staining of tumor tissue before germ-line genetic testing. LS characterized by the presence of glioblastomas is called Turcot This difference in testing approach, although not always possible, syndrome. Turcot syndrome is more commonly caused by muta- allows for targeted genetic analysis and, in most cases, reduced cost. tions in the APC gene but has been described in individuals with Here, we review key considerations in genetic counseling for LS. mismatch repair (MMR) deficiency, as well.15

Cancer Risks CLINICAL CLASSIFICATION: AMSTERDAM CRITERIA AND BETHESDA GUIDELINES CRCs and ECs are the two most common LS-associated malignancies, and there have been several calculations of lifetime cancer In 1991, the International Collaborative Group on Hereditary risks reported in the literature. Differences in ascertainment and Non-Polyposis CRC wrote the Amsterdam I criteria16 and revised testing approaches have led not only to a wealth of data, but also them in 1999 (Amsterdam II criteria)17 to clinically classify families to a wide range of risk estimates for consideration by clinicians and as having LS (Table 59.1). The Amsterdam criteria rely heavily on patients. Consistently, studies have found that the lifetime CRC extensive family history and do not take into account the full spec- risk for men with LS is higher than the risk for women with LS. trum of possible LS-associated tumors. The less stringent Bethesda The lifetime CRC risk for males is 27% to 92%, whereas the risk guidelines (written in 1997 and revised in 2004)18,19 (Table 59.2) for females is 22% to 68%.4,5 The most recent large study of carriers were written to include these less common LS-associated tumors of MLH1, MSH2, and MSH6 mutations estimated lifetime CRC as well as pathologic features that are common in LS-associated risks for males and females to be 38% and 31%, respectively.6 The CRCs. Unlike the Amsterdam criteria, which were meant to diag- average age at CRC diagnosis tends to be younger in LS (estimated nose LS based on familial criteria, the Bethesda guidelines were 45 to 59 years) than that in the general population.6,7 The lifetime meant to determine who should have tumor screenings for LS and risk of EC for women with LS based on recent data is estimated relied less on family history. It has been repeatedly shown, however, to be 33% to 39%.6,8 Individuals with LS who have already been that these clinical classification systems do not reliably predict LS diagnosed with CRC also have an increased risk (10-year risk of in all patient populations, particularly for those populations out- 16%) of developing a second primary CRC.9 side the cancer genetics clinics dedicated to high-risk patients.1,20 In addition to sex differences in LS-associated cancer risks, there appear to be some differences in gene-specific–associated cancer risks, as well. MLH1 and MSH2 seem to be associated with TUMOR SCREENING a higher overall cancer risk than risks associated with MSH6 or PMS2.10,11 A variable expression of phenotype both within and Microsatellites are pieces of DNA sequence where a single nucleo- among families with LS is common. Therefore, as a general rule, tide or group of nucleotides is repeated multiple times. In gen- management of families with LS (discussed later) should always eral, the number of repeated nucleotide sequences should remain take into account the family history. the same within a person’s cells, but when this number of repeats 819 820 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 59.1 TABLE 59.3 Revised Amsterdam Criteria Genetic Testing Strategies Based on IHC Pattern

≥3 relatives with colorectal, endometrial, small bowel, ureter, Absence MLH1 methylation and/or BRAF testinga OR and/or renal pelvis cancer AND MLH1 and MLH1 germ-line testingb a PMS2 ■ If negative, consider PMS2 germ-line One of these relatives is a first-degree relative of the other two 20 AND testing ≥2 successive generations are affected AND Absence PMS2 germ-line testing PMS2 only ■ If negative consider MLH1 germ-line At least one diagnosis is at the age of <50 y testing21 Familial adenomatous polyposis is excluded Absence MSH2 germ-line testing Tumors should be verified pathologically/histologically MSH2 and ■ If negative, TACSTD1 deletion testing MSH6 ■ If negative, MSH6 germline testing a First-degree relative: parent, sibling, or child. From Vasen HF, Watson P, Mecklin JP, et al. New clinical criteria for hereditary Absence MSH6 germ-line testing nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed MSH6 only ■ If negative, consider MSH2 germ-line testing by the International Collaborative group on HNPCC. Gastroenterology 1999;116:1453–1456. a If personal/family history highly suggestive of LS, it is appropriate to forgo MLH1 methylation/BRAF testing. b Unless otherwise noted, “germ-line testing” here refers to sequencing/ large rearrangement testing. differs in one or two alleles, MSI is present.21 In the case of LS, five microsatellite markers are used as the standard with which to measure MSI, and a tumor is considered to have a high level of MSI (MSI-H) if at least 40% of the markers are unstable.22 Nearly the context of this IHC result, it is generally not necessary to test for mutations in MLH1 and/or PMS2. Strategies for genetic testing all LS-associated tumors display MSI, but the presence of MSI is 25,26 not diagnostic of LS, given that approximately 10% to 15% of all based on IHC results are included in Table 59.3. In comparing CRCs, in general, also display MSI.23,24 MSI testing, however, can tumor screening strategies, using MSI and IHC staining together be used as a screening tool to help identify individuals for whom will identify the majority of LS cases. Because the sensitivity of either test is not 100%, using either test alone will leave 5% to 10% germ-line genetic testing for mutations in MLH1, MSH2, MSH6, 27,28 and/or PMS2 is indicated. A clinical diagnosis of LS can be made of LS cases undetected. if a person has an MSI-H CRC and meets the Amsterdam II crite- Epigenetic events unrelated to LS can cause a tumor to ria (see Table 59.1). demonstrate MSI and an absence of MLH1 and PMS2 pro- Immunohistochemistry can be used to determine the presence teins upon IHC staining. These results can often be attributed or absence of MMR proteins in a tumor specimen and is another to hypermethylation of the MLH1 promoter and/or a somatic available screening test for LS. The absence of one or more MMR BRAF mutation (V600E). Several studies have shown that the V600E BRAF mutations are not associated with LS, and there proteins in tumor tissue indicates dysfunction of the corresponding 11,29 MMR gene, but additional analyses are required to determine if have been very few exceptions. Both of these tests can be the dysfunction is germ line or somatic in nature. The benefit of performed on CRC tissue to help determine whether germ- performing IHC staining over MSI testing is that results from IHC line genetic testing should be pursued, further streamlining staining can direct the approach to genetic testing. For instance, the genetic testing process, but this should be interpreted in if a patient has CRC that demonstrates an absence of MSH2 and the context of clinical familial presentation because sensitivi- MSH6 proteins, testing for MSH2 with procession to testing for ties and specificities for these tests are not 100%. It is impor- MSH6 if the MSH2 test results are negative is recommended. In tant to note that it is possible but rare to have inherited MLH1 promoter hypermethylation.30 Similar approaches to screening EC with MSI and/or IHC staining are appropriate. However, because somatic BRAF muta- TABLE 59.2 tions are uncommon in ECs, BRAF testing is not an appropriate test for ECs that are MSI-H and/or MLH1- and PMS2-protein Revised Bethesda Guidelines deficient.31 There are less data to support MSI and/or IHC testing using other LS-associated tumor tissue, but many reports sug- Individuals with CRC should be tested for MSI if they have any of gest that it is at least feasible in the absence of additional testing the following: options.32 ■ CRC at the age of <50 y In 2009, the Evaluation of Genomic Application in Practice ■ Synchronous CRC (>1 CRC at the same time) or and Prevention Working Group recommended that individuals metachronous CRC (>1 CRC diagnosed at different times) or with newly diagnosed CRCs be offered genetic testing for LS. Al- other LS-associated tumorsa though the Evaluation of Genomic Application in Practice and ■ CRC with MSI-H histology (tumor-infiltrating lymphocytes, Prevention Working Group did not specify the best approach for Crohnlike lymphocytic reaction, mucinous or signet-ring genetic testing, performing a tumor analysis with IHC staining differentiation, medullary growth pattern) in a patient aged allows for more targeted genetic testing and was considered to be <60 y an acceptable strategy.33 In addition, multiple reports have shown ■ CRC or LS-associated tumora diagnosed at the age of <50 y in that tumor screening with IHC staining is a cost-effective strategy FDR for identifying LS in the CRC patient population.34,35 Ladabaum ■ CRC or LS-associated tumora in 2 FDR and/or SDR at any age et al.35 compared the differences among multiple testing strategies a CRC, EC, stomach, small bowel, ovary, pancreas, ureter and renal pelvis, with regard to effect of life-years, cancer morbidity and mortal- biliary tract, brain tumor, sebaceous adenomas, keratoacanthomas. ity, and cost. They concluded that IHC staining with inclusion FDR, first-degree relative (parent, sibling, child); SDR, second-degree relative of BRAF gene testing if the MLH1 protein was absent was the (grandparent, aunt, uncle, grandchild). 35 From Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines preferred method of identifying LS among CRC patients. The for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and effectiveness of screening for LS in these reports has been depen- microsatellite instability. J Natl Cancer Inst 2004;96:261–268. dent on the ability to test family members of the initially diagnosed

tahir99 - UnitedVRG Chapter 59 Genetic Testing in Colon Cancer (Nonpolyposis Syndromes) 821

LS patient; therefore, genetic counseling and dissemination of MANAGEMENT OF LYNCH SYNDROME information to relatives of probands are crucial for an effective diagnosis and the prevention of cancer. Individuals with LS require personalized management planning with the goal of reducing their cancer risks. Although many groups have put forth screening recommendations in the literature, the LS GENETIC TESTING surveillance and screening recommendations from the National Comprehensive Cancer Network, which are updated annually, In many situations, as mentioned previously, tumor screening are commonly used in clinical practice. Based on these current tests are performed before germ-line genetic testing, but there recommendations, individuals with LS should have colonoscopy are situations where this is not possible or desired (e.g., suffi- every 1 to 2 years beginning at the age of 20 to 25 years or 2 to cient tumor tissue is unavailable, all individuals affected with 5 years earlier than the youngest CRC in the family if diagnosed cancer in a family are deceased). In the absence of IHC results before the age of 25 years. (A colonoscopy may be recommended to direct genetic testing, germ-line testing is typically done in a to start at the age of 30 years in families with MSH6 and PMS2 stepwise fashion beginning with MLH1 and MSH2, which ac- mutations if the CRC age at onset in the family is not younger count for 32% and 38% of mutations, respectively.9 If no muta- than the age of 30 years given the reduced penetrance with these tions are identified, testing for mutations inMSH6 and PMS2 genes.) Given that there is no clear evidence to support screen- is indicated. Mutations in these two genes are less common and ing for endometrial and/or ovarian cancers, women with LS are account for 14% and 15% of LS, respectively.9 It is important for recommended to consider a prophylactic hysterectomy and a bi- testing to include sequencing as well as an analysis of deletions lateral salpingo-oophorectomy upon completion of childbearing. and duplications because all mutation types have been reported Some clinicians may find endometrial sampling, transvaginal in the MMR genes. ultrasound, and CA-125 serum screening to be helpful; however, Recently, deletions in TACSTD1 (also known as EPCAM), these tools should be used at their discretion. To screen for gastric which is not an MMR gene, have been reported to cause an and small-bowel cancers, individuals with LS should consider an inactivation of MSH2 and a lack of expression of the MSH2 pro- esophagogastroduodenoscopy with an extended duodenoscopy tein when IHC staining is performed. Therefore, testing for dele- and a capsule endoscopy every 2 to 3 years beginning at the age tions in TACSTD1 is indicated when the MSH2 protein is absent of 30 to 35 years. An annual urinalysis beginning at the age of 25 on IHC staining, but no germ-line MSHS2 mutation has been to 30 years can be used to screen for urothelial cancers, and an identified.36 annual physical examination to assess for symptoms of central nervous system tumors is reasonable.38 A 2011 study by Burn et al.39 showed through a randomized GENETIC COUNSELING FOR LYNCH trial with postintervention double-blind follow-up that daily use

SYNDROME of 600 mg of aspirin for a minimum of 25 months reduced the OF ONCOLOGY PRACTICE risk of CRCs by almost 60% in individuals with LS. Like other Inherited in an autosomal dominant manner, first-degree relatives studies of aspirin use on cancer risk, cumulative use seemed to of individuals with LS have a 50% chance of having inherited the make a difference in the study because a reduced risk became evi- syndrome as well, making the communication of these risks to fam- dent over time. The optimum dose and duration of use of aspirin ily members of patients with LS very important. Data have shown in individuals with LS still need to be established, but based on that compliance with the screening recommendations, as follows, this evidence, many clinicians are considering aspirin therapy as is effective at reducing the risk of dying of cancer in individuals chemoprevention in this population. with LS, and this should be communicated to at-risk families. A large study of MMR mutation carriers in Finland found that despite the increased risks of CRCs and ECs, cancer mortality was ACKNOWLEDGMENT not increased when individuals followed the intensive screening protocol and/or opted to have prophylactic surgery.37 The author thanks Kory Jasperson for his review of the manuscript.

REFERENCES

1. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syn- 9. Palomaki GE, McClain MR, Melillo S, et al. EGAPP supplementary evi- drome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005;352: dence review: DNA testing strategies aimed at reducing morbidity and mor- 1851–1860. tality from Lynch syndrome. Genet Med 2009;11:42–65. 2. Hampel H, Panescu J, Lockman J, et al. Comment on: Screening for Lynch 10. Baglietto L, Lindor NM, Dowty JG, et al. Risks of Lynch syndrome cancers syndrome (hereditary nonpolyposis colorectal cancer) among endometrial for MSH6 mutation carriers. J Natl Cancer Inst 2010;102:193–201. cancer patients. Cancer Res 2007;67:9603. 11. Senter L, Clendenning M, Sotamaa K, et al. The clinical phenotype of 3. Barrow E, Robinson L, Alduaij W, et al. Cumulative lifetime incidence of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 2008; extracolonic cancers in Lynch syndrome: a report of 121 families with proven 135:419–428. mutations. Clin Genet 2009;75:141–149. 12. Win AK, Young JP, Lindor NM, et al. Colorectal and other cancer risks for 4. Vasen HF, Wijnen JT, Menko FH, et al. Cancer risk in families with heredi- carriers and noncarriers from families with a DNA mismatch repair gene tary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastro- mutation: A prospective cohort study. J Clin Oncol 2012;30:958–964. enterology 1996;110:1020–1027. 13. Lynch HT, Lynch PM, Pester J, et al. The cancer family syndrome. Rare cutane- 5. Quehenberger F, Vasen HF, van Houwelingen HC. Risk of colorectal and ous phenotypic linkage of Torre’s syndrome. Arch Intern Med 1981;141:607–611. endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 14. South CD, Hampel H, Comeras I, et al. The frequency of Muir-Torre syn- gene: correction for ascertainment. J Med Genet 2005;42:491–496. drome among Lynch syndrome families. J Natl Cancer Inst 2008;100:277–281. 6. Bonadona V, Bonaiti B, Olschwang S, et al. Cancer risks associated with 15. Hamilton SR, Liu B, Parsons RE, et al. The molecular basis of Turcot’s syn- germline mutations in MLH1, MSH2, and MSH6 genes in Lynch syndrome. N Engl J Med 1995;332:839–847. drome. JAMA 2011;305:2304–2310. 16. Vasen HF, Mecklin JP, Khan PM, et al. The International Collaborative 7. Hampel H, Stephens JA, Pukkala E, et al. Cancer risk in hereditary non- Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis polyposis colorectal cancer syndrome: Later age of onset. Gastroenterology Colon Rectum 1991;34:424–425. 2005;129:415–421. 17. Vasen HF, Watson P, Mecklin JP, et al. New clinical criteria for heredi- 8. Stoffel E, Mukherjee B, Raymond VM, et al. Calculation of risk of colorectal tary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed and endometrial cancer among patients with Lynch syndrome. Gastroenter- by the International Collaborative group on HNPCC. Gastroenterology ology 2009;137:1621–1627. 1999;116:1453–1456. 822 Practice of Oncology / Cancers of the Gastrointestinal Tract

18. Rodriguez-Bigas MA, Boland CR, Hamilton SR, et al. A National Cancer 29. Loughrey MB, Waring PM, Tan A, et al. Incorporation of somatic BRAF Institute workshop on hereditary nonpolyposis colorectal cancer syndrome: mutation testing into an algorithm for the investigation of hereditary non- meeting highlights and Bethesda guidelines. J Natl Cancer Inst 1997; polyposis colorectal cancer. Fam Cancer 2007;6:301–310. 89:1758–1762. 30. Hitchins MP, Ward RL. Constitutional (germline) MLH1 epimutation as 19. Umar A, Boland CR, Terdiman JP, et al. Revised Bethesda guidelines for he- an aetiological mechanism for hereditary non-polyposis colorectal cancer. reditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite J Med Genet 2009;46:793–802. instability. J Natl Cancer Inst 2004;96:261–268. 31. Mutch DG, Powell MA, Mallon MA, et al. RAS/RAF mutation and defec- 20. Morrison J, Bronner M, Leach BH, et al. Lynch syndrome screening in tive DNA mismatch repair in endometrial cancers. Am J Obstet Gynecol newly diagnosed colorectal cancer in general pathology practice: from the 2004;190:935–942. revised Bethesda guidelines to a universal approach. Scand J Gastroenterol 32. Weissman SM, Bellcross C, Bittner CC, et al. Genetic counseling consider- 2012;46:1340–1348. ations in the evaluation of families for Lynch syndrome—a review. J Genet 21. de la Chapelle A, Hampel H. Clinical relevance of microsatellite instability Couns 2011;20:5–19. in colorectal cancer. J Clin Oncol 2010;28:3380–3387. 33. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) 22. Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Insti- Working Group. Recommendations from the EGAPP Working Group: Ge- tute Workshop on Microsatellite Instability for cancer detection and familial netic testing strategies in newly diagnosed individuals with colorectal cancer predisposition: development of international criteria for the determination aimed at reducing morbidity and mortality from Lynch syndrome in rela- of microsatellite instability in colorectal cancer. Cancer Res 1998;58:5248– tives. Genet Med 2009;11:35–41. 5257. 34. Mvundura M, Grosse SD, Hampel H, et al. The cost-effectiveness of genetic 23. Hampel H, Frankel WL, Martin E, et al. Feasibility of screening for Lynch testing strategies for Lynch syndrome among newly diagnosed patients with syndrome among patients with colorectal cancer. J Clin Oncol 2008;26: colorectal cancer. Genet Med 2010;12:93–104. 5783–5788. 35. Ladabaum U, Wang G, Terdiman J, et al. Strategies to identify the Lynch syn- 24. Samowitz WS, Curtin K, Lin HH, et al. The colon cancer burden of ge- drome among patients with colorectal cancer: A cost-effectiveness analysis. netically defined hereditary nonpolyposis colon cancer. Gastroenterology Ann Intern Med 2011;155:69–79. 2001;121:830–838. 36. Niessen RC, Hofstra RM, Westers H, et al. Germline hypermethylation of 25. Niessen RC, Kleibeuker JH, Westers H, et al. PMS2 involvement in pa- MLH1 and EPCAM deletions are a frequent cause of Lynch syndrome. tients suspected of Lynch syndrome. Genes Chromosomes Cancer 2009;48: Genes Chromosomes Cancer 2009;48:737–744. 322–329. 37. Jarvinen HJ, Renkonen-Sinisalo L, Aktan-Collan K, et al. Ten years after muta- 26. Zighelboim I, Powell MA, Babb SA, et al. Epitope-positive truncating MLH1 tion testing for Lynch syndrome: cancer incidence and outcome in mutation-pos- mutation and loss of PMS2: Implications for IHC-directed genetic testing for itive and mutation-negative family members. J Clin Oncol 2009;27:4793–4797. Lynch syndrome. Fam Cancer 2009;8:501–504. 38. National Comprehensive Cancer Network. NCCN Guidelines & Clini- 27. Lindor NM, Burgart LJ, Leontovich O, et al. Immunohistochemistry versus cal Resources. NCCN Guidelines for Detection, Prevention, and Risk Re- microsatellite instability testing in phenotyping colorectal tumors. J Clin On- duction [v.1.2012]. 2012. http://www.nccn.org/professionals/physician_gls/ col 2002;20:1043–1048. recently_updated.asp 28. Ruszkiewicz A, Bennett G, Moore J, et al. Correlation of mismatch re- 39. Burn J, Gerdes AM, Macrae F, et al. Long-term effect of aspirin on cancer pair genes immunohistochemistry and microsatellite instability status in risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 HNPCC-associated tumours. Pathology 2002;34:541–547. randomised controlled trial. Lancet 2011;378:2081–2087.

tahir99 - UnitedVRG 60 Cancer of the Rectum

Steven K. Libutti, Christopher G. Willett, Leonard B. Saltz, and Rebecca A. Levine

INTRODUCTION mesorectum is usually used as the structure to define the extent of a total mesorectal excision (TME), with most of the perirectal Information concerning epidemiology and systemic approaches to fatty tissue and perirectal lymph nodes (LN) contained within its the management of both colon and rectal cancer was given in an- boundaries. other chapter in this book. This chapter will focus on issues unique to rectal cancer with an emphasis on radiation, combined modal- Lymphatic Drainage ity therapy, and sphincter-preserving surgery. The lymphatic drainage of the upper rectum follows the course of the superior hemorrhoidal artery toward the inferior mesenteric ANATOMY artery. Lymph nodes that are above the midrectum and therefore drain along the superior hemorrhoidal artery are often part of the The anatomy of the rectum can be very confusing as there are dif- mesentery that is removed during resections of the intraperitoneal fering definitions of the relevant landmarks. In the upper portion portion of the colon. Lesions that arise in the rectum below ap- of the rectum, there are changes both in the musculature of the proximately 6 cm are in a region of the rectum that is drained large bowel and in the relationship to the peritoneal covering that by lymphatics that follow the middle hemorrhoidal artery. Nodes roughly coincide. In the lower portion of the rectum, the mucosal involved from a cancer in this region can include the internal iliac changes occur at roughly the same location as the anal sphincter.

nodes and the nodes of the obturator fossa. These regions deserve OF ONCOLOGY PRACTICE The anatomy of the rectum is usually divided into three por- particular attention during the resection and irradiation of lesions tions (Fig. 60.1). The lower rectum is the area approximately from in this location. When lesions occur below the dentate line, the 3 to 6 cm from the anal verge. The midrectum goes from 5 to 6, lymphatic drainage is via the inguinal nodes and external iliac to 8 to 10 cm, and the upper rectum extends approximately from chain, which has major therapeutic implications, especially for 8 to 10, to 12 to 15 cm from the anal verge, although the retro- the radiation fields. The corollary of this high risk of inguinal node peritoneal portion of the large bowel often reaches its upper limit involvement for the very low-lying tumors is that tumors located approximately 12 cm from the anal verge. In some patients, espe- above the dentate line are at low risk of inguinal node involve- cially elderly women, the peritonealized portion of the large bowel ment, and these nodes as well as the external iliacs do not need can be located much lower than these definitions. The determina- to be treated. tion of the location of the boundary between rectum and sigmoid colon is important in defining adjuvant therapy, with the rectum usually being operationally defined as that area of the large bowel Bowel Function that is at least partially retroperitoneal. Externally, the upper extent of the rectum can be identified Fecal continence is maintained through the function of both the where the tenia spread to form a longitudinal coat of muscle. The sphincter mechanism and the preservation of the normal pelvic upper third of the rectum is surrounded by peritoneum on its an- floor musculature, which creates a neorectal angle or rectal sling. terior and lateral surfaces but is retroperitoneal posteriorly without The pelvic floor is composed of the levator ani muscles, which any serosal covering. At the rectovesical or rectouterine pouch, the separate the pelvis from the perineum and ischiorectal fossa. The rectum becomes completely extra-/retroperitoneal. The rectum urethra, vagina, and anus pass through the levator muscles. follows the curve of the sacrum in its lower two-thirds. It enters the Preservation of fecal continence during surgery for rectal anal canal at the level of the levator ani. The anorectal ring is at cancer is therefore dependent on a thorough understanding of the level of the puborectalis sling portion of the levator muscles. the anatomic relationships of the musculature and the sphincter The location of a rectal tumor is most commonly indicated by mechanism. Maintenance of the sphincter apparatus without the distance between the anal verge, dentate (pectinate or muco- preservation of the muscular angles will not have the desired re- cutaneous) line, or anorectal ring and the lower edge of the tumor. sult. These anatomic constraints, especially with respect to lateral These points of reference are all different for different individu- margins, make the use of adjuvant chemotherapy and radiation als. Also, these measurements differ depending on the method of therapy critical to a successful surgical outcome. This is true from measurement. This can be important clinically, as the measure- both an oncologic as well as a bowel function perspective. ment from a flexible endoscopy can substantially overestimate the distance to the tumor from the anal verge or other landmark. Autonomic Nerves The distance from the anal sphincter musculature is clinically of more importance than the distance from the anal verge, as it has The preservation of both bladder and sexual function depends on implications for the ability to perform sphincter-sparing surgery. the surgeon’s understanding of the autonomic nerve supply to the The lack of a peritoneal covering over most of the rectum is a pelvic organs.1,2 The hypogastric plexus is formed from the sympa- major reason for the higher risk of local failure after primary surgi- thetic trunks as they converge over the sacral promontory. These cal management of rectal cancer compared to colon cancer. The sympathetic nerves are found beneath the pelvic peritoneum

823 824 Practice of Oncology / Cancers of the Gastrointestinal Tract

Left upper valve of Houston Portion Cm from of rectum anal verge Right middle valve of Houston Upper third Peritoneum

Middle third Ampulla of rectum

15 Left lower 11 valve of Houston Lower third 7

Figure 60.1 Division of the rectum into Anal verge upper, middle, and lower thirds. along the lateral pelvic sidewalls lateral to the mesorectum. The pathologic (postoperative) stage. Initial therapy with chemoradia- second, third, and fourth sacral nerve roots give rise to parasym- tion can produce substantial downstaging (approximately 15% of pathetic fibers to the pelvic viscera. The parasympathetic fibers patients will have a pathologic complete response, and as many as proceed laterally as the nervi erigentes to join the sympathetic fi- 40% in those with more favorable tumors). While some believe bers at the site of the pelvic plexus that is just lateral and somewhat that the degree of response to neoadjuvant therapy should alter anterior to the tips of the seminal vesicle in men.1,2 In order to pre- subsequent treatment, and this is in fact an area of active investiga- serve these structures and, therefore, sexual and bladder function, tion (see later discussion), the current standard of care dictates that a sharp rather than a blunt technique should be used to dissect the all surgical planning and adjuvant therapy be determined based on mesorectum.3–6 the initial clinical stage regardless of tumor response. This guideline is based in part on the idea that a good tumor response locally to chemoradiation does not translate into reduced risk of having STAGING micrometastatic disease, and thus does not lessen the need for adjuvant postoperative chemotherapy. Whether this will continue to Standard clinicopathologic staging is the best indicator of progno- be true in the face of newer data and more aggressive neoadjuvant sis for patients with rectal cancer. For rectal cancer, it is increas- regimens remains to be seen. Numerous studies have indicated ingly common to use clinical staging as the basis for the decision that tumor response to neoadjuvant therapy is an important pre- to initiate neoadjuvant chemoradiation therapy. Therefore, the dictor of multiple oncologic end points for patients completing accuracy of that initial staging is critically important, both for the full course of multimodal therapy. Patients with pathologic management and for prognosis. There have been a large number complete response in particular demonstrate excellent long-term of studies that have evaluated other prognostic markers, includ- results, with local recurrence rates as low as 0.7%, and significantly ing pathologic, socioeconomic, and molecular, as described more improved disease-free survival (DFS) and overall survival (OS) fully in Chapter 57. However, even though many of these appear compared to nonresponders at 5 years (odds ratio [OR] = 3.28 and to have prognostic value, there are none that are commonly used OR = 4.33, respectively).10–12 It is unclear at this time whether to define management. This is related to the large number of tests such a favorable outcome can be maintained should the course of that could be used, the lack of standardization of these tests, as treatment be altered based on postneoadjuvant reassessment. well as the lack of knowledge as to how to incorporate them into Although it is not standard practice to alter treatment based on the patient management scheme. The molecular marker that has local response to neoadjuvant therapy, preoperative restaging prior engendered the most interest is the deletion of 18q.7 These mark- to surgery may still be valuable not only as a prognostic predic- ers have been fully reviewed elsewhere.8,9 tor but also for detecting interval metatastic progression. Multiple The staging system that should be used in the evaluation of studies recommend repeating serum carcinoembryonic antigen patients with rectal cancer is the American Joint Committee on (CEA) levels, for example, between chemoradiation and surgery Cancer/International Union Against Cancer TNM (tumor, node, as this value as well as the pre- to posttreatment ratio may be more metastases) staging system (fully described in Chapter 57), which important in predicting survival than the initial measurement.13–15 has been recently revised to subcategorize patients with stage III In addition, Ayez et al.16 advocate restaging with chest and abdomi- (node-positive) tumors. The Dukes staging system or its multiple nal computed tomography (CT), as this changed management in modifications has been used for many years, but provides less in- 12% of their patients, and spared 8% from undergoing noncura- formation than the TNM system and should not be used. There tive rectal surgery, due to new findings of progressive metastatic have been gradual changes in the TNM system that primarily re- disease.16 flect the stage grouping rather than the system itself. The other The major change that has occurred in the newest version of systems should be acknowledged for their historical interest and the staging system is the acknowledgment that both the T stage for initially defining many of the high-risk factors for this disease. and the N stage have independent prognostic importance for local Patients now often have both a clinical (preoperative) stage, control, DFS, and OS.17,18 Thus, for patients with N0 and N1 which may define the need for neoadjuvant therapy, and a tumors viewed separately, the extent of the primary tumor in the

tahir99 - UnitedVRG Chapter 60 Cancer of the Rectum 825 rectum is of additional prognostic importance. Patients with T1- 2N1 tumors have a relatively favorable prognosis and an outcome superior to that of other stage III patients. In fact, patients with T3N0M0 disease (stage II) have outcomes slightly inferior to those with T1-2N1M0, demonstrating the independent prognostic importance of T stage. These distinctions may allow future decisions to be more individualized as to the adjuvant therapy required. Although at one level staging is very straightforward, the actu- ality of proper staging is much more difficult as it relies on multiple quality control issues that can mislead the clinician regarding proper therapy. For instance, it has been well demonstrated that for patients with colon and rectal cancer who are pathologically staged as N0, the prognosis is markedly improved for those in whom more than 12 to 14 nodes were identified by the pathologist compared with those in whom fewer nodes were identified.19 This could be a surgical issue (fewer nodes were removed) or a pathologist issue (fewer nodes were identified), but it suggests that many patients were inappropriately understaged, which could result in inappropriate therapy. Others have shown that staging accuracy continues to improve as the pathologist recovers more nodes, with accuracy leveling off at approximately 12 to 20 nodes recovered.20,21 (See discussion in Chapter 57). In rectal cancer, however, N staging presents a particular challenge as there are often fewer LNs in the specimen and preoperative radiotherapy is thought to reduce that number even further.22–24 In fact, one re- Figure 60.2 Endorectal ultrasound of a T3 tumor of the rectum, cent report suggests that LN harvests <12 in pretreated specimens extension through the muscularis propria, and into perirectal fat. may be a marker of high tumor response and improved rather than compromised oncologic outcome. In this study of 237 patients, local recurrence rates were significantly higher in the LN> 12 group as compared to those with “inadequate” LN retrieval (11% overstaging of approximately 10% to 20% in T2 disease because versus 0%; p = 0.004).25 As with colon cancer, the percentage of of an inability to distinguish a desmoplastic response and postbi-

positive nodes is likely of greater prognostic importance than total opsy changes from local tumor invasion, and approximately a 10% OF ONCOLOGY PRACTICE LN number (M. Meyers, 2007, personal communication).26–28 rate of understaging because of an inability to detect microscopic The same issue relates to T-stage determination. If the pathologist tumor extension. 31–33 does not look carefully for evidence of extension of tumor through EUS is less accurate in determining N stage than for T stage, the muscularis propria, the patient can be understaged, resulting with an overall accuracy rate of 62% to 83%.31,32 Understaging oc- in inappropriate treatment. Close or positive circumferential mar- curs because many nodal metastases from rectal cancer are small, gins are a poor prognostic factor, which can only be found if the even micrometastatic, and not easily detected by EUS. In addi- pathologist assiduously evaluates the radial margins.29,30 tion, some nodes are located beyond the range of the ultrasound The standard staging procedure for rectal cancer entails a his- transducer and thus cannot be seen during the procedure. Over- tory, physical examination, complete blood cell count, liver and staging is often related to an inflammatory response, perhaps sec- renal function studies, as well as CEA evaluation. The routine lab- ondary to previous biopsy or manipulation. EUS is not accurate oratory studies are quite insensitive to the presence of metastatic for determining tumor regression after preoperative radiation and disease, but they are usually ordered as a screen of organ function chemotherapy, as inflammatory changes and scarring can persist prior to surgery or chemoradiation therapy. High CEA levels are in the rectal wall or in perirectal soft tissue and may not reflect associated with poorer survival (see Chapter 57) and give an indi- persisting tumor. Newer ultrasound techniques, such as three- cation as to whether follow-up CEA determinations are likely to be dimensional ultrasound, are being explored but have not yet made useful. A careful rectal examination by an experienced examiner it into standard practice. is an essential part of the pretherapy evaluation in determining dis- Endorectal coil MRI allows discernment of the layers of the tance of the tumor from the anal verge or from the dentate line, bowel wall and is similar in accuracy to EUS. Thin-section pelvic involvement of the anal sphincter, amount of circumferential in- MRI with a surface coil also allows one to visualize the mesorectal volvement, clinical fixation, sphincter tone, and so forth, and has fascia and thus to predict the likely distance of the surgical resection not been replaced by imaging studies or endoscopy. Colonoscopy margin when performing a TME. The MERCURY Study Group or barium enema to evaluate the remainder of the large bowel is confirmed this key advantage of MRI in their landmark 2005 mul- essential (if the patient is not obstructed) to rule out synchronous ticenter trial, where specificity for predicting clear margins in 408 tumors or the presence of polyposis syndromes. patients with varying stages of rectal cancer was 92%.34 Although Local staging is completed with one of two imaging modalities, there has been great interest in this technique since then, follow- endorectal ultrasound (EUS) or pelvic magnetic resonance imag- up studies still show a disappointing overall accuracy for T and N ing (MRI). Each provides similar overall accuracy in T and N de- staging, which fails to surpass EUS in experienced hands. In one termination, and each has its advantages as well as drawbacks. The study of 96 patients who had MRI followed by TME, of 22 patients decision of which to use generally depends on local institutional classified as having T2 disease on MRI, 3 had T1 and 6 had T3 tu- expertise and resource availability. mors. Of 61 patients classified as having T3 disease on MRI, 8 had EUS defines five interface layers of the rectal wall: mucosa, T2 tumors and 2 had T4. Thus, 6 of 22 (27%) patients who might muscularis mucosa, submucosa, muscularis propria, and peri- have benefited from preoperative therapy for T3 disease would not rectal fat, as shown in Figure 60.2. Rectal tumors are generally have received that therapy. Eight of sixty-one patients (13%) would hypoechoic and disrupt the interfaces depending on the level of have received preoperative treatment inappropriately based on the tumor extension. The accuracy of EUS depends heavily on the MRI T stage.35 For nodal status, 8 of 33 MRI-positive nodes were experience and skill of the operator. In experienced hands, EUS clinically negative, and 7 of 57 MRI- negative nodes were patho- has an overall accuracy rate for T stage of 75% to 95% with an logically positive.36 The presence of nodal disease identified by 826 Practice of Oncology / Cancers of the Gastrointestinal Tract

MRI is also primarily determined by size, so the accuracy is similar A 2013 study has re-emphasized this point, reporting that preoper- to that of CT (<80%), although defining node positivity based on ative PET/CT had no impact on disease management in 96.8% of irregular border or mixed signal intensity could help improve sen- enrolled patients and advocating against its routine use for primary sitivity and specificity.35 staging.47 PET is probably most valuable in restaging patients with While the accuracy of MRI in determining T and N stage is im- recurrence or suspected recurrence to detect additional metastatic perfect, newer studies have focused on other radiographic features sites prior to attempted resection of metastatic disease. that may prove more relevant to prognosis and treatment planning than the traditional American Joint Committee on Cancer classification. In addition to defining the circumferential resection SURGERY margin (CRM) of a low rectal cancer, high-resolution MRI can be used to predict tumor regression grade (TRG) after neoadjuvant The surgical management of primary rectal cancer presents therapy. TRG in the surgical specimen is a measure of response unique problems for the surgeon based in large part on the ana- to preoperative chemoradiation and has been shown to correlate tomic constraints of the pelvis. The primary goal of achieving a strongly with OS and DFS. In the first prospective study to ad- complete oncologic resection must be balanced with the desire 37 dress MRI-predicted TRG, Shihab et al. found this too was sig- for optimal nerve and sphincter preservation, which can be quite nificantly associated with long-term outcomes. A prognostic role challenging in such a confined space. was also demonstrated for pretreatment MRI, specifically in the characterization of tumor invasion into the pelvic floor muscles. Based on these results, the authors postulate that MRI-defined Stage I factors may be extraordinarily useful for modifying treatment in both the pre- and postneoadjuvant settings.37 Patel et al.38 offer The treatment of early-stage rectal cancer can be confusing as a similar conclusion in their subgroup analysis from the original there are many approaches that can be used, and patient selection MERCURY study, which likewise found MRI-predicted TRG and is critical to outcome. In addition, the risk of nerve injury and dam- CRM to be significant prognostic markers. age to the anal sphincter is substantial for low-lying tumors and Two studies have taken this issue a step further by investigat- must be taken into consideration, along with the desire not to have ing exactly how MRI parameters can and should alter therapy. In a permanent colostomy for early-stage disease. Thus, the options another extension of the MERCURY trial, Taylor et al.39 identi- for these patients are primarily those of local therapies without ab- fied patients with “good prognosis” MRI (as defined by predicted dominal surgery, abdominal resection of the rectum with anasto- negative CRM, absence of extramural venous invasion, and T2/ mosis and retention of the anal sphincter, and abdominal-perineal T3a/T3b regardless of N stage) and referred them directly for resection. The last two options are discussed in detail in “Stages II TME resection without chemoradiation. Survival and recurrence and III Rectal Cancer.” outcomes were highly favorable, suggesting that early MRI can Small early-stage lesions of the rectum that are diagnosed on improve patient stratification for more selective and appropriate physical examination or by colonoscopy/proctoscopy can often be targeting of preoperative therapy.39 In the postneoadjuvant setting, managed with local resection. Local resection can be performed MRI can be used to identify poor responders who may require al- colonoscopically (as described in the Chapter 57), or lesions can ternative treatments or more radical resection such as the extra- be removed via a transanal excision with the patient positioned in levator abdominoperineal approach described by Shihab et al.40 a prone or lithotomy position. Appropriate retractors can provide Finally, pelvic MRI may also help predict which patients are visualization, and resection should extend into the perirectal fat at increased risk for distant synchronous metastases and would with a surrounding margin of normal tissue.48 For selected T1 and therefore benefit from more extensive pretreatment imaging such T2 lesions without evidence of nodal disease, transanal excision as positron emission tomography (PET)/CT or liver MRI. Hunter often provides an adequate resection of the primary tumor mass et al.41 found that adverse features demonstrated on pelvic MRI and can spare the patient the morbidity of a more extensive rectal (extramural venous invasion, extramural spread of >5 mm or T4, resection. However, it does not stage the nodal drainage areas and involved CRM or intersphincteric plane for low tumors) were sig- therefore cannot provide as complete staging and management nificantly associated with a higher incidence of distant metastases of the tumor as a definitive resection. In the effort to minimize (OR = 6.0; p <0.001). The authors recommend using MRI-based the risk of locoregional failure, criteria for local excision have risk stratification to identify patients who may benefit not only been established: the tumor must be within 8 to 10 cm of the anal from more meticulous staging but also from more aggressive treat- verge, be well or moderately well differentiated, encompass <40% ment regimens.41 of the circumference of the bowel wall, and contain no evidence M staging for rectal cancer is determined in the same way as of lymphovascular invasion on biopsy. For T2 lesions, local resec- colon cancer: with a baseline CT scan to evaluate the chest, abdo- tion should be followed by adjuvant chemoradiation. While these men, and pelvis.42 There has been much debate about the relative criteria are not strongly evidence-based (and are evolving along value of CT versus MRI or PET, particularly in assessing the liver, with surgical technology), a growing body of literature supports without any clear resolution. This decision depends heavily on the this approach particularly for T1 lesions. In a review of 677 T1 institutional expertise and the equipment available. and T2 cancers after TME, Saraste et al.49 identified three signifi- CT has an overall sensitivity of 70% to 85%, which might be cant risk factors for LN invasion (and hence relative contraindica- improved with multidetector-improved CT technology, although tions for local excision): T2 stage (OR = 2.0), poor differentiation the data do not yet prove that contention.43 MRI is superior in char- (OR = 6.5), and vascular infiltration (OR = 3.4) with likelihood acterizing liver lesions and distinguishing cysts and hemangiomas of LN positivity ranging from 6% to 78% depending on how many from tumor, especially with the use of enhancement with gado- were found. Further support for these criteria comes from a study linium or other agents.44 PET with [18F]fluorodeoxyglucose shows of 25 high-risk T1 rectal cancers, half of which were treated by promise as the most sensitive study for the detection of metastatic transanal excision only (due to comorbidities or patient refusal to disease in the liver and especially in abdominal LNs for which CT undergo resection) and the remainder with immediate conven- and MRI are relatively insensitive. In addition, a meta-analysis of tional reoperation after local excision. Local recurrence was sig- whole-body PET showed a sensitivity of 97% and a specificity of nificantly higher in patients undergoing local excision only (50% 76% in evaluating for recurrent colorectal cancer.45 However, PET versus 7.7%, mean follow-up 62 months), and there was a trend is not standardly used in preoperative staging, or recommended toward decreased 5-year survival (63% versus 89%). There were by National Comprehensive Cancer Network guidelines, and the no differences in age, gender, or tumor characteristics between incremental gain from routine PET scan appears to be small.46 the two groups.50 On the other hand, for low-risk T1 lesions in

tahir99 - UnitedVRG Chapter 60 Cancer of the Rectum 827 the prospective phase 2 Cancer and Leukemia Group B study, Stages II and III Rectal Cancer local excision alone was associated with low recurrence and good survival rates that remained durable with long-term follow-up. For The primary treatment of patients with stages II and III rectal can- T2 lesions, however, even with adjuvant therapy, the role of local cer (T3-4 and/or node-positive) is surgical. However, in contrast to excision is less clear, as Saraste et al.49 would predict, these were the treatment of patients with stage I disease, there is a strong body 51 associated with higher recurrence rates. Whether the addition of information to suggest that combined modality therapy with ra- of neoadjuvant therapy might be helpful is a focus of multiple diation therapy and chemotherapy should be used in conjunction investigations. The American College of Surgeons Oncology with surgical resection. This conclusion is based on both patterns Group has published preliminary results from its recently com- of failure data, which demonstrate a substantial incidence of local, pleted phase 2 trial of neoadjuvant capecitabine, oxaliplatin, and regional, as well as distant disease failure, and the fact that this radiation therapy followed by local excision for ultrasound T2 tu- incidence of tumor recurrence at all sites is decreased with the use 52 mors (ACOSOG Protocol Z6041). The authors report that 49 of trimodality therapy. of 77 patients were downstaged and 44% achieved a complete The desire when performing a resection for rectal cancer is pathologic response (pCR). There was one positive margin and to preserve intestinal continuity and the sphincter mechanism one patient with a positive node. Rates of treatment-related toxic- whenever possible while still maximizing tumor control. There- ity and perioperative complications were high, however, requiring fore, careful preoperative screening is crucial in the determina- dose reduction and potentially compromising response. Follow- tion of the location of the lesion and its depth of invasion. As up trials are planned to improve upon the therapeutic ratio of 53 previously described, it is convenient to think of the rectum as this approach and better evaluate long-term efficacy. More divided into thirds for the purposes of the evaluation and preop- long-term results are reported from another prospective trial that erative determination of the surgical approach for resection. The supports the role of local excision following neoadjuvant therapy 54 upper third of the rectum is often considered the region of large in selected T2N0 lesions with favorable features. Lezoche et al. intestine from the sacral prominence to the peritoneal reflection. randomized 100 patients to either endoluminal resection or to These lesions are in almost all cases managed with a low ante- laparoscopic or open TME, following neoadjuvant chemoradia- rior resection in much the same way as a sigmoid colon cancer tion. Downstaging and pCR rates were similar in both groups, oc- (see Chapter 57). An adequate 1- to 2-cm distal mucosal mar- curring in 51% and 28% of patients, respectively. With a mean gin can be achieved for these lesions well above the sphincter follow-up of 9.6 years, oncologic outcomes were also essentially mechanism, and intestinal continuity can be restored using ei- equivalent—with similar local recurrence rates and incidence of ther a hand-sewn technique or a circular stapling device inserted distant metastases (8% versus 6% and 4% versus 4%, respectively) through the rectum.61,62 and no difference in DFS.54 Tumors in the middle and lower thirds of the rectum can be Performing a good transanal excision requires substantial tech- considered as lying entirely below the peritoneal reflection. The nical expertise as the surgeon must retain control over the primary OF ONCOLOGY PRACTICE resection of these tumors can be challenging because of the con- tumor and obtain adequate mucosal margins as well as deep re- fines of the pelvic skeletal structure, and the ability to perform a section into the perirectal fat. Once removed, the tumor must be well laid out for the pathologist so that all relevant margins can resection with an adequate distal margin is significantly influenced be properly evaluated. There is some experience using preopera- by the size of the lesion. Nevertheless, tumors of the middle third tive radiation therapy and chemotherapy for small lesions, but care of the rectum in most cases can be safely resected with a low ante- must be taken to have the site of the primary tumor well marked rior resection, with restoration of intestinal continuity and preser- with a tattoo if this approach is taken, as excellent regression could vation of a continent sphincter apparatus. make identification of the primary site difficult. Lesions in the distal third of the rectum, defined as those Newer techniques for transanal excision, including transanal within 6 cm of the anal verge, can present the greatest challenge endoscopic microsurgery (TEMS) and transanal minimally inva- to the surgeon with respect to sphincter preservation. This is often sive surgery, have recently gained popularity based on improved influenced by the extent of lateral invasion of the lesion into the visualization of the lesion. TEMS makes use of a standard lapa- muscles of the sphincter apparatus and how close distally the roscopic light source and monitoring system combined with tumor is to the musculature of the anal canal. The abdominal peri- specialized instruments and scopes. The technique allows for neal resection (APR) has historically been considered the standard videoscopic magnification and the placement of instruments treatment for patients with rectal cancers located within 6 cm of through an operating sigmoidoscope. TEMS and its counterpart the anal verge. This procedure requires a transabdominal as well transanal minimally invasive surgery, which uses the more basic as a transperineal approach with removal of the entire rectum and single port laparoscopic technology, may be applied, in general, sphincter complex. A permanent end colostomy is created and the to the same patients who are candidates for traditional transanal perineal wound either closed primarily or left to granulate in after resection. However, these methods are most useful for excising closure of the musculature. more proximal lesions that are beyond the reach of standard surgi- Although an APR is associated with a relatively low rate of local cal instruments and too large for removal through a colonoscope. recurrence, it is not without the obvious problems of the need for a Preliminary data supports the role of TEMS in both benign and permanent colostomy and loss of intestinal continuity and sphinc- early-stage malignant lesions with improved margin negativity and ter function. Therefore, intense interest has been focused on de- DFS compared to transanal resection for T1 and T2 lesions in veloping approaches to the resection of tumors in the distal third a recent report.55 Another meta-analysis found significant reduc- of the rectum that would both avoid local regional recurrence and tions in morbidity and mortality compared to conventional surgery preserve intestinal continuity and sphincter continence. and equivalent 5-year survival rates for T1 tumors.56 Studies that Traditionally, tumors within 1 to 2 cm of the dentate line—that include T2 lesions and selective use of adjuvant therapy have dem- is, those that can be removed with at least a 1-cm distal margin— onstrated 5-year OS and cancer-specific survivals over 90%, with have been considered candidates for sphincter preservation and recurrence rates between 4% to 9%.57,58 Moreover, the TEMS pro- restoration of intestinal continuity via a coloanal anastomosis, cedure fairs quite favorably with respect to long-term quality of life which is commonly protected by a diverting loop ileostomy that and functional outcome as most defecatory parameters return to can be reversed in 6 to 12 weeks.63,64 Newer data suggest that when baseline by 5 years, according to prospective data.59 Other reports TME and preoperative radiotherapy are routinely employed, even are less encouraging with recurrence rates following TEMS resec- smaller margins are acceptable without oncologic compromise, tion as high as 30%,60 and therefore close endoscopic surveillance as long as they are microscopically negative.65 In fact, one of the is recommended. advantages of neoadjuvant therapy is thought to be an increase 828 Practice of Oncology / Cancers of the Gastrointestinal Tract in sphincter-sparing procedures due to reduction in tumor bulk, which would normally preclude identification of this slight but critical margin.63,66 A recent systematic literature review identified seven studies addressing this topic, most of which implemented Waldeyer’s pre- or postoperative radiotherapy, and three of which reported re- Investing layer fascia sults related to a margin of <5 mm. There were no statistically sig- of mesorectum nificant differences in local recurrence rates regardless of margin status. This data contributes to the growing evidence that a 1 cm (or even 5 mm) margin may be unnecessary and, more importantly, that strategies employed solely to achieve this margin (such as an APR or intersphincteric resection [ISR] for distal T1 lesions) may in fact be unnecessary as well.67 While controversial in the United States, ISR has been described extensively abroad as a method involving at least partial resection of the internal sphincter designed to improve margin status without sacrificing sphincter function.68 Recently, a large systematic review addressed the efficacy of this approach, identifying 14 (mostly retrospective) studies with 1,289 patients who underwent both open and laparoscopic ISR. Median follow-up was 56 (range, 1 to 227) months. Overall oncologic outcomes did not appear to be compromised with R0 resection achieved in 97% and a mean local recurrence rate of 6.7% (range, 0% to 23%). In addition, mean 5-year OS and DFS rates were 86.3% and 78.6%, respectively. Functional outcomes, however, were widely variable with only 51.2% of patients reporting “perfect continence,” while an average of 29.1% experienced fecal soiling, 23.8% incontinence Figure 60.3 Total mesorectal excision. to flatus, and 18.6% complained of urgency.69 It has been postulated that neoadjuvant chemoradiation, while improving locoregional control and rates of margin-negative resection, has a deleterious effect on long-term functional outcomes, particularly after surgery for ultralow tumors. How- In the rectum, the mesorectum is the structure that contains ever, a recent multivariate analysis did not support this in ISR the blood supply and lymphatics for the upper, middle, and lower cases, finding the only significant predictors of continence were rectum. Most involved LNs for rectal cancers are found within distance of the tumor from the anal ring and distance of the anas- the mesorectum, with T1 lesions associated with positive LNs in tomosis from the anal verge. There was also no difference with 5.7% of cases, T2 lesions having positive LNs in 20% of cases, and age or extent of internal sphincter resection.70 Another report did T3 and T4 lesions having positive LNs in 65% and 78% of cases, find significant functional differences when comparing partial respectively.73 ISR (resection above the dentate line), subtotal ISR (resection at The anatomy and approach to mesorectal excision is depicted the dentate line), and total ISR (resection from the intersphinc- in Figure 60.3. This operation involves a sharp dissection occur- teric groove). Patients with more extensive sphincter resection ring in an avascular plane between the fascia propria of the rec- had higher fecal incontinence scores, more frequent nocturnal tum and the presacral membrane, beyond the region where most leakage, and more problems with discrimination. In addition, of the nodes are located. After a TME, the specimen is typically manometric studies at 12 months showed greater reductions in shiny and bilobed in contrast to the irregular and rough surface mean resting pressure. Overall though, quality of life was main- after a blunt dissection, where much of the mesorectal fat is left tained in the majority of patients and function improved over behind. TME attempts not only to clear involved LNs but also to time in both studies.71 adequately manage the radial margins of the rectal tumor. These Chemoradiation should be used preoperatively when perform- radial margins have been shown to be more important with respect ing sphincter-preserving resections for T3 or T4 rectal lesions or for to the risk of local regional recurrence than the distal mucosal mar- any node-positive disease stages II or III. There is some evidence gin.66,74 Distal mucosal margins of ≥1 cm are adequate for local that preoperative radiation results in less morbidity than postopera- control; however, the margin on the mesorectum should extend tive radiation therapy when a coloanal anastomosis is planned. In beyond the distal mucosal margin in order to ensure a successful a study of 109 patients treated with a low anterior resection and surgical outcome.64,66 Numerous studies have demonstrated the a straight coloanal anastomosis, those receiving preoperative ra- benefit of TME, and it is now considered the standard of care for diation therapy had a lower incidence of adverse effects on anal the surgical management of middle and lower third rectal can- function than those receiving postoperative radiation.72 The au- cers.5,75–77 Although some studies have suggested that an adequate thors attributed this to sparing of the neorectum from these effects. TME might in and of itself be sufficient management for T2 and Relative benefits and outcomes for preoperative chemoradiation T3 rectal cancers, the majority of the literature still supports the versus postoperative chemoradiation will be discussed in detail in use of adjuvant chemoradiation for stages II and III disease even following sections. when combined with TME. Large studies of proctectomy with TME have demonstrated a reduction in the overall incidence of local recurrence to <10%.4 Total Mesorectal Resection The consequences of TME can be impairment in erectile and bladder function because of disruption of parasympathetic nerves The goal of the resection of rectal tumors is the removal of the that are located in proximity to the mesorectum. Several authors tumor with an adequate margin as well as removal of draining LNs have stressed the importance of the experience of the surgeon and lymphatics to properly stage the tumor and to reduce the risk performing the procedure, and some have suggested specific tech- of recurrence and spread. For lesions in the intraperitoneal colon, niques for monitoring modalities that can be used during this pro- the lymphatics and vascular supply are found in the mesentery as- cedure to minimize morbidity.5,6 A careful understanding of the sociated with that region of bowel. anatomy and adequate visualization during sharp dissection will

tahir99 - UnitedVRG Chapter 60 Cancer of the Rectum 829 help in minimizing injury to the parasympathetic nerves and the parameters, postoperative complications, or recurrence rates at a consequent morbidity.3,4 median of 15 months follow-up. When compared to open TME in Adequate visualization in the deep pelvis can often be a chal- another case-matched study, the robotic approach was superior in lenge. This may be a situation where the visual magnification and terms of LN harvest, distal margin length, blood loss, and length ability to enter tight spaces that are unique to the laparoscopic ap- of stay.101 Other potential benefits include decreased conversion proach may be an advantage. Several groups have demonstrated rates in three large meta-analyses as well as a trend toward reduced the feasibility of laparoscopic TME for low rectal cancer as part anastomotic leaks and CRM positivity with complete autonomic of a sphincter-preserving operation.78–80 Some of the larger series, preservation in a recent systematic review of 1,549 patients.102–105 while demonstrating that TME using laparoscopic techniques can Whether this data will translate into meaningful long-term advan- be performed safely, do not have adequate follow-up to demon- tages that justify the significantly higher cost of this approach re- strate whether there were any oncologic disadvantages to such an mains to be seen. approach. Unfortunately, the prospective random assignment trial The Robotic versus Laparoscopic Resection for Rectal Cancer conducted in the United States to evaluate the role of laparoscopic (ROLARR) trial is a prospective, randomized, controlled, multi- surgery for colon cancer excluded patients with low rectal lesions. center superiority trial that began enrollment in 2010, with a target In addition, subgroup analysis from the UK CLASICC trial re- recruitment of 400 patients. It will evaluate differences in conver- ported a 34% conversion rate and double the frequency of positive sion rates; CRM positivity, 3-year local recurrence, DFS and OS, margins compared to open cases (12% versus 6%), prompting the as well as operative morbidity and mortality, quality of life, and authors to advise against routine practice of laparoscopic proctec- cost-effectiveness. Investigators also wish to explore the purported tomy outside of the research setting.81 While these results have clinical benefits of robotics including preservation of normal blad- raised serious concerns regarding oncologic outcomes, follow-up der and sexual function. Results from this ambitious trial are anx- reports are more encouraging. Multiple single-institution experi- iously awaited.106 ences have now been published demonstrating not only similar surgical parameters (margin status, LN harvest numbers) but also comparable recurrence and 5-year survival data.82–86 Furthermore, Resection of Contiguous Organs and Total in a study based on National Surgical Quality Improvement Pro- Pelvic Exenteration gram data from 5,420 patients, Greenblatt et al.87 reported significant short-term advantages to laparoscopy, including decreased Although aggressive surgical approaches to rectal cancer have re- length of stay (5 days versus 7 days; p <0.0001) and 30-day morbid- sulted in improvement in locoregional recurrence rates, these rates ity (20.5% versus 28.8%; p <0.0001). Smaller randomized trials as can still be as high as 33%. Not infrequently, large rectal lesions well as two recent large meta-analyses of randomized controlled tri- will invade through the wall of the rectum into contiguous struc- als also support the oncologic equivalence of the two approaches, tures such as the bladder, prostate, vagina, and uterus. Carefully 88–90 although short-term benefits are mixed. In 10-year follow-up selected patients with recurrent or locally advanced rectal cancers OF ONCOLOGY PRACTICE data from a pooled analysis of three randomized controlled trials may benefit from an aggressive approach such as a total pelvic ex- (including 136 laparoscopic and 142 open cases), continued long- enteration. Local recurrences remain localized to the pelvis in a term oncologic safety of the laparoscopic approach was demon- significant number of patients, with autopsy studies demonstrating strated with no significant differences compared to open in terms the incidence of pelvic recurrence to be as high as 50%.107 of locoregional recurrence (5.5% versus 9.3%), cancer-specific Recurrences in the pelvis can result in significant morbidity survival (82.5% versus 77.6%), or OS (63% versus 61.1%). Addi- such as tenesmus, pain, bowel obstruction, and fistula. Although tionally, there was a trend toward lower recurrence among stage III some of these can be ameliorated with radiation, these problems patients in the laparoscopic group (17.7% versus 25.3%), though are best managed by preventing their occurrence. Although the this did not reach statistical significance.91 Lujan et al.92 also re- impact of total pelvic exenteration on survival has been debated, ported similar rates of local recurrence and OS in a prospective the potential benefits on controlling locoregional disease and pre- cohort of 4,405 patients but found decreased complication rates venting morbidity keeps this technique as one of the tools in the (38.3% versus 45.6%) and improved oncologic parameters with surgeon’s armamentarium when approaching large rectal lesions. laparoscopy, including decreased margin involvement and more Existing literature on multivisceral resection of both primary complete TME. Finally, in a smaller study by Westerholm et al.,93 and recurrent tumors has been recently evaluated in a systematic laparoscopic surgery was found to be an independent predictor of review of 22 studies comprising 1,575 patients. The authors re- DFS on multivariate analysis with 5-year DFS rates of 50.3% com- ported a 4.2% perioperative mortality rate with morbidity of 42.5%. pared to 71.0% after open resection. Definitive recommendations The overall 5-year survival rate was 50.3% with, not surprisingly, await the results of three ongoing multicenter phase 3 randomized worse outcomes in patients with recurrent compared to primary trials: the European COLOR II, the Japanese JCOG 0404, and the disease (19.5% versus 52.8%). R0 resection was achieved in 79.5% ACOSOG Z6051 from the United States.94 of cases and, also not surprisingly, was the strongest factor associ- While laparoscopic TME may be technically feasible, it re- ated with long-term survival.108 Another review focusing only on quires a high level of expertise and can be particularly challeng- locally recurrent tumors, reported R0 resection rates from 30% to ing to perform within the confines of a deep and narrow pelvis. 45% and 5-year global survival ranging from 30% to 40%, with More recently, robotic technology has been applied to rectal authors stressing the importance of careful patient selection.109 To dissection, overcoming many of the limitations associated with this end, a panel of 36 colorectal surgeons were recently recruited conventional laparoscopy including limited dexterity, inadequate to establish a scoring system for determining patient suitability for visualization, and tremor. Robotic surgery offers the advantages pelvic exenteration. A comprehensive list of clinicopathologic and of a stable, three-dimensional image, enhanced ergonomics and radiographic criteria were considered and ranked by importance articulating instruments with seven degrees of freedom, in addi- and utility in predicting negative resection margin. The authors tion to operator-controlled camera and retraction.95 Embraced by hope to apply this quantitatively toward improving outcomes for urologists and gynecologists over the past decade, this technology this highly invasive and morbid intervention.110 is ideally suited to pelvic procedures and has the potential to yield For symptomatic tumors that are not resectable, other pal- enhanced oncologic and functional outcomes in rectal cancer sur- liative options to consider include debulking and ablation. Ripley gery as well. Limited studies so far have demonstrated feasibility et al.111 reported some benefit associated with sequential open and acceptable short-term outcomes.95–99 In a case-control analy- radiofrequency ablation and surgical debulking in 16 patients, sis of 118 patients undergoing laparoscopic versus robotic resec- achieving a median survival of 12 months, with OS 24% at 36 tion, Kwak et al.100 reported no differences in surgical oncologic months, and 3 patients remaining with no evidence of disease at 9, 830 Practice of Oncology / Cancers of the Gastrointestinal Tract

48, and 84 months. There were four cases of significant postopera- TABLE 60.1 tive morbidity, however, and variable levels of symptom relief.111 Pusceddu et al.112 reported far better palliation with CT-guided Results of Dutch Total Mesorectal Excision Trial radiofrequency ablation in 12 patients with painful pelvic recur- ± Preoperative Radiotherapy Total rence. At the end of follow-up (23 23 months), 92% of patients (5 Gy × 5) + Total Mesorectal were symptom free, with a 16% treatment-related morbidity (one Technique Mesorectal Excision Excision Alone rectovesical fistula and one rectal abscess).112 Finally, transrectal high-intensity focused ultrasonography has now been described in Percentage of Patients the palliative treatment of rectal cancer. As the only completely Stage 0 or I 30 noninvasive thermal therapy, it can be delivered by either an intra- Local failure (2 y) 2.4 8.2 cavitary or extracorporeal device, causing focal ablation via coagu- lative necrosis. In the first case report, it was well-tolerated and led Local failure (4 y) 3 10 113 to immediate symptom relief. Local Failure (Distance from Anal Verge) 0–5 cm 5.8 10 Combined Modality Therapy (Stage II and III) 5–10 cm 1 10.1 The use of adjuvant radiation therapy is based on the substantial in- 10–15 cm 1.3 3.8 cidence of locoregional failure with surgical therapy alone. Older Stage III (4-y 20 studies demonstrate local failure rates of up to 50% in patients with estimate) T3-4 or node-positive disease (Table 60.1).114–120 The locoregional recurrence rates in these studies are in the range of 25% to 50% for From Kapiteijn E, Marijnen CA, Nagtegall ID, et al, Preoperative radiotherapy combined with total mesorectal excision for resectable rectal cancer. N Eng J patients with T3-4 and/or node-positive disease and is a dominant Med 2001;345:638–646, with permission. pattern of failure, although distant recurrence is also of great importance. Local failure is related not just to the stage of the disease, but also the location of the tumor in the rectum (tumors located low in the rectum have a higher incidence of local failure) and the recurrence risks could be decreased by limiting the surgeons experience and ability of the surgeon. However, the relevance of who were authorized to perform rectal surgery to those who were these older local recurrence data has been brought into question trained and certified in the procedure, and by having educational with the advent of the use of TME, as previously described. It is sessions for those who were performing the surgery.5 This raised important to realize that the data on local recurrence after primary the question of what is the true rate of local failure after TME to surgical resection come from selected series with operations per- help define which patients really require adjuvant therapy. formed by experienced surgeons who have been specially trained The most important analysis on local recurrence rates with in TME and may not be relevant to the operations performed by TME are the data from the Dutch TME study in which patients general surgeons who perform the operation only occasionally and were randomized to receive either TME alone or a short course who are not specially trained. of preoperative radiation therapy followed by TME.77 All patients Although initial studies reported locoregional failure rates of with rectal cancer were eligible, including those with early-stage <5% after TME without the use of any adjuvant therapy,75,77,121–123 disease. Special attempts were made to have good surgical and there was concern that these excellent results could not be repli- pathology quality control. The early results (2 years) relating to cated in larger population-based studies. A number of European local tumor recurrence have been reported and are summarized countries or regions have shown that the overall locoregional in Table 60.2. The study demonstrates that there are subsets of

TABLE 60.2 Local Failure of Rectal Cancer Surgery Alone (Local Failure Rate Percentage/Number of Patients in Cohort)

Mendenhall, Gunderson Rich Minsky Martling Million, and Pilipshen Bonadeo and Sosin117 et al.119 et al.211 et al.120 Pfaff114 et al.116 et al.228 Clinical First Failure— Total Local Exam + Clinical Exam Recurrence— First Total Local Reoperation Surgery + Surgery (5-y Total Local 5-y Follow-up Failure— Recurrence— Analysis (Crude) (Crude) Actuarial) Recurrence Clinical Clinical Clinicala T1N0 8%/39 11%/11 9%/78 0/6 0%/5 3%/103 T2N0 3%/36 38%/16 14%/128 T3N0 67%/6 24%/42 23%/60 34%/80 40%/30 30%/111 4%/181 T4N0 53%/15 11%/9 T1-2N+ 24%/17 50%/4 14%/11 37%/93 71%/17 22%/49 24%/133 T3N+ 83%/40 47%/34 25%/31 65%/17 49%/89 T4N+ 67%/6 22%/10 Total 64%/75 30%/142 15%/168 27%/251 46%/90 a Local recurrence highly dependent on site in rectum—18% overall for tumors ≤7 cm from anal verge.

tahir99 - UnitedVRG Chapter 60 Cancer of the Rectum 831

TABLE 60.3 Local Control and Survival with and without Radiotherapy—Preoperatively, Postoperatively, and with or without Chemotherapy

Disease-Free Study/Institutiona (Ref.) No. of Patients Local Failure (%) Survival (%) Survival (5 y) (%) NSABP RO-1129 Surg/Surg + 184/187 25/16 No difference No difference RT (postoperative RT) NSABP RO-2130 Surg + chemo/Surg + 348/346 13/8 chemo + RT (postoperative RT) GITSG127 Surg/Surg + RT/Surg + chemo + 58/50/46 25/20/10 44/50/65 26/33/45 RT (postoperative RT) Swedish215 Surg/Surg + RT (preoperative RT) 27/11 48/58 Stockholm II120 Surg/Surg + 34/16 Stage II RT (preoperative RT) 37/21 Stage II MRC132 Surg/Surg + RT (postoperative RT) 235/234 34/21 38/41

NSABP, National Surgical Adjuvant Breast and Bowel Project; Surg, surgery; RT, radiotherapy; chemo, chemotherapy; GITSG, Gastrointestinal Study Group; MRC, Medical Research Council. a Randomized studies in either all patients or patients with stage II and III disease.

patients in whom TME alone is likely sufficient for obtaining interval [CI] = 0.27 to 0.58; p <0.0001) and an absolute differ- good pelvic control, including patients with high rectal tumors ence at 3 years of 6.2% (4.4% preoperative radiotherapy versus (some of these may have been sigmoid cancers, rather than rec- 10.6% selective postoperative CRT; 95% CI = 5.3–7.1). A rela- tal) and low-stage tumors (T1-2, N0). On the other hand, low- tive improvement in DFS of 24% for patients receiving preop- = = = lying rectal tumors that are moderately advanced (T3-4 and/or erative radiotherapy (HR 0.76; 95% CI 0.62 to 0.94; p OF ONCOLOGY PRACTICE node-positive) had a higher incidence of locoregional failure. 0.013), and an absolute difference at 3 years of 6.0% (77.5% Local failure after TME alone was 15% in node-positive patients versus 71.5%; 95% CI = 5.3 to 6.8) was observed. OS did not at 2 years, not corrected for site of the primary, and longer-term differ between the groups (HR = 0.91; 95% CI = 0.73 to 1.13; follow-up will undoubtedly demonstrate higher local failure p = 0.40). These findings provide further evidence that short- rates. In addition, as these results were obtained in a controlled course preoperative radiotherapy is an effective treatment for setting, one would likely not obtain similarly good results when patients with operable rectal cancer.125 surgery is done with less careful quality control. There was a The data are excellent that radiation therapy, especially when consistent decrease in local failure rate by the addition of pre- combined with chemotherapy, can decrease the local failure rate. operative radiation therapy, but the absolute magnitude of the This is shown by a Swedish study of preoperative radiation therapy effect varied by the tumor characteristics previously discussed. compared with surgery,126 the Dutch TME trial in the preop- Long-term results from the Dutch TME study have now been erative setting,76 and by multiple studies in the postoperative set- published demonstrating a stable, persistent >50% reduction in ting.127–132 There are also excellent data to show that locoregional recurrence risk for the radiotherapy group after a median follow- failure is decreased by the use of radiation therapy and is further up of 12 years. For patients with a negative circumferential mar- decreased by the use of concurrent 5-FU–based chemotherapy gin, the benefit was even greater, with the 10-year cumulative (Table 60.3).127,128,133 Most studies have demonstrated that local incidence of local recurrence 3% after radiotherapy versus 9% failure decreases by about 50% with the use of adjuvant radiation after surgery alone (p <0.0001) and the incidence of distant re- therapy, with a greater effect when concurrent 5-FU is used with currence 19% versus 24% (p = 0.06). In addition, the incidence irradiation. This appears to provide a strong justification for the of cancer-specific death at 10 years was 17% for the irradiated use of adjuvant radiation therapy. What is less clear is whether tri- group versus 22% for surgery alone (p = 0.04). OS rates, how- modality therapy with radiation therapy improves survival, if radio- ever, were equivalent.124 chemotherapy should be given preoperatively or postoperatively, A trial similar to the Dutch TME study was recently re- and precisely which patients should be irradiated. To that effect, ported. This phase 3 trial randomized 1,350 patients with oper- Schrag et al.134 investigated the use of a neoadjuvant chemother- able adenocarcinoma of the rectum to short-course preoperative apy utilizing a 5-FU–leucovorin-oxaliplatin (FOLFOX)-based radiotherapy (25 Gy in five fractions;n = 674) or to initial sur- regimen, with selective use of chemoradiation therapy only in gery with selective postoperative chemoradiotherapy (CRT; 45 those patients who had failed to demonstrate tumor improvement Gy in 25 fractions with concurrent 5-fluorouracil [5-FU]) re- on neoadjuvant chemotherapy. Of the 30 patients treated with- stricted to patients CRM involvement (n = 676). The primary out radiation therapy in this small pilot trial, none experienced outcome measure was local recurrence. At the time of analysis, local recurrence with a minimum follow-up of 4 years.134 Three 330 patients had died (157 preoperative radiotherapy group ver- patients experienced distant failure, all in the lungs. This inter- sus 173 selective postoperative CRT), and median follow-up of esting pilot trial has led to the current phase 3 cooperative group surviving patients was 4 years. A total of 99 patients developed trial comparing this approach of neoadjuvant chemotherapy plus local recurrence (27 preoperative radiotherapy versus 72 selec- selective use of radiation versus standard neoadjuvant chemoradia- tive postoperative CRT). A reduction was noted of 61% in the tion therapy. Pending any new information from this randomized relative risk of local recurrence for patients receiving preopera- trial, neoadjuvant chemoradiation therapy remains appropriate tive radiotherapy (hazard ratio [HR] = 0.39; 95% confidence standard practice. 832 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 60.4 with the use of radiation therapy (and presumably with concurrent chemoradiation therapy) is beneficial, and that trimodality Results of Meta-Analysis, Preoperative therapy, especially when chemoradiation therapy is used preopera- Radiotherapy Versus Surgery Alone tively, can improve survival. Result Preoperative Radiotherapy vs. Surgery Overall 5-y mortality OR = 0.84 (p = 0.03) PREOPERATIVE RADIATION THERAPY 5-y cancer mortality OR = 0.71 (p <0.001) The second issue of importance is whether adjuvant therapy = < 5-y local recurrence OR 0.49 (p 0.001) should be given preoperatively or postoperatively and the exact 5-y distant metastases OR = 0.93 (p = 0.54) timing of the chemotherapy. Current data clearly favor the preoperative approach. OR, overall recovery. From Camma C, Giunta M, Fiorica F, et al. Preoperative radiotherapy for Perhaps the most important study addressing the issue of resectable rectal cancer: A meta-analysis. JAMA 2000;284:1008–1015, with pre- versus postoperative adjuvant therapy is a German trial of permission. preoperative versus postoperative chemoradiation with radiation therapy given at 1.8 Gy per fraction and using continuous- infusion 5-FU chemotherapy as a 120-hour infusion, for which results have been reported by Sauer et al.137 This study demonstrates an DOES ADJUVANT RADIATION THERAPY advantage in sphincter preservation with the use of preoperative IMPACT SURVIVAL? therapy. Of the patients thought to need an APR at initial assessment, only 19% had a sphincter-preserving surgery when opera- Although there have been multiple randomized trials addressing tion was done immediately versus 39% after preoperative radiation the use of adjuvant radiation therapy or chemoradiation therapy, therapy, although there was no difference in the overall sphincter and although they consistently show an improvement in local preservation rate. There was a statistically significant decrease in control with adjuvant radiation therapy, the survival outcome data local failure with preoperative radiation therapy compared to post- have been mixed. In the past, there have been two meta-analyses operative treatment (6% versus 13%; p = 0.006). The relative risk 135,136 performed. Table 60.4 shows the results of a meta-analysis by of local failure in the pre- versus postoperative treatment group was 136 Camma et al. showing a decreased local recurrence rate, cancer 0.46. The 5-year DFS showed a small advantage to preoperative mortality rate, and overall mortality rate with the use of preop- therapy (68% versus 65%; p = 0.32), which was not statistically sig- erative radiation therapy, although without a decrease in distant nificant. There was a decrease in late anastomotic strictures with metastasis rate. The Colorectal Cancer Collaborative Group study preoperative therapy, and acute toxicity was also decreased by the (Table 60.5) demonstrates no improvement in the likelihood of use of preoperative radiation and chemotherapy, both statistically curative surgery with preoperative therapy or of OS with all types significant. This provides strong evidence of the superiority of pre- 135 of radiation therapy combined. Preoperative radiation therapy, operative adjuvant treatment in patients in whom it is determined however, was shown to improve local control, DFS, and OS com- that adjuvant therapy is needed. Eleven-year follow-up data for this pared with surgery alone, although deaths within the first year after study have just been published, demonstrating a persistently sig- surgery were higher after radiation therapy. Local recurrence with nificant improvement in local control for pre- versus postoperative preoperative radiation therapy was 46% lower than surgery alone, chemoradiation (local relapse rates 7.1% versus 10.1%; p = 0.48). and cancer deaths were decreased from 50% to 45%. Postoperative However, there was still no effect on OS or distant metastases, radiation therapy was shown to improve local control (although highlighting the need for more effective systemic therapy than just less than preoperative therapy), but did not impact long-term sur- 5-FU–based regimens.138 vival. Lending substantial strength to the conclusion that there was As multimodality treatment regimens are intensified to achieve a true advantage to radiation therapy is the fact that there was a even better outcomes, it is important to identify subgroups of dose response demonstrated for the radiation effect on local con- patients at higher risk for severe toxicity and treatment interrup- trol (i.e., better control was obtained with higher radiation dose). tion, both through investigation of predictive markers as well as This observation strengthens the conclusion, as it demonstrates a attention to basic clinical parameters. In an unplanned analysis direct correlation between the amount of therapy and outcome. of the German trial data, Wolff et al.139 found female gender to be The data from this analysis are heavily influenced by the results of significantly associated with CRT-induced acute toxicity but also a single Swedish study that showed a long-term survival advantage associated with improved 10-year OS (62.7% versus 58.4%; p = to the use of preoperative radiation therapy compared with sur- 0.066). Men with no acute organ toxicities had much poorer OS 126 gery alone. Thus, these data show that improving local control compared to the rest, leading the authors to conclude that acute toxicity was a significant prognostic parameter and possibly a surrogate for treatment response. Future efforts will need to focus on mitigating this toxicity in susceptible patients without compromis- TABLE 60.5 ing treatment intensity.139 Colorectal Cancer Collaborative Group 2001 Similar to the goals of the German trial, the National Surgical Adjuvant Radiation Therapy in Rectal Cancer Adjuvant Breast and Bowel Project (NSABP) R-03 trial compared neoadjuvant versus adjuvant CRT in the treatment of locally ad- Preoperative Postoperative vanced rectal carcinoma. Patients with clinical T3 or T4 or node- RT vs. Surgery RT vs. Surgery positive rectal cancer were randomly assigned to preoperative or postoperative CRT. Chemotherapy consisted of 5-FU and leuco- Yearly risk of local recurrence 46% decrease 37% decrease vorin with 45 Gy in 25 fractions with a 5.40-Gy boost within the with RT with RT original margins of treatment. In the preoperative group, surgery Death rate 5% less than No difference was performed within 8 weeks after completion of radiotherapy. with surgery from surgery In the postoperative group, chemotherapy began after recovery from surgery but no later than 4 weeks after surgery. The pri- RT, radiotherapy. From Colorectal Cancer Collaborative Group. Adjuvant radiotherapy for rectal mary end points were DFS and OS. A total of 267 patients were cancer: a systematic overview of 8507 patients from 22 randomised trials. randomly assigned to NSABP R-03. The intended sample size Lancet 2001;358:1291–1304, with permission. was 900 patients. Excluding 11 ineligible and 2 eligible patients

tahir99 - UnitedVRG Chapter 60 Cancer of the Rectum 833

without follow-up data, the analysis used data on 123 patients recurrence continues to increase with time. In addition, late toxici- randomly assigned to preoperative and 131 to postoperative CRT. ties may manifest many years following treatment. Surviving patients were observed for a median of 8.4 years. The Another question is whether the time interval between radia- 5-year DFS for preoperative patients was 64.7% versus 53.4% for tion and surgery is more important than the duration of the preop- postoperative patients (p = 0.011). The 5-year OS for preoperative erative treatment itself. Pettersson et al.144 evaluated 112 patients patients was 74.5% versus 65.6% for postoperative patients (p = who underwent short-course radiotherapy (25 Gy over 5 to 7 days) 0.065). A pCR was achieved in 15% of preoperative patients. No with delayed surgery >4 weeks and found a significant downstag- preoperative patient with a pCR has had a recurrence. The in- ing effect not previously seen with immediate resection.144 An- vestigators concluded that preoperative CRT, compared with post- other study in which 154 patients receiving short-course radiation operative CRT, significantly improved DFS and showed a trend were prospectively randomized to immediate surgery (7-day to toward improved OS.140 10-day interval) versus delayed (4 weeks to 5 weeks) also demon- In addition to improving survival, another reason for using strated a higher downstaging rate in the latter group (13% versus preoperative chemoradiation therapy is to increase the chance for 44.2%; p = 0.0001). In addition, there was reduced systemic re- sphincter preservation for patients with low-lying tumors of the rec- currence (2.8% versus 12.3%; p = 0.035) and a trend toward im- tum, where an abdominoperineal resection would be convention- proved 5-year survival (73% versus 63%). Interestingly, however, ally used. The NSABP R-03 trial was able to obtain worthwhile delayed surgery was not associated with superior locoregional information regarding this issue. When a patient was first seen, control or increased rates of sphincter-saving procedures and cu- the surgeon was asked (for both preoperative and postoperative rative resections.145 Further trials are necessary to determine the patients) what operation was needed. In the patients randomized ideal schedule of radiotherapy and surgery that optimizes both to postoperative radiation therapy (i.e., immediate surgery), the downstaging and overall oncologic outcomes. Some clinicians are determination in the office corresponded extremely well to the op- advocating even more extended intervals between radiation and eration actually performed. However, in the patients who received surgery. In a review of 1,593 patients, the median interval from the preoperative radiation therapy, sphincter-preserving surgery was start of radiotherapy was 14 weeks (range, 6 weeks to 85 weeks; in- done in 50% of patients compared with 33% of those who had terquartile range, 12 weeks to 16 weeks) with the highest pCR rate initial surgery.141 However, the data have been inconsistent overall found in patients undergoing resection at 15 weeks to 16 weeks in demonstrating an advantage to preoperative therapy in terms (18%; p = 0.013).146 of sphincter preservation. The analyses are complicated because There are theoretical reasons to believe that radiation ther- the decision as to whether sphincter-preserving surgery should be apy delivered preoperatively would decrease the toxicity of ther- done is heavily dependent on the biases of the surgeon. If the sur- apy. With postoperative radiation therapy, the soft tissues of the geon believes that the same operation should be done regardless perineum are at risk for involvement after an APR because of sur- of tumor regression, then clearly the same surgery will be done. gical manipulation and, therefore, need to be irradiated with its

There are some surgeons who will do sphincter-preserving op- attendant acute skin toxicity. This is not needed with preopera- OF ONCOLOGY PRACTICE erations after preoperative irradiation, when they would not have tive therapy. With postoperative radiation therapy, normal bowel done so if the surgery had been done first. is moved into the pelvis for the anastomosis after a low anterior If one is using preoperative radiotherapy to try to improve the resection and therefore is irradiated and at risk for late toxicity. In likelihood of sphincter preservation, the radiation must be given in the preoperative setting, much of the irradiated bowel is removed such a way as to maximize the likelihood of this occurring. Spe- with the surgical specimen and therefore is not at risk for produc- cifically, a “standard” long course of irradiation to a dose of ap- ing late bowel injury. There is also likely to be a higher risk of proximately 50 Gy at 18 to 20 Gy per fraction over 5 to 5.5 weeks having small bowel fixed in the pelvis after surgery secondary to (as given in the German trial mentioned previously) has been adhesions, which could also lead to late toxicity. On the other thought by most US investigators to be optimal. The short-course hand, many studies have demonstrated that acute surgical morbid- therapy with immediate surgery (typically 50 Gy for five fractions ity and mortality are not substantially increased with the use of pre- given over 1 week), as often used in Europe, followed by imme- operative irradiation, although many surgeons routinely perform diate surgery is not likely to produce enough tumor shrinkage to a temporary diverting colostomy in order to avoid the problems allow for sphincter preservation in patients with very low-lying associated with an anastomotic leak. Except for the German trial tumors. Bujko et al.142 have published data that suggest that the previously mentioned, which shows decreased acute and late toxic- short course is as effective in producing local control as the longer ity, data on late toxicity are not available to directly compare the course of therapy. A total of 312 patients were randomized to either two techniques when used with concurrent chemotherapy and the 25 Gy in 5 fractions followed by surgery within 1 week, or 50.4 Gy commonly used dose/fractionation schedules. in 28 fractions with concurrent bolus 5-FU and leucovorin and To better evaluate the impact of preoperative chemoradia- surgery 4 to 6 weeks later. DFS was respectively (short- versus long- tion on long-term functional outcome, Loos et al.147 performed course therapy) 58.4% versus 55.6%; local recurrence, 9% versus a systematic review and meta-analysis of 25 studies and 6,548 pa- 14.2%; severe late toxicity, 10.1% versus 7.1%; and acute toxicity, tients, including six randomized controlled trials and previously 3.2% versus 18.2%. There was no improvement in sphincter pres- published data from the Dutch TME trial. Although there was ervation with long-course treatment. Although this was a relatively substantial heterogeneity of the included trials and low methodo- small study, it provides important evidence to support the value of logic quality, the authors suggest that preoperative treatment has a short-course preoperative therapy. A second randomized trial from largely negative impact on long-term anorectal function but does the Australian Intergroup randomized 326 patients with T3 rectal not significantly affect sexual or urinary performance compared cancer within 12 cm of the anal verge to short-course radiotherapy to surgery alone. Without better designed trials, however, that in- (25 Gy in five fractions) or CRT (50.4 Gy with continuous infusion clude standardized pre- and postoperative assessment of these pa- 5-FU). Both arms received adjuvant chemotherapy. The primary rameters as well as direct comparison to postoperative treatment, end point, locoregional recurrence at 3 years, was not significantly no definitive conclusions can be drawn.147 different at 7.5% for short-course radiotherapy and 4.4% for CRT As the retrospective meta-analyses have generally shown bet- with no difference in distant recurrence rates or OS. At median fol- ter tumor control locally and better evidence of a survival advan- low-up of 6 years, there were no differences in late toxicity rates.143 tage secondary to preoperative irradiation, many gastrointestinal Both the Polish and Australian Intergroup trials were relatively oncologists prefer preoperative CRT for the patient who clearly small and not powered to show equivalence of long-course CRT requires adjuvant radiation therapy. A reasonable strategy at pres- and short-course radiotherapy. Both trials have relatively short fol- ent is to use preoperative CRT for patients in whom there is little low-up and, as indicated by other randomized trials, locoregional doubt about the advisability of adjuvant therapy (T3 node-positive 834 Practice of Oncology / Cancers of the Gastrointestinal Tract or T4 disease) or patients with low-lying tumors in whom an APR T1-2N1 disease,17,18,151 those with primary tumors located high in may still be avoided, but to use initial surgery for other patient the rectum, those with wide circumferential margins on the final cohorts, with postoperative CRT used based on the operative and pathology specimen,29,30 those with node-negative disease after pathologic findings. multiple (12 to 14 or more) nodes have been evaluated,19–21,152 and Another issue of importance is the timing of chemotherapy. It those in whom TME surgery had been performed by an experi- has been assumed by many investigators that concurrent preop- enced colorectal oncologic surgeon.153,154 In the preoperative set- erative chemotherapy and postoperative adjuvant chemotherapy ting, only some of this information will be available at the time a is the proper way of delivering treatment. A study by the Euro- therapeutic decision must be made, but some information will be pean Organization for Research and Treatment of Cancer, how- available (including knowledge of the surgeon). In addition, one ever, questions these assumptions.148 Patients were randomized to must consider the known inaccuracy of transrectal ultrasound in receive either preoperative radiation therapy alone, preoperative staging and the experience of the ultrasonographer.33,60 However, CRT, preoperative radiation therapy and postoperative chemo- if most of these conditions are met, it is possible that routine adju- therapy, or preoperative CRT and postoperative chemotherapy. vant radiation therapy, and perhaps chemotherapy, is not required Chemotherapy was bolus 5-FU (350 mg/m2 per day for 5 days) for the lower-stage tumors. and leucovorin (20 mg/m2 for 5 days) with two cycles given with Another question is which patients are unlikely to respond to radiation therapy and four cycles postoperatively for the appropri- chemoradiation at all and would only be disadvantaged by the tox- ate groups. Local recurrence rates were roughly similar for all pa- icities and delay in surgical treatment. Numerous biomarkers and tients receiving chemotherapy regardless of timing (7% to 9%) and tumor-related features are under investigation as potential predic- significantly improved compared with those patients not receiving tive factors of response, and this will have important implications any chemotherapy (17%). There was no difference in survival out- for preoperative patient selection as well.155–165 Among these bio- comes based on the timing of chemotherapy. The 5-year DFS rates markers, KRAS has received quite a lot of attention, but results are were 52.2% and 58.2% in the no adjuvant treatment groups and conflicting. Previous reports suggest that mutated tumors are less the adjuvant treatment groups, respectively (p = 0.13). likely to develop a pCR compared to wild-type. Duldulao et al.166 Two recent Cochrane reviews have addressed the role of has recently published follow-up data that support this (13% versus adding chemotherapy to preoperative radiation regimens. The 33% pCR in KRAS mutant versus wild-type; p = 0.006).166 How- first included six randomized controlled trials, with a total of ever, a larger meta-analysis of eight series and 696 patients showed 247 patients, comparing preoperative CRT to radiation alone in no association between KRAS status and pCR, tumor downstag- the treatment of stage III cancers. Thirty-day mortality, sphincter ing, or cancer-related mortality. Although limited by the hetero- preservation rates, and late toxicity events were similar between geneity of its included studies, this report highlights the need for groups. A significant increase in acute grade 3/4 toxicity was seen caution when considering biomarkers in the context of clinical in patients who received CRT versus radiation alone. While there decision making.167 Another newly described method for predict- was no difference in OS, CRT was associated with significantly ing response to neoadjuvant therapy involves measuring histologic less local recurrence (OR = 0.56; p <0.0001).149 A second meta- changes in the tumor soon after the initiation of treatment. Suzuki analysis, including five randomized controlled trials, addressed et al.168 evaluated biopsies obtained 7 days into the CRT course, similar questions in stage II-III disease and reported similar find- comparing expression levels of various apoptotic markers and cel- ings. The addition of chemotherapy increased grade 3/4 toxicity lular changes to pretreatment findings as well as to the final surgical with no impact on postoperative mortality, anastomotic leak rate, specimen. Markers and cellular features of apoptosis at 7 days were or sphincter preservation. There was also a significant reduction in strongly correlated with pCR and tumor regression. This study of- 5-year local recurrence rate (OR = 0.39 to 0.72; p <0.001) as well fers another potential strategy for identifying patients who might as an increase in pCR (OR = 2.12 to 5.84; p <0.00001) in the benefit from early alternative interventions.168 At the present time, CRT group, but again no differences in survival. Additional studies most patients treated outside clinical trials that have T3-4 and/or with longer follow-up are needed to determine the full benefit of node-positive disease should probably receive neoadjuvant CRT if preoperative chemotherapy as well its impact on functional out- there are no extenuating circumstances. However, for patients who come and quality of life.150 meet the previously mentioned favorable criteria, especially those with high rectal T3 N0 tumors, avoiding neoadjuvant radiation therapy and perhaps chemotherapy can be considered. Clinical WHICH PATIENTS SHOULD RECEIVE trials will need to be performed to help resolve which subsets of ADJUVANT THERAPY? patients do not require routine adjuvant radiation therapy. New data suggests that for the subset of patients who are confirmed to For either pre- or postoperative therapy, the physician needs to ad- be node-negative after neoadjuvant chemoradiation and curative dress the issue of precisely which patients need to receive adjuvant surgery, little benefit may be derived from additional postopera- radiation therapy and chemotherapy. At the present time, these tive treatment. In two studies, long-term survival and recurrence two modalities have been completely linked in US clinical trials, outcomes were compared between patients with ypN0 rectal can- so it is not possible to determine if there are subsets of patients cer who did and did not receive adjuvant chemotherapy. Overall, who might benefit from one modality and not the other. In addi- there was minimal difference between the two groups with prog- tion, recent US trials have all used chemotherapy concurrent with nosis primarily determined by pathologic stage.169,170 However, the radiation therapy in addition to postradiation chemotherapy, these nonrandomized data should be regarded as preliminary and so it is not possible to determine the relative importance of each hypothesis-generating; postoperative chemotherapy should be the modality. default position in these patients, and deviations from this plan Based on the historical patterns of failure data, which dem- should only be made on an individual basis after a detailed review onstrated high local failure rates with surgery alone for patients of the patient’s comorbidities, relative risks, and benefits, and a de- with T3 and/or node-positive disease, virtually all US studies have tailed discussion of this with the patient. evaluated this entire patient population. However, many of these Another important area of investigation is whether patients who studies predate the routine use of now-standard TME surgery, and have a complete clinical response to neoadjuvant therapy can be more detailed analyses have allowed us to define characteristics safely managed with a nonoperative, “watch and wait” approach. In that help define relatively low-risk and relatively high-risk patient other words, can the organ-preserving multidisciplinary algorithm, subsets. As mentioned earlier, among the patients conventionally which is now the standard of care for anal cancer, be adopted for treated with adjuvant CRT, a number of relatively lower risk cat- rectal malignancy as well? This “wait and see” approach was first egories have been identified. Those include patients with T3N0 or seriously addressed in a seminal study by Habr-Gama et al.,171

tahir99 - UnitedVRG Chapter 60 Cancer of the Rectum 835 which compared the outcomes of 71 clinically complete respond- have been reported. Cercek et al.176 reported a retrospective series ers who were observed without surgery to a well-matched group of 61 patients who received some or all of their planned chemo- of patients with pCR who were resected. After a mean follow-up therapy as initial treatment for rectal cancer. Of these 61, 19 (31%) of 57 months, there were no cancer-related deaths in the obser- had either a pCR (14 patients) or had a complete clinical response vation group and recurrence rates were extremely low regardless and elected to pursue nonoperative management (5 patients). of treatment strategy.171 Another more recently published study Perez et al.177 reported preliminary results of a prospective trial from a different group reported similar results. In this report, 21 of this approach in 36 patients and concluded that a larger pro- patients who achieved a clinical complete response were followed portion of patients were able to complete all planned FOLFOX without surgery for a mean of 25±19 months and compared to chemotherapy than would have been expected from postoperative 20 patients who underwent resection with pCR.172 There was one administration. Given the expense of a large-scale trial of initial local recurrence in the observed group, treated with local exci- versus postoperative chemotherapy, it is clear that an adequately sion, and two deaths in the control group. In addition (not surpris- powered trial comparing these two approaches will never be done. ingly) functional outcome was significantly better in the patients The potential benefits of initial chemotherapy are several. Firstly, who did not undergo surgery. Despite the small sample size and it allows for administration of full-dose chemotherapy earlier in the short follow-up, these results lend further credibility to the “wait course of treatment and appears to permit greater dose intensity, and see” approach in carefully selected patients with rectal cancer. which may improve treatment of distant micrometastases and so A similar report from yet a third group noted that in 32 patients improve long-term outcome. It also allows for patients requiring carefully selected over a 5-year period, with a median follow-up of temporary ostomies after resection to have those ostomies closed 28 months, 6 patients experienced local recurrence (3 of whom after only 2 months and to not have to tolerate chemotherapy dur- also had distant recurrence), and all 6 patients were able to un- ing the time they have an ostomy. In addition, the approach of dergo resection of the recurrent primary to achieve local control. delivering all planned chemotherapy and radiation therapy pre- When compared in an exploratory analysis to a control group of operatively allows for a favorable platform from which to consider patient treated in the same institution who had undergone resec- nonoperative management in carefully selected patients. tion and had been found to have a pCR, 2-year distant DFS and A critical component of the “wait and see” approach is the abil- OS appeared to be similar. Of course, these numbers are small and ity to accurately identify pathologic complete responders in the nonrandomized, and follow-up is short; however, the experience preoperative setting. While many strategies have been utilized to- further supports the investigation of selective nonoperative man- ward this end, including endoscopic evaluation, imaging, and tis- agement in patients who achieve a clinical complete response.173 sue biopsy, there is no consensus on the optimal method and each Given continued improvements in adjuvant therapies as well has significant limitations. Endoscopic evaluation and close sur- as the increasingly sophisticated imaging modalities available veillance have long been considered important tools for detecting for follow-up, a new organ-sparing algorithm for treatment war- residual or recurrent malignancy. A recent expert consensus article

rants further consideration. At present such an approach outside described the cardinal signs of incomplete tumor response: deep OF ONCOLOGY PRACTICE a clinical trial represents a clear departure from standard practice, ulceration with or without necrosis, superficial ulceration or mu- and should only be considered in a fully informed patient who cosal irregularity, a palpable nodule despite mucosal integrity, or is willing and able to comprehend and accept the inherent risks. significant stenosis.178 Using these criteria, Smith et al.179 reported Logically, this approach seems most appropriate for consideration that an endoscopic, or “clinically complete,” response was 90% in those patients with distal tumors, in whom either an APR or a predictive of pCR. Sensitivity of this assessment was low, however, low anastomosis with poor functional outcome would be required. with 61% of the pathologic complete responders demonstrating As noted previously, PET scans have insufficient sensitivity and ultimately false signs of incomplete clinical response.179 specificity to be relied on in terms of determining the presence or A variety of imaging modalities have been applied to evaluate absence of a complete clinical response, and should not be used tumor burden after neoadjuvant therapy as well. Most are lim- for this purpose. ited by the inability to differentiate postradiation fibrosis from re- One aspect of combined modality therapy, which is undergo- sidual cancer cells. Guillem et al.180 found PET and CT equally ing reconsideration at some centers, is the order of administration inadequate in distinguishing complete from partial pathologic of modalities of therapy. As noted in detail previously, preopera- responders in a prospective analysis of 121 patients. Among the tive chemoradiation followed by surgery followed by postopera- 26 patients with a complete response, only 54% and 19% were tive chemotherapy is the most commonly used approach. The correctly classified by PET and CT scans, respectively. And of the role of administering all therapy, both chemotherapy and CRT 95 patients with an incomplete response, 66% and 95% were ap- prior to surgery has become of increasing interest, however. Chau propriately recognized by these techniques.180 Perez et al.181 also et al.174 were the first to publish an experience using induction found PET/CT lacking in its ability to definitively identify pCR. capecitabine plus oxaliplatin (Cape/Ox) for 3 months prior to In a series of 99 patients, imaging yielded 5 false-negative and 10 radiation plus capecitabine in 77 patients with poor-risk rectal false-positive results, giving PET/CT a 93% sensitivity, 53% speci- cancer.174 The response rate to Cape/Ox chemotherapy alone was ficity, 73% negative predictive value, and 87% positive predictive 88%, with 86% of patients achieving symptomatic relieve within a value for the detection of residual cancer. Accuracy of PET/CT median of 32 days of starting therapy. Fernandez-Martos et al.175 was 85%, which was inferior to that of clinical assessment alone published a small randomized phase 2 trial in which a total of at 91%.181 Much attention has focused on the role of MRI in 108 patients with rectal cancer were randomly assigned to either evaluating tumor burden at all stages of rectal cancer manage- standard order chemoradiation followed by surgery followed by ment. Diffusion-weighted MRI has been particularly useful for Cape/Ox chemotherapy, or to Cape/Ox chemotherapy first, fol- predicting tumor response in multiple sites and has the advantage lowed by surgery. As might be anticipated from the small size of of providing a quantitative measurement (apparent diffusion co- this trial, there were no differences between the arms in terms of efficient), which can be tracked longitudinally and compared to efficacy, with pCR rates and R0 resection rates being essentially pretreatment values. However, this modality is also limited in its the same; however, greater dose intensity of both oxaliplatin and ability to distinguish residual solitary tumor cells from a complete capecitabine was achieved in the group receiving preoperative response.182 chemotherapy, and higher grades 3 and 4 adverse events were Endoscopic biopsies seem to be the most unreliable measure seen during postoperative versus preoperative chemotherapy. The of tumor response, with one study reporting a negative predictive toxicities and dose intensities during the combined CRT were es- value of 11% (only 3 of the 28 negative biopsies were associated sentially the same in the two arms. Subsequently, several other an actual tumor-free specimen after definitive resection).183 These single-institution experiences with this total neoadjuvant approach disappointing results might be explained by the fact that residual 836 Practice of Oncology / Cancers of the Gastrointestinal Tract tumor cells do not necessarily reside in the most superficial lay- trial showed no benefit for the inclusion of oxaliplatin, with sub- ers of the bowel wall. In fact, Duldulao et al.184 reports that, in stantially increased toxicity in the oxaliplatin-containing arm. analysis of 94 patients with yPT2-4 tumors, only 13% had cancer A large trial of capecitabine versus bolus 5-FU confirmed that cells remaining in the mucosa and only 56% in the submucosa. capecitabine is noninferior to 5-FU in this setting. Final results The majority of tumor burden after neoadjuvant therapy appears from this trial are now published, demonstrating superior 5-year to be located at the invasive front, or deepest layer of the bowel OS (76% versus 67%; p = 0.05) and 3-year DFS (75% versus wall, suggesting that only a full-thickness or excisional biopsy 67%; p = 0.07) for patients who received capecitabine in both could accurately detect residual malignancy.184 The question adjuvant and neoadjuvant cohorts. There were similar rates of then becomes where to perform this biopsy. In a recent study, local recurrence in each group (6% versus 7%), but fewer pa- Hayden et al.185 found that a significant amount of “tumor scat- tients receiving capecitabine developed distant metastases (19% ter” occurs after neoadjuvant therapy, with 49.1% of cancer cells versus 28%; p = 0.04).191 These findings suggest greater systemic located outside the visible ulcer or deep to normal-appearing mu- efficacy of capecitabine compared to bolus 5-FU and mirror the cosa. Moreover, the mean distance of distal scatter was 1.0 cm conclusions drawn from the most recent X-ACT trial data for from the visible edge to a maximum of 3 cm, indicating that nei- stage III colon cancer. Long-term follow-up from this study over a ther gross ulceration nor the traditional 2 cm margin can be used median of 6.9 years demonstrated that capecitabine significantly to adequately guide biopsy or excision of the potential residual improved both DFS and OS with a better overall safety profile tumor.185 Additionally, even if complete full-thickness excision than 5-FU/folinic acid in the adjuvant setting.192 of the tumor site and all remaining potential cancer cells within There has been greater interest in the use of oxaliplatin added the bowel wall were accomplished, a sterile specimen does not to 5-FU and radiation therapy, although thus far the results have guarantee complete nodal response. While the rate of LN involve- been disappointing. A phase 1/2 study performed by the Cancer ment in patients with a ypT0 lesion is small, it is not zero (7.7% and Leukemia Group B demonstrated the feasibility of concur- and 9.1% in recent reports), and therefore there is ultimately no rent oxaliplatin, 5-FU, and radiation therapy,193 as did a German conclusive method for determining a pCR short of total mesen- multicenter phase 2 trial,194 and the previously mentioned Radia- teric excision.186,187 tion Therapy Oncology Group randomized phase 2 trial.195 The NSABP, as part of their R-04 trial, is doing a second randomization to the use of weekly oxaliplatin (50 mg/m2 per day) with an CONCURRENT CHEMOTHERAPY evaluation of pCR and local control as end points. However, phase 3 results have begun to emerge, and they are not as encour- The use of adjuvant chemotherapy has centered on the use of aging as had been hoped.196 The French ACCORD cooperative 5-FU chemotherapy, although this drug has been in use for over group reported a trial in which 598 patients with locally advanced 50 years and is not very effective for colon or rectal cancer. The rectal cancer were randomly assigned to preoperative treatment initial trials of trimodality therapy in rectal cancer used bolus with 5 weeks of radiation therapy (45 Gy in 25 fractions) with 5-FU at a dose of 500 mg/m2 per day for 3 days during weeks 1 concurrent capecitabine 800 mg/m2 twice daily 5 days per week and 5 of the radiation therapy. This was the approach routinely or the same regimen plus oxaliplatin 50 mg/m2 once weekly.197 used until the results of the North Central Cancer Treatment There was not a statistically significant difference in the primary Group study testing the use of long-term continuous infusion end point of the trial, the pCR rate, which was 13.9% without 5-FU with postoperative radiation therapy (bolus 5-FU was used and 19.2% with oxaliplatin (p = 0.09). More preoperative grade both before and after the radiation therapy) were reported.133 3–4 toxicity occurred in the oxaliplatin group (25% versus 1%; This study demonstrated an advantage to continuous infusion p <0.001). There were no statistically significant differences be- 5-FU (only during radiation therapy) compared with bolus tween groups in the rate of sphincter-preserving operations (75%), 5-FU in terms of local control, DFS, and OS. Because of this and no differences in terms of rates of serious medical or surgi- result and the encouraging results found with more aggressive cal complications or postoperative deaths at 60 days (0.3%). The therapy in colon cancer, it was logical to think that further inten- authors concluded that the trial did not support the addition of sification of chemotherapy would be of value both for local and oxaliplatin to this regimen, and that oxaliplatin should not be systemic control. used with concurrent irradiation in standard practice. They did Unfortunately, this expectation has not been borne out. Two not detect an improvement in the frequency of clear circumferen- large US Gastrointestinal Intergroup trials have been run testing tial radial margins, and they speculated that further investigations intensification with either more aggressive 5-FU and leucovorin, are warranted in selected populations. Secondary end point data additional continuous infusion 5-FU, and other combinations, from this trial have just been published demonstrating no advan- with data demonstrating no advantage.188,189 Thus, we are left with tage in clinical outcomes with the addition of oxaliplatin either. evidence that continuous infusion 5-FU during radiation therapy At 3 years follow-up, there were no significant differences in local is of value in improving local control, distant metastases, and sur- recurrence, OS, or DFS.198 vival, but no evidence that anything other than simple 5-FU or A large Italian cooperative group phase 3 trial reached a similar 5-FU plus leucovorin should be used during the chemotherapy result.199 A total of 747 patients were randomly assigned to either portion of the therapy. As will be discussed in the following, at 5-FU infusion (225 mg/m2 per day) concomitant with external present we do not have compelling evidence that addition of other beam pelvic radiation (50.4 Gy in 28 daily fractions) or the same agents, such as oxaliplatin, irinotecan, bevacizumab, cetuximab, regimen plus weekly oxaliplatin (60 mg/m2 × 6). The primary end or panitumumab, should be included with fluoropyrimidines con- point was OS. Data are not yet mature for this end point; however, currently with radiation therapy. a secondary end point of primary tumor response to preoperative In practice, most gastrointestinal oncologists now use cape- treatment, as well as toxicity data, have been reported. Overall citabine or continuous infusion 5-FU during radiation therapy. grade 3–4 toxicity rates on treated patients (mainly diarrhea) were The 1,608-patient phase 3 randomized NSABP R-04 trial has 8% without oxaliplatin and 24% in the oxaliplatin-containing arm definitively established that capecitabine is noninferior to infu- (p <0.001). Eighty-two percent of patients receiving oxaliplatin sional 5-FU when used concurrently with preoperative radiation got five or more doses of this drug. pCR rates were 15% and 16% therapy in patents with rectal cancer.190 There were no statis- in the 5-FU only and 5-FU–oxaliplatin arms, respectively. The au- tically significant differences in pCR rates, rate of sphincter- thors concluded that the addition of weekly oxaliplatin to standard sparing surgery, surgical downstaging, or treatment-related 5-FU–based preoperative CRT significantly increases toxicity with- toxicities. This study also was a 2 × 2 randomization to include out affecting local tumor response. Survival data requires further concurrent oxaliplatin with radiation therapy of not. This large maturation.

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As a follow-up to the seminal publication by Sauer et al.,137 not reach their anticipated goal, it was a substantial improvement another German trial has been initiated to better evaluate the over both 5-FU–only regimens and 5-FU/oxaliplatin combinations integration of oxaliplatin into neoadjuvant and adjuvant regimens from previous reports. The high incidence of grade 3-4 diarrhea for rectal cancer. This randomized phase 3 study, entitled CAO/ with one toxic death, however, mandates modification of this regi- ARO/AIO-04, hopes to achieve an impact on DFS not seen in men in future trials.206 previous reports. Only preliminary data has been published thus Most recently, in a study evaluating pre- and postoperative far supporting the feasibility of an oxaliplatin-based regimen, with Cape/Ox regimens with and without weekly cetuximab, the ad- good compliance and acceptable toxicity and surgical morbidity. dition of cetuximab significantly improved radiologic response as Interestingly, in an unplanned analysis, the pCR rate was found to well as OS (HR = 0.27; p = 0.34).207 These results are tempered be significantly higher in the oxaliplatin group compared to 5-FU by the negative phase 2 trial of cetuximab in the adjuvant treat- alone (17% versus 13%; p = 0.038). Longer follow-up is needed ment of KRAS wild-type stage III colon cancer. Outside of a clini- to address the primary end point of DFS, and the finding must be cal trial, neither cetuximab nor panitumumab should be used in considered in the context of the multiple negative trials regard- the adjuvant or neoadjuvant treatment of locally advanced rectal ing concurrent use of oxaliplatin and radiation therapy previously cancer. noted.200 The role of bevacizumab in neoadjuvant therapy is also Postresection use of adjuvant chemotherapy based on the promising, although dosing schedules, appropriate use of syner- results in colon cancer has become a widespread practice, with gistic medications, and patient selection have yet to be defined. oncologists using primarily FOLFOX (biweekly oxaliplatin, 5-FU, When combined with 5-FU ± oxaliplatin in the most recent stud- and leucovorin; see Chapter 57) as the postradiation chemother- ies, toxicity levels were manageable and pCR rates ranged from apy. This is based on the reasonable, albeit unproven, extrapola- 13% to 36%. In addition, Spigel et al.208 reported an 85% 1-year tion from data showing that the addition of oxaliplatin to 5-FU/ DFS.209,210 However, the negative outcomes of bevacizumab trials leucovorin improves DFS and OS in the postoperative manage- in colon cancer adjuvant therapy have greatly dampened enthusi- ment of patients with colon cancer (see Chapter 57). In addition asm for pursuing this approach. Outside of a clinical trial, the use to studies that have substituted fluoropyrimidines, there is also sub- of bevacizumab in the adjuvant treatment of rectal cancer is not stantial interest in the use of other agents added to fluoropyrimi- recommended. dines with concurrent radiation therapy. There have been studies with the addition of irinotecan,201 but because of the overlapping toxicity of diarrhea with radiation therapy and 5-FU, plus the dem- SYNCHRONOUS RECTAL PRIMARY AND onstrated lack of efficacy of irinotecan in the adjuvant treatment METASTASES of colon cancer, use of irinotecan in the combined mode has not been, and most likely ought not be, heavily pursued. A small The use of pelvic radiotherapy in patients with synchronous randomized phase 3 study showed no benefit to the addition of presentation of primary and metastatic disease is controversial. OF ONCOLOGY PRACTICE irinotecan to 5-FU/leucovorin in the nonradiation portion of the 202 Primary combination chemotherapy can provide substantial pal- treatment. The Radiation Therapy Oncology Group completed liation and can be considered as initial therapy in many patients a small randomized phase 2 trial of concurrent capecitabine, with rectal cancer and metastatic disease.211 Endoscopically irinotecan, and radiation therapy versus concurrent oxaliplatin, 195 placed expandable metal stents can be considered for palliation capecitabine, and radiation therapy. Both on the basis of a lack or protection from impending obstruction. Control of disease in of data supporting adjuvant irinotecan and a superior pCR rate the pelvis can have important implications for patient quality of in the oxaliplatin-containing arm, no further development of the life; therefore, combined modality therapy, including radiation, irinotecan- containing schedule is planned. chemotherapy, and in some cases palliative surgery, can be As biologic agents have a substantial appeal when used in appropriate, especially when extrapelvic metastatic disease is combination with conventional cytotoxics, they also have a large small volume and the patient’s prognosis is favorable enough that appeal in combination with radiation therapy. There is evidence pelvic complications could be anticipated as a long-term prob- for a beneficial effect of both cetuximab and bevacizumab when lem. No firm guidelines can be made in the management of these combined with cytotoxics in patients with metastatic colon and complex patients, and treatment decisions must be made on an rectal cancer (see Chapter 57). There are good laboratory data individual basis. demonstrating radiation sensitization when these (and similar) agents are used in vitro, and a substantial improvement has been shown in survival in patients with head and neck cancer when cetuximab is added to radiation therapy.203 Only preliminary MANAGEMENT OF UNRESECTABLE studies have been done,204 but given the lack of encouraging PRIMARY AND LOCALLY ADVANCED complete responses and the negative results with cetuximab in DISEASE (T4) adjuvant colon cancer (see Chapter 57), it is unlikely that there will be substantial further investigations in this area, and neither Although the majority of patients who present with stage II and III cetuximab nor panitumumab should be used in standard practice disease have primary tumors that are technically easily resectable, with radiation therapy for rectal cancer. Similarly, bevacizumab there are a group of patients who have T4 tumors with deep local has failed to demonstrate a benefit in adjuvant colon cancer, invasion into adjacent structures, which makes primary resection and should not be used in the routine management of locally for cure difficult, if not impossible. Some T4 tumors invade into advanced rectal cancer. the vagina, which is easily resectable, but others invade into pel- The literature on this topic continues to grow with a number of vic sidewall or sacrum, where a complete surgical resection may new phase 2 trials reporting on the feasibility, safety, and even po- be impossible (the coccyx and distal sacrum can be resected, if tential superiority of neoadjuvant regimens that incorporate these appropriate), and others invade into bladder or prostate, where agents. Kim et al.205 found that adding cetuximab to preoperative a more extensive surgical resection can be done, but often at the radiotherapy with irinotecan and capaceitabine was well tolerated expense of major morbidity or functional loss. Although there are in 39 patients and achieved a much higher pCR rate of 23.1%, few randomized trials to define optimal therapy in this group of compared to 10% to 15% with conventional 5-FU regimens. Pinto patients, there are data suggesting that it is appropriate to treat et al.206 reported a similarly improved pCR rate of 21.1% in the these patients with preoperative radiation therapy combined with StarPan/STAR-02 Study, which evaluated panitumumab, oxali- chemotherapy, in a manner similar to that described for T3 dis- platin, and 5-FU with concurrent radiotherapy. While this did ease, generally with concurrent 5-FU–based chemotherapy. This 838 Practice of Oncology / Cancers of the Gastrointestinal Tract will often result in a good clinical response that will allow for a the surgical findings and frozen section pathologic evaluation. For potentially curative resection to be performed. It is preferable electron beam intraoperative radiotherapy, a treatment cylinder is to treat a patient preoperatively to try to avoid leaving residual placed over the high-risk region, often on a pelvic sidewall or the disease rather than attempting to salvage a patient after a clearly sacrum, and the cylinder is then aligned to the radiation machine, inadequate operation. which is either in the operating room or in the radiation therapy The use of adjuvant radiation therapy in this clinical situation department. The cylinder acts both to hold normal tissues outside also allows for treatment of the lymphatics draining the locally in- the radiation beam and to confine the electron beam. The use of vaded organ, such as the internal or external iliacs, that are not electrons allows the radiation oncologist to adjust the depth of pen- typically resected in a low anterior resection or APR, but which etration of the beam to conform to the local tumor extent. When may be at substantial risk of secondary involvement from an in- using brachytherapy, carriers for the radioactive sources are placed vaded organ, such as the bladder. Although the definition of “un- over the high-risk region, and the radiation is then given either resectable” is very subjective, a number of studies have shown that during the surgery (high-dose rate) or the radioactive sources are preoperative radiation therapy can convert a substantial number inserted approximately 5 days after surgery and left in place for 1 of these patients to having resectable disease with substantial cure or 2 days (low-dose rate). In all situations, the radiation dose is in rates.212–215 the range of 10 to 20 (most commonly 15) Gy when used as a boost In a randomized phase 3 trial of 207 patients with locally non- to conventional therapy. In both approaches, care must be taken resectable T4 primary rectal carcinoma or local recurrence from to ensure that normal tissues such as small bowel are out of the rectal cancer, patients received chemotherapy (5-FU/leucovorin) irradiated volume. administered concurrently with radiotherapy (50 Gy) and adjuvant Techniques similar to this have been used for a number of years for 16 weeks after surgery (98 patients) or radiation therapy (50 Gy) and have shown encouraging results, although formal randomized alone (109 patients). The two groups were well balanced according trials have not been performed. Data suggest fairly good levels of to pretreatment characteristics. An R0 resection was performed in local control and long-term survival if a gross total resection can 82 patients (84%) in the CRT group and in 74 patients (68%) in be accomplished, with poorer results if there is gross residual the radiation therapy group (p = 0.009). Local control (82% versus (Table 60.6).217–220 Use of intraoperative radiotherapy boosts often 67% at 5 years; log-rank p = 0.03), time to treatment failure (63% requires specialized radiation facilities and expertise as well as an versus 44%; p = 0.003), cancer-specific survival (72% versus 55%; experienced team of radiation oncologists, surgical oncologists, p = 0.02), and OS (66% versus 53%; p = 0.09) all favored the CRT urologists, and plastic surgeons. Similar types of surgical and ra- group. There was no difference in late toxicity.216 Although the diation therapy approaches can produce surprisingly good results. use of preoperative radiation therapy with concurrent 5-FU–based For patients who still cannot have a surgical resection performed, chemotherapy, as described earlier, appears of value in patients either because of the tumor extent or because of coexisting medi- with locally advanced disease, there is still a substantial incidence cal problems, attempts should be made to maximize palliation of local failure. Therefore, a number of investigators have explored and perhaps local control. Boost doses of radiation are appropri- ways to increase the radiation dose to the highest risk region to try ately delivered to the residual tumor to doses of >60 Gy if sensi- to improve local tumor control. Three main techniques have been tive normal tissues (primarily small bowel) can be removed from used: supplemental postoperative external beam radiation boost, the radiation fields. Only a small percentage (5%) of patients with intraoperative electron beam radiation therapy boost, and intraop- these advanced tumors will be locally controlled and cured by erative brachytherapy boost. such an approach, but a substantial percentage will obtain good There are relatively few data on the use of postoperative ex- palliation.221–223 ternal beam as a boost, largely because of concerns of normal tissue tolerance after the use of the relatively large fields delivered preoperatively, extensive surgical resection, and the prolonged RADIATION THERAPY TECHNIQUE delay between initial external beam therapy and the final boost after recovery from surgery. The two intraoperative techniques are There have been primarily two dosing schemes for radiation ther- philosophically the same, although the technique of radiation de- apy that have been used in the treatment of rectal cancer. In the livery is different. After a high dose (50 Gy) of preoperative CRT preoperative setting, many European centers have favored a rapid and then a 4- to 6-week break, surgical resection is performed, the short-course treatment of doses of approximately 25 Gy in five extent of which depends on the location and extent of tumor. Areas fractions followed by immediate surgery, whereas US centers have considered at high risk for residual tumor are determined both by generally favored doses of 50.4 Gy given at 1.8 Gy per fraction

TABLE 60.6 Intraoperative Radiation Therapy for Locally Advanced Rectal Cancera

Mayo Clinic Massachusetts General Hospital Overall Survival Disease-Specific Resection No. of Patients Local Failure (%) (5 y) (%) No. of Patients Local Failure (%) Survival (%) Complete 18 b 76940 963 resection Partial resection 35 ∼20 ∼40 24 37 35 No resection 1 — 0 — — — Tot al 56 16 46 64 — — Recurrent locally 42 40 19 — — — advanced tumor a External beam radiotherapy + resection + intraoperative radiotherapy, no prior radiation therapy. b Two additional patients with no tumor in specimen—both without any tumor recurrence. These are included in the totals.

tahir99 - UnitedVRG Chapter 60 Cancer of the Rectum 839 with a delay of 4 to 8 weeks until surgery. As previously mentioned, small bowel and, in some patients (most commonly, obese), the an advantage of the long-course therapy is that it provides time to volume of small bowel increased. have tumor regression, which appears to facilitate sphincter preservation, although it is more expensive and time-consuming for the patient. In addition, there was substantial late toxicity from the Radiation Fields short-course treatment in earlier series, although this was most evident when the radiation therapy techniques were less sophisticated The precise radiation fields that are used should depend on the in- and simple anteroposterior/posteroanterior fields alone were used, dividual clinical situation, although the principles of the radiation which were at times quite large224; those techniques are not used treatment remain the same. The locoregional failures in rectal at present. cancer occur both because of residual disease in the soft tissues of Although major late toxicity is relatively uncommon, functional the pelvis as well as from residual pelvic nodal disease. The nodal gastrointestinal disturbances are relatively common. These relate disease can be in the internal iliac chain for very low-lying le- to both surgical effects on bowel with lack of a good reservoir func- sions, but only involves the external iliac nodes if the anal canal or tion and possible nerve dysfunction, as well as long-term radiation sphincter is involved or if an organ is involved that drains into the effects on bowel compliance and neural functioning.225,226 Many external iliac system. The internal iliac nodes are not usually dis- patients continue to have some rectal urgency and food intoler- sected by the surgeon, so it is important to treat these for low rectal ance (especially to roughage), but symptoms tend to improve over cancers, but the external iliacs should not be routinely irradiated. time and most patients can live a relatively normal life regarding The proximal extent of nodal radiation is arbitrary, but the pri- their gastrointestinal tract. Detailed discussions with the patient mary drainage of all rectal cancers is along the mesenteric system, about the type of foods likely to cause worsening bowel symptoms, and those nodes should primarily be treated surgically. Extending attention to the superimposed problems that can occur from other radiation fields to cover para-aortic nodes is not indicated unless difficulties such as lactose intolerance, and use of agents such as there is evidence of disease in those chains. loperamide all can help the patient deal with bowel problems. Because many of the local recurrences occur in the soft tis- Small bowel–related complications are directly proportional to sues of the pelvis, the radiation oncologist must be sure to treat the the volume of small bowel in the radiation field and the radia- regions that are least well treated by the surgeon. These include tion dose. In patients receiving combined modality therapy, the extension to the pelvic sidewall and presacral space, and to the volume of irradiated small bowel limits the ability to escalate the prostate in men and vagina in women. The proximal extent of the dose of 5-FU. A number of simple radiotherapeutic techniques are radiation field should generally extend to the sacral promontory, available to decrease radiation-related small bowel toxicity. First, as that is the level at which there is an attachment of the posterior small bowel contrast or CT scanning during treatment planning peritoneum and where the retroperitoneal rectum becomes the allows identification of the location of the small bowel so that intraperitoneal colon. Above this level, there is little risk of pelvic

fields can be designed to minimize its treatment. Multiple-field soft tissue invasion for standard rectal cancer. OF ONCOLOGY PRACTICE techniques (preferably a three- or four-field technique) are now The lower extent of the radiation field is more complex. Often, standard to minimize normal tissue irradiation. The use of lateral the surgeon will rely on the radiation oncologist to sterilize the fields for the boost as well as positioning the patient in the prone most distal extent of the primary tumor in order to perform a position can further decrease the volume of small bowel in the sphincter-preserving operation, so the distal margins should be lateral radiation fields. at least a couple of centimeters below the primary tumor mass. The treatment should be designed with the use of computer- Although rectal tumors tend to have only a minimal amount of ized radiation dosimetry and be delivered by high-energy linear longitudinal spread along the mucosal margin, they can spread fur- accelerators that deliver a higher dose to the target volume while ther distally in the perirectal fat and in the LNs in the mesorectum. relatively sparing surrounding normal structures. The advantage of In fact, this is part of the rationale for a TME. Attempts should thus combining a multiple-field technique, high-energy photons, and be made for treatment to at least the level of the dentate line for computerized dosimetry produces a homogenous dose distribution most low-lying rectal cancers, although this is likely not necessary throughout the target volume and minimizes the dose to the small for rectal cancers in the proximal third. However, it is also likely bowel. Although not well studied to date, newer developments in true that a substantial part of the late toxicity from pelvic radia- intensity-modulated radiation therapy may allow more conformal tion therapy is related to dysfunction of the anal sphincter. Thus, radiation dose distributions and a decrease in the irradiation of it is important to try to minimize the amount of sphincter that is small bowel. To date, intensity-modulated radiation therapy has irradiated. Although many textbooks define the lower edge of the not been shown to be of additional value in the adjuvant treatment radiation field relative to the bones of the pelvis, this is not the of rectal cancer. proper way to think about irradiating such tumors. The locations After pelvic surgery, the small bowel commonly fills the pelvis. of bony anatomic landmarks such as the ischial tuberosity have no Adhesions can form, resulting in fixed loops of small bowel in the consistent relationship to the anal sphincter, anal verge, dentate radiation fields. In this situation, despite treatment of the patient line, or the rectal cancer. The radiation oncologist must identify in the prone position, the use of multiple-field techniques may be the location of these structures as best as possible using radiopaque of limited value. In contrast, when radiation therapy is delivered markers and rectal contrast, and then determine the balance be- preoperatively to a patient who has not undergone prior pelvic sur- tween adequate distal coverage of the tumor as well as minimizing gery, the small bowel is usually mobile. When no small bowel fixa- irradiation of the anal sphincter and the perineum (acute toxicity). tion is present, treatment in the prone position can exclude much For anteroposterior or posteroanterior fields, the lateral borders of the small bowel from the posteroanterior field and completely should extend to treat the pelvic sidewall, a possible region for soft from the lateral fields. tissue extension. The lateral fields should have a similar superior Various physical maneuvers to exclude small bowel from the and inferior margin. The posterior border should include all of the pelvis have been examined. Gallagher et al.227 determined the vol- presacral soft tissue so the posterior extent of the field should cover ume, distribution, and mobility of small bowel in the pelvis after the anterior border of the sacrum with at least a 1.5-cm margin a variety of maneuvers. Regardless of the prior surgical history, a for patient motion and dosimetric variation. The anterior border significant decrease was seen in the average small bowel volume of the lateral fields should cover at least the posterior border of when the patients were treated in the prone position with abdomi- the vagina or the prostate, the anterior extent of the primary rectal nal wall compression and bladder distention compared with the tumor, and the anterior edge of the sacral promontory. Examples supine position. Treatment in the prone position without abdomi- of typical radiation fields as depicted by a CT simulation are shown nal wall compression was not consistently effective in displacing in Figure 60.4. 840 Practice of Oncology / Cancers of the Gastrointestinal Tract

A B

Figure 60.4 Posteroanterior (A) and lateral digitally (B) reconstructed radiograph of the radiation fields for preoperative radiation therapy of a T3N1 rectal adenocarcinoma. The clinical target volume and rectum are outlined. There is a marker at the anal verge to help avoid irradiating the entire anal canal. The field treats the mesorectum and the lymph nodes to the level of the sacral promontory. (C) Transverse cut at the middle of the C radiation field.

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71. Barisic G, Markovic V, Popovic M, et al. Function after intersphincteric re- 157. Nishioka M, Shimada M, Kurita N, et al. Gene expression profile can predict section for low rectal cancer and its influence on quality of life.Colorectal pathological response to preoperative chemoradiotherapy in rectal cancer. Dis 2011;13:638–643. Cancer Genomics Proteomics 2011;8:87–92. 76. Kapiteijn E, Marijnen CA, Nagtegall ID, et al. Preoperative radiotherapy 159. Grimminger PP, Danenberg P, Dellas K, et al. Biomarkers for cetuximab- combined with total mesorectal excision for resectable rectal cancer. N Eng based neoadjuvant radiochemotherapy in locally advanced rectal cancer. J Med 2001;345:638–646. Clin Cancer Res 2011;17:3469–3477. 87. Greenblatt DY, Rajamanickam V, Pugely AJ, et al. Short-term outcomes af- 162. Edden Y, Wexner SD, Berho M. The use of molecular markers as a method ter laparoscopic-assisted proctectomy for rectal cancer: results from the ACS to predict the response to neoadjuvant therapy for advanced stage rectal ad- NSQIP. J Am Coll Surg 2011;212:844–854. enocarcinoma. Colorectal Dis 2012;14:555–561. 89. Huang MJ, Liang JL, Wang H, et al. Laparoscopic-assisted versus open sur- 163. Casado E, Garcia VM, Sanchez JJ, et al. A combined strategy of SAGE and gery for rectal cancer: a meta-analysis of randomized controlled trials on quantitative PCR Provides a 13-gene signature that predicts preoperative oncologic adequacy of resection and long-term oncologic outcomes. Int J chemoradiotherapy response and outcome in rectal cancer. Clin Cancer Res Colorectal Dis 2011;26:415–421. 2011;17:4145–4154. 91. Ng SS, Lee JF, Yiu RY, et al. Long-term oncologic outcomes of laparoscopic 171. Habr-Gama A, Perez RO, Nadalin W, et al. Operative versus nonoperative versus open surgery for rectal cancer: a pooled analysis of 3 randomized con- treatment for stage 0 distal rectal cancer following chemoradiation therapy: trolled trials. Ann Surg 2014;259:139–147. long-term results. Ann Surg 2004;240:711–717, discussion 717–718. 92. Lujan J, Valero G, Biondo S, et al. Laparoscopic versus open surgery for 172. Maas M, Beets-Tan RG, Lambregts DM, et al. Wait-and-see policy for clini- rectal cancer: results of a prospective multicentre analysis of 4,970 patients. cal complete responders after chemoradiation for rectal cancer. J Clin Oncol Surg Endosc 2013;27:295–302. 2011;29:4633–4640. 94. Soop M, Nelson H. Laparoscopic-assisted proctectomy for rectal cancer: on 173. Smith JD, Ruby JA, Goodman KA, et al. Nonoperative management of rectal trial. Ann Surg Oncol 2008;15:2357–2359. cancer with complete clinical response after neoadjuvant therapy. Ann Surg 103. Trastulli S, Farinella E, Cirocchi R, et al. Robotic resection compared with 2012;256:965–972. laparoscopic rectal resection for cancer: systematic review and meta-analysis 174. Chau I, Brown G, Cunningham D, et al. Neoadjuvant capecitabine and ox- of short-term outcome. Colorectal Dis 2012;14:e134–e156. aliplatin followed by synchronous chemoradiation and total mesorectal exci- 106. Collinson FJ, Jayne DG, Pigazzi A, et al. An international, multicentre, pro- sion in magnetic resonance imaging–defined poor-risk rectal cancer. J Clin spective, randomised, controlled, unblinded, parallel-group trial of robotic- Oncol 2006;24:668–674. assisted versus standard laparoscopic surgery for the curative treatment of 176. Cercek A, Goodman KA, Hajj C, et al. Chemotherapy first, followed by rectal cancer. Int J Colorectal Dis 2012;27:233–241. chemoradiation and then surgery, in the management of locally advanced 108. Mohan HM, Evans MD, Larkin JO, et al. Multivisceral resection in colorec- rectal cancer. J Natl Compr Canc Netw 2014;12:513–519. tal cancer: a systematic review. Ann Surg Oncol 2013;20:2929–2936. 180. Guillem JG, Ruby JA, Leibold T, et al. Neither FDG-PET Nor CT can dis- 110. Chew MH, Brown WE, Masya L, et al. Clinical, MRI, and PET-CT criteria tinguish between a pathological complete response and an incomplete re- used by surgeons to determine suitability for pelvic exenteration surgery for sponse after neoadjuvant chemoradiation in locally advanced rectal cancer: recurrent rectal cancers: a Delphi study. Dis Colon Rectum 2013;56:717–725. a prospective study. Ann Surg 2013;258:289–295. 111. Ripley RT, Gajdos C, Reppert AE, et al. Sequential radiofrequency ablation 184. Duldulao MP, Lee W, Streja L, et al. Distribution of residual cancer cells and surgical debulking for unresectable colorectal carcinoma: thermo-surgi- in the bowel wall after neoadjuvant chemoradiation in patients with rectal cal ablation. J Surg Oncol 2013;107:144–147. cancer. Dis Colon Rectum 2013;56:142–149. 112. Pusceddu C, Sotgia B, Melis L, et al. Painful pelvic recurrence of rectal 190. Roh MS, Yothers GA, O’Connell MJ, et al. The impact of capecitabine and cancer: percutaneous radiofrequency ablation treatment. Abdom Imaging oxaliplatin in the preoperative multimodality treatment in patients with car-

2013;38:1225–1233. cinoma of the rectum: NSABP R-04. J Clin Oncol 2011;29:Abstr 3503. OF ONCOLOGY PRACTICE 117. Gunderson LL, Sosin H. Areas of failure found at reoperation (second or 191. Hofheinz RD, Wenz F, Post S, et al. Chemoradiotherapy with capecitabine symptomatic look) following “curative surgery” for adenocarcinoma of the versus fluorouracil for locally advanced rectal cancer: a randomised, multi- rectum. Cancer 1974;34:1278–1292. centre, non-inferiority, phase 3 trial. Lancet Oncol 2012;13:579–588. 121. Heald RJ. The “Holy Plane” of rectal surgery. J Royal Soc Med 1988;81:503–508. 192. Twelves C, Scheithauer W, McKendrick J, et al. Capecitabine versus 5-fluor- 125. Sebag-Montefiore D, Stephens RJ, Steele R, et al. Preoperative radiotherapy ouracil/folinic acid as adjuvant therapy for stage III colon cancer: final results versus selective postoperative chemoradiotherapy in patients with rectal can- from the X-ACT trial with analysis by age and preliminary evidence of a phar- cer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. macodynamic marker of efficacy. Ann Oncol 2012;23:1190–1197. Lancet 2009;373:811–820. 198. Gerard JP, Azria D, Gourgou-Bourgade S, et al. Clinical outcome of the 126. Swedish Rectal Cancer Trial. Improved survival with preoperative radiother- ACCORD 12/0405 PRODIGE 2 randomized trial in rectal cancer. J Clin apy in resectable rectal cancer. N Engl J Med 1997;336:980–987. Oncol 2012;30:4558–4565. 127. Prolongation of the disease-free interval in surgically treated rectal carcinoma. 199. Aschele C, Pinto C, Cordio S, et al. Preoperative fluorouracil (FU)-based Gastrointestinal Tumor Study Group. N Engl J Med 1985;312:1465–1472. chemoradiation with and without weekly oxaliplatin in locally advanced rec- 128. Krook JE, Moertel CG, Gunderson LL, et al. Effective surgical adjuvant tal cancer: pathologic response analysis of the Studio Terapia Adiuvante Retto therapy for high-risk rectal carcinoma. N Engl J Med 1991;324:709–715. (STAR)-01 randomized phase III trial. J Clin Oncol 2009;27:Abstr CRA4008. 133. O’Connell MJ, Martenson JA, Wieand HS, et al. Improving adjuvant therapy 204. Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF- for rectal cancer by combining protracted-infusion fluorouracil with radia- specific antibody bevacizumab has antivascular effects in human rectal can- tion therapy after curative surgery. N Engl J Med 1994;331:502–507. cer. Nat Med 2004;10:145–147. 134. Schrag D, Weiser M, Goodman K, et al. Neoadjuvant chemotherapy without 207. Dewdney A, Cunningham D, Tabernero J, et al. Multicenter randomized routine use of radiation therapy for patients with locally advanced rectal phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and cancer: a pilot trial. J Clin Oncol 2014;32:513–518. preoperative radiotherapy with or without cetuximab followed by total meso- 138. Sauer R, Liersch T, Merkel S, et al. Preoperative versus postoperative chemo- rectal excision in patients with high-risk rectal cancer (EXPERT-C). J Clin radiotherapy for locally advanced rectal cancer: results of the German CAO/ Oncol 2012;30:1620–1627. ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. 209. Nogue M, Salud A, Vicente P, et al. Addition of bevacizumab to XELOX in- J Clin Oncol 2012;30:1926–1933. duction therapy plus concomitant capecitabine-based chemoradiotherapy in 139. Wolff HA, Conradi LC, Beissbarth T, et al. Gender affects acute organ toxic- magnetic resonance imaging-defined poor-prognosis locally advanced rectal ity during radiochemotherapy for rectal cancer: long-term results of the Ger- cancer: the AVACROSS study. Oncologist 2011;16:614–620. man CAO/ARO/AIO-94 phase III trial. Radiother Oncol 2013;108:48–54. 211. Saltz L, Raben D, Minsky BD, et al. Rectal cancer: presentation with meta- 140. Roh MS, Colangelo LH, O’Connell MJ, et al. Preoperative multimodality static and locally advanced disease. American College of Radiology. ACR therapy improves disease-free survival in patients with carcinoma of the rec- Appropriateness Criteria. Radiology 2000;215:1491–1499. tum: NSABP R-03. J Clin Oncol 2009;27:5124–5130. 216. Braendengen M, Tveit KM, Berglund A, et al. Randomized phase III study 143. Ngan SY, Burmeister B, Fisher RJ, et al. Randomized trial of short-course ra- comparing preoperative radiotherapy with chemoradiotherapy in nonresect- diotherapy versus long-course chemoradiation comparing rates of local recur- able rectal cancer. J Clin Oncol 2008;26:3687–3694. rence in patients with T3 rectal cancer: Trans-Tasman Radiation Oncology 217. Gunderson LL, Nelson H, Martenson JA, et al. Locally advanced primary Group trial 01.04. J Clin Oncol 2012;30:3827–3833. colorectal cancer: intraoperative electron and external beam irradiation +/− 147. Loos M, Quentmeier P, Schuster T, et al. Effect of preoperative radio(chemo) 5-FU. Int J Radiat Oncol Biol Phys 1997;37:601–614. therapy on long-term functional outcome in rectal cancer patients: a system- 220. Harrison LB, Minsky BD, Enker WE, et al. High dose rate intraoperative atic review and meta-analysis. Ann Surg Oncol 2013;20:1816–1828. radiation therapy (HDR-IORT) as part of the management strategy for locally 148. Bosset JF, Collette L, Calais G, et al. Chemotherapy with preoperative radio- advanced primary and recurrent rectal cancer. Int J Radiat Oncol Biol Phys therapy in rectal cancer. N Engl J Med 2006;355:1114–1123. 1998;42:325–330. 153. Stocchi L, Nelson H, Sargent DJ, et al. Impact of surgical and pathologic 223. Brierley JD, Cummings BJ, Wong CS, et al. Adenocarcinoma of the rectum variables in rectal cancer: a United States community and cooperative group treated by radical external radiation therapy. Int J Radiat Oncol Biol Phys report. J Clin Oncol 2001;19:3895–3902. 1995;31:255–259. 154. Martling AL, Holm T, Rutqvist LE, et al. Effect of a surgical training pro- 225. Frykholm GJ, Glimelius B, Pahlman L. Preoperative or postoperative irradiation gramme on outcome of rectal cancer in the Country of Stockholm. Lancet in adenocarcinoma of the rectum: final treatment results of a randomized trial 2000;356:93–96. and an evaluation of late secondary effects. Dis Colon Rectum 1993;36:564–572. 61 Cancer of the Anal Region

Brian G. Czito, Shahab Ahmed, Matthew Kalady, and Cathy Eng

INTRODUCTION and Caucasian females had the highest mortality rate (0.3 out of 100,000 each) among all races, whereas at the same time, both Carcinoma of the anal canal is a rare malignancy, although its male and female Asians had the lowest mortality rate (0.1 out of incidence is steadily increasing. The development of anal cancer 100,000 each) (see Fig. 61.1). is a multifocal process largely associated with the human papil- The incidence of anal cancer has been increasing over the last lomavirus (HPV). The treatment approach to this disease has 30 years in the United States as well as globally.2,3 This is likely evolved significantly over recent decades and serves as a model related to the increase in infections by the sexually transmitted for organ-preserving therapy, transitioning from radical surgery HPV and HIV, which may have a significant impact on anal by abdominal perineal resection (APR, entailing permanent co- cancer incidence. In one large case-control series, an increasing lostomy placement with associated high pelvic recurrence rates) number of sexual partners was associated with the development of to a nonsurgical approach of definitive chemoradiotherapy with anal cancer in both men and women (odds ratio of 4.5 for women 5- fluorouracil (5-FU) and mitomycin C (MMC), leading to and 2.5 for men with ≥10 sexual partners). This study also dem- successful preservation of anorectal function in the majority of onstrated that a history of anal warts was associated with a higher patients. Anal cancer is relatively unique amongst gastrointes- risk of developing anal cancer, as was receptive anal intercourse tinal malignancies in that it has a low propensity for metastatic in women.3 spread, making local–regional control a paramount endpoint in the approach to this disease. Over the past 2 decades, published Human Papillomavirus Infection randomized trials have demonstrated the superiority of chemoradiotherapy with 5-FU and MMC over radiation therapy alone, ra- High-risk HPV type-16 has been detected in almost 90% of cases of diation with concurrent 5-FU, as well as induction cisplatin/5-FU squamous cell carcinoma of the anus.4 A recent meta-analysis sug- alone followed by concurrent radiotherapy using the same regi- gests that HPV-16 is found more frequently (75%) and HPV-18 less men. Additionally, randomized trials have failed to demonstrate frequently (10%) in anal carcinomas than in cervical carcinomas. a definitive benefit for radiation dose escalation nor superiority Moreover, approximately 80% of anal cancers demonstrated more when substituting cisplatin for MMC. Treatment with chemora- than one HPV genotype.5 Anal cancer, now considered to be a pre- diotherapy is associated with significant acute and chronic toxicity dominantly HPV-related cancer, has an incidence 15 times higher rates, and improvement in radiation therapy techniques has been in homosexual men than in heterosexual men.6 In most cases, anal shown to decrease such. Current investigations include the use of infection with HPV is sexually transmitted, and the risk for cancer novel cytotoxic and inhibitor targeted agents, including epidermal is increased in patients with a history of receptive anal intercourse growth factor receptor, in efforts to improve outcomes in patients in women and homosexual activity in men.7 It is also been shown with more advanced disease, as well as further understanding the that women with high-grade cervical or vulvar dysplasia are more molecular etiology and resistance of this disease. This chapter susceptible to develop anal cancer, as cervical or vulvar HPV in- provides an overview of the background, epidemiology, diagnosis, fection escalates anal HPV infection risk.8 multidisciplinary treatment, and outcomes of tumors arising in the anal canal and perianal skin, as well as anal canal adenocarcinoma and melanoma. HIV Infection

The incidence of anal cancer in patients who are infected with EPIDEMIOLOGY AND ETIOLOGY HIV is estimated to be twice that of HIV-negative patients. Highly active antiretroviral therapy (HAART) has resulted in Anal cancer is the least prevalent among all gastrointestinal (GI) patients with HIV living longer and the development of related cancers. It has been reported that anal cancers account for 1% to malignancies. In contrast to other HIV-associated malignancies, 2% of all large bowel malignancies. According to the 2014 Ameri- the incidence of anal cancer has actually risen following imple- can Cancer Society statistics, about 7,210 men and women (37% mentation of HAART.9–11 According to the National Cancer men and 63% women, a ratio of almost 1:2 for men to women) Institute (NCI), the rise in anal cancer incidence rates during will be diagnosed with anal cancer, and it is estimated that 950 1980 to 2005 was predominantly seen in male patients with HIV, (or 13%) of those diagnosed with anal cancers will die from their relative to their female counterparts.12 Although HIV has been disease.1 considered to be a major factor in anal cancer incidence, it is The median age at diagnosis for anal, anal canal, and anorec- also suggested that HIV may have an impact on the survival of tal cancers was 60 years during 2006 to 2010. This data showed patients with anal cancer, with one report demonstrating that that among all races, Caucasian females experienced the high- HIV-positive patients with anal cancer tended to develop earlier est incidence rate (2.1 out of 100,000), whereas Asian males had recurrences than HIV-negative patients by 20 months, although the lowest incidence rate (0.5 out of 100,000) during that time the median survival for HIV-positive patients (34 months) and frame (Fig. 61.1). The median age at death was 64 years dur- HIV-negative patients (39 months) were similar (non-significant) ing this period. It was estimated that African American males (discussed as follows).13

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tahir99 - UnitedVRG Chapter 61 Cancer of the Anal Region 843

the general population for anal cancer, there are high-risk groups that may benefit from such, most prominently patients infected White with HIV. Although the natural history of SIL is still being unrav- eled, studies show increased rates of progression in HIV-positive Male Hispanic patients with a relative risk of 2.4 and increasing to 3.1 for those Female with CD4 counts below 200.17,18 The rationale for screening for SIL is based on the following: there is a high incidence of Black the anal cancer within the proposed screening population (i.e., Rate HIV-positive patients), available screening tests are effective and cost-efficient, and early detection can change the outcome of the Asian disease. The initial recommended screening test is an “anal Pap smear” that evaluates cells in the anal canal for abnormal cytology through swabbing. Patients with abnormal cytology should All then be evaluated by high-resolution anoscopy, which facilitates the visualization of abnormal lesions, allowing biopsy and/or 19,20 0.0 0.5 1.0 1.5 2.0 2.5 removal. Algorithms for the management of low-grade and high-grade SILs remain controversial as more data are needed to Frequency/100,000 determine the effectiveness of intervention on decreasing long- term rates of anal SCC. Treatment options of high-grade AIN include ablation with White electrocautery, topical trichloroacetic acid, topical 5-FU, or imiquimod,21–23 with estimated lesion control rates ranging from Male 60% to 80%. A 2012 Cochrane Review highlights the dearth of Hispanic evidence addressing the efficacy of available interventions for SIL. Female This review resulted in one randomized trial being identified. This trial evaluated the medication imiquimod versus placebo. Black Although underpowered, results showed no statistically significant Rate benefit for treatment. The authors concluded that, given the rising incidence of AIN and anal cancer, well-designed randomized con- Asian trolled trials are urgently needed to address this topic, with emphasis on AIN resolution, downstaging, recurrence, and progression to 24 All invasive disease in both HIV-positive and -negative populations. OF ONCOLOGY PRACTICE A promising strategy for the prevention of anal dysplasia and malignancy is HPV vaccination. Two vaccines (Cervarix and 0.0 0.1 0.2 0.3 Gardasil) are now approved by the U.S. Food and Drug Admin- istration and have been shown to protect against cervical can- Frequency/100,000 cer in women.25,26 The quadrivalent HPV vaccine Gardasil has Figure 61.1 Anal cancer distribution among different races. (Top) demonstrated efficacy for prevention of HPV 6-, 11-, 16-, and Incidence rate. (Bottom) Death rate. 18-related genital warts and has been shown to protect against cancers of the anus, vagina, and vulva.27 In a large, double blind study, 602 healthy men who have sex with men were randomized Other Risk Factors to receive the quadrivalent HPV vaccine versus placebo. With a 36-month median follow-up for the development of AIN and/or According to the American Society of Colon and Rectal Surgeons high-risk HPV infection, significantly reduced rates of high-grade (ASCRS), risk factors other than HIV and HPV infections include: anal dysplasia and high-risk HPV infection were demonstrated in the vaccinated group.28 No cases of anal cancer or vaccine-related ■ Age: 67% >55 years. serious events were noted. In the context of limited availability and ■ Smoking: There are reports demonstrating that that smoking suboptimal outcomes of AIN screening programs, vaccination may is a risk factor for anal cancer development. According to one reflect the best long-term approach for reducing anal cancer risk study, the relationship between smoking and anal cancer per- and is recommended for girls and boys at age 11 or 12 years and sists for both gender types (adjusted odds ratio for women = 3.8, girls 13 to 26 years of age who have not been previously vaccinated. 95% confidence interval [CI], 2.3 to 6.2; adjusted odds ratio for men = 3.9, 95% CI, 1.9 to 8.0). Similarly, the risk of anal cancer appears to be related to the pack-year history of smoking, PATHOLOGY with more extensive histories associated with a higher risk.14 ■ Immunosuppression: Solid organ transplant recipients with A variety of malignancies can arise in the anal canal and perianal chronic immunosuppressive therapy have a six times higher skin. The typical gross appearance of SCC of the anal canal con- risk to develop anal cancer relative to the general population.15 sists of a lesion with rolled edges, often with central ulceration, with Benign anal lesions are no longer thought to contribute to the a minority consisting of polypoid lesions (Fig. 61.2). On a practi- development of this disease, although anal cancers are frequently cal level, these can be divided into squamous and nonsquamous misdiagnosed as these conditions. histologies. The vast majority of anal canal tumors are classified as SCC, which encompasses tumors previously described as basaloid, cloacogenic, transitional, mucoepidermoid, and verrucous muco- SCREENING AND PREVENTION epidermoid varieties (Fig. 61.3). These subtypes generally referred to tumors arising in the anal transitional zone, where the anal squa- Anal squamous intraepithelial lesions (SIL) or anal intraepithe- mous histology transitions into the glandular epithelium seen in the lial neoplasia (AIN) have been recognized as precursors that can colorectum. From a treatment standpoint, these are all approached progress to anal squamous cell carcinoma (SCC).16 Although as SCC. The current World Health Organization (WHO)29 classi- there are no published guidelines that recommend screening of fication does not include thesesubtypes. The majority of these are 844 Practice of Oncology / Cancers of the Gastrointestinal Tract

Figure 61.2 A 60-year-old male with advanced squamous cell carcinoma of the anal verge, exhibiting rolled edges with central ulceration. Figure 61.3 A microscopic image of a biopsy revealing nonkeratinizing nonkeratinizing, although tumors arising below the dentate line squamous cell carcinoma. often display keratinizing properties. Most squamous lesions are moderately to poorly differentiated and display koilocytic changes consistent with HPV infection. sexual intercourse with men.31 The incidence of AIN is believed to It is believed that most anal cancers arise from precancerous be much greater in patients with HIV as exemplified by a French changes (i.e., AIN) of the anal canal and perianal skin epithelium. study analyzing 8,153 routine hemorrhoidectomy specimens, find- AIN is a multifocal process associated with HPV, analogous to ing that only 3 cases of AIN (0.04%) were seen,32 as compared to cervical dysplasia. There is a progression from normal epithelium 20 cases out of a 103 (19.4%) in specimens from HIV-positive men to condyloma and grade I AIN (associated with mild dysplasia), (Fig. 61.4).33 later progressing to grade II AIN (with moderate dysplasia), and Additional nonsquamous cell histologies arising in the anal ultimately grade III AIN with severe dysplasia, as well as in situ canal include adenocarcinoma, small cell carcinoma/neuroendo- disease. Once disease has reached grade III AIN, it rarely regresses. crine tumors, as well as undifferentiated carcinomas, melanomas, It has been estimated that approximately 5% of AIN III patients and rarely, lymphomas and sarcomas. Neuroendocrine tumors are progress to invasive malignancy, often occurring over a multiyear thought to arise from endocrine cells in the transitional zone and, period. This incidence of progression of AIN III is substantially like neuroendocrine tumors arising from other sites, tend to dis- increased in patients who are immunocompromised.17,30 The seminate widely. A suspected anal adenocarcinoma may actually prevalence of AIN among HIV-negative homosexual men is high reflect an extension from a distal rectal adenocarcinoma in some (>36%), and almost universal among HIV-positive men who have situations. Mucinous adenocarcinoma is generally thought to arise

Low-grade squamous High-grade squamous intraepithelial lesion (LSIL) intraepithelial lesion (HSIL)

Condyloma AIN grade 1 AIN grade 2 AIN grade 3

Moderate Severe In situ Normal Very mild to mild dysplasia dysplasia dysplasia carcinoma

Koilocytes Microinvasive carcinoma

Figure 61.4 A schematic representation of an anal intraepithelial neoplasia progression. Note that the increasing severity as a proportion of epithelium is replaced by progressive increase in immature-appearing cells, ultimately leading to invasive disease with violation of the basement membrane. (Goldstone SE. Diagnosis and treatment of HPV related squamous intraepithelial neoplasia in men who have sex with men. PRN Notebook 2005;10:11–16.)

tahir99 - UnitedVRG Chapter 61 Cancer of the Anal Region 845 in the anal glands and ducts and is uncommon. It should be noted ultrasound or pelvic magnetic resonance imaging (MRI) can be that histology is generally more important than location within the considered to assess tumor size and involvement with local struc- anal canal and usually dictates overall patient management. tures such as the anal sphincters and vagina or prostate. Computed Tumors of the perianal skin are similar to that seen in the anal tomography (CT) scans of the chest, abdomen, and pelvis are canal, primarily comprised of SCC. These tumors are generally commonly employed to evaluate distant disease and adenopathy, well differentiated and keratinizing. Verrucous carcinoma—also particularly in the inguinal regions. Of all patients presenting with sometimes known as a giant condyloma or Buschke-Lowenstein palpable inguinal lymph nodes, only 50% are malignant; there- tumor—was initially described in 1925. These tumors are some- fore, fine-needle aspiration is often recommended in suspected times mistakenly considered to be benign and misdiagnosed as cases, and a positive result may guide radiation field design and condylomata acuminata, with a subsequent histologic analysis dose. Some oncologists have suggested a routine sentinel lymph revealing invasion. These are often locally destructive and HPV node (SLN) evaluation as a staging technique. A systematic review related. They are often slow growing and can be present for many of 16 published series evaluating the outcome of SLN biopsy of in- years before coming to medical attention. Local recurrence rates guinal nodes included 323 patients, and the success in identifying following excision are high and malignant transformation can be the SLN was 86%. However, the exact role of SNL in the pretreat- seen in up to 50%.34 Additional precursor lesions seen in the peri- ment evaluation remains undetermined.35 anal skin include Bowen disease, which consist of a slow growing A number of recent studies have investigated the role of intraepidermal SCC that may mimic perianal dermatitis, as well positron-emission tomography (PET)-CT scans for staging anal as Paget disease, which is similar to the entity seen associated with cancer. One review described outcomes of patients undergoing breast cancer, with an eczematous appearance. Approximately conventional staging with ultrasound as well as PET-CT scans. Of half of Paget disease patients will harbor an underlying adenocar- 95 patients, the authors found that PET-CT scans were particularly cinoma, notably in the colorectum. valuable in detecting more extensive nodal and metastatic disease as well as the detection of synchronous malignancies. Upstaging was noted in 14% of patients, and 23% had a change in treatment CLINICAL PRESENTATION AND STAGING plan relative to ultrasound staging.36 Another study comparing the use of conventional imaging with CT scans and MRI found that the Symptoms of anal cancer can be diverse and include bleeding, addition of PET-CT scans upstaged patients in 20%, downstaged pain, sensation of a mass, itching, anal discharge, tenesmus, and a 25%, and altered management in 37%. These authors concluded sense of fullness or a lump in the anal canal. The most common that PET-CT scans should be a routine part of initial staging of presentation is bleeding from the anus. More extensive lesions may all anal cancers. A lesser impact was seen in patients evaluated in present with more ominous symptoms such as incontinence, pas- follow-up where PET-CT scans upstaged 11% and downstaged in sage of gas or stool from the vagina, or significant change in bowel 6% of cases; however, these changes also led to an altered manage-

habits. Less frequently, an enlarged inguinal lymph node is re- ment in 17%, indicating a potential role for selected PET-CT scan OF ONCOLOGY PRACTICE ported, and 20% of patients are initially asymptomatic. Symptoms use when there is a question of recurrence or salvage surgery is may often be dismissed as hemorrhoids or other benign causes, planned.37 A study by Vercellino and colleagues38 similarly found and it is crucial to further evaluate by a physical examination and that PET-CT scans were useful in the avoidance of unnecessary anoscopy. Any mass should be biopsied for a diagnosis. biopsies and surgery, with a negative predictive value of 94%, ul- Clinical staging is performed by a combination of clinical, timately impacting on treatment plans in 22% of follow-up cases. endoscopic, and radiographic examinations (Table 61.1). History Finally, PET-CT scans may have prognostic value as well, with should include an assessment of anal sphincter function as well as one study demonstrating a significant correlation between meta- HIV risk factors. Digital rectal examination can identify fixation bolic response posttreatment and progression-free as well as over- to the sphincter complex or adjacent organs such as the vagina all survival.39 National Comprehensive Cancer Network (NCCN) and prostate. Proctoscopy provides information about the extent treatment guidelines include the use of FDG-PET scans with CT of mucosal spread, including the relationship to the dentate line, scans as part of the staging evaluation, notably for patients with T2- and facilitates biopsy. It may be necessary to examine patients 4N0 disease or those with involved lymph nodes.40 After the previ- under anesthesia secondary to pain and sphincter muscle spasms. ously mentioned evaluation, staging is assigned according to the Female patients should undergo a gynecologic examination to de- American Joint Committee on Cancer 2010 (AJCC) (Table 61.2). termine vaginal involvement and to exclude other HPV-associated cancers, including evaluation of the cervix. Imaging is used to better delineate the local extent of disease and regional adenopathy, PROGNOSTIC FACTORS and to determine the presence of distant metastases. An endoanal Clinical TABLE 61.1 T and N stages are the most important prognostic factors for anal Recommended Diagnostic Evaluation in cancer. According to the AJCC, the 5-year observed overall survival Newly Diagnosed Anal Cancer (OS) rates of anal cancer for stage I, II, IIIA, IIIB, and IV are 69.5%, 68.1%, 45.6%, 39.6%, and 15.3%, respectively. It has also been dem- ■ onstrated that the 5-year OS rates for T1, T2, T3, T4, N0, and node- Digital rectal examination with tumor characterization (location, 41 fixation, extent) positive anal cancer are 86%, 86%, 60%, 45%, 76%, and 54%. ■ Examination of inguinal lymph nodes; consideration of biopsy There are relatively few studies available that analyze prognostic factors for anal cancer. According to the Radiation Ther- if deemed suspicious > ■ apy Oncology Group (RTOG) 98-11 study, tumor size ( 5 cm), Endoscopy/proctoscopy + ■ involved lymph nodes (N ), and male sex were associated with Gynecologic examination in females to rule out vaginal 42 invasion as well as exclude gynecologic primary worse 5-year disease-free survival (DFS) and OS. Results from ■ Positron-emission tomography/computed tomography European Organisation for Research and Treatment of Cancer (PET-CT) scan (EORTC) 22861 study indicated that skin ulceration, lymph node ■ Complete blood count with serum chemistries as well as HIV involvement, and male sex were independent variables associated testing/CD4 levels in the presence of risk factors with local–regional failure (LRF) and OS in multivariate analysis.43 A secondary analysis of the UK Coordinating Committee on 846 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 61.2 colleagues,48 there was no significant difference found in survival analysis among cloacogenic, well-differentiated, and moderately or TNM Anus Staging According to the poorly differentiated anal carcinomas. American Joint Committee on Cancer

Primary Tumor (T) Molecular TX Primary tumor cannot be assessed Prognostic biomarkers provide information on patient outcomes T0 No evidence of primary tumor regardless of therapy, whereas predictive biomarkers provide in- 49 Tis Carcinoma in situ (Bowen disease, high-grade squamous formation about the effect of specific therapeutic intervention. intraepithelial lesion [HISL], anal intraepithelial neoplasia The ultimate goal of determining prognostic factors is to improve [AIN] II–III) patient survival. Disease processes and progression result from molecular and pathologic pathways, and by targeting altered T1 Tumor 2 cm or less in greatest dimension pathways, potential avenues for therapeutic interventions that T2 Tumor more than 2 cm but not more than 5 cm in could facilitate improvements in survival may emerge. Similarly, greatest dimension molecular analyses of anal cancer to predict treatment response 50 T3 Tumor more than 5 cm in greatest dimension and survival outcomes are essential. Lampejo and colleagues performed a systematic review on anal cancer prognostic bio- T4 Tumor of any size invades adjacent organ(s) (e.g., vagina, markers after reviewing 29 studies for final analysis. The authors urethra, bladder) (direct invasion of rectal wall, perirectal found that 13 biomarkers were associated with anal cancer out- skin, subcutaneous tissue or sphincter muscle is not comes in only one study, whereas the tumor suppressor genes classified as T4) p53 and p21 as prognostic markers were established by more than Regional Lymph Nodes (N) one study. The p53 gene is located in the short arm of chromosome 17 NX Regional lymph nodes cannot be assessed (17p13.1), which encodes a protein (393-amino acid nuclear phos- N0 No regional lymph node metastasis phoprotein) that regulates the cell cycle and is responsible for 51,52 N1 Metastasis in perirectal lymph nodes(s) cell apoptosis. Accumulation of nuclear proteins was seen by immunohistochemistry in the cases of muted p53 genes in some N2 Metastasis in unilateral internal iliac and/or unilateral studies.53–55 These studies found that in anal carcinoma, p53 was inguinal lymph node(s) overexpressed with a range of 34% to 100%. Wong et al.52 de- N3 Metastasis in perirectal and inguinal lymph nodes and/or scribed that increased p53 expression was associated with worse bilateral internal iliac and/or inguinal lymph nodes local–regional control (p = 0.02) and DFS (p = 0.01). Another Distant Metastases (M) study of 64 patients suggested that mutant p53 was responsible for inferior LRF rates relative to wild type, although nonsignificant M0 No distant metastasis (48 versus 27%, p = 0.14).56 Allal and colleagues57 reported that M1 Distant metastasis anal cancer patients with p53-positive lesions had a lower local– regional control rate (relative risk [RR], 0.38; p = 0.03) and shorter Anatomic Stage/Prognostic Group DFS (RR, 0.29; p = 0.003). Stage 0 Tis N0 M0 The p21 gene protein, a cyclin-dependent kinase (CDK) in- 58 Stage I T1 N0 M0 hibitor, is considered to be a mediator of the p53 gene function. Some studies have indicated that the lack of p21 expression is as- Stage II T2 N0 M0 sociated with poor prognosis in patients with squamous cell carci- T3 N0 M0 noma of the anal canal (SCCA). Holm et al.59 reported that a lack = Stage IIIA T1, T2, T3 N1 M0 of p21 expression was associated with reduced OS (p 0.013), whereas Nilsson and colleagues60 reported that absence of the T4 N0 M0 same p21 expression was also responsible for an increased LRF Stage IIIB T4 N1 M0 rate (p < 0.05). Ajani and colleagues55 reported epidermal growth factor recep- Any T N2, N3 M0 tor (EGFR) expression was observed in 86% of patients with anal Stage IV Any T Any N M1 cancer, but the study was unable to determine the significant correlation between degree of staining and DFS. The same study’s From Edge SB, Byrd DB, Compton CC, et al., eds. AJCC Cancer multivariate models suggested that Ki67 (negatively, coefficient: Staging Manual, 7th ed. New York: Springer-Verlag; 2010: 171. −0.04), nuclear factor kappa B (NF-κB) (positively, coefficient: 0.07), Sonic Hedgehog (SHH) (positively, coefficient: 0.05), and Gli-1 (positively, coefficient: 0.03) were associated with DFS (p = 0.005, 0.002, 0.02, and 0.02, respectively). Further investi- Cancer Research (CCCR) Anal Cancer Trial (ACT) 1 trial indi- gation into the molecular prognostic factors of anal carcinoma is cated that palpable lymph nodes as well as male sex portended a needed.50 poor prognosis, similar to previous studies. In addition, after adjusting for these factors, these investigators also reported that lower hemoglobin and higher white blood cell counts were also prog- TREATMENT OF LOCALIZED SQUAMOUS nostic in terms of anal cancer death and worsened overall survival, CELL CARCINOMA respectively. Tumor site, T classification, and platelet levels had no influence on outcomes.44 However, not all studies have confirmed gender as an independent prognostic factor in terms of local con- Surgery trol, metastasis, or overall survival.45,46 Although well-differentiated histologies have been shown to As with any disease, treatment decisions in anal cancer are made portend more favorable outcomes in other cancers, the histologic following a consideration of the risks and benefits. Wide local exci- subtypes of anal cancer have not yet been demonstrated as substan- sion may be considered in a highly select subset of patients of anal tial prognostic factors.47 According to a study by Schlienger and cancer patients. This approach should generally be reserved for

tahir99 - UnitedVRG Chapter 61 Cancer of the Anal Region 847 small, well-differentiated, superficial lesions confined to the anal two groups in terms of late morbidity.70,71 Although not statistically margin, not involving the internal sphincter, and without nodal insignificant, an absolute improvement in 12-year survival of 5.6% volvement.61 For lesions that have residual microscopic disease or was seen. have close surgical margins less than 1 mm, further local excision, A similar but smaller trial conducted by the EORTC random- if technically possible, may be pursued, or adjuvant chemoradia- ized 103 patients with T3-4N0-3 or T1-2N1-3 anal cancer to tion should be considered.40 radiation therapy (45 Gy, with a boost dose of 15 to 20 Gy follow- Prior to the mid 1970s, the standard surgical approach to anal ing a 6-week break, based on disease response), with or without cancer was abdominal perineal resection (APR), which required concurrent chemotherapy using infusional 5-FU (750 mg/m2 per a permanent colostomy following the removal of the rectum, is- day, days 1 through 5 and days 29 through 33) with MMC (given chiorectal fat, levator sling, perirectal and superior hemorrhoidal on day 1 at 15 mg/m2). Surgery was reserved for patients with nodes, as well as a wide area of perianal skin, with associated long- less than a partial response. Outcomes from this study revealed term sequelae of sexual and urinary dysfunction. Collectively, that patients treated with concurrent chemotherapy had a higher long-term DFS results with a surgery alone approach were ap- complete response rate (80% versus 54%) with significant im- proximately 50%. A review at the Mayo Clinic of 118 anal cancers provement in local–regional control (68 versus 50%), colostomy- treated with APR reported an OS rate of 70% and overall recur- free (72% versus 40%) and event-free survival with the addition of rence rate of 40%. Of these, greater than 80% established recur- chemotherapy at 5 years. Similarly, OS was improved in patients rence sites had either local recurrence alone or some component receiving chemotherapy (3 year: 72% versus 65%), although this of such.62 Similarly, other surgical series using surgery alone results did not reach statistical significance. Rates of high-grade toxic- suggested high rates of regional recurrence (up to 60%) following ity were deemed similar between the two groups, although rates local excision or APR alone across a variety of stages.63 of late anal ulceration were higher with the use of concurrent chemotherapy.43 The results from these two trials demonstrated that the addition Definitive Chemoradiotherapy of chemotherapy to definitive radiation therapy significantly improves LRF rates as well as relapse-free and colostomy-free survival Given the relatively poor outcomes obtained with APR alone, rates, although at the expense of increased toxicity. Nigro et al., from Wayne State University pioneered incorporating concurrent pelvic radiation therapy and chemotherapy (5-FU The Role of Mitomycin in the Combined Modality and MMC) prior to surgical resection, resulting in high rates of Therapy Approach of Anal Cancer pathologic complete response and survival, later verified by other investigators.64–69 This led to significant interest in a definitive Although MMC was delivered concurrently with 5-FU in the afore- chemoradiotherapy approach. mentioned trials, it’s necessity was questioned given the association

Initially, the UK CCCR conducted the ACT I study. In this with significant toxicities, including significant myelosuppression, OF ONCOLOGY PRACTICE study, 585 patients with SCC of the anal canal or perianal skin dermatitis, as well as less common side effects of pulmonary fibrosis, were randomized to receive radiation therapy alone (45 Gy in 20 hemolytic-uremic syndrome and therapy-related myelodysplastic or 25 fractions), followed by additional radiation dose in patients syndrome. Given this, a randomized trial conducted by the RTOG achieving at least a 50% response (delivering an additional 15 to 25 and ECOG attempted to deintensify therapy by omitting MMC Gy using either external beam radiation therapy or brachytherapy in efforts to preserve oncologic efficacy while eliminating MMC- following a 6-week break) versus a similar radiation approach deliv- related toxicity. In this study, patients with anal cancer of any T or ered concurrently with infusional 5-FU (750 mg/m2 or 1,000 mg/ N stage were randomized to radiation therapy (45 to 50.4 Gy, with m2 for 5 days given during the first and last weeks of radiation an additional 9 Gy to patients with biopsy-proven persistence of therapy) along with MMC (12 mg/m2 delivered on day 1 of treat- disease 4 to 6 weeks following the completion of initial therapy) ment). Note that ACT I local failure rates captured several events, with infusional 5-FU (1,000 mg/m2 per day on days 1 to 4 and days including persistence of primary disease following combined mo- 29 to 32), with patients randomized to MMC (10 mg/m2 days 1 and dality therapy, the requirement for surgery or colostomy because 29) versus not. Note that in patients with a positive biopsy following of treatment failure, as well as ongoing requirement for colostomy the first 4- to 6-week treatment, an additional cycle of cisplatin and at 6 months following the completion of treatment. On the initial 5-FU with radiotherapy was delivered. A second biopsy was later report, following a median follow-up of 42 months, the 3-year local obtained and, if positive for residual tumor, patients proceeded to failure rate was significantly lower in patients receiving chemora- APR. This study enrolled 310 patients, of which 291 were analyz- diotherapy (39% versus 61%; p <0.0001), although at the expense able. Colostomy-free and disease-free survival rates were signifi- of increased treatment-related morbidity. In particular, hemato- cantly higher in patients receiving MMC (71% versus 59% and logic, skin, GI, and genitourinary toxicities were higher with the 73% versus 51%, respectively) with significantly lower colostomy addition of chemotherapy, with six (2%) treatment-related deaths (9% versus 22%) and local failure rates (16% versus 34%). OS was in the chemoradiation arm versus two (0.7%) for the radiation- not improved, although as in the previously described randomized alone arm. Although no statistically significant advantage was seen studies, was numerically superior (76% versus 67%). Also of note is in terms of OS (3-year OS 72% versus 65%; p = 0.17), with the ad- that all grade 4 and 5 toxicities were considerably higher in patients dition of chemotherapy, anal cancer-related mortality was signifi- receiving MMC.47 Table 61.3 summarizes the results of random- cantly improved (28% versus 39%; p = 0.02), leading the authors to ized phase III clinical trials evaluating combined modality therapy conclude that patients with SCC of the anal canal could be treated with radiation, 5-FU, and mitomycin versus radiation therapy alone with definitive chemoradiotherapy with surgery reserved for sal- or radiation therapy with 5-FU. vage. In a report of long-term follow-up of this trial, no significant differences were seen in terms of long-term morbidity, although The Role of Cisplatin Concurrent with Radiation an excess in non–anal cancer deaths was seen in the combined Therapy in Anal Cancer modality group in the first 10 years following treatment (cardiovascular, treatment related, pulmonary disease, and second malig- Given the aforementioned toxicities associated with MMC, there nancy), but not beyond. LRF rates remained significantly higher has been interest in substituting with a platinum-based chemo- in patients treated with radiation therapy alone (25% absolute dif- therapy when delivered concurrently with radiation therapy. ference at 12 years), with a corresponding improvement in relapse- Initial results using this approach from a Cancer and Leukemia free survival (12% absolute at 12 years) through the addition of Group B (CALGB) pilot study demonstrated that the use of in- chemotherapy, with no significant difference reported between the duction 5-FU with cisplatin for advanced anal cancers (T3 to 4, or 848 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 61.3 Summary of Randomized Phase III Clinical Trials Evaluating Combined Modality Treatment with Mitomycin-C/5-FU Versus Radiation Therapy Alone Or Radiation Therapy/5-FU for Anal Cancer

Study Treatment Local–Regional Relapse-Free Colostomy- Overall (Reference) Armsa Failure Survival Free Survival Survival Acute Toxicity UKCCR/ (1) Radiation (1) 59.1% (1) 17.7% (1) 20.1% (1) 27.5% (1) “Severe” skin toxicity = 39%; ACT I70,71 “severe” GI toxicity = 5% (2) Radiation + (2) 33.8% (2) 29.7% (2) 29.6% (2) 33.1% (2) “Severe” skin toxicity = 50%; 5-FU + MMC (at 12 years) (at 12 years) (at 12 years) (at 12 years) “severe” GI toxicity = 14% p = NS EORTC43 (1) Radiation 18% N/A 32% 7% (1) Grade 3–4 diarrhea = 8%; improvement in improvement improvement in grade 3–4 Dermatologic = 50% arm 2 in arm 2 arm 2 p = NS (2) Radiation + (2) Grade 3–4 diarrhea = 20%; 5-FU + MMC grade 3–4 dermatologic = 57% RTOG/ (1) Radiation + (1) 34% (1) 51% (1) 59% (1) 67% (1) Grade 4–5 heme = 3%; ECOG47 5-FU grade 4–5 nonheme = 4% (2) Radiation + (2) 16% (2) 73% (2) 73% (2) 76% (2) Grade 4–5 heme = 18%; 5-FU + MMC (disease-free (at 4 years) (at 4 years) grade 4–5 nonheme = 7% survival at p = NS 4 years)

NS, not stated. Note: + P values significant for comparisons unless otherwise noted. a Details of treatment arms noted in text.

node positive) followed by definitive chemoradiotherapy (45 Gy, pelvic radiation therapy (50.4 Gy) plus MMC (12 mg/m2 on with or without a 9 Gy boost) with 5-FU and MMC resulted in day 1) versus cisplatin (60 mg/m2 on day 1 and 29) with the same an 80% complete response rates with 56% and colostomy-free 5-FU– radiation regimen. A second randomization was performed survival.72 These and other data led to increasing interest in sub- following completion of the combined treatment course to no stituting cisplatin for MMC. The RTOG subsequently conducted further therapy versus two additional cycles of cisplatin and 5-FU. a phase III trial (RTOG 98-11), which randomized 644 patients to Grade 3 to 4 acute nonhematologic toxicity rates were similar be- (1) a standard arm of concurrent chemoradiotherapy (45 to 59 Gy) tween the regimens (60% versus 65%; p = 0.17). Not unexpec- with continuous infusional 5-FU (1,000 mg/m2 per day) and bolus tantly, grade 3 and higher hematologic toxicity rates were greater MMC (10 mg/m2) weeks 1 and 5 versus (2) an experimental arm in the mitomycin group (25% versus 13%; p < 0.001), although of two cycles of induction continuous 5-FU (1,000 mg/m2 per day) no toxic deaths were reported in the trial. In terms of the trial and bolus cisplatin (75 mg/m2) alone on weeks 1 and 5, followed primary endpoint of complete clinical response at 6 months, there by concurrent chemoradiotherapy with two cycles of continuous was no significant difference between the two groups, and at a me- 5-FU (1,000 mg/m2 per day) and bolus cisplatin (75 mg/m2) on dian follow-up of 5.1 years, clinical complete response at 26 weeks weeks 9 and 13. The trial primary endpoint was DFS and second- was 91% in the MMC group compared to 90% in the cisplatin ary endpoint included toxicity analysis. On the initial report, no group. Additionally, the 3-year colostomy rate was similar between significant difference was seen in 5-year DFS (60% versus 54%; the two groups (14% mitomycin versus 11% cisplatin). The use of p = 0.17), OS (75% versus 70%; p = 0.10), or local–regional maintenance therapy in this trial showed no obvious benefit, with relapse (25% versus 33%; p = 0.07). However, the 5-year colos- 3-year recurrence-free survival of 75% in both arms, similar OS tomy rate was 10% in the mitomycin group versus 19% in the rates between the maintenance versus no maintenance groups cisplatin-containing arm (p = 0.02).73 An update of this trial dem- (85% versus 84%), with 3-year PFS rates of 74% in the mainte- onstrated a significant improvement in 5-year DFS (68% versus nance group versus 73% in the nonmaintenance group. The au- 58%; p = 0.005), OS (78% versus 71%; p = 0.02), and border- thors concluded that MMC given concurrently with 5-FU and line colostomy-free survival (72% versus 65%; p = 0.05) in the radiation therapy should remain the standard in the treatment of MMC-containing arm, albeit at the expense of increased grade 3 anal cancer, given the following: (1) the high grade hematologic and higher hematologic toxicities (61% versus 42%; p < 0.001). toxicity seen with MMC did not significantly increase sepsis rates; However, nonhematologic toxicity rates were equivalent in both (2) the MMC course was delivered over approximately 10 min- arms, with similar rates of late toxicity.74 Critics of this study have utes compared to two courses of either all day or overnight in- pointed out that the prolonged the overall treatment duration as- travenous (IV) hydration with cisplatin, with similar efficacy and sociated with the use of induction chemotherapy with cisplatin overall toxicities between the regimens; (3) fewer chemotherapy may have allowed for accelerated tumoral repopulation prior to cycles were required; (4) there was requirement for fewer nonche- radiation therapy initiation. motherapy drugs; (5) there was lesser expense; and (6) there was A follow-up study from the UK CCCR (the ACT II trial) no risk of neuropathy.75 performed a more direct comparison of the use of cisplatin in Another phase III trial conducted by the French Federation conjunction with radiation therapy compared to MMC. In this Nationale des Centres de Lutte Contre La Cancer ACCORD (the largest of anal cancer randomized trials, 950 patients with anal ACCORD-03 trial) randomized patients with stage II to III anal or perianal skin cancer were randomized using a 2 × 2 facto- cancer to one of four treatment arms: (1) neoadjuvant 5-FU + rial design, with patients randomized to receive infusional 5-FU cisplatin alone followed by 5-FU cisplatin radiation therapy (45 (1,000 mg/m2 per day, on days 1 to 4 and days 29 to 32) with Gy) with a radiation therapy boost (15 Gy) using either external

tahir99 - UnitedVRG Chapter 61 Cancer of the Anal Region 849 beam or brachytherapy techniques; (2) same as the first arm, ex- were improved in the IMRT study (20% versus 47%; p < 0.001) cept utilizing a higher dose radiation boost (20 to 25 Gy); (3) same as were rates of grade 3 or higher GI and genitourinary toxicity as the first arm, but no neoadjuvant chemotherapy; and (4) same (22% versus 36%; p = 0.014). Additionally, median radiation dura- as the second arm, but no neoadjuvant chemotherapy. Of note is tion was 42.5 days in the IMRT study compared to 49 days in 98- that a 3-week break was mandated following the completion of the 11, with similar 2-year disease-related outcomes when compared initial 45 Gy, prior to boost treatments. Following a median 50- to RTOG 98-11.84,85 An important caveat to this trial was that a month follow-up, there was no significant difference in 5-year co- central reviewer performed pretreatment quality assurance on all lostomy-free survival rates (70% to 82%). Similarly, no significant patients. Of initially submitted plans, 81% required planning revi- differences were seen between the arms in terms of LRF, cause- sions, with 46% of plans requiring two or more revisions. Although specific survival, and OS. The most intensified treatment arm of this trial did not formally meet its primary endpoints in reduction induction chemotherapy with high-dose radiation boost demon- and acute toxicities, it does suggest that the use of IMRT can sig- strated a numerically improved local control (88% versus 72% to nificantly reduce high-grade GI, genitourinary, and skin toxicities 83% on the additional arms). The trial authors indicated that in- without compromising treatment-related outcomes, and that there duction chemotherapy does not improve outcomes, with the role is also a significant learning curve for the use of IMRT in the treat- of radiation dose escalation in this disease remaining uncertain, ment of anal cancer. Figure 61.5 demonstrates an example of an but felt that that the combination of induction chemotherapy and anal cancer plan implementing IMRT. radiation dose escalation should be explored further.76 The results of randomized trials evaluating cisplatin are shown in Table 61.4. Follow-Up Management

Novel Biologic Radiosensitizing Agents Given that SCC of the anus can regress slowly following treatment completion (up to 12 months), it is generally recommended To date, no biologic agent has been granted U.S. Food and Drug that patients who have regressive disease do not undergo repeat Administration (FDA) approval as an effective radiosensitizer in biopsies given this may lead to nonhealing ulceration and chronic anal cancer. Early reports have described outcomes of combined wound infection in previously irradiated tissues.45,86 Exempli- treatment modality with EGFR inhibitors, with varying degrees of fying this phenomena, in a preliminary report from the ACT II response and toxicity.79,80 These and other studies are warranted trial, 72% of patients who had not achieved a clinical complete to assess the role of treatment intensification, particularly in more response at 11 weeks ultimately achieved such at 26 weeks from advanced disease where outcomes are less favorable. treatment initiation,87 indicating that premature biopsy following definitive chemoradiotherapy may result in the aforementioned Traditional Radiation and Intensity Modulated complications as well as premature salvage surgery in some cases. Radiation Therapy Of the 265 patients in the ACT II trial not in complete response at week 11, only 83 ultimately had progression/persistent disease. OF ONCOLOGY PRACTICE The use of combined modality therapy in the definitive treat- Approximately 20% to 25% of patients with SCC treated by ment of anal cancer results in significant acute as well as late chemoradiation will either fail to completely respond or relapse toxicities. All the previously mentioned randomized trials used within the first 3 years after treatment. Posttreatment evaluation is radiation therapy planned and delivered using either conventional critical to assess the effectiveness of therapy and to detect a persis- 2-dimensional or 3-dimensional radiation planning techniques. tent or recurrent tumor.86 The first evaluation typically is between This approach frequently entails treating large volumes of nontar- 8 to 12 weeks after the completion of chemoradiation. The physi- get tissues (bowel, bladder, bone, genitalia), leading to the afore- cal examination should include a visual inspection, a digital rectal mentioned morbidities. Although 3-dimensional planning results exam, an anoscopy, and palpation of the inguinal nodal regions. in potentially improved normal tissue sparing through the use of Ongoing clinical evaluation typically occurs every 3 to 6 months axial CT images to define the target volume as well as normal for the first 2 years, then every 6 to 12 months until 5 years fol- tissue structures, results remain suboptimal. Intensity-modulated lowing completion of chemoradiation. It may be appropriate to radiation therapy is an advanced form of 3-dimensional conformal conduct less intense follow-ups following 3 years, given that only radiation therapy that implements multiple beams using a non- 7% of relapses occur beyond this time point.88 Lesions persisting uniform dose delivery. This can be accomplished in a variety of beyond 3 months following treatment are more concerning for ways, all of which entail the use of collimating leafs that sweep residual disease; however, as stated previously, it is important to across the beam path during treatment delivery. Through inverse assess changes over time. If a tumor continues to shrink, then close computer planning techniques, the radiation dose can be more clinical surveillance is advised. Chronically persistent or recurrent tightly conformed to target tissues with dose reductions to adja- tumors should be biopsied for confirmation of SCC.61 Discretion cent, nontarget organs. With this technique, there is a significant regarding the size and depth of biopsies is needed because exten- potential to reduce both acute and long-term morbidity associated sive biopsies may result in nonhealing ulcers and chronic wound with anal cancer treatments. Multiple institutional studies have infection.45 As an adjunct to physical examination, imaging stud- indicated that, compared to patients treated with non–intensity- ies for posttreatment surveillance should be considered.61 Current modulated radiation therapy (IMRT) techniques, a significant NCCN guidelines recommend a CT scan of the chest, abdomen, reduction of treatment-related toxicity can be accomplished.81,82 and pelvis annually for 3 years for patients who had T3 or T4 dis- Additionally, with corresponding reductions in acute toxicity, there ease or positive inguinal nodes. may be a reduction in the need for treatment breaks, with the potential to further influence disease-related outcomes.83 A prospective trial evaluating IMRT for anal cancer was conducted through Treatment for HIV Population the RTOG (0529 study). In this phase II trial, patients received concurrent 5-FU with MMC. Radiation therapy was delivered Unfortunately, the majority of pivotal phase III trials did not allow through a dose-painting technique, whereby differing target vol- the inclusion of HIV-positive patients. There are studies suggesting umes received differing doses of radiation therapy during any one that anal cancer patients with HIV comorbidities have comparable treatment as defined by the study. The primary endpoint of this rates of response to HIV-negative patients while being treated study included an assessment of grade 2 or higher GI and genito- with chemoradiation.89–91 Earlier studies suggested that there was urinary toxicities as compared to the previously described RTOG a potential for HIV-positive patients to experience higher toxici- 98-11 trial (MMC-containing arm). In 52 analyzable patients (out ties and inferior treatment compliance, which could ultimately of 63 accrued), rates of grade 3 or higher dermatologic toxicity alter their outcomes.92,93 Most studies addressing the application 850 Practice of Oncology / Cancers of the Gastrointestinal Tract b or large 1% bowel: (6/625) 2% (14/844) colostomy: colostomy: 3% (9/307) Late Toxic Toxic Late Effects (%; n/N) Grade 4 small Colostomy: Grade 4 b Group 2 Group 4 + + (240/324) (239/320) (294/472) (316/468) diarrhea: 9% diarrhea: (14/150) diarrhea: 12% 12% diarrhea: (18/157) Grade 3 or 4 Grade Nonhematological n/N) (%; Effects Toxic Group 1: 74% Group 1: 74% Group 2: 74% 62% Mitomycin: Cisplatin: 68% Group 1 Group 3 b Group 2: Group 4: + + (199/324) (134/320) (29/150) 19% (124/472) (73/468) 12% (19/157) 12% Grade 3 or 4 Grade Toxic Hematological n/N) (%; Effects Group 1: 61% Group 1 Group 2: 42% Group 3 26% Mitomycin: Cisplatin: 16%

+ + + + a 78.3% 70.7% Group 2: 75% Group 4: 71% Group 3: 71% Group 4: 74 % 84% 86% 83% 82% Overall Overall Survival (%) Group 1: Group 2: Group 1 Group 3 Group 1 Group 2 Group 1: Group 2: Group 3: Group 4: a Group 1: 71.9% Group 2: 65.0% Group 1: 69.6% Group 2: 82.4% Group 3: 77.1% Group 4: 72.7% Group 1: 72% Group 2: 75% Group 3: 75% Group 4: 73% Colostomy- Survival Free (%)

+ 15 Gy 15 → rest → EBRT EBRT EBRT EBRT EBRT (45 Gy) EBRT → → 20–25Gy → → fluorouracil and rest fluorouracil and fluorouracil and fluorouracil and + fluorouracil and + + + fluorouracil and fluorouracil and → + + + 15 Gy 15 20–25 Gy → → fluorouracil and cisplatin fluorouracil and cisplatin + rest rest → fluorouracil and cisplatin fluorouracil and cisplatin → → → + cisplatin cisplatin mitomycin (45–59 Gy) (45 Gy) fluorouracil and cisplatin cisplatin mitomycin cisplatin mitomycin Group 3: EBRT (45 Gy) Group 3: EBRT (45 Gy) Group 4: EBRT Group 1: EBRT (45–59 Gy) Group 1: EBRT Group 2: fluorouracil and cisplatin Group 1: fluorouracil and cisplatin Group 2: fluorouracil and cisplatin (50.4 Gy) Group 2: EBRT (50.4 Gy) Group 3: EBRT (50.4 Gy) Group 4: EBRT Group1: EBRT (50.4 Gy) Group1: EBRT + or N 4cm, 4cm – N0 to N3 ≥ < plus N1 to N3 N 682T4, T2 to 307 940T4, T1 to Anal canal Anal canal Anal canal or anal margin Primary Primary site N Stage Treatments 76 78 , 77 affected population/total population. affected 75 = 98-11 TABLE 61.4 TABLE Phase III Randomized Trials Evaluating the Role of Cisplatin in Anal Cancer the Role of Cisplatin in Evaluating Trials Phase III Randomized Study Study (Reference) RTOG ACCORD ACTII (n/N) At 5 years in RTOG 98-11 and ACCORD3; at 3 years in ACT II. ACT in at 3 years ACCORD3; and 98-11 in RTOG At 5 years a b

tahir99 - UnitedVRG Chapter 61 Cancer of the Anal Region 851

negative) controls.97 More recently, however, a single institution French study98 reported significantly poorer outcomes for their HIV-positive compared to HIV-negative patients. Local control was achieved in 50% versus 77%, with corresponding 5-year OS rates of 30% versus 84% and DFS rates of 37% versus 75%, respectively. In addition, HIV-infected patients were more likely to be younger and male, although no significant differences were seen in terms of stage or other tumor characteristics. These investigators postulated that the worsened outcomes may have resulted from a higher frequency of advanced disease in their population relative to other studies and a reflection of lack of routine and local screening programs. However, a follow-up study at Case Western University showed that both HIV-positive and HIV-negative patients treated with HAART had comparable Figure 61.5 An axial CT slice of an intensity-modulated radiation therapy treatment efficacy and toxicity rates.99 Finally, a pooled analysis plan of a 56-year-old male with clinical T3N3 squamous cell carcinoma of of 121 patients with anal cancer treated in the HAART era re- the anal canal treated with definitive chemoradiotherapy. Note relative vealed similar complete response and OS rates among HIV-pos- organ sparing and bending of isodose curves around normal structures including anteriorly based (genitalia) and femora bilaterally while still itive and HIV-negative patients, although HIV-positive patients encompassing the primary target volume of his gross tumor (red) as well were much more likely to experience local failure (5-year 62% as local–regional lymph nodes basins (perirectal and inguinal). Note that versus 13%; p = 0.008) along with increased acute dermatologic colored lines (isodose curves) represent varying radiation doses. and hematologic toxicities with treatment.100 There is a general concern that cancer patients receiving chemotherapy are predisposed to develop immunosuppression, particularly in the setting of an immunodeficiency disease such as and outcomes of standard combined regimens for the treatment HIV, thus complicating the treatment choice and follow-up plan. of anal cancer with HIV-positive patients describe small sample There is also a potentially greater chance of experiencing adverse sizes. There are several studies where investigators endeavored to treatment reactions that can hinder treatment compliance. Al- describe the outcomes of treatment modalities for anal carcino- though it is usually not necessary to alter standard management mas based on CD4 cell count.94,95 According to Hoffman et al.,94 recommendations, HIV-infected patients, especially those with patients with CD4 count ≥200/mm3 tolerated combined therapy a CD4 count less than 200/μL, should be monitored for an in- (5-FU/MMC/radiation) better (decreased likelihood of toxicity) creased risk of toxicity when treated with chemoradiation. Given 3 compared with patients who had CD4 counts <200/mm . In the previously described ACT I and EORTC trial results, che- OF ONCOLOGY PRACTICE the Cook County Hospital AIDS Malignancy Project (CHAMP) motherapy omission is generally not recommended. Thus, factors study, median survival in the HIV-positive versus HIV-negative including pretreatment CD4 cell count, HAART compliance, patients was 34 versus 39 months (p > 0.5). In the HIV-negative posttreatment CD4 cell count, and performance status, must population, 22% survived 120 months, whereas no HIV patient sur- come into account in order to formulate a favorable combined vived over 90 months, and time to local recurrence was 20 months treatment modality for anal cancer patients on a personalized, shorter in the HIV-positive arm (p < 0.5), with the authors specu- case-by-case basis. lating this may imply more aggressive disease. OS based on CD4 count did not differ.13 Preliminary safety and efficacy results were presented on Salvage Therapy for Local Recurrence the administration of two doses of cetuximab, cisplatin, 5-FU and with radiation therapy (45 to 54 Gy) in immunocompetent APR is recommended for patients who have chronically persis- (ECOG 3205, n = 28) and HIV-positive (AMC045, n = 45) tent disease or who develop recurrence. Restaging is performed patients with non-metastatic (stage I to III) squamous cell car- to evaluate the extent of the disease and determine the pres- cinoma of anal canal.96 These results showed that the PFS and ence of extrapelvic metastases. Curative surgery must attain OS rates in the subsequent 2 years were 80% and 89% for HIV- negative margins for oncologic success, and tumor invasion positive patients with anal cancer, compared to 92% and 93%, re- into adjacent organs warrants en bloc resection. Invasion of spectively for HIV-negative patients. The authors concluded that local structures, including the vagina or prostate, should be ap- combined cetuximab, cisplatin, 5FU and radiation combination proached with an intent of resecting with negative margins. therapy in HIV positive patients with anal cancer yielded favor- This may involve a multivisceral resection. In instances where able outcomes based on feasibility, safety and efficacy. Further there may be close or involved margins at resection, the use data on these two companion studies are indicated and evaluation of intraoperative radiotherapy or brachytherapy may enhance within a randomized clinical trial would be required to determine local control rates. In highly selected cases, there may be a whether patients with anal cancer benefit from an EGFR-targeted role for low-dose reirradiation with concurrent chemotherapy therapeutic agent. followed by resection and intraoperative radiotherapy. The HAART is important for bolstering CD4 cell counts in pa- majority of published series describing outcomes with salvage tients with HIV. To analyze the impact of HAART on patients surgery have small patient numbers given the relative rarity of with anal cancer receiving combined modality therapy (CMT), such. Five-year survival following resection generally ranges Place and colleagues95 completed a small study in which pa- between 30% to 70%, with DFS rates ranging from 30% to 40% tients were divided into two groups: one group received CMT (Table 61.5). The most important prognostic factor of survival before HAART implementation, and the other group received after resection is margin status, and patients with negative CMT following HAART therapy. The authors concluded that margins (R0) have up to a 75% 5-year OS.101 Further predic- the patients who received CMT after the advent of HAART tors of a poor OS outcome following surgery include inguinal had better outcomes, although it was speculated interpretation lymph node involvement, tumor size greater than 5 cm, adja- could be hampered by the fact HAART alone might have altered cent organ involvement, male gender, and comorbidities.102,103 the immune status of the patients.95 In a French study, clinical In one of the largest series describing salvage surgery in anal outcomes of anal cancer patients with HIV treated with HAART cancer, Correa et al.104 proposed a scoring system predicting and chemoradiation were similar to immunocompetent (HIV postoperative survival. The three factors included were lymph 852 Practice of Oncology / Cancers of the Gastrointestinal Tract

TABLE 61.5 Results of Salvage Surgery for Residual or Recurrent Anal Cancer

Negative Margin 5-Year Survival Based on Study Patient Number After Surgery (R0) Margin Status Overall 5-Year Survival Akbari et al., 2004102 62 85% R0 = 38% 33% R½ = 0% Nilsson et al., 2002105 35 91% NS 52% Ghouti et al., 2005106 36 NS NS 69.4% (DFS, 31.1%) Renehan et al., 2005107 73 75% R0 = 61.4% 40% R½ = 0% Schiller et al., 2007103 40 83% NS 39% (DFS, 30%) Ferenschild et al., 2005109 18 78% NS 30% Sunesen et al., 2009101 45 78% R0 = 75% 61% R1 = 40% R2 = 0% Eeson et al., 2011110 51 63% R0 = 42% 29% R½ = 0% Lefevre et al., 2012111 105 82% R0 = 69% 61% R1 = 0%

R0, clear margin; R1, microscopic positive margin; R2, grossly positive margin; NS, not stated.

node involvement, involved surgical margins, and perineural of 48 patients who underwent salvage APR reported no delays in and/or lymphovascular invasion.104 Patients who had none of wound healing or infectious complications when a VRAM flap these factors (i.e., a score of 0), had an estimated 5-year survival was used.101 of 55%; however, those with scores of 1 to 3 did much worse, with 5-year survival of 0.03% in patients with all of the factors. The utility of such a system is to define a subgroup that would Management of Metastatic Disease potentially benefit from additional postoperative treatments. The majority of reported series describing salvage surgery in- Randomized studies have demonstrated that patients treated dicate that persistence of disease (as opposed to recurrence) with chemoradiation can develop metastatic disease in 10% to following combined modality therapy was the primary reason 17% of cases.43,70 Currently, systemic chemotherapy is the treat- for such an approach. In patients undergoing salvage surgery, ment of choice for metastatic anal cancer. However, there is even with R0 resection, patients with disease persistence tend little published data in the setting of metastatic disease. Much to have worse outcomes, with 5-year overall survival rates rang- of the treatment has been extrapolated from more common ing from 31% to 33% as compared to 51% to 82% for truly squamous cell cancers such as head and neck cancer, cervical recurrent patients.102,105 It is been hypothesized that persistent cancer, etc. A 5-FU/cisplatin combination is recommended by tumors may harbor a more aggressive tumor biology resistant the NCCN40 guidelines as the first-line regimen to treat meta- to chemoradiotherapy, leading to worse outcomes. Overall, static anal SCC. length of time to recurrence following resection varies from There are a few small studies that report the benefit of adminis- 1 to 50 months.101,103,106,107 tration of the previous mentioned regimen in patients with meta- Salvage resection is associated with significant morbidity in static SCCA.86,112–115 Most notably, according to Faivre et al.,112 up to 72% of patients, including side effects of delayed perineal survival at 1 and 5 years were 62.2% and 32.2%, respectively, wound healing, pelvic abscesses, perineal wound hernia, urinary whereas the median survival was 34.5 months. retention, as well as the development of impotence. Perineal MMC and 5-FU may also be considered for first-line therapy116 wound healing difficulties are a result of both the large soft tis- for metastatic SCCA. One study showed that patients treated with sue defect created in fully excising these tumors as well as poten- this regimen ultimately achieved better response that included tially impacted by prior radiation therapy. Closure of the wound tumor size shrinkage, pain management, and performance im- by primary intention produces suboptimal results if not combined provement. There are additional combination chemotherapy trials with flap placement. In one series of 22 patients undergoing sal- and single agent case reports available that are described briefly in vage APR with primary closure, 59% experience perineal wound Table 61.6.117 break down, with 1 requiring reconstructive operation.107 Com- Cetuximab has shown favorable outcomes for the treatment monly used tissue flaps include an omental pedicle flap, a gracilis of SCC of the head and neck while delivered concurrently with muscle flap, and the vertical rectus abdominis myocutaneous flap radiation therapy.125 However, the data supporting the adminis- (VRAM). In one series of 95 patients undergoing salvage APR, tration of cetuximab in metastatic SCCA is scant. According to patients undergoing an omental pedicle flap, as compared to a a few small studies and case reports, the maximum clinical re- VRAM flap, had more perineal wound complications and slower sponse achieved was a partial response, with varying ranges of healing.108 In another smaller series, the perineal wound break- PFS with cetuximab/irinotecan combination therapy.126–128 Due down rate with the use of omental flap reconstruction was 36% to the very small sample sizes of these studies, a further evaluation versus 0% with a VRAM flap following APR.110 Finally, a series is warranted.

tahir99 - UnitedVRG Chapter 61 Cancer of the Anal Region 853

TABLE 61.6 Studies Demonstrating Survival and Response Data on Metastatic Anal Cancer.

Study Type Response Rate or Progression-Free (Reference) Patient Number Agent(s) Clinical Response Survival in Months Combination118 15 Vincristine/bleomycin/methotrexate 25% 2 Combination119 7 (anal only) Paclitaxel/carboplatin/5-FU 65% 26 Combination120 20 Mitomycin-C/Adriamycin/cisplatin/bleomycin 60% 8 Combination121 77 5-FU/cisplatin versus Carboplatin/paclitaxel 8 versus 4 Single-agent Carboplatin Partial 9 case report122 Single-agent Semustine Partial 15 case report123 Single-agent Irinotecan Partial Not reported case report124

Like other GI cancers, the liver is the primary site of metastasis A generally accepted, contemporary definition includes the from anal cancer. Data on the resection of an isolated hepatic le- area extending from the anal verge radially 5 cm outward on sion are sparse, and currently, a definitive surgical treatment proto- the perianal skin. The onset of this disease is frequently seen in col remains largely undefined in the metastatic setting. That said, the 7th and 8th decades of life, with a slight female predomi- surgical resection of metastatic disease can be considered when nance.116,132,133 The majority of these tumors are well differenti- appropriate, based on the extent of disease and performance sta- ated, indicating a slow growing nature with the development of tus. According to Eng et al.,121 the median PFS and OS of 33 out distant metastases rare.116,134,135 The primary drainage is to the of 77 patients with metastatic anal SCCA who received curative inguinal region and regional nodal metastases directly related to surgical treatment for their metastatic disease were 16 (95% CI, tumoral size. Once series136 describes that tumors less than 2 cm

9.2 to 22.8) and 53 months (95% CI, 28.3 to 77.6), respectively. rarely exhibit lymph node metastases, 2 to 5 cm tumors associ- OF ONCOLOGY PRACTICE Previously, a multicenter study129 comprising of 52 patients also ated with an approximately 23% node positive rate, and in tumors suggested that a subset of patients might benefit from surgical re- larger than 5 cm, rates as high as 67%. Therefore, it is important section. According to the study, among 27 metastatic squamous that these tumors be approached on an individual basis based cell anal carcinoma patients pretreated with systemic therapy, on size, location, and histologic characteristics. Tumors whose the median PFS and OS were 9.6 and 22.3 months, respectively, epicenter is distal to the anal verge may be managed as skin tu- although definitive selection criteria for surgical resection were mors. Potential treatment options for these patients include local lacking. excision with or without adjuvant radiation therapy, or radiation Outcome, benefit, and toxicity analysis on chemoradiation for with or without chemotherapy. Treatment considerations in these metastatic anal cancer is limited. A small study130 (n = 6) from the patients must take into account expected morbidity with such ap- M.D. Anderson Cancer Center of patients with para-aortic nodal proaches. For smaller tumors, wide local excision with a 1-cm involvement was reported. In this study, all the patients were treated margin is often sufficient. However, surgery for larger tumors with IMRT with concurrent infusional 5-FU and cisplatin. The may require more aggressive removal, which may entail APR; results showed that 3-year actuarial local–regional control, distant combined modality therapy may be an appropriate alternative in control, and survival rates were 100%, 56%, and 63%, respectively. such cases, particularly where the risk of lymph node involve- In another study, a short course of chemoradiation comprised of ment is high. Therefore, surgery is often reserved for tumors <2 30 Gy with concurrent 5-FU demonstrated good local–regional cm in greatest dimension without adverse histologic features and control (73% at the median follow-up of 16 months) in elderly no involvement of the anal sphincter. APR should generally be patients (median age 81 years).131 Combined chemoradiation may reserved for patients with recurrent disease following radiation/ also be used to palliate symptoms related to metastatic disease. chemoradiation or recurrence not amenable to local excision. The International Rare Cancer Initiative (IRCI) in collabora- Chapet and colleagues137 reviewed an experience of 26 patients tion with the NCI has expressed interest specifically focusing on with tumors of the perianal skin, 5 with involvement of the anal establishing guidelines for metastatic anal cancer squamous carci- canal. Most were ≤5 cm in diameter. Fourteen received defini- noma patients, including diagnostic imaging, staging, surveillance, tive radiation therapy, with or without chemotherapy, and 12 re- and survivorship. The first initiative is an international collabora- ceived radiation therapy following initial local excision. Actuarial tion with the United Kingdom, EORTC, and ECOG/ACRIN on local control rate was 61%, and with salvage surgical treatment, a randomized phase II trial of 5-FU/cisplatin versus carboplatin/ this increased to 81%, with a 5-year cause-specific survival of 88%. paclitaxel in treatment-naïve patients (InterAACT). Khanfir et al.138 reported similar results in a series of 45 patients. Twenty-nine patients underwent local excision prior to radiation therapy. Five-year local–regional control was 78% with 5-year TREATMENT OF OTHER SITES AND DFS of 86%. Balmucki et al.139 updated at University of Florida PATHOLOGIES experience with definitive radiotherapy and chemoradiotherapy in 26 patients with SCC of the perianal skin. Two patients developed local recurrence and two developed regional nodal recur- Squamous Cell Carcinoma of the Anal Margin rence, resulting in a 10-year cause-specific survival of 92%. Of note, two patients who had clinically node-negative disease who The definition of anal margin tumors has varied over time, rang- did not receive prophylactic inguinal nodal radiation developed ing from perianal skin to the distal aspect of the anal canal. inguinal recurrences. 854 Practice of Oncology / Cancers of the Gastrointestinal Tract

Anal Canal Adenocarcinoma of cases.34 Therefore, appropriate imaging and fiber-optic endoscopy studies are recommended to rule out synchronous underly- Primary adenocarcinoma of the anal canal is an uncommon ing malignancies. tumor. In many situations, this will represent growth of a distal rectal adenocarcinoma into the anal canal and is managed as such. In some instances, this disease is believed to arise from glan- Melanoma of the Anorectal Region dular epithelium in the anal canal, accounting for less than 5% of all anal malignancies.140 Occasionally, adenocarcinoma may Anorectal melanoma is a rare disease that accounts for approximately occur in patients with ulcerative colitis or Crohn’s disease who 1% of all malignant melanomas and 0.5% of tumors of anorectal have ileal pouch–anal anastomosis.141–143 A study from the Rare area.147–149 Symptoms are rather nondescript, with bleeding mani- Cancer Network registry of 82 patients diagnosed with anal adeno- festing as the most common complaint.150 The gross appearance var- carcinoma was analyzed based on the treatment approach. The ies from a small, pigmented lesion to an ulcerated mass. Anal canal actuarial local–regional relapse rate at 5 years was 37%, 36%, and melanomas are usually pigmented lesions, but can be amelanotic 20%, respectively, in the radiation/surgery, combined chemoradia- in as many as 29% of cases.151 A SEER database review reported tion therapy alone, and APR alone groups. The 5-year OS rate was a 5-year OS of 2.5%,152 although some series report up to a 20% 29%, 58%, and 21% and 5-year DFS rate 25%, 54%, and 22%, survival.149,150,153 Surgery is the cornerstone of treatment with debate respectively. A multivariate analysis revealed four independent regarding the optimal approach. Traditionally, surgeons adopted a prognostic factors for survival: T stage, N stage, histologic grade, more radical approach utilizing APR with a radical lymph node dis- and treatment modality (chemoradiotherapy). The authors con- section. However, this approach was associated with significant mor- cluded that they observed better survival rates after combined bidity without improving OS. Kiran et al.154 reviewed 109 patients chemoradiotherapy and recommended using APR only for salvage with anorectal melanoma from the SEER database between 1982 treatment.144 In contrast, a Surveillance, Epidemiology, and End and 2002 and reported no significant difference between patients Results (SEER) study evaluated 165 patients with nonmetastatic treated by APR or local resection. A retrospective review of 251 pa- adenocarcinoma of the anal canal. Of these, 30 patients were tients from the Swedish National Cancer Registry between 1960 and treated with an APR only, 42 patients with an APR and radiation, 1999 demonstrated similar findings.155 A recent systematic review and 93 patients with radiation alone. The 5-year survival for APR comparing APR to wide local excision in anal melanoma patients only, APR and radiation, and radiation alone was 58%, 50%, and reported similar median survivals regardless of treatment approach 30%, respectively (p = 0.04). A multivariate analysis confirmed (21 months for APR, N = 369; 20 months for local excision, N = factors accounting for the survival differences included age, nodal 324). Similarly, the treatment approach did not significantly impact stage, and treatment groups. The authors concluded definitive sur- 5-year survival (14% for APRs, 15% for local excision).156 gical treatment in the form of an APR with or without radiation is There are some centers that advocate more aggressive treat- associated with improved survival in these patients.145 An institu- ment for localized disease, arguing for better oncologic outcomes tional report from the M. D. Anderson Cancer Center analyzed in select subsets. In an older Memorial Sloan Kettering experi- 16 patients with anal adenocarcinoma and compared outcomes ence, factors associated with long-term survival following APR in- with definitive chemoradiotherapy to similarly treated patients cluded female gender, negative lymph nodes, and tumor size less with squamous cell tumors.146 At 5-years, local failure rate was 54% than 2.5 cm, concluding APR may be considered in the subset in the adenocarcinoma group compared to 18% for patients with of patients with these features.150 A Japanese study that included SCC, with corresponding 5-year DFS of 19% versus 77%, respec- 79 patients with anorectal melanoma reported 3- and 5-year sur- tively, and OS rates of 64% versus 85%. Given this, patients with vival rates of 34.8% and 28.8%, respectively (median survival primary anal adenocarcinoma are generally treated as if they had 22 months), for patients treated by APR.157 Therefore, the authors rectal adenocarcinomas of similar stage, with surgery remaining as of that study recommended local excision for patients with stage a cornerstone therapy and neoadjuvant radiation therapy or com- 0 melanoma, whereas those with stage 1 cancers or T1 tumors bined modality therapy generally implemented in patients with should undergo an APR with lymph node dissection. Ballo et al.158 high-risk features (T3 or T4 and/or nodal involvement). reported on 23 patients treated at the M. D. Anderson Cancer Anal Paget disease is an intraepithelial adenocarcinoma arising Center with sphincter sparing excision and adjuvant radiation from the dermal apocrine sweat glands, most commonly found in therapy using a hypofractionated regimen of 30 Gy delivered in females and in older patients.34 Although progression from peri- five fractions. Nine patients received systemic therapy. Five-year anal Paget disease to invasive disease is seen in approximately 5% actuarial overall, disease-free, distant metastases-free, local, and of cases, invasive cancers have been reported up to 40% of patients regional nodal control rates were 31%, 37%, 35%, 74%, and 84%, with untreated Paget disease. Association with tubo-ovarian adeno- respectively, comparing favorably to varying reports using local carcinoma was seen in 7% to 24% and GI cancers in 12% to 14% excision alone.

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Acta Oncol 1993;32: 46. Das P, Bhatia S, Eng C, et al. Predictors and patterns of recurrence after 33–35. definitive chemoradiation for anal cancer. Int J Radiat Oncol Biol Phys 2007; 87. Glynne-Jones R, James R, Meadows H, et al, eds. Optimum time to assess 68:794–800. complete clinical response (CR) following chemoradiation (CRT) using mi- 47. Flam M, John M, Pajak TF, et al. Role of mitomycin in combination with tomycin (MMC) or cisplatin (CisP), with or without maintenance CisP/5FU fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive in squamous cell carcinoma of the anus: Results of ACT II. Paper presented nonsurgical treatment of epidermoid carcinoma of the anal canal: results of at: 2012 ASCO Annual Meeting; 2012; Chicago, IL. a phase III randomized intergroup study. J Clin Oncol 1996;14:2527–2539. 88. Sebag-Montefiore D, James R, Meadows H, et al. The pattern and timing of 50. Lampejo T, Kavanagh D, Clark J, et al. Prognostic biomarkers in squa- disease recurrence in cancer of the anus: mature results from the NCRI ACT mous cell carcinoma of the anus: a systematic review. Br J Cancer 2010;103: II trial. J Clin Oncol. 2012;30. 2012 ASCO Annual Meeting. 1858–1869. 92. Oehler-Janne C, Seifert B, Lutolf UM, et al. Local tumor control and toxic- 55. Ajani JA, Wang X, Izzo JG, et al. Molecular biomarkers correlate with dis- ity in HIV-associated anal carcinoma treated with radiotherapy in the era of ease-free survival in patients with anal canal carcinoma treated with chemo- antiretroviral therapy. Radiat Oncol 2006;1:29. radiation. Dig Dis Sci 2010;55:1098–1105. 93. Kauh J, Koshy M, Gunthel C, et al. Management of anal cancer in the HIV- 56. Bonin SR, Pajak TF, Russell AH, et al. Overexpression of p53 protein and positive population. Oncology (Williston Park) 2005;19:1634–1638. outcome of patients treated with chemoradiation for carcinoma of the anal 94. Hoffman R, Welton ML, Klencke B, et al. The significance of pretreatment canal: a report of randomized trial RTOG 87-04. Radiation Therapy Oncol- CD4 count on the outcome and treatment tolerance of HIV-positive patients ogy Group. Cancer 1999;85:1226–1233. with anal cancer. Int J Radiat Oncol Biol Phys 1999;44:127–131. 856 Practice of Oncology / Cancers of the Gastrointestinal Tract

98. Munoz-Bongrand N, Poghosyan T, Zohar S, et al. Anal carcinoma in HIV- 131. Charnley N, Choudhury A, Chesser P, et al. Effective treatment of anal can- infected patients in the era of antiretroviral therapy: a comparative study. Dis cer in the elderly with low-dose chemoradiotherapy. Br J Cancer 2005;92: Colon Rectum 2011;54:729–735. 1221–1225. 99. Seo Y, Kinsella MT, Reynolds HL, et al. Outcomes of chemoradiotherapy with 132. Cutuli B, Fenton J, Labib A, et al. Anal margin carcinoma: 21 cases treated 5-Fluorouracil and mitomycin C for anal cancer in immunocompetent versus at the Institut Curie by exclusive conservative radiotherapy. Radiother Oncol immunodeficient patients. Int J Radiat Oncol Biol Phys 2009;75:143–149. 1988;11:1–6. 100. Oehler-Janne C, Huguet F, Provencher S, et al. HIV-specific differences in 133. Peiffert D, Bey P, Pernot M, et al. Conservative treatment by irradiation of outcome of squamous cell carcinoma of the anal canal: a multicentric cohort epidermoid carcinomas of the anal margin. Int J Radiat Oncol Biol Phys study of HIV-positive patients receiving highly active antiretroviral therapy. 1997;39:57–66. J Clin Oncol 2008;26:2550–2557. 134. Chawla AK, Willett CG. Squamous cell carcinoma of the anal canal and 102. Akbari RP, Paty PB, Guillem JG, et al. Oncologic outcomes of salvage sur- anal margin. Hematol Oncol Clin North Am 2001;15:321–344. gery for epidermoid carcinoma of the anus initially managed with combined 136. Papillon J, Chassard JL. Respective roles of radiotherapy and surgery in the modality therapy. Dis Colon Rectum 2004;47:1136–1144. management of epidermoid carcinoma of the anal margin. Series of 57 pa- 103. Schiller DE, Cummings BJ, Rai S, et al. Outcomes of salvage surgery tients. Dis Colon Rectum 1992;35:422–429. for squamous cell carcinoma of the anal canal. Ann Surg Oncol 2007;14: 137. Chapet O, Gerard JP, Mornex F, et al. Prognostic factors of squamous cell 2780–2789. carcinoma of the anal margin treated by radiotherapy: the Lyon experience. 104. Correa JH, Castro LS, Kesley R, et al. Salvage abdominoperineal resection Int J Colorectal Dis 2007;22:191–199. for anal cancer following chemoradiation: a proposed scoring system for pre- 138. Khanfir K, Ozsahin M, Bieri S, et al. Patterns of failure and outcome in dicting postoperative survival. J Surg Oncol 2013;107:486–492. patients with carcinoma of the anal margin. Ann Surg Oncol 2008;15: 108. Lefevre JH, Parc Y, Kerneis S, et al. Abdomino-perineal resection for anal 1092–1098. cancer: impact of a vertical rectus abdominis myocutaneous flap on survival, 139. Balamucki CJ, Zlotecki RA, Rout WR, et al. Squamous cell carcinoma of the anal recurrence, morbidity, and wound healing. Ann Surg 2009;250:707–711. margin: the university of Florida experience. Am J Clin Oncol 2011;34:406–410. 110. Eeson G, Foo M, Harrow S, et al. Outcomes of salvage surgery for epider- 144. Belkacemi Y, Berger C, Poortmans P, et al. Management of primary anal moid carcinoma of the anus following failed combined modality treatment. canal adenocarcinoma: a large retrospective study from the Rare Cancer Net- Am J Surg 2011;201:628–633. work. Int J Radiat Oncol Biol Phys 2003;56:1274–1283. 111. Lefevre JH, Corte H, Tiret E, et al. Abdominoperineal resection for squa- 145. Kounalakis N, Artinyan A, Smith D, et al. Abdominal perineal resection mous cell anal carcinoma: survival and risk factors for recurrence. Ann Surg improves survival for nonmetastatic adenocarcinoma of the anal canal. Ann Oncol 2012;19:4186–4192. Surg Oncol 2009;16:1310–1315. 112. Faivre C, Rougier P, Ducreux M, et al. [5-fluorouracile and cisplatinum 150. Brady MS, Kavolius JP, Quan SH. Anorectal melanoma. A 64-year expe- combination chemotherapy for metastatic squamous-cell anal cancer]. Bull rience at Memorial Sloan-Kettering Cancer Center. Dis Colon Rectum Cancer 1999;86:861–865. 1995;38:146–151. 117. Dewdney A, Rao S. Metastatic squamous cell carcinoma of the anus: time for 151. Quan SH, White JE, Deddish MR. Malignant melanoma of the anorectum. a shift in the treatment paradigm? ISRN Oncol 2012;2012:756591. Dis Colon Rectum 1959;2:275–283. 119. Hainsworth JD, Burris HA 3rd, Meluch AA, et al. Paclitaxel, carboplatin, and 152. Metildi C, McLemore EC, Tran T, et al. Incidence and survival patterns long-term continuous infusion of 5-fluorouracil in the treatment of advanced of rare anal canal neoplasms using the surveillance epidemiology and end squamous and other selected carcinomas: results of a Phase II trial. Cancer 2001; results registry. Am Surg 2013;79:1068–1074. 92:642–649. 153. Slingluff CL Jr, Seigler HF. Anorectal melanoma: clinical characteristics and 121. Eng C, Rogers J, Chang GJ, et al. Choice of chemotherapy in the treat- the role of abdominoperineal resection. Ann Plast Surg 1992;28:85–88. ment of metastatic squamous cell carcinoma of the anal canal. J Clin Oncol 154. Kiran R, Rottoli M, Pokala N, et al. Long-term outcomes after local excision 2012;30:abstr 4060. and radical surgery for anal melanoma: data from a population database. Dis 125. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for Colon Rectum 2010;53:402. squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354: 155. Nilsson PJ, Ragnarsson-Olding BK. Importance of clear resection margins in 567–578. anorectal malignant melanoma. Br J Surg 2010;97:98–103. 129. Pawlik TM, Gleisner AL, Bauer TW, et al. Liver-directed surgery for meta- 156. Kanaan Z, Mulhall A, Mahid S, et al. A systematic review of prognosis and static squamous cell carcinoma to the liver: results of a multi-center analysis. therapy of anal malignant melanoma: a plea for more precise reporting of Ann Surg Oncol 2007;14:2807–2816. location and thickness. Am Surg 2012;78:28–35. 130. Hodges JC, Das P, Eng C, et al. Intensity-modulated radiation therapy for the 158. Ballo MT, Gershenwald JE, Zagars GK, et al. Sphincter-sparing local ex- treatment of squamous cell anal cancer with para-aortic nodal involvement. cision and adjuvant radiation for anal-rectal melanoma. J Clin Oncol Int J Radiat Oncol Biol Phys 2009;75:791–794. 2002;20:4555–4558.

tahir99 - UnitedVRG Section 4 Cancers of the Genitourinary System

Molecular Biology 62 of Kidney Cancer

W. Marston Linehan and Laura S. Schmidt

INTRODUCTION chromosome 3p25-26, leading to the cloning of the VHL gene in 1993.5 VHL is a tumor suppressor gene in which both copies of Kidney cancer or renal cell carcinoma (RCC) affects more than VHL must be inactivated for tumor initiation. Germ-line VHL mu- 271,000 people annually worldwide, resulting in 116,000 deaths tations that predispose individuals to VHL encompass the entire each year.1 A variety of risk factors, including obesity, hyperten- mutation spectrum, including large deletions, protein-truncating mu- sion, tobacco smoking, and certain occupational exposures, have tations, and missense mutations that exchange the amino acid in the been shown to increase one’s risk for developing RCC. Our cur- VHL protein. Over 700 different VHL mutations have been identified rent understanding of the molecular genetics of kidney cancer has in more than 945 VHL families worldwide. Mutations are located come from studies of families with an inherited predisposition to throughout the entire gene with the exception of the first 35 residues develop renal tumors. Individuals with a family history of RCC in the acidic domain.12 With the development of new methods for have a 2.5-fold greater chance for developing renal cancer during detection of deletions, VHL mutation detection rates are approach- their lifetimes2 and comprise about 4% of all RCCs. ing 100%.14,15 VHL subclasses based on the predisposition to develop Kidney cancer is not a single disease, but rather is classified into pheochromocytomas and a high or low risk of RCC have been estab- tumor subtypes based on histology.3 Over the past 2 decades, studies lished with clear genotype–phenotype associations emerging.16 of families with inherited renal carcinoma enabled the identifica- PRACTICE OF ONCOLOGY PRACTICE tion of five inherited renal cancer syndromes and their predisposing Gene Mutated in Renal Cancer Families with genes (Table 62.1), which implicate diverse biologic pathways in Chromosome 3p Translocations renal cancer tumorigenesis.4 The von Hippel-Lindau (VHL) tumor suppressor gene was discovered in 1993.5 Subsequently, activating In 1979, Cohen et al.17 described a family with a constitutional mutations were identified in theMET protooncogene in patients t(3;8)(p14;q24) balanced translocation that cosegregated with bi- with hereditary papillary renal carcinoma (HPRC).6 More recently, lateral multifocal clear cell renal tumors. Loss of the derivative germ-line mutations in the gene for Krebs cycle enzyme fumarate chromosome carrying the 3p segment and different somatic mu- hydratase (FH), responsible for hereditary leiomyomatosis and tations in the remaining copy of VHL were identified in the tu- renal cell carcinoma (HLRCC),7 and in FLCN, the gene for Birt– mors from this translocation family. Based on these data, Schmidt Hogg–Dubé (BHD) syndrome, were identified.8 Germ-line muta- et al.18 proposed a three-step tumorigenesis model in 3p translocations in the genes encoding subunits B, C, and D of another Krebs tion families: (1) inheritance of the constitutional translocation, cycle enzyme, succinate dehydrogenase (SDHB/SDHC/SDHD), (2) loss of the derivative chromosome bearing 3p25, and (3) mu- have been found in patients with familial renal cancer.9–11 Discov- tation of the remaining copy of VHL, resulting in inactivation ery of the genes for the inherited forms of renal cancer has enabled of both copies of VHL and predisposing individuals to clear cell the development of diagnostic genetic tests for presymptomatic RCC. A number of chromosome 3 translocation families have diagnosis and improved prognosis for at-risk individuals. been described.19,20 Loss of the derivative chromosome concomitant with the somatic mutation of the remaining copy of VHL in VON HIPPEL-LINDAU DISEASE these families provides strong evidence for the three-step tumorigenesis model and implicates VHL loss in clear cell RCC that Von Hippel-Lindau (VHL) disease is an autosomal-dominant in- develops in chromosome 3 translocation kindreds. herited multisystem neoplastic disorder that is characterized by clear cell renal tumors, retinal angiomas, central nervous system Gene for Sporadic Clear Cell Kidney Cancer hemangioblastomas, tumors of the adrenal gland (pheochromocytoma), endolymphatic sac and pancreatic islet cell, and cysts in Somatic mutation of the VHL gene with associated loss of the the pancreas and kidney. VHL occurs in about 1 in 36,000 and wild-type allele is found in a high percentage of tumors from pa- develops during the 2nd to 4th decades of life with nearly 70% tients with clear cell kidney cancer.21 Nickerson et al.22 recently penetrance by age 60. Bilateral, multifocal renal tumors with clear identified mutation or methylation of theVHL gene in 92% of cell histology develop in 25% to 45% of VHL patients12 that can clear cell kidney cancers. The VHL gene mutation is not found in have metastatic potential when they reach 3 cm. papillary, chromophobe, collecting duct, medullary, or other types of kidney cancer. Genetics of VHL Function of the VHL Protein Loss of heterozygosity (LOH) on chromosome 3p in clear cell renal tumors suggested the location of a predisposing gene for RCC.13 The most well-understood function of the VHL protein pVHL Positional cloning in VHL kindreds defined the disease locus to is the substrate recognition site for the hypoxia-inducible factor 857 858 Practice of Oncology / Cancers of the Genitourinary System

TABLE 62.1 Hereditary Renal Cancer Syndromes

Frequency of Gene Mutations Chromosome Predisposing Sporadic Syndrome Location Gene Histology Germ Line RCC Von Hippel-Lindau (VHL) disease 3p25 VHL Clear cell 100%14 92%22 Hereditary papillary renal 7q31 MET Type 1 papillary 100%6,41,42 13%45 carcinoma type 1 (HPRC) Birt-Hogg-Dubé syndrome (BHD) 17p11.2 FLCN Chromophobe, 90%65 11% 76 hybrid Hereditary leiomyomatosis and 1q42–43 FH Type 2 papillary 93%105 TBD renal cell carcinoma (HLRCC) Succinate dehydrogenase (SDH)– 1p35–36 SDHB Clear cell, TBD TBD associated familial renal cancer 1q23.3 SDHC chromophobe, 11q23 SDHD oncocytic neoplasm Tuberous sclerosis complex (TSC) 9q34 TSC1 Angiomyolipoma, 80%–90% TBD 16p13.3 TSC2 all histologies

TBD, to be determined.

(HIF)-α family of transcription factors targeting them for (GLUT-1).16 HIF-α–dependent upregulation of target genes ubiquitin- mediated proteasomal degradation (Fig. 62.1).16 pVHL involved in neovascularization provides an explanation for the binds through its α domain to elongin C and forms an E3 ubiq- increased vascularity of central nervous system (CNS) heman- uitin ligase complex with elongin B, cullin-2, and Rbx-1. Under gioblastomas and clear cell renal tumors in VHL. Germ-line normal oxygen conditions, HIF-α becomes hydroxylated on criti- VHL mutations frequently occur in the pVHL binding domains cal prolines by a family of HIF prolyl hydroxylases (PHD) that re- for HIF-α and elongin C.23 HIF-2α (rather than HIF-1α) stabi- quire α-ketoglutarate, molecular oxygen, ascorbic acid, and iron lization appears to be critical for renal tumor development.24,25 as cofactors. pVHL then binds to hydroxylated HIF-α through Additional HIF-independent functions for pVHL have been re- its β domain, targeting HIF-α for ubiquitylation by the E3 ligase ported,12,16,26 including an increase of p53 activity through the complex. Under hypoxic conditions when PHDs are unable to suppression of MDM2-mediated ubiquitination and nuclear function or when pVHL is mutated—thereby altering its binding export,27 modulation of nuclear factor κ B (NF-κB) through ca- to HIF-α or elongin C—HIF-α cannot be recognized by pVHL. sein kinase 2 binding and inhibitory phosphorylation of NF-κB HIF-α accumulates and transcriptionally upregulates a number agonist CARD9,28 microtubule stabilization,29 maintenance of of genes important in blood vessel development (EPO, VEGF), primary cilium,30 and extracellular matrix formation affecting cell proliferation (PDGFβ, TGFα), and glucose metabolism cell–cell adhesion.31,32

E2 VHL CUL2 Normoxia Elongin B Hypoxia Elongin B Rbx1 complex CUL2 CUL2 Elongin B Elongin C disrupted Elongin C Rbx1 Elongin C Rbx1 VHL ␤-domain ␣-domain E2 VHL␤-domain ␣-domain E2 Mutant ␤-domain Mutant ␣-domain VHL protein UB UB PHD 2-OG UB OH OH UB O O HIF-␣ HIF-␣ HIF1-␣ D O HIF2-␣ D O D D D D D D

HIF-␣ HIF-␣ degradation accumulation VEGF GLUT1 PDGF

VEGF GLUT1 A PDGF B

Figure 62.1 The von Hippel-Lindau (VHL) E3 ubiquitin ligase complex targets hypoxia-inducible factor (HIF)-α for ubiquitin-mediated degradation. (A) Under normal oxygen conditions, HIF-α is hydroxylated on critical prolines by HIF prolyl hydroxylase (PHD), requiring molecular oxygen, α-ketoglutarate (2-OG), and iron as cosubstrates. The VHL protein (pVHL) can then recognize and bind hydroxylated HIF-α, enabling ubiquitylation by the VHL E3 ligase complex and degradation by the proteasome. Under hypoxic conditions, PHD is unable to function properly, pVHL cannot recognize HIF-α, and HIF-α accumulates, leading to the upregulation of HIF-target genes (VEGF, GLUT1, PDGF) that support tumor growth and neovascularization. (B) When VHL is mutated and pVHL is unable to bind HIF-α, HIF-α stabilization leads to transcriptional upregulation of HIF target genes. (From Linehan WM, Srinivasan R, Schmidt LS. The genetic basis of kidney cancer: a metabolic disease. Nat Rev Urol 2010;7:277–285.)

tahir99 - UnitedVRG Chapter 62 Molecular Biology of Kidney Cancer 859

Additional Genes for Clear Cell Kidney Cancer XP11.2 TRANSLOCATION RENAL CELL CANCER Studies using next-generation sequencing approaches to identify the genetic basis of clear cell kidney cancer have revealed a consider- Xp11.2 translocation renal cell carcinomas, typically presenting able number of genetic alterations in chromatin remodeling genes with papillary architecture and clear or eosinophilic cytoplasm, important for the maintenance of chromatin states. Significantly are rare tumors in adults (1.6%), but are the cause of 20% to mutated genes identified in sporadic clear cell kidney cancer in ad- 45% of renal cancers in children and young adults. Transloca- dition to VHL include PBRM1, a subunit of the PBAF SWI/SNF tions involving Xp11.2 and 1q21.2 associated with sporadic papil- 33 chromatin remodeling complex (41%), histone methyl transferase lary renal carcinoma, and first described in a 2-year-old child,52 34 35 SETD2 (4%) histone demethylases JARID1C (KDM5C; 3%) generate a fusion between a novel gene, PRCC, and the basic 35 and UTX (KMD6A; 3%), and the novel tumor suppressor gene, helix-loop-helix-leucine zipper transcription factor gene, TFE3, a 36 BAP1 (15%), a histone deubiquitinase. BAP1 is also mutated, al- member of the microphthalmia (MiT) family of transcription fac- beit rarely, in the germ line of inherited clear cell kidney cancer tors.53 The encoded fusion protein, PRCC-TFE3, acts as a stronger 37,38 39 families and is associated with poor survival outcome. transcriptional activator than native TFE3, and a loss of the majority of native TFE3 transcripts is observed in these tumors. This deregulation of normal TFE3 transcriptional control caused by the HEREDITARY PAPILLARY RENAL chromosomal translocation may be important to the development CARCINOMA TYPE 1 of sporadic papillary renal cell carcinoma.54,55 Xp11.2 translocation renal cell carcinomas involving at least five different TFE3 HPRC is an autosomal-dominant hereditary cancer syndrome in gene fusions and resulting in deregulation of TFE3 transcription which affected individuals are at risk for the development of mul- activity have been described, including NonO-TFE3, PSF-TFE3, tifocal, bilateral papillary type 1 kidney cancer.40 HPRC develops CLTC-TFE3, and ASPL-TFE3.56 Tsuda et al.57 have shown that in the 5th and 6th decades, with age-dependent penetrance esti- these TFE3 fusion proteins are strong transcriptional activators mated at 67% by 60 years of age41; however, early-onset HPRC has of the MET gene, resulting in inappropriate MET-directed cell been described.42 This rare disorder has been reported in less than proliferation and invasive growth. Given the physiologic conse- 40 kindreds worldwide.40 quences of TFE3 fusion protein expression, therapeutic targeting of MET may be an effective treatment for Xp11.2 translocation Genetics of Hereditary Papillary Renal renal tumors. The fusion of another member of the MiT family, TFEB, with Carcinoma: MET Proto-oncogene the Alpha gene has been described in renal tumors harboring t(6;11)(p21;q13) chromosomal translocation.58 The first case of 43 In 1995, Zbar et al. described 10 families in which multifocal, renal cancer involving a third MiT family member, MITF, was OF ONCOLOGY PRACTICE bilateral papillary renal tumors were inherited in an autosomal- recently reported, in which an activating MITF mutation was dominant fashion and suggested that these families might repre- identified in the germ-line of family members affected with renal sent a hereditary counterpart to sporadic papillary tumors. Schmidt tumors.59 et al.6 localized the HPRC disease locus to chromosome 7q31.1-34 by genetic linkage analysis. Because the trisomy of chromosome 7 was described as a hallmark feature of papillary renal tumors,44 BIRT-HOGG-DUBÉ SYNDROME a gain-of-function oncogene seemed a likely candidate disease gene; in fact, germ-line missense mutations were identified in the BHD syndrome is a rare autosomal-dominant inherited cancer tyrosine- kinase domain of the MET protooncogene located at 7q31 syndrome characterized by benign tumors of the hair follicle in affected HPRC family members.6 Mutations of the MET gene ( fibrofolliculoma), pulmonary cysts and spontaneous pneumotho- have been detected in 13% of sporadic papillary renal tumors.6,45 rax, and a sevenfold increased risk for renal cancers.60–63 Fibro- Further studies to determine the role of MET and related genes in folliculomas and lung cysts are the most common manifestations papillary type 1 kidney cancer are currently under way. (>85%) of BHD patients.64–66 Renal tumors with variable histologies develop in about 30% of BHD-affected individuals (median Hereditary Papillary Renal Carcinoma: age, 48 to 50 years), most frequently chromophobe renal carcinoma and hybrid oncocytic tumors.64,67 Metastases may develop Functional Consequences of MET Mutations from BHD renal tumors, but they are uncommon. The MET protooncogene encodes the hepatocyte growth factor/ scatter factor (HGF/SF) receptor tyrosine kinase. Binding of ligand Genetics of Birt-Hogg-Dubé Syndrome: HGF to MET triggers autophosphorylation of critical tyrosines in Folliculin Gene the intracellular tyrosine kinase domain, subsequent phosphorylation of tyrosines in the multifunctional docking site, and recruit- A genetic linkage analysis performed in BHD kindreds led to the ment of a variety of transducers of downstream signaling cascades localization of the disease locus on the short arm of chromosome that regulate cellular programs leading to cell growth, branching 1768,69 and the identification of the BHD gene, FLCN.8 Almost morphogenesis, differentiation, and “invasive growth.”46 Although all BHD-associated FLCN mutations are predicted to truncate the MET overexpression has been demonstrated in a number of epi- BHD protein, folliculin, including insertion or deletion, nonsense, thelial cancers,47 HPRC was the first cancer syndrome for which and splice-site mutations,8,64,65,70 but recently, several missense mu- germ-line MET mutations were identified. The missenseMET mutations located in conserved amino acid residues and partial gene tations in HPRC are constitutively activating without ligand stimu- deletions have been described.65,71–73 The mutation detection rate lation, display oncogenic potential in vitro,48,49 and are predicted by in several large BHD cohorts approached 90%, and germ-line mu- molecular modeling to stabilize active MET kinase.50 Nonrandom tations were distributed throughout the entire length of the FLCN duplication of the chromosome 7 bearing the mutant MET allele gene with no clear genotype–phenotype correlations.64,65,74 Vocke was demonstrated in papillary renal tumors from HPRC patients51 et al.75 identified second “hit” somatic mutations or LOH in 70% and may represent the second step in HPRC tumor pathogenesis. of renal tumors from BHD patients, supporting a role for FLCN The presence of two copies of mutant MET may give kidney cells a as a tumor suppressor gene that predisposes individuals to renal proliferative growth advantage and lead to tumor progression. tumors when both copies are inactivated. FLCN mutations have 860 Practice of Oncology / Cancers of the Genitourinary System

Growth factor Growth factor

P13K PTEN P13K PTEN

Akt mTORC2 Akt mTORC2 Putative negative feedback loop to TSC2 P13K–AKT–mTOR TSC2 TSC1 LKB1 TSC1 LKB1 Energy and Energy and nutrient nutrient sensing sensing mTORC1 AMPK mTORC1 AMPK

S6K FNIP1 FNIP2 S6K FNIP1 FNIP2 FLCN

Translational Translational FLCN control of HIF-␣ control of HIF-␣

AB Figure 62.2 The putative Birt-Hogg-Dubé gene (FLCN) pathway. (A) FLCN binds through FNIP1/2 to AMP–activated protein kinase (AMPK) and may become phosphorylated by AMPK or by a rapamycin-sensitive kinase (i.e., mTOR). (B) When FLCN is inactivated and, presumably, FLCN protein is absent, mTOR is dysregulated, potentially driving kidney tumor formation in BHD patients. (From Linehan WM, Srinivasan R, Schmidt LS. The genetic basis of kidney cancer: a metabolic disease. Nat Rev Urol 2010;7:277–285.) been found infrequently in chromophobe renal cell carcinomas DENN domain, which has guanine exchange factor (GEF) activ- (11%),76 and only rarely in other histologic variants of RCC.77–79 ity toward RabGTPases.101 Two recent reports have shown FLCN/ FNIP1/FNIP2 interaction with RagGTPases and proposed a role 100,102 Function of the Birt-Hogg-Dubé Protein: of this complex in amino acid sensing for mTOR activation. In addition to a role for FNIP1 in facilitating FLCN interaction Folliculin with AMPK, Fnip1 knockout mice displayed a defect in pro- to preB cell differentiation demonstrating a unique requirement for The FLCN gene encodes a novel protein, folliculin (FLCN), the FLCN-FNIP1 complex in B-cell development.103 with no characteristic functional domains. Baba et al.80 identified a novel FLCN-interacting protein, FNIP1, and showed that FNIP1 interacts with the γ subunit of 5' adenosine monophos- HEREDITARY LEIOMYOMATOSIS AND phate (AMP)–activated protein kinase (AMPK), an energy sensor RENAL CELL CARCINOMA in cells that negatively regulates mammalian target of rapamycin (mTOR), the master switch for protein translation and cell pro- HLRCC is an autosomal-dominant inherited disorder that predis- liferation, through TSC1/2.81,82 A second folliculin interacting poses individuals to the development of skin and uterine leiomyo- protein, FNIP2, was subsequently identified that displayed similar mas and an aggressive form of type 2 papillary renal carcinoma. biochemical properties to FNIP1.83,84 FLCN, through FNIP1/2, Fewer than 150 HLRCC families have been reported world- may play a role in the regulation of the AMPK-TSC1/2–mTOR wide.104,105 Renal tumors, which are often unilateral and soli- signaling pathway (Fig. 62.2). Published data from in vivo models tary,104,106 may develop with early age of onset in 15% to 25% of and BHD renal tumors, supporting mTOR activation85,86 as well affected individuals104,105 and can be aggressive, metastasize, and as mTOR inhibition87–89 as a consequence of FLCN inactivation, cause death within 5 years of diagnosis. has led to the hypothesis that the mechanism by which FLCN 89 interacts with and modulates mTOR is context dependent. Genetics of Hereditary Leiomyomatosis Additional functional roles for FLCN in transforming growth factor β (TGF-β) signaling,90,91 modulation of HIF-α and its tar- and Renal Cell Carcinoma: Fumarate get genes,92 ciliogenesis,93 peroxisome proliferator-activated re- Hydratase Gene ceptor γ coactivator 1α (PGC-1α) regulation and mitochondrial biogenesis,94,95 cell–cell adhesion,96,97 exit from embryonic stem A genetic linkage analysis localized the HLRCC disease locus to cell pluripotency,98 and regulation of lysosome function through chromosome 1q42-43,107 but an association with renal cancer was cytoplasmic sequestration of the transcription factors TFE399 and not appreciated until Launonen et al.108 demonstrated a linkage to TFEB100 have been reported. The resolution of C-terminal FLCN chromosome 1q in two Finnish multiple cutaneous and uterine crystal structure has demonstrated structural homology to the leiomyomata (MCUL) kindreds with solitary, highly aggressive

tahir99 - UnitedVRG Chapter 62 Molecular Biology of Kidney Cancer 861 papillary type 2 renal tumors. The disorder was renamed hereditary missense mutations significantly lowered FH activity compared leiomyomatosis and renal cell carcinoma and the locus was subse- to truncating mutations,109 suggesting that mutant FH monomers quently mapped to a 1.6-Mb region of 1q42. Germ-line mutations might act in a dominant negative manner to alter proper confor- were identified in the fumarate hydratase FH( ) gene, a Krebs cycle mation of FH tetramers. Loss of FH activity in HLRCC leads to enzyme that converts fumarate to malate in HLRCC-affected accumulation of fumarate and, to a lesser extent, succinate, due family members.7 FH mutations in HLRCC include missense, to a block in the Krebs cycle.113,114 Pollard et al.113 have con- frameshift, nonsense, and splice-site mutations, as well as par- firmed that the accumulation of fumarate and succinate resulted tial and complete gene deletions.104,106,109,110 Missense mutations in the elevation of HIF-1α and HIF-target genes (VEGF, BNIP), are the most common (57%) and occur mainly at evolutionarily and increased microvessel density115 in HLRCC- associated uter- conserved residues.106,109,110 Mutations are found throughout the ine fi broids. Isaacs et al.114 showed that stabilization of HIF-1α entire length of the FH gene excluding exon 1, which encodes a resulted from the competitive inhibition of the HIF PHD co- mitochondrial signal peptide, and no clear genotype–phenotype substrate, α-ketoglutarate, by fumarate accumulation, leading associations have been reported.104 FH acts as a classic tumor sup- to the abrogation of PHD function and release of HIF-1α from pressor gene with a loss or somatic mutation of the wild-type FH proteasomal degradation. This pseudohypoxic drive, resulting allele at high frequency in renal tumors and skin and uterine leio- from loss of FH activity, HIF-1α stabilization, and upregulation myomata.7 FH mutations are rarely detected in sporadic uterine of HIF-inducible genes, contributes to the aggressive nature of and skin leiomyomata or sporadic RCCs.111 HLRCC-associated renal tumors (Fig. 62.3). Xiao et al.116 have demonstrated that accumulated fumarate and succinate can act as competitive inhibitors of multiple α-ketoglutarate–dependent Functional Consequences of Fumarate dioxygenases, including histone demethylases and the ten-eleven Hydratase Mutations translocation (TET) family of 5-methylcytosine hydroxylases leading to more global alterations in histone and DNA methylation. FH mutations reduce FH activity by 20% to 80%7,109,112 in lym- Additionally, Sudarshan et al.117 showed that FH mutations in an phoblastoid cell lines from HLRCC patients. HLRCC- associated HLRCC-derived cell line led to glucose-mediated generation of PRACTICE OF ONCOLOGY PRACTICE

Figure 62.3 Fumarate hydratase (FH)–deficient kidney cancer, an aggressive form of type 2 papillary kidney cancer, is found in patients affected with the hereditary cancer syndrome, HLRCC. FH-deficient kidney cancer is characterized by a metabolic shift to aerobic glycolysis. Mitochondrial function is impaired by a decrease in FH function, and the cell depends on aerobic glycolysis for adenosine triphosphate (ATP) production needed for rapid growth. The increased ATP leads to decreased activation of AMPK, which results in increased mTOR/phosphoS6 activity and increased Acetyl CoA carboxylase (ACC)/fatty acid production. Increased fumarate, a result of decreased fumarate hydratase activity, inhibits HIF PHD, resulting in increased HIF1α levels. The increased fumarate also inhibits KEAP1 activity, resulting in increased Nrf2 transcriptional activity that is critical for the survival of these cells, which are characterized by high oxidative stress. (From Linehan WM, Rouault TA. Molecular pathways: fumarate hydratase-deficient kidney cancer: targeting the Warburg effect in cancer.Clin Cancer Res 2013;19:3345–3352.) 862 Practice of Oncology / Cancers of the Genitourinary System

129,130 reactive oxygen species (ROS) and ROS-dependent HIF-1α sta- and later with familial and sporadic pheochromocytomas. bilization, supporting an alternate mechanism by which pseu- Subsequently, inactivating mutations in SDHB were found in dohypoxic drive could support renal tumorigenesis in HLRCC. kindreds with familial pheochromocytoma only and with HPGL, 131 Further, Sullivan et al.118 determined that the increase in ROS was and in one case of sporadic pheochromocytoma. Later, early due to the succination of antioxidant glutathione by accumulated onset clear cell RCC was diagnosed in two individuals with 9 fumarate (see the following) to produce the oncometabolite suc- HPGL and germ-line SDHB mutations. Renal carcinomas with cinated glutathione, an alternate substrate to glutathione reduc- various histologies have been reported in patients with germ- tase, resulting in a decrease in NADPH levels, enhanced ROS and line missense, frameshift, and nonsense mutations in SDHB, C, 10,11,126–128,132 HIF1-α activation. and D. Recent in vivo and in vitro evidence supports a role for fumarate accumulation in activation of the nuclear factor Functional Consequences of Succinate (erythroid-derived 2)–like 2 (Nrf2)-mediated antioxidant signaling pathway.119 Kelch-like erythroid-derived Cap-n-Collar homol- Dehydrogenase Subunit B and D Mutations ogy (ECH)–associated protein 1 (KEAP1), an electrophile sensor and substrate recognition site for cullin-3 (CUL3)–based E3 Mutational inactivation of the SDH gene results in reduced SDH ubiquitin ligase, binds to Nrf transcription factors under low elec- enzyme activity and the accumulation of succinate in renal tu- trophile conditions facilitating interactions with CUL3 for ubiq- mors. In a mechanism similar to FH mutations in HLRCC (see uitin-mediated degradation. However, intracellular accumulated Fig. 62.3), the accumulation of succinate serves to competitively α 113,114 fumarate in FH-deficient kidney cancer (HLRCC) reacts with inhibit -ketoglutarate and block PHD activity. In the ab- α exposed cysteines on the KEAP1 protein (succination), resulting sence of PHD, HIF- accumulates and drives transcriptional α in a conformational change that inhibits KEAP1–Nrf2 binding activation of HIF- target genes that support tumor neovascular- (see Fig. 62.3). Consequently Nrf2 becomes available for tran- ization, growth, and invasion. scriptional activation of its target genes that are regulated through antioxidant response elements (ARE) in their promoters.120,121 In support of this model, somatic inactivating mutations in KEAP1 TUBEROUS SCLEROSIS COMPLEX and CUL3, and activating mutations in NRF2, have been identified in sporadic papillary RCC type 2.122 Inhibiting upregulated The tuberous sclerosis complex (TSC) is a multisystem, autosomal- Nrf2-target genes (i.e., heme oxygenase1 [HMOX1], which is dominant disorder affecting both children and adults and is important for heme oxygenation)123 that promote cancer cell sur- characterized by facial angiofibromas, renal angiomyolipomas, vival may provide a novel therapeutic approach to HLRCC and lymphangiomyomatosis of the lung, and disabling neurologic man- sporadic PRCC2 treatment. ifestations. The disease is phenotypically heterogeneous, and many Finally, cells normally generate energy through the Krebs cycle patients have only minimal symptoms of disease.133 coupled to oxidative phosphorylation, but FH-deficient kidney The predominant renal manifestations in TSC are bilateral cancer cells lack the enzyme to convert fumarate to malate, result- multifocal angiomyolipomas (AML), benign tumors composed ing in a block in the Krebs cycle. Mullen et al.124 showed that FH- of abnormal vessels, immature smooth muscle cells, and fat cells. deficient kidney cancer cells that lack a fully functional electron The lifetime risk of renal cancer in TSC patients is 2% to 3%, transport chain use glutamine-dependent reductive carboxylation which is similar to the general population.133 The most common via isocitrate dehydrogenases 1 and 2 to produce acetyl coenzyme histologic type of renal tumor is clear cell; however, there are A (CoA) for lipid synthesis and Krebs cycle intermediates. Meta- rare reports of papillary RCCs, chromophobe RCCs, and onco- bolic reprogramming of FH-deficient kidney cancer cells enables cytoma in TSC patients.133 TSC is caused by mutations in one of the elevated production of ribose from glucose via increased flux two genes—TSC1 that encodes hamartin134 or TSC2 that encodes through the pentose phosphate pathway to meet the high demand tuberin135—leading to a loss of TSC1/2-negative regulation of for nucleotides.125 mTOR signaling.81,82,136 Drug therapy targeting the mTOR pathway may be most effective for treating TSC-associated AMLs and renal tumors.137 FAMILIAL RENAL CANCER: SUCCINATE DEHYDROGENASE GENE CONCLUSION Bilateral multifocal renal tumors with early onset (<40 years of age) have been reported in the setting of hereditary head Twelve renal cancer predisposing genes—VHL, MET, FLCN, and neck paragangliomas (HPGL) and adrenal or extra-adrenal TFE3, TFEB, MITF, TSC1, TSC2, PTEN, FH, SDHB, and pheochromocytomas.9 Most frequently, a unique form of onco- SDHD—have been identified mainly through studies of in- cytic RCC develops; however, clear cell RCC, chromophobe herited renal cancer syndromes, including VHL, HPRC, RCC, papillary type 2 RCC, and renal oncocytoma have been BHD, HLRCC, SDH-related familial renal cancer, and TSC described.126–128 (Fig. 62.4). These studies have provided valuable insight into the genetic events that lead to the development of renal tumors and the biochemical mechanisms that contribute to their progression Genetics of Familial Renal Cancer: Succinate and, ultimately, in some cases, to metastasis. These findings have Dehydrogenase Subunit B and D Mutations enabled the development of diagnostic genetic testing and provided the foundation for the development of targeted therapeu- Germ-line mutations in the gene encoding succinate dehydro- tic agents for patients with the common form of sporadic kidney genase subunit D (SDHD) were initially associated with HPGL cancer.

tahir99 - UnitedVRG Chapter 62 Molecular Biology of Kidney Cancer 863

HGF

MET

P13K PTEN LKB1

mTORC2 Akt Energy sensing AMPK Nutrient sensing

TSC2 FNIP1 FNIP2 TSC1 FLCN TFEB MITF TFE3 Rheb FH

mTORC1 SDHB SDHD Translational control PHD

HIF␣ VHL

Oxygen sensing Iron sensing OF ONCOLOGY PRACTICE Figure 62.4 The genetic basis of kidney cancer. Twelve renal cancer predisposing genes—VHL, MET, FLCN, TFE3, TFEB, MITF, TSC1, TSC2, PTEN, FH, SDHB, and SDHD— have been identified mainly through studies of inherited kidney cancer syndromes. These genes interact through common oxygen, iron, nutrient, and energy sensing pathways and demonstrate that kidney cancer is fundamentally a metabolic disease. Our understanding of the molecular mechanisms by which these genes interact in these pathways has enabled the development of targeted therapeutic agents to benefit kidney cancer patients. (From Linehan WM, Ricketts CJ. The metabolic basis of kidney cancer. Semin Cancer Biol 2013;23:46–55.)

SELECTED REFERENCES

The full reference list can be accessed at lwwhealthlibrary.com/oncology. 23. Stebbins CE, Kaelin WG, Pavletich NP. Structure of the VHL-ElonginC- ElonginB complex: implications for VHL tumor suppressor function. Science 4. Linehan WM, Srinivasan R, Schmidt LS. The genetic basis of kidney cancer: 1999;284:455–461. a metabolic disease. Nat Rev Urol 2010;7:277–285. 26. Li M, Kim WY. Two sides to every story: the HIF-dependent and HIF- 5. Latif F, Tory K, Gnarra JR, et al. Identification of the von Hippel-Lindau independent functions of pVHL. J Cell Mol Med 2011;15:187–195. disease tumor suppressor gene. Science 1993;260:1317–1320. 33. Varela I, Tarpey P, Raine K, et al. Exome sequencing identifies frequent mu- 6. Schmidt LS, Duh FM, Chen F, et al. Germline and somatic mutations in tation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature the tyrosine kinase domain of the MET proto-oncogene in papillary renal 2011;469:539–542. carcinomas. Nat Genet 1997;16:68–73. 35. Dalgliesh GL, Furge K, Greenman C, et al. Systematic sequencing of renal carci- 7. Tomlinson IP, Alam NA, Rowan AJ, et al. Germline mutations in FH predis- noma reveals inactivation of histone modifying genes. Nature 2010;463:360–363. pose to dominantly inherited uterine fibroids, skin leiomyomata and papil- 37. Farley MN, Schmidt LS, Mester JL, et al. A novel germline mutation in lary renal cell cancer. Nat Genet 2002;30:406–410. BAP1 predisposes to familial clear-cell renal cell carcinoma. Mol Cancer Res 8. Nickerson ML, Warren MB, Toro JR, et al. Mutations in a novel gene 2013;11:1061–1071. lead to kidney tumors, lung wall defects, and benign tumors of the hair fol- 48. Jeffers M, Schmidt LS, Nakaigawa N, et al. Activating mutations for the met licle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell 2002;2: tyrosine kinase receptor in human cancer. Proc Natl Acad Sci U S A 1997; 157–164. 94:11445–11450. 9. Vanharanta S, Buchta M, McWhinney SR, et al. Early-onset renal cell carci- 53. Sidhar SK, Clark J, Gill S, et al. The t(X;1)(p11.2;q21.2) translocation in noma as a novel extraparaganglial component of SDHB-associated heritable papillary renal cell carcinoma fuses a novel gene PRCC to the TFE3 tran- paraganglioma. Am J Hum Genet 2004;74:153–159. scription factor gene. Hum Mol Genet 1996;5:1333–1338. 10. Ricketts CJ, Shuch B, Vocke CD, et al. Succinate dehydrogenase kidney 56. Armah HB, Parwani AV. Xp11.2 translocation renal cell carcinoma. Arch cancer: an aggressive example of the Warburg effect in cancer. J Urol 2012; Pathol Lab Med 2010;134:124–129. 188:2063–2071. 57. Tsuda M, Davis IJ, Argani P, et al. TFE3 fusions activate MET signaling by 11. Malinoc A, Sullivan M, Wiech T, et al. Biallelic inactivation of the SDHC transcriptional up-regulation, defining another class of tumors as candidates gene in renal carcinoma associated with paraganglioma syndrome type 3. for therapeutic MET inhibition. Cancer Res 2007;67:919–929. Endocr Relat Cancer 2012;19:283–290. 59. Bertolotto C, Lesueur F, Giuliano S, et al. A SUMOylation-defective MITF 16. Kaelin WG Jr. The von Hippel-Lindau tumour suppressor protein: O2 sens- germline mutation predisposes to melanoma and renal carcinoma. Nature ing and cancer. Nat Rev Cancer 2008;8:865–873. 2011;480:94–98. 17. Cohen AJ, Li FP, Berg S, et al. Hereditary renal-cell carcinoma 62. Zbar B, Alvord WG, Glenn GM, et al. Risk of renal and colonic neoplasms associated with a chromosomal translocation. N Engl J Med 1979;301: and spontaneous pneumothorax in the Birt-Hogg-Dubé syndrome. Cancer 592–595. Epidemiol Biomarkers Prev 2002;11:393–400. 864 Practice of Oncology / Cancers of the Genitourinary System

63. Menko FH, van Steensel MA, Giraud S, et al. Birt-Hogg-Dubé syndrome: 120. Ooi A, Wong JC, Petillo D, et al. An antioxidant response phenotype shared diagnosis and management. Lancet Oncol 2009;10:1199–1206. between hereditary and sporadic type 2 papillary renal cell carcinoma. 80. Baba M, Hong SB, Sharma N, et al. Folliculin encoded by the BHD Cancer Cell 2011;20:511–523. gene interacts with a binding protein, FNIP1, and AMPK, and is involved 122. Ooi A, Dykema K, Ansari A, et al. CUL3 and NRF2 mutations confer an in AMPK and mTOR signaling. Proc Natl Acad Sci U S A 2006;103: NRF2 activation phenotype in a sporadic form of papillary renal cell carci- 15552–15557. noma. Cancer Res 2013;73:2044–2051. 109. Alam NA, Rowan AJ, Wortham NC, et al. Genetic and functional analyses of 133. Crino PB, Nathanson KL, Henske EP. The tuberous sclerosis complex. FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary N Engl J Med 2006;355:1345–1356. leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum 134. van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the tuber- Mol Genet 2003;12:1241–1252. ous sclerosis gene TSC1 on chromosome 9q34. Science 1997;277:805–808. 114. Isaacs JS, Jung YJ, Mole DR, et al. HIF overexpression correlates with 135. The European Chromosome 16 Tuberous Sclerosis Consortium. Identifica- biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in tion and characterization of the tuberous sclerosis gene on chromosome 16. regulation of HIF stability. Cancer Cell 2005;8:143–153. Cell 1993;75:1305–1315.

tahir99 - UnitedVRG 63 Cancer of the Kidney

Brian R. Lane, Daniel J. Canter, Brian I. Rini, and Robert G. Uzzo

INTRODUCTION calculated a relative risk of 1.07 per increase in unit body mass index and concluded that nearly a third of RCC cases may be at- Cancer of the kidney is neither common enough to cause a large tributable to obesity. Data suggesting a stronger association of obe- percentage of cancer-related deaths nor uncommon enough to sity and RCC in women lead to hypotheses that the relationship be considered an “orphan” malignancy. In that context, the prog- may be due to dysregulation of sex hormones, insulin metabolism, ress made in uncovering the genetic basis of renal cell carcinoma or the immune system.3 The relationship between hypertension (RCC), its molecular pathways, and the approval of novel therapies and RCC is based largely upon retrospective and/or population- to perturb those pathways over the last decade is indeed remarkable. based epidemiologic data. In an analysis of 13 case controlled Over a relatively short time, the management options for localized studies, Grossman et al.12 noted hypertensive patients exhibited a kidney cancer have evolved from near universal acceptance of open pooled odds ratio of 1.75 of having RCC. While there may be a radical nephrectomy (RN) to the routine use of minimally invasive relationship between severity and duration of hypertension, given partial nephrectomy (PN), thermal ablation (TA), and active sur- the limits of the data, if such an association exists it is difficult to veillance (AS). Concurrently, metastatic RCC has progressed from ascertain.3 Finally, exposure to chronic diuretics,13 nonsteroidal marginally treatable, with a low incidence of spontaneous and/or analgesics,14 and tricholorethylene, a cleaning agent, have all been immune-induced durable regression, to overall response rates (com- associated with an increased risk of RCC.3 plete response + partial response + stable disease) of >50% and a While screening for kidney and other potentially lethal diseases near doubling of cancer-specific survival. Looking forward, it is an- is enticing, a risk benefit analysis argues against it given the low ticipated that kidney cancer will soon become a chronic disorder as overall prevalence of RCC in the general population. One large we better understand the biologic heterogeneity and systemic thera- study, in which over 200,000 adults were screened for abdomi- OF ONCOLOGY PRACTICE pies for RCC. Herein, we review the current and rapid evolution in nal malignancy with ultrasound, found only 192 cases of RCC our understanding and management of cancer of the kidney. (0.09%).15 Screening has, therefore, been proposed in target populations, including individuals with familial RCC syndromes such as von Hippel-Lindau disease (VHL) and those on hemodialysis, EPIDEMIOLOGY, DEMOGRAPHICS, AND who are known to be more likely to be diagnosed with RCC. In pa- RISK FACTORS tients on dialysis, while there appears to be an increased incidence of RCC in the native kidneys or even in a transplanted allograft, this Kidney cancer accounts for approximately 2% of malignancies may be due to their medical follow-up. Indeed, most patients with worldwide with about 300,000 cases diagnosed per year and end-stage renal disease will have been “screened” during the evalu- 100,000 deaths.1 Data suggest the incidence of RCC is more ation and management of their renal failure/allograph, making the common in industrialized countries, which may be related to reasons for this association difficult to dissect. This is distinctively increased incidental detection. In the United States, tumors of different than an emerging population of patients with increased the kidney account for 3% to 4% of all cancer diagnoses with an genetic risk for cancer, but whose kidneys have not yet been im- estimated 65,000 cases and 14,000 deaths.2 There is a male-to- aged. In families who carry known mutations in the genes respon- female predominance with the lifetime risk of a RCC diagnosis of sible for VHL, hereditary papillary RCC, hereditary leiomyoma 1:69 in men and 1:116 in women.3 While kidney cancer remains RCC, Birt-Hogg-Dubé syndrome (BHD), potentially tuberous scle- predominantly a tumor of the elderly (median age at diagnosis of rosis, and/or autosomal dominant polycystic kidney disease, a renal 65 years), the number of new kidney cancer cases appears to be ultrasound may be an inexpensive, low-risk, and judicious means of rising in younger individuals.2 This may be explained by either targeted screening. The initial timing, frequency, and effectiveness the increasing use of noninvasive imaging in younger patients4–6 of screening in these at-risk populations are not yet established. or perhaps true biologic differences in the disease.7 Similarly, racial differences have also been described with increased rates and decreased survival noted in African Americans and improved sur- PATHOLOGY OF RENAL CELL CARCINOMA vival in Asian populations.8 Whether this represents differences in health-care access or disease biology is unclear. Pathologic classifications assist in diagnosis and prognosis, and The most commonly cited risk factors for the development inform therapy. Most pathologic classifications emphasize a tu- of RCC include smoking, obesity, and hypertension.9 The data mor’s morphology and histology—although, increasingly they are regarding smoking as a risk factor for RCC appear strong. In a incorporating genetic characteristics.16 There are 10 tumor sub- meta-analysis evaluating 19 case control studies and 5 cohort stud- types in the current World Health Organization classification sys- ies, Hunt et al.10 found a 38% increased risk in current and former tem for RCC (Table 63.1). The major histologic variants include smokers, noting not only a dose-risk relationship, but also an abate- clear cell, papillary, chromophobe, and collecting duct tumors, ment of risk with smoking cessation >10 years. The relationship which account for 90% to 95% of renal carcinomas,17 although between obesity and RCC is less well studied, although the epi- less common subtypes and an “unclassified” category also exist. demiology seems to point to a causal association. In a quantitative Uncommon subtypes of RCC, not included in the World Health review of the literature between 1966 and 1998, Renehan et al.11 Organization classification, include tubulocystic carcinoma, clear

865 866 Practice of Oncology / Cancers of the Genitourinary System

TABLE 63.1 2004 World Health Organization Classification of Sporadic Renal Cell Carcinoma with Genetic and Clinical Correlates

Type Genetics Clinical ccRCC (70% to 80%) Deletion, mutation or methylation of 3p25-26 Most common variant (VHL) Prognosis predicted by stage and grade Multilocular cystic ccRCC Deletion, mutation, or methylation of 3p25-26 Variant of ccRCC (uncommon) (VHL) Distant metastases uncommon Papillary RCC (10% to 15%) Gain of 7 or 17 (trisomy or tetrasomy), loss of 10% to 15% of RCC Y, deletion of 9p. Mutations of 7q31 when 95%+ 5-year cancer-specific survival in type I associated with hereditary papillary RCC papillary RCC Response to tyrosine-kinase inhibitors less robust Chromophobe RCC (3% to 5%) Extensive chromosomal loss of Y, 1, 2, 6, 5% of RCC 10, 13, 17, 21 Mutations of 17p11.2 when Affects men and women equally with overall associated with BHD excellent prognosis Collecting duct carcinoma (Bellini Highly variable Male preponderance (2:1) tumor) (<1%) Losses of 1q, 6p, 8p, 9p, 13q, 19q, 21q Mean age 55 Microscopically high grade, may resemble urothelial spectrum of cancers, Overall poor prognosis Renal medullary carcinoma (rare) Not defined Associated with sickle cell trait Aggressive and lethal within 12 mo Mean age 19 y Male>female Xp11 translocation carcinoma Translocation of TFE3 gene on XP11.2 Children and young adults (rare) May present at advanced state and act more aggressively in adults Renal carcinoma associated with Not defined Morphologically and microscopically similar to neuroblastoma (rare) ccRCC Mucinous tubular and spindle cell Not defined Female preponderance (4:1) carcinoma (rare) Rarely metastasize Unclassified RCC (1% to 3%) Varied Generally poor prognosis ccRCC, clear cell renal cell carcinoma; RCC, renal cell carcinoma. Adapted from Deng FM, Melamed J, Zhou M. Pathology of renal cell carcinoma. In: Libertino JA, ed. In Renal Cancer: Contemporary Management. New York: Springer; 2013:51–69. cell tubulopapillary RCC, thyroid-like follicular carcinoma, and an incidentally detected renal mass. While the suspicion for RCC acquired cystic disease–associated RCC. The relatively rapid move- may be high in cases such as these, RCC is a pathologic/tissue ment in RCC toward molecular classification follows advances in diagnosis, not a clinical one (Fig. 63.2). Proper radiographic our molecular understanding of these variants and may soon sup- evaluation of a renal mass requires a pre- and postcontrast com- plant simple morphologic classification. puted tomography or magnetic resonance imaging (MRI) to assess Other pathologically relevant variables in RCC include nuclear enhancement.20 Duplex ultrasound, renal mass biopsy, and non- grade, sarcomatoid and rhabdoid differentiation, tumor necrosis, contrast diffusion-weighted MRI with antibody drug conjugates and vascular invasion. Nuclear grade usually follows the Fuhrman mapping may be useful adjunctive tests in various clinical set- grading system18 and is most often and best used for clear cell RCC tings. deoxy-2[18F]fluoro-d-glucose positron emission tomography (ccRCC) as the prognostic value in non-ccRCC remains largely un- exhibits a low sensitivity for the diagnosis of RCC and is therefore proven. Sarcomatoid differentiation exists in 5% of RCC and can be not recommended for the evaluation of RCC. ImmunoPET with seen in any subtype. As such it is not considered a distinct entity, but G-250 using an iodine-labeled antibody against carbonic anhy- rather a high-grade or poorly differentiated component. The pres- drase IX (CA-IX), which is known to be overexpressed in ccRCC, ence and extent of micro- or macronecrosis has been correlated with exhibits near 90% sensitivity and specificity for this RCC subtype.21 prognosis in ccRCC.19 Micro- or macrovascular invasion is thought The differential diagnosis of the renal mass is broad and includes to be a requisite step toward systemic disease; however, correlation a long list of benign, malignant, and inflammatory conditions. between the extent of invasion and prognosis remains imprecise. Clinical and radiographic features can assist the astute clinician in narrowing down the diagnosis of the renal mass, particularly for benign and inflammatory lesions. Cystic lesions, for example, are DIFFERENTIAL DIAGNOSIS AND STAGING frequently benign,22 and fat-containing solid lesions are most commonly found to be angiomyolipomas (also benign). About 20% Most patients with RCC present with an incidental, radiographi- of enhancing renal masses and 15% of surgically removed masses cally detected renal mass (Fig. 63.1). While symptoms includ- are nonmalignant, with the most common diagnoses being onco- ing microscopic or gross hematuria, flank pain, gastrointestinal cytoma and fat-poor angiomyolipoma.23–25 Young to middle-aged disturbances and/or pain, bleeding or systemic disturbances re- women, in particular, are more likely to have benign pathology, lated to metastases may lead to the diagnosis, the use of routine as high as 40% in some series, while the likelihood of malignancy cross-sectional imaging has led to the more common scenario of gradually decreases with age in men.24,26 Tumor size is the most

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A B Figure 63.1 Cross-sectional imaging of kidney cancer using computed tomography and magnetic resonance imaging. (A) Contrast-enhanced computed tomography imaging (parenchymal phase) reveals a left renal mass with tumor thrombus within the left renal vein. (B) Magnetic resonance imaging in the same patient shows that the renal vein thrombus extends within the renal vein, but not to the confluence with the inferior vena cava (level 0 thrombus). m, mass; v, vein. important determinant of pathology and biologic aggressiveness are used to communicate risk for treatment decision making and with larger tumors more likely to be high grade, locally invasive, clinical trials planning. There have been several staging systems and/or of adverse histologic subtype.23,24,27 Incorporation of readily for RCC proposed. The most widely used is version 7 of the TNM available features can allow the physician to provide an individu- (tumor, node, metastasis) staging system of the American Joint alized risk of cancer (ranging between ∼50% and ∼99%), but a Committee on Cancer and the Union for International Cancer certain diagnosis requires pathologic confirmation.24,28 The most Control, updated in 2010 (Table 63.2). It distinguishes T1a from accurate nomogram currently available gives estimates of preop- T1b and T2a from T2b based on tumor size.35 Additionally, adre- erative prediction of tumor histology with an area under the curve nal involvement was changed from pathologic stage T3a to T4 and of 0.76 and high-grade malignancy with an area under the curve venous invasion was separated into renal vein/segmental branches OF ONCOLOGY PRACTICE of 0.73.28 (T3a) and inferior vena cava (IVC) below (T3b) or above the dia- Percutaneous renal mass sampling is now being performed phragm (T3c). Nodal and metastatic disease are only classified as with increased regularity at many centers.29 There is a strong ra- negative (N0/M0) or positive (N1/M1). Other potential prognostic tionale for biopsy when the findings will change management, features of the primary tumor not included in the TNM classifica- such as when there is reason to suspect lymphoma/leukemia or tion include necrosis, urothelial involvement, microvascular inva- abscess or to guide systemic therapy for metastatic disease. Even sion and molecular features. Review of these and other prognostic for clinically localized renal tumors, conventional renal mass bi- features of RCC are available.36 opsy can provide a definitive diagnosis in 80% to 90% of cases, and the ability to subtype and grade RCC can increase with the use of immunohistochemical and other molecular analyses.30,31 There- fore, renal mass sampling should be considered in patients with HEREDITARY KIDNEY CANCER enhancing renal masses who are candidates for a wide range of SYNDROMES, GENETICS, AND management strategies.30–34 However, younger, healthier patients MOLECULAR BIOLOGY who are unwilling to accept the uncertainty associated with renal mass biopsy as well as elderly, frail patients who will be managed While most renal cancers are believed to occur sporadically, fa- conservatively (independent of biopsy results) should still be man- milial clusters have led to the discovery of at least seven RCC aged without a biopsy. susceptible syndromes (Table 63.3). It is estimated that approxi- Clinical and pathologic staging systems provide a basis of stan- mately 4% of RCC have a hereditary basis.37 In these cases, in dardized communication, comparison, and prognostication. They addition to a provocative family history, tumors tend to be bilateral,

Histological type: Clear cell Papillary type 1 Papillary type 2 Chromophobe Oncocytoma Angiomyolipoma TFE3 Oncocytic Clear/chromophobe

Hereditary gene: VHL Met FH FLCN TSC1, TSC2 MITF SDHB, SDHD PTEN

Sporadic gene: VHL (89%) Met (89%) TBD* TBD* TSC1, TSC2 TFE3, TFEB TBD* TBD* Figure 63.2 Human renal epithelial neoplasms. Renal cortical tumors do not conform to a single pathology. There are a number of different tumor subtypes that display the full range of oncologic activity, ranging from benign to indolent to aggressive. Each histologic type is characterized by distinct gross and microscopic appearance, gene associated with their familial forms, and genetic changes commonly detected in sporadic cases. (Used with permission from Linehan WM, Ricketts CJ. The metabolic basis of kidney cancer. Semin Cancer Biol 2013;23:46–55.) 868 Practice of Oncology / Cancers of the Genitourinary System

TABLE 63.2 multifocal, and arise at an early age of onset. Importantly, the study of hereditary kidney cancer has dramatically changed our under- International Tumor, Node, Metastasis standing of the genetic and molecular basis of RCC and has led Staging System for Renal Cell Carcinoma and to the development of effective, approved therapeutic agents as Survival Rates similar cytogenetic and molecular alterations appear to be shared between sporadic and hereditary RCC (see Fig. 63.2).38 Five-Year The molecular alterations in RCC appear to converge on simi- T: Primary Tumor Survival (%) lar pathways involved in dysregulated oxygen sensing/angiogenesis, TX Primary tumor cannot be assessed iron metabolism, and energy/nutrient sensing.39,40 The predomi- T0 No evidence of primary tumor nant genetic and molecular defects in RCC known to date include VHL loss of function (ccRCC), neurofibromatosis type 2 loss of T1a Tumor ≤4 cm and confined to the kidney 90–100 function (ccRCC), MET gain of function (papillary type I RCC), T1b Tumor >4 cm and ≤7 cm and confined 80–90 NRF2 gain of function and alterations in fumarate hydratase (pap- to the kidney illary type II RCC), CCND1 gain of function and folliculin loss T2a Tumor >7 cm and ≤10 cm and confined 65–80 of function (oncocytoma/chromophobe RCC), and MiTF-TFE3 to the kidney gain of function (translocation RCC). Additionally, inactivation of chromatin modifying proteins including PBRM1, BAP1, and his- > T2b Tumor 10 cm and confined to the kidney 50–70 tone methylases/demethylases, as well as inactivation of electron T3a Tumor grossly extends into the 40–65 transporters, may represent early or common events in multiple renal vein or its segmental (muscle subtypes.41 While important, the associations of these aberrant containing) branches, or tumor invades pathways with various subtypes of RCC likely represent an overly perirenal and/or renal sinus fat but not simplified model of renal tumor development.42 A variety of small beyond Gerota fascia nucleotide mutations, structural mutations, and large chromosomal abnormalities characterizes RCC, with as many as 5 to 70 small so- T3b Tumor grossly extends into the vena 30–50 42 cava below the diaphragm matic mutations found in individual renal tumor cells. Moreover, variable gene expressions may reflect differences in cell types from T3c Tumor grossly extends into the vena 20–40 which RCC originates, suggesting that genetic aberrations require cava above the diaphragm or invades a specific cellular context for dysregulated growth. The develop- the wall of the vena cava ment of rapid sequencers continues to redefine the molecular char- T4 Tumor invades beyond Gerota fascia 0–20 acterization of RCC from which a genetic profile/classification is (including contiguous extension into the emerging with important implications for the development of the ipsilateral adrenal gland) next generation of targeted therapeutic molecules.43,44 N: Regional Lymph Nodes Von Hippel-Lindau Disease NX Regional lymph nodes cannot be assessed N0 No regional lymph nodes metastasis VHL is a syndrome characterized by the development of highly vas- N1 Metastasis in regional lymph node(s) 0–20 cular tumors of the retina, central nervous system, pancreas, adrenal, and kidney (ccRCC). It is inherited in an autosomal dominant fash- M: Distant Metastases ion with an incidence of 1:35,000.39 Loss of VHL function (3p25.1) MX Distant metastasis cannot be assessed by genetic or epigenetic means in a classic tumor suppressor fashion M0 No distant metastasis is the known cause. In an established genotype-phenotype relationship, type 1 VHL (absence of pheochromocytoma) is due to germ- M1 Distant metastasis present 0–10 line deletions, insertions, and nonsense mutations, whereas type II Stage Grouping VHL (with pheochromocytoma) is associated with missense mutations.45 Between 25% to 60% of patients with VHL develop bilateral Stage I T1 N0 M0 multifocal cystic and solid RCC, which represents a common cause Stage II T2 N0 M0 of death (Fig. 63.3). Management of renal tumors in patients with Stage III T3 Any N M0 VHL now includes surveillance of smaller tumors (<3 cm) and resection of larger ones (>3 cm) by PN with the goal of preventing T1 or T2 N1 M0 metastases and optimizing renal function by “resetting the biologic Stage IV T4 Any N M0 clock” through appropriately timed surgeries.46 The goal of complete Any T Any N M1 tumor removal with wide negative surgical margins is less appropriate for these patients where management of localized lesions supplants 39,46 Modified from American Joint Committee on Cancer. Edge S, Byrd DR, Compton cure. Patients should be evaluated and followed by a team of clini- CC, et al, eds. AJCC Cancer Staging Manual. 7th ed. New York: Springer-Verlag; cians familiar with the complexities of multisystem genetic disorders. 2010. Data from Hafez KS, Fergany AF, Novick AC. Nephron sparing surgery for localized renal cell carcinoma: impact of tumor size on patient survival, tumor recurrence, and TNM staging. J Urol 1999;162(6): 1930-1933; Leibovich BC, Hereditary Papillary Renal Cell Carcinoma Cheville JC, Lohse CM, et al. Cancer specific survival for patients with pT3 renal cell carcinoma—can the 2002 primary tumor classification be improved?J Urol 2005;173(3):716–719; Thompson RH, Cheville JC, Lohse CM, et al. Reclassification Hereditary papillary RCC is perhaps the least common familial of patients with pT3 and pT4 renal cell carcinoma improves prognostic accuracy. RCC syndrome, with manifestations that appear to only affect Cancer 2005;104:53–60; Lane BR, Kattan MW. Prognostic models and algorithms the kidney. Affected individuals develop bilateral multifocal type in renal cell carcinoma. Urol Clin North Am 2008;35:613–625; Campbell L, Nuttall I papillary RCC due to mutations in the MET gene located at R, Griffiths D, et al. Activated extracellular signal-regulated kinase is an 7q31. MET is a tyrosine kinase receptor with hepatocyte growth independent prognostic factor in clinically confined renal cell carcinoma.Cancer 47 2009; 115:3457–3467; Martinez-Salamanca JI, Huang WC, Millán I, et al; factor as its ligand. The syndrome is transmitted in an autoso- International Renal Cell Carcinoma-Venous Thrombus Consortium. Prognostic mal dominant fashion and tumors usually appear after the age of impact of the 2009 UICC/AJCC TNM staging system for renal cell carcinoma 30.39 As with VHL, management of renal tumors recognizes the with venous extension. Eur Urol 2011;59:120–127; Haddad H, Rini BL. Current treatment considerations in metastatic renal cell carcinoma. Curr Treat Options need to remove larger lesions and observe smaller ones. While no Oncol 2012;13:212–229. size cutoff for intervention has been established, the biology of type I papillary RCC appears to be more indolent that ccRCC,

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TABLE 63.3 Familial Renal Cell Carcinoma Syndromes

Syndrome Gene (Chromosome) Major Clinical Manifestations von Hippel-Lindau VHL gene (3p25-26) Clear cell RCC Retinal angiomas Central nervous system hemangioblastomas Pheochromocytoma Other tumors Hereditary papillary RCC c-met proto-oncogene (7q31) Multiple, bilateral type 1 papillary RCCs Familial leiomyomatosis and RCC Fumarate hydratase (1q42-43) Type 2 papillary RCC Collecting duct RCC Leiomyomas of skin or uterus Uterine leiomyosarcomas Birt-Hogg-Dubé Folliculin (17p11) Multiple chromophobe RCC, hybrid oncocytic tumor, oncocytomas Occasional clear cell (occasionally) Papillary RCC (occasionally) Facial fibrofolliculomas Lung cysts Spontaneous pneumothorax Succinate dehydrogenase RCC Succinate dehydrogenase complex subunits: Chromophobe, clear cell, type 2 papillary RCC, SDHB (1p36.1-35) or SDHD (11q23) oncocytoma Paragangliomas (benign and malignant) Papillary thyroid carcinoma Tuberous sclerosis TSC1 (9q34) or TSC2 (16p13) Multiple renal angiomyolipomas Clear cell RCC (occasionally) Renal cysts/polycystic kidney disease Cutaneous angiofibromas PRACTICE OF ONCOLOGY PRACTICE Pulmonary lymphangiomyomatosis PTEN hamartoma tumor syndrome PTEN (10q23) Breast tumors (malignant and benign) (Cowden syndrome) Epithelial thyroid carcinoma Papillary RCC or other histology

PTEN, phosphatase and tensin homolog; RCC, renal cell carcinoma. Adapted from Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the kidney. J Urol 2003; 170(6 Pt 1):2163-2172. and Linehan WM, Ricketts CJ. The metabolic basis of kidney cancer. Semin Cancer Biol 2013;23:46–55. suggesting the risk of death from kidney cancer in these patients is Renal tumors in HLRCC tend to be aggressive and lethal. The most low. Again, PN with renal preservation is emphasized despite the common histology observed is type II (eosinophilic) papillary RCC.39 diffuse micro- and macromultifocality of these lesions. Unlike other hereditary forms of RCC, given the aggressive nature of these tumors, AS with delayed intervention is not recommended. Birt-Hogg-Dubé Syndrome TREATMENT OF LOCALIZED RENAL CELL BHD is characterized by cutaneous fibrofolliculomas, a 50-fold increased risk of pneumothorax, and bilateral multifocal solid CARCINOMA renal tumors. It is an autosomal dominant disorder with an incidence of around 1:200,000. Linkage analysis has mapped the gene Greater use of cross-sectional imaging has contributed to earlier de- 2,49,50 for BHD (folliculin), a tumor suppressor, to 17p11.2. Folliculin tection of RCC in many cases. Between 50% to 70% of RCC 51 is thought to be a downstream effector of activated protein kinase are detected incidentally, and the majority are “small renal masses and mammalian target of rapamycin (mTOR).39 Renal tumors (SRM),” or clinically localized renal cortical tumors up to 4 cm in associated with BHD are more indolent in nature, occurring in size. Our perspectives about treatment of clinical T1 renal masses approximately 20% of individuals, with <5% developing metas- have changed substantially in the past 20 years. While all had been tases. While the histology of renal tumors associated with BHD is presumed to be malignant and managed aggressively, we now recog- most often chromophobe RCC, oncocytoma, or hybrids of both, nize the tremendous biologic heterogeneity of these lesions, and mul- clear cell or papillary tumors may rarely occur as well. tiple management strategies are now available, including RN, PN, TA, and AS.52–57 Once controversial, elective PN is now accepted as a standard of care, based in part on the appreciation of the deleteri- Hereditary Leiomyomatosis Renal Cell ous renal functional consequences of RN (Fig. 63.4).53,55,58 Ongo- Carcinoma ing analysis of the relative merits of PN, RN, and other management strategies has produced vibrant literature over the past few years.46, 59–62 Hereditary leiomyomatosis RCC is also characterized by dermatologic Both the American Urologic Association (AUA) and the European manifestations. Patients with HLRCC exhibit cutaneous leiomyomas, Association of Urology have released guidelines for the manage- early onset of uterine fibroids, macronodular adrenal hyperplasia, ment of localized renal masses in recent years providing a robust and kidney cancer. Linkage analysis has localized the HLRCC gene analysis of the available studies.9,63–67 Each approach has associated (fumurate hydratase), a key Kreb cycle enzyme, to 1p42.3 (FN).48 risks and benefits, and no one approach is best in all circumstances 870 Practice of Oncology / Cancers of the Genitourinary System

A B

C D Figure 63.3 The von Hippel-Lindau (VHL) gene is responsible for the inherited form of clear cell renal cell carcinoma (ccRCC): VHL syndrome. (A) Axial computed tomography image showing multifocal and bilateral renal tumors and cysts. (B) Gross image of nephrectomy specimen showing typical yellow-gold appearance of ccRCC present in multiple portions of this kidney from a patient with VHL. (C) Histologic appearance of ccRCC, showing the clearing of the cytoplasm around the darker nuclei typical of these “clear cells.” (D) Structure of the VHL gene with sites of point mutations and truncations indicated. (Used with permission from Linehan and colleagues’ prior work. DeVita VT, Lawrence TS, Rosenberg SA, et al, eds. DeVita, Hellman, and Rosenberg’s Cancer: Principles and Practice of Oncology. 9th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2011.)

(Table 63.4). The involvement of an urologist with expertise in the tumors) or the relatively limited subgroup of patients with clinical management of RCC is essential for selection of the optimal strategy T1 tumors that are not amenable to nephron-sparing approaches.78 based on the individual features of each patient and tumor. The surgical approach for RN depends on the size and location of the tumor, as well as the patient’s habitus and medical/surgical history. For locally advanced disease and/or bulky lymphadenopa- Radical Nephrectomy for Renal Cell thy, an open surgical approach using either an extended subcostal, Carcinoma midline, or thoracoabdominal incision is generally used.79 Current minimally invasive approaches allow all of the essential The objective of surgical therapy for RCC is to excise all of the steps of RN to be performed, with the associated benefits of shorter cancer with an adequate surgical margin. Simple nephrectomy was convalescence and reduced morbidity.80–83 Laparoscopic RN is now practiced for many decades, but was replaced by RN when Robson established as a preferred approach for moderate to large volume and colleagues (1969) established this procedure as the “gold stan- tumors (≤10 cm to 12 cm), without invasion of adjacent organs, dard” approach for localized RCC.68 “RN” as currently practiced with limited (or no) venous involvement, and having manageable may be better termed “total nephrectomy,” as it often omits several of (or no) lymphadenopathy. Therefore, a minimally invasive approach the components of the original, “radical” nephrectomy, which always is suitable for most patients with renal tumors, even including some included extrafascial nephrectomy, adrenalectomy, and extended patients with features previously thought to mandate open RN. lymphadenectomy from the crus of the diaphragm to the aortic bi- On the other hand, RN has fallen out of favor for smaller renal furcation. Perifascial dissection is still routinely practiced for larger tumors due to concerns about chronic kidney disease (CKD), tumors, as ≥25% of these tumors extend into the perinephric fat.69,70 and it should only be performed when necessary in this popula- Removal of the ipsilateral adrenal gland is no longer recommended, tion.53,58,78,84 Several studies have shown an increased risk of CKD unless there is suspicion of direct invasion of the gland by tumor or on longitudinal follow-up after RN.58,85,86 Huang et al. first re- a radiographically or clinically suspicious adrenal tumor, because of ported that 26% of patient populations with a small renal mass, the similar propensity of RCC to metastasize to the ipsilateral or con- normal opposite kidney, and “normal” serum creatinine had pre- tralateral adrenal gland.71–73 Finally, extended lymphadenectomy has existing grade 3 CKD (estimated glomerular filtration rate [eGFR] been shown to be of no benefit for patients with clinically localized <60 ml/min per 1.73 m2). After surgery, stage 3b or higher CKD RCC and remains controversial for those with higher-risk disease.74–77 (eGFR <45 ml/min per 1.73 m2) was more common after RN RN is still a preferred option for many patients with local- than PN (36% versus 5%, p <0.001). CKD has been proven to ized RCC, such as those with very large tumors (most clinical T2 lead to increased rates of cardiovascular events and death, with

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last 50 years.93–95 Kidney-sparing surgery entails complete local resection of the tumor while leaving the largest possible amount of normal functioning parenchyma in the involved kidney (see Fig. 63.4). Initially described for patients with an “absolute” indication for kidney-sparing surgery or for the “elective” indication of a small renal tumor in the setting of a normal contralateral kidney, PN is now strongly considered whenever preservation of renal function is potentially important. Common indications include conditions that pose a threat to future renal function, such as hypertension, diabetes mellitus, peripheral or coronary artery disease, or neph- rolithiasis, and patients with baseline CKD, an abnormal contralateral kidney, or those with multifocal or familial RCC.96,97 PN is generally considered feasible for the vast majority of localized renal masses <5 cm in size and often for tumors ≥7 cm by those with expertise with kidney-sparing surgery.98–101 Particularly for those with a strong rationale for nephron-sparing surgery, PN can even be performed for tumors that deeply invest the renal vascular structures or with limited venous thrombus, but such procedures clearly carry higher perioperative morbidity.95,102 Local recurrence rates after PN for imperative indications have averaged 3% to 5% or higher in historical series.103 The decision to perform a PN in such circumstances should be individualized, weighing the potential increased technical and oncologic risks of such an operation with the renal functional consequences of RN (see Fig. 63.4). PN clearly leads to improved functional outcomes, when compared with RN, even for complicated situations.104,105 Temporary or permanent renal replacement therapy has been reported to be necessary in <5% of patients undergoing PN in a solitary kidney and is rarely needed for patients with a functioning contralateral Figure 63.4 Partial nephrectomy. The intention of kidney-sparing surgery, kidney.106,107 In fact, the vast majority of patients will avoid perma-

or “nephron-sparing surgery,” is to achieve complete local resection of nent dialysis, even following multiple surgeries for multiple tumors OF ONCOLOGY PRACTICE the tumor while leaving as much functioning parenchyma in the involved in both kidneys, so long as at least 30% of a well-functioning rem- kidney as possible. An assessment of volume preservation can be made nant kidney is preserved.95 For situations in which PN is deemed by accounting for both the amount of parenchyma replaced by tumor and impossible, RN with ensuing hemodialysis is sometimes necessary, the adjacent uninvolved parenchyma removed or devascularized during 61 but presurgical therapy with a tyrosine-kinase inhibitor is an alter- the procedure. The amount of volume preservation and the quality of 108–111 the functioning renal remnant are the most important determinants of native approach that has proven successful in some patients. renal function after renal surgery. Partial nephrectomy and other kidney- For patients with clinical T1 renal masses, local recurrence sparing alternatives provide definite renal functional benefits that must rates are 1% to 2% after PN and most commonly located distant be weighed against the potential for increased risk of cancer recurrence, from the initial resection. Cancer-free survival is achieved in well when compared with radical nephrectomy.287 (Artwork courtesy of Kristen above 90% of patients.104 The contralateral kidney is also at risk Tobert.) for metachronous disease, which also occurs in 1% to 2% of patients, even with contemporary imaging modalities. This provides further rationale to avoid unnecessary RN for tumors amenable to nephron-sparing surgery. The goal of PN is resection of all grossly proportionally greater impact with higher CKD stage (and lower > appreciated tumor with negative microscopic surgical margins; GFR). For example, in a population-based study of 1 million this is generally performed with a thin rim of normal parenchyma subjects, the relative death rates were 1.2, 1.8, 3.2, and 5.9 for 2 based on prior literature indicating that margin width is imma- eGFR (ml/min per 1.73 m ) of 45 to 60, 30 to 45, 15 to 30, and terial.67,112–117 Some centers now routinely perform enucleation <15, respectively, even after controlling for hypertension, diabe- 87 of renal tumors with excellent oncologic outcomes, although tes, and other potential confounding factors. Coupled with the enthusiasm for more widespread use of this approach has been biologic heterogeneity of small renal masses, many of which will tempered by the somewhat higher recurrence rate among patients never lead to compromised survival, the potential negative conse- with RCC with positive margins and the propensity of some RCC quences of RN on renal function have highlighted the importance 53,58,72,88–90 subtypes to invade the pseudocapsule that is generally present. of nephron-sparing approaches. Within the last decade, substantial progress has been made with minimally invasive PN, which is now the most commonly Partial Nephrectomy for Renal Cell Carcinoma performed procedure for small renal masses. Laparoscopic PN, with or without robotic assistance, is performed according to the Kidney-sparing surgery for renal tumors was first described by same principles as open PN. Margin status and oncologic out- Czerny in 1890; however, significant morbidity limited its use for comes with laparoscopic and open PN appear equivalent in series the next half century.91 Vermooten (1950) revisited the concept of of patients in which patients were selected appropriately for each local excision with a margin of normal parenchyma for encapsu- of these approaches.101,118 Although early to intermediate experi- lated and peripherally located renal tumors.92 The use of PN for ence with laparoscopic PN suggested increased urologic compli- RCC has subsequently been stimulated by experience with renal cations compared with open RN,119 subsequent experience with vascular surgery for other conditions, advances in renal imaging, pure laparoscopic PN and more prevalent use of robotic PN have growing numbers of incidentally discovered small renal masses, substantially reduced perioperative morbidity.104,120–125 Tumor greater appreciation of the deleterious effects of CKD, introduc- complexity remains a major predictor for intraoperative and post- tion of minimally invasive techniques, and encouraging long-term operative complications, regardless of surgical approach, and open survival in patients undergoing this form of treatment during the PN should be considered for particularly challenging situations.126 872 Practice of Oncology / Cancers of the Genitourinary System

TABLE 63.4 Treatments for Localized Renal Cell Carcinoma

Advantages Disadvantages Main Indications ORN Traditional surgical approach for renal cancer, Morbidity of surgical incision (flank, Large tumor (>12 cm) effective in removing tumor with surrounding subcostal, midline, thoracoabdominal) Locally advanced tumor structures and lymph nodes when indicated Renal functional implications of Bulky adenopathy removing entire kidney (average 35% decrease in GFR) MIRN Reproducible and effective surgery for most Many tumors up to 7 cm can be treated Medium to large tumor (up to 10 localized renal tumors with PN to 12 cm) Minimally invasive surgery, with decreased pain, Renal functional implications of High tumor complexity morbidity and convalescence compared to ORN removing entire kidney (average 35% decrease in GFR) OPN Oncologic outcomes appear similar to RN, Morbidity of flank incision (bulge, longer Small to medium tumors (up to although selection biases limit this conclusion recovery) 7 cm and occasionally larger) Maximizes renal functional preservation when Potential for local recurrence due to Moderate to high-complexity performed with precise tumor excision and incomplete excision or de novo tumors judicious use of regional hypothermia tumors in the renal remnant MIPN Kidney-sparing surgery, with preservation of renal Higher complication rate for high Small renal masses (up to 5 cm function when warm ischemia kept to limited complexity tumors and in less- and occasionally larger) duration (<20 to 25 min) experienced hands Low to moderate (and selected Minimally invasive surgery, with decreased pain, Positive surgical margins and local high) complexity tumors morbidity, and convalescence compared to OPN recurrence rates may be higher in such situations TA Kidney-sparing approach, with renal functional Relatively high rate of local failure Prior ipsilateral surgery for renal benefits versus RN Imprecision of histopathologic diagnosis tumor Can be performed outside of OR (percutaneous) or Increased and challenging radiographic Poorer surgical candidates with minimally invasive approach (laparoscopic) follow-up unwilling to undergo For small (<3 cm) tumors, provides comparable surveillance control of metastasis to PN and RN AS Least invasive and kidney-sparing of all strategies Tumor remains in place and untreated Poor surgical candidates Most SRMs have limited oncologic potential and Oncologic nature of tumor unknown Limited life expectancy can be safely managed with initial short interval (without biopsy) follow-up imaging Intensity of surveillance can be tailored to patient and tumor characteristics

ORN, open radical nephrectomy; GFR; glomerular filtration rate; MIRN, minimally invasive radical nephrectomy; OPN, open partial nephrectomy; RN, radical nephrectomy; MIPN, minimally invasive partial nephrectomy; TA, thermal ablation; OR, operating room; PN, partial nephrectomy; AS, active surveillance; SRM, small renal mass.

Thermal Ablation of Renal Cell Carcinoma does not allow for reliable treatment of lesions >4 cm and success rates appear to be highest for tumors <2.5 cm to 3 cm.132–135 TA, including renal cryosurgery and radiofrequency ablation Clinical experience and follow-up of patients after renal cryo- (RFA) have emerged as alternative kidney-sparing treatments for surgery suggests successful local control in about 90% of patients, patients with small (<3 cm) renal tumors.127,128 Both can be ad- although many studies provide limited and often incomplete, ministered percutaneously or with laparoscopic exposure and thus follow-up.136–140 Diagnosis of local recurrence after TA can be offer the potential for reduced morbidity and more rapid recovery challenging because evolving fibrosis within the tumor bed can compared with extirpative approaches.128,129 In general, the long- be difficult to differentiate from residual cancer. In general, cen- term efficacy of TA has not been well established when compared tral or nodular enhancement within the tumor bed on extended to surgical excision, and current data suggest that the local recur- follow-up has been considered diagnostic of local recurrence and rence rates are somewhat higher than that reported with extirpative the clinical experience with cryoablation has thus far supported approaches.55,63 Another concern has been the lack of accurate his- this.141,142 Other findings that suggest local recurrence include tologic and pathologic information obtained with these modalities failure of the treated lesion to regress over time, a progressive in- because the treated lesion is left in situ. crease in size of an ablated neoplasm, new nodularity in or around The ideal candidates for TA are patients with advanced age and/ the treated zone, or satellite or port site lesions.143 If these features or significant comorbidities who prefer a proactive approach (over are found, biopsy and possible retreatment should be considered. surveillance), but are not optimal candidates for conventional sur- The AUA guidelines for surveillance after TA include cross-sec- gery, patients with local recurrence after previous kidney-sparing tional scanning (computed tomography or MRI) with and without surgery, and patients with hereditary renal cancer who present with intravenous contrast at 3 and 6 months following ablative therapy multifocal lesions for which multiple PNs might be cumbersome.55 and annually with chest X-ray for 5 years thereafter.143 Patient preference must also be considered as some patients not fit- More mature data from a limited number of studies now pro- ting these criteria may select TA after balanced counseling about vide encouraging outcomes for smaller tumors, particularly those the current status of these modalities.130,131 Tumor size is an im- <3 cm, yet the cumulative experience continues to suggest that portant factor in patient selection because the current technology local control after cryoablative therapy remains suboptimal when

tahir99 - UnitedVRG Chapter 63 Cancer of the Kidney 873 compared to surgical excision.55,138 The 5-year local recurrence that radiographically localized small renal masses, most of rates in two series were 8% to 9%,52,144 which is significantly higher which are RCC,154,152 exhibit slow linear/volumetric growth than the 1% to 2% consistently reported with surgical excision of (0.3 cm/year on average) with a low metastatic potential (1.1% analogous small renal masses.53 Other concerns with TA relate to to 1.4%) over the first 24 to 36 months following diagnosis.154,152 surgical salvage and potential morbidity. Most local recurrences Moreover, in patients with localized small renal tumors at di- can be salvaged with repeat ablation, but some patients with pro- agnosis, the risk of metastases appears to be related to both the gressive disease eventually require surgical extirpation. Nguyen size of the primary tumor and perhaps more importantly the and colleagues (2008b) have shown that PN and minimally inva- growth kinetics of the lesion.155 Interestingly, as many as 20% sive approaches are occasionally precluded in this setting due to to 30% of small renal tumors exhibit zero radiographic growth the extensive fibrotic reaction induced by TA.78 As expected, the over the initial 24 months following diagnosis.55 Given these incidence of treatment failure or complications after TA correlates data, the practice of AS with delayed intervention informed with tumor size and complexity.145 by an objective assessment of risk in the elderly, infirm, and/or The experience with RFA has been even more variable, likely well-informed is emerging.156 This practice is a calculated risk related to surgeon experience, the availability of different platforms accepted by the patient and managed by the physician. Percu- for the procedure, and inability to monitor treatment progress.128 taneous biopsy and emerging biologic and genetic markers will Local control after RFA is estimated to be 80% to 90%, although continue to improve the decision-making process. In the mean- the definitions of local recurrence within the literature have been time, AS remains a viable option for highly motivated patients inconsistent.53,55 Although loss of enhancement on cross-sectional and highly engaged physicians. imaging within the lesion has generally been accepted as an indicator of success, viable cancer cells have been detected at biopsy Follow-Up for Localized Renal Cell Carcinoma of the tumor bed even in the absence of enhancement on the MRI 6 months after treatment.142 The issue of potential false-negative Follow-up for cancer survivors focuses broadly on early detection and false-positive imaging findings after TA remains a concern, of cancer recurrence. With earlier diagnosis of many cancers and and more strict definitions of local control after TA were recently a longer length of life after diagnosis and treatment, an increasing advocated by an AUA guidelines panel.143,146 The technology for number of survivors remain under the care of cancer specialists RFA continues to improve with most contemporary series report- and primary care physicians. Wide variations in recommended ing relatively low rates of local recurrence. Some patients require practice have led to the development of guidelines by various orga- repeat treatments to achieve local control, which is an infrequent nizations. The AUA released guidelines for follow-up of clinically event with cryoablation and rarely required with conventional localized RCC in 2013 that reflect a consistent approach that also surgical treatments for localized RCC.128 One recent series docu- takes into account the heterogeneity of the population of cancer 143 mented local control in 91% of 179 patients with biopsy proven survivors (Table 63.5). Clinicians should be aware that in man- 135 aging adult cancer survivors they are not only looking for RCC RCC at median follow-up of 27 months. Some RFA series report OF ONCOLOGY PRACTICE even more encouraging results, particularly for tumors <3 cm di- recurrence, but also monitoring for secondary malignancy and ameter,132 but others have reported 5-year local recurrence rates as the effects of cancer treatment, implementing therapies to prevent high as 39%.147 recurrences or new tumors, understanding the consequences of Complications from ablation are uncommon, but have in- cancer and its treatment effects, and coordinating the overall care cluded acute renal failure, stricture of the ureteropelvic junction, between cancer specialists and the primary care physician to meet necrotizing pancreatitis, and lumbar radiculopathy; therefore, each individual’s needs. careful and judicious selection of patients is essential.128 Direct comparisons between cryoablation and RFA are inevitable, but perhaps unfair because RFA is earlier in its development and re- TREATMENT OF LOCALLY ADVANCED cent reports suggest great promise.128,132 Other new technologies, RENAL CELL CARCINOMA such as high-intensity focused ultrasound and frameless, image- guided radiosurgical treatments (CyberKnife), are also under development and may allow extracorporeal treatment of small renal Surgery for Tumor Thrombus in the Inferior tumors in the future.148–150 However, at present cell kill with these Vena Cava modalities is not sufficiently reliable and they should still be considered developmental.151 Renal tumors are unique in their ability to form tumor thrombi that can propagate from the ipsilateral renal vein into the IVC and extend as far as the patient’s right atrium. Approximately 4% to Active Surveillance of Clinically Localized 10% of patients who present with renal masses will have a concom- Renal Cell Carcinoma itant tumor thrombus. The level of tumor thrombus is classified as level 0 (thrombus limited to the renal vein), level I (thrombus The concept of overdiagnosis and overtreatment of kidney can- extending into the inferior vena cava ≤2 cm above the renal vein), cers is a relatively new concept. The risks and consequences level II (thrombus extending into the inferior vena cava >2 cm associated with unnecessary treatment of low-risk RCC are an above the renal vein, but below the hepatic veins), level III (throm- unintentional, yet underappreciated harm associated with in- bus extending into the inferior vena cava to or above the level of cidental detection of these tumors. While early detection leads the hepatic veins, but still remaining below the diaphragm), and to “cure,” lead time biases in reported surgical series and the level IV (thrombus extending into the inferior vena cava and above growing recognition that some localized renal tumors exhibit an the level of the diaphragm) (Fig. 63.5). A tumor thrombus should indolent natural history have challenged the “find it, excise it” be suspected in patients with a renal tumor who also have new practice pattern. As the data emerge, AS remains a rational thera- onset lower extremity edema, an isolated right-sided varicocele or peutic option, particularly in the elderly or infirm where compet- one that does not collapse with recumbency, dilated superficial ing health, surgical, or renal functional risks may exceed that of abdominal veins, proteinuria, pulmonary embolism, right atrial the tumor’s biology.152,153 mass, or nonfunction of the involved kidney. Objectifying and comparing the risks of treatment (excision/ Five-year cancer-specific survival for patients with RCC and ablation) versus AS remains difficult as the data upon which venous extension ranges from 45% to 70%, and surgical therapy competing risks models are based remain largely retrospective in the form of RN and IVC thrombectomy can be curative. In- and incomplete.28 Nonetheless, data have emerged to suggest terestingly, many patients with vena cava extension will present 874 Practice of Oncology / Cancers of the Genitourinary System

TABLE 63.5 level can be cured with surgical resection, even level IV, in the absence of metastases and other adverse features.165–168 Guidelines for Follow-Up of Clinically More recent series have re-evaluated the clinical variables pre- Localized Renal Cell Carcinoma dictive of survival after surgery for patients with tumor thrombi. In a single institutional series of 99 patients, median survival for Follow-up Measure Recommendation patients with level I/II tumor thrombus was 6.6 years compared to Physical exam and History and physical examination directed 1.4 years for patients with level III/IV tumor thrombi. Higher level history at detecting signs and symptoms of of tumor thrombus ([III/IV versus I/II], hazard ratio [HR] = 1.84 metastatic spread or local progression 95% confidence interval [CI]= 1.03 to 3.30, p = 0.041) and the Laboratory testing Basic laboratory testing including blood presence of metastatic disease at the time of surgery (HR = 2.97, urea nitrogen/creatinine, urinalysis and 95% CI = 1.65 to 5.36, p <0.001) both portended a worse OS 169 estimated glomerular filtration rate for on multivariate analysis. Other investigators have examined the all patients impact of tumor histology on clinical and pathologic outcomes in Progressive renal insufficiency should patients with venous tumor extension. Authors at the Mayo Clinic prompt nephrology referral found that patients with non–clear cell histology presented with a Complete blood count, lactate significantly larger tumor size, greater rate of lymph node disease, dehydrogenase, liver function tests, higher nuclear grade, and more frequent sarcomatoid differentia- 170 alkaline phosphatase, and serum tion. As a result of these clinical and pathologic variables, these calcium per discretion of the physician patients had a considerably worse 5-year cancer-specific survival as compared with patients with clear cell histology (p = 0.03).170 Abdominal imaging Obtain a baseline abdominal scan (CT Similarly, a recent international multi-institutional retrospective or magnetic resonance imaging) study analyzed the role of tumor histology on survival in patients within 3 to 6 mo following surgery, undergoing RN and caval thrombectomy. In this series of 1,774 and periodically thereafter based on patients, the overall 5-year cancer-specific survival was 53.4%.171 In individual risk factors (e.g., every 6 mo this series’ multivariable analysis, papillary histology (HR = 1.62, for 3 y for moderate to high-risk RCC) 95% CI = 1.01 to 2.61, p <0.05), fat invasion (HR = 1.49, 95% Perform site-specific imaging as CI = 1.10 to 2.03, p <0.01), and thrombus level (p <0.01) were symptoms warrant all independent predictors of a poor cancer-specific survival.171 In Imaging beyond 5 y may be performed at contrast to the Mayo series, when the authors restricted their analy- the discretion of the clinician sis to only N0M0 patients, thrombus level and papillary histology Chest imaging Low-risk RCC: Chest X-ray annually for were still significantly associated with a decreased cancer-specific 3 y and only as clinically indicated survival.170,171 beyond that time period Surgery remains an integral part in the treatment paradigm for Moderate to high-risk RCC: baseline patients with tumor venous extension because of the sequelae of chest CT 3 to 6 mo after surgery with such vascular involvement. The surgical approach and technique continued imaging (chest X-ray or CT) to treat these challenging tumors are tailored to the level of IVC every 6 mo for at least 3 y thrombus, but uniformly begin with careful mobilization of the Imaging beyond 5 y is optional and kidney and early ligation of the arterial blood supply.164,172,173 With should be based on individual patient an increasing tumor thrombus level, more advanced surgical tech- characteristic and tumor risk factors niques are required for vasculature control and complete tumor Bone scan Elevated alkaline phosphatase, clinical extirpation, including veno-venous bypass and cardiopulmonary symptoms such as bone pain, and/or bypass potentially with hypothermic circulatory arrest for some radiographic findings suggestive of a cases. Specifically for level III and level IV thrombi, a multidisci- bony neoplasm should prompt a bone plinary surgical team is often required for advanced surgical ma- scan neuvers, including a liver surgeon to aid in mobilization of the Bone scan should not be performed liver and exposure of the intrahepatic IVC and a vascular and/or in the absence of these signs and cardiac surgeon if bypass is required. symptoms Despite the surgical ability to resect these tumor thrombi, perioperative mortality rates associated with RN and IVC throm- Central nervous Acute neurologic signs should lead to bectomy have been reported to be as high as 5% to 10% in some system imaging prompt neurologic cross-sectional series, depending on patient comorbidities and tumor character- imaging of the head or spine based on istics.164,166 Although there may be a palliative role for surgery in localized symptoms some patients with metastasis who experience severe disability from intractable edema, ascites, cardiac dysfunction, or associated CT, computed tomography; RCC, renal cell carcinoma. Adapted from Donat SM, Diaz M, Bishoff JT, et al. Follow-up for clinically local symptoms such as abdominal pain and hematuria, most such localized renal neoplasms: AUA guideline. J Urol 2013;190:407–416. patients will not benefit due to risk of perioperative morbidity and limited life expectancy.174,175

without metastatic disease.157,158 The prognostic significance of Lymphadenectomy IVC thrombus level has been controversial. Most studies suggest that the incidence of locoregional or systemic progression is higher The need for extensive lymphadenectomy in patients undergoing in patients with level III-IV IVC thrombus, which may account for RN remains a subject of debate. Despite the fact that multiple prior the reduced survival reported in this subgroup in some series.159–162 studies have shown a survival benefit with a lymph node dissection Other series have shown that any IVC involvement is worse than performed at the time of nephrectomy,75,176,177 a recent random- renal vein involvement without distinction with regard to IVC ized trial failed to show a distinct advantage.74 Although this trial level; in these series, other factors, such as nodal or metastatic in- represents level I evidence, its generalizability is limited since the volvement and tumor grade, have more impact on overall survival trial included many patients at low risk for nodal metastasis (81% (OS).163,164 Despite this debate, patients with any tumor thrombus of patients had grade 1 or 2 tumors and 72% had organ-confined

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Diaphragm

Hepatic vein

Renal vein PRACTICE OF ONCOLOGY PRACTICE

Prognostic and surgical staging systems of IVC tumor thrombus Anatomic landmark Staging systems

TNM Neves Novick Hinman Robson

RV T3b 0 I I IIIa

IVC <2 cm above RV I II

IVC >2 cm above RV and below hepatic veins II

IVC above hepatic veins and below diaphragm III III II

IVC above diaphragm T3c IV IV III

Figure 63.5 Classification of renal cell carcinoma venous tumor thrombi. Level 0 (green): Thrombus within main renal vein (RV) or its branches and not reaching into the inferior vena cava (IVC). Level I (yellow ): IVC thrombus is present within the IVC, <2 cm above renal vein. Level II (orange): IVC thrombus extends along the IVC, but not to the level of the main hepatic veins. Level III (purple): IVC thrombus extends within the IVC above the level of the main hepatic veins, but below the diaphragm. Level IV (red): IVC thrombus extends above the diaphragm, near to or into the right atrium and occasionally beyond. TNM, tumor, node, metastasis. (Reproduced with permission from Pouliot F, Shuch B, Larochelle JC, et al. Contemporary management of renal tumors with venous tumor thrombus. J Urol 2010;184:833–841.)

disease).74 Furthermore, in the entire cohort, lymph node metas- region, the ipsilateral great vessel, and the interaortocaval region. tases were present in only 4% of patients undergoing complete This dissection should extend from the crus of the diaphragm lymph node dissection.74 Based on this trial, a compelling argu- to the common iliac artery. In a retrospective study, 45% of pa- ment for lymph node dissection in patients with clinically local- tients had positive lymph nodes outside of the renal hilar region, ized RCC cannot be supported. mandating a broader template.177 Finally, a recently published Of greater impact is the study from Blute and colleagues164 retrospective study of 1,983 patients treated for RCC assessed who elucidated pathologic features associated with increased risk the factors predictive of lymph node invasion and/or progression. for nodal metastases: tumor grade (grade 3 or 4), presence of a In this study, the overall prevalence of lymph node invasion was sarcomatoid component, tumor size ≥10 cm, tumor stage pT3 6.1% and the clinical factors that were independently predictive or pT4, and histologic tumor necrosis. Based on this study and a of lymph node involvement were tumor stage (T3-T4), clinical subsequent prospective evaluation of this approach, patients with nodal status, the presence of metastatic disease, and tumor size as two or more of these risk factors should be considered for exten- a continuous variable.178 Using these variables, the authors created sive lymph node dissection incorporating the ipsilateral renal hilar a nomogram that calculates a patient’s probability of having lymph 876 Practice of Oncology / Cancers of the Genitourinary System node disease at the time of nephrectomy or in disease follow-up.178 Network Guidelines for kidney cancer list cytoreductive nephrec- It appears fair to conclude that a lymph node dissection is not rou- tomy (CN) with or without metastasectomy prior to systemic treat- tinely needed for organ-confined disease; however, the presence of ment as the primary treatment option for patients with stage IV multiple adverse pathologic features (e.g., large tumor size, locally RCC.180 The data supporting this recommendation come from advanced disease, etc.) seems to favor performing a lymph node three randomized trials demonstrating a survival benefit for pa- dissection that is more extensive than simply the hilar region. tients who received systemic immunotherapy with interferon (IFN)-alfa after surgical removal of the primary tumor.181–183 Fla- nigan et al.181 found the median survival of 120 patients assigned ADJUVANT THERAPY FOR RENAL CELL to surgery followed by IFN-alfa to be 11.1 months compared to CARCINOMA 8.1 months in 121 patients assigned to IFN-alfa alone (p = 0.05). Similarly, Mickisch et al.183 found time to progression (5 months Although a significant proportion of patients can be considered versus 3 months) and median duration of survival to be better in to be cured or in remission after surgical treatment for nonmeta- patients randomized to surgery plus IFN-alfa compared to those static RCC, distant metastases are detected in 20% to 35% and randomized to IFN-alfa alone. Combining the survival data from local recurrence in 2% to 5% of patients.54,94 Patients with locally all these trials resulted in a median survival of 13.6 months versus advanced RCC and other high-risk features are at greater risk of 7.8 months for patients undergoing surgery in addition to IFN-alfa 181,183–185 recurrence and various predictive tools can be used to provide as compared to IFN-alfa alone. an individualized estimate.54 Despite the significant likelihood More recent data accounting for the current use of targeted of recurrence in patients with poor-risk features, no therapy has therapies as first-line systemic therapy for patients with metastatic ever been shown to be of benefit in the adjuvant setting. Prior trials RCC have confirmed the survival advantage associated with CN. = have evaluated hormone therapy, radiotherapy, immunotherapy, In one retrospective study, patients (n 201) who underwent CN and tumor vaccines, all with essentially negative results. Based on had an independent statistically significant survival advantage as = = the significant antitumor activity of targeted molecular therapies compared to patients (n 113) who did not (HR 0.68; 95% = = 186 in advanced RCC, a number of randomized trials evaluating the CI 0.46 to 0.99, p 0.04). This survival advantage was pres- ability of these agents to prevent metastasis have completed enroll- ent even when adjusting for contemporary adverse prognostic risk ment and results of these trials can be expected as early as 2015 factors (e.g., performance status, time from diagnosis to therapy (Table 63.6). initiation, anemia, hypercalcemia, neutrophilia, and thrombocytosis).187 Despite these promising results, other studies have shown that CN may not confer a survival advantage in patients with non–clear cell histology, especially those with sarcomatoid SURGICAL MANAGEMENT OF ADVANCED 172,188,189 RENAL CELL CARCINOMA features. Fortunately, a prospective study evaluating the benefit of surgery in combination with sunitinib versus sunitinib alone is currently ongoing in patients with metastatic RCC. Cytoreductive Nephrectomy Although the use of laparoscopic/minimally invasive techniques in patients with advanced disease can potentially provide Approximately 30% to 40% of patients will present with metastatic a less invasive and less morbid method for cytoreduction as prepa- or advanced RCC.179 For these patients, multimodal therapy, ration for administration of systemic therapies, CN is still not which includes surgery, has produced improved progression-free without risk, and surgical risk assessment needs to be considered survival (PFS) and OS. The National Comprehensive Cancer preoperatively. According to prior reports, patients that are most

TABLE 63.6 Clinical Trials of Adjuvant Treatment for Nonmetastatic Renal Call Carcinoma

Trial Study Groups Treatment Duration Inclusion Criteria ASSURE: Adjuvant Sorafenib or Sunitinib for Sunitinib vs. sorafenib 1 y Clear cell and non–clear cell RCC eligible Unfavorable Renal Cell Carcinoma vs. placebo pT1b and G3-4; pT2/pT3/pT4; N1 if complete dissection performed SORCE: Sorafenib for Patients with Resected Sorafenib (for 1 or 3 y) 3 y Clear cell and non–clear cell RCC eligible Primary Renal Cell Carcinoma vs. placebo Mayo Clinic progression score 3–11 S-TRAC: Sunitinib vs. Placebo for the Sunitinib vs. placebo 1 y Clear cell predominant histology eligible Treatment of Patients at high risk for High-risk RCC according to UISS Recurrent Renal Cell Cancer EVEREST: Everolimus for Renal Cancer Everolimus vs. placebo 1 y Clear cell and non–clear cell RCC eligible Ensuing Surgical Therapy pT1b and G3-4; pT2/pT3/pT4; N1 if complete dissection performed ATLAS: Adjuvant Axitinib Treatment of Renal Axitinib vs. placebo 3 y Clear cell predominant (>50%) eligible Cancer pT2 and G3-4; pT3a and >4 cm; pT3b/pT3c/pT4; N1 PROTECT: Pazopanib as an Adjuvant Pazopanib vs. placebo 1 y Clear cell predominant (>50%) eligible Treatment for Locally Advanced Renal Cell pT2 and G3-4; pT3/pT4; N1 Carcinoma

RCC, renal cell carcinoma; pT: pathologic T stage; G: Fuhrman nuclear grade; . UISS: University of California, Los Angeles, integrated staging system. Source: Zisman A, Pantuck AJ, Chao DH, et al. Renal cell carcinoma with tumor thrombus: is cytoreductive nephrectomy for advanced disease associated with an increased complication rate? J Urol 2002;168:962–967.

tahir99 - UnitedVRG Chapter 63 Cancer of the Kidney 877 likely to benefit from CN are those patients with lung-only meta- Patients with a solitary synchronous metastatic lesion have de- static disease, good prognostic features as defined by Motzer (or creased survival when compared with patients who develop other) criteria, and a good performance status.175,190 Conversely, metastasis after the primary tumor is removed.199 Nevertheless, predictors of short survival for patients with advanced RCC in- surgical resection of metastatic disease either alone or in combi- clude an elevated serum lactate dehydrogenase (LDH; >1.5 times nation with immunotherapy/targeted therapy has been shown to upper limit of normal), a hemoglobin level 10 mg/dl, an interval of who did not undergo consolidative metastasectomy. However, <1 year from original diagnosis to the start of systemic therapy, a these data must be interpreted in the context that only a small Karnofsky performance score ≤70, and two or more sites of organ subset of patients will be optimal candidates for surgical extirpa- metastasis.191 However, the challenge associated with these risk tion of metastatic lesions. In a large series from the Mayo Clinic, criteria is that they mostly account for the risk associated with the 887 patients were identified with multiple metastatic sites of dis- disease and do not consider the perioperative risk to the patient, ease from RCC who underwent surgical resection. Of this large which is not insignificant. cohort, only 125 (14%) patients underwent a complete resection For example, Abdollah et al.192 identified 17,688 patients of their metastatic disease, whereas 698 (78.7%) patients had died within the Florida Inpatient Database that underwent nephrec- of RCC at a median of 1.2 years after the first occurrence of their tomy between the years 1999 to 2008. They identified 1,063 (6%) metastatic disease.200 In this analysis, the authors demonstrated patients who underwent a CN and found that these patients were that complete surgical resection of metastatic disease, across all more likely to have a longer length of stay (8.4 versus 5.7 days, subgroups, was predictive of improved survival. For example, p <0.001), a secondary surgical procedure (28.3% versus 10%, the median RCC specific and OS for patients who underwent p <0.001), an in-hospital mortality (2.4% versus 0.9%, p <0.001), complete metastatectomy were 4.8 and 4.0 years, respectively.200 and a postoperative complication (26.5% versus 18.9%, p <0.001). Comparative RCC-specific and OS rates for patients where com- In this report, increasing age was predictive of increasing in-hos- plete surgical resection was not achieved were 1.3 and 1.3 years, pital mortality and complications for patients undergoing CN. A respectively. Also, patients experienced an improved survival if similar analysis was conducted by Trinh et al193 using the Nation- they underwent complete surgical resection regardless of meta- wide Inpatient Sample registry. Thirty one percent of the study static sites (lung versus nonlung, p <0.001), number of metastatic population (n = 16,285) experienced a perioperative complica- sites (p <0.001), and timing of metastatic disease—synchronous tion, and patients ≥75 years old who had a comorbidity score ≥3 (p <0.001) and asynchronous (p = 0.002).200 Finally, on multi- were more likely to experience a complication after CN (both variate analysis, patients in whom surgery did not achieve a com- p <0.001).193 Of the patients (n = 4,974) that experienced an plete metastasectomy were almost three times more likely to die adverse event, 5% (n = 245 patients) died during their hospital- of RCC (HR = 2.91; 95% CI = 2.17 to 3.90, p <0.001).200 In ization.193 Finally, it is worth noting that despite the survival ad- this series, approximately half of the patients (45.6%) received

vantage garnered from a CN followed by targeted therapy, it is not some form of systemic therapy during their treatment course and OF ONCOLOGY PRACTICE universally received. In a single institutional study from the Fox the receipt of systemic therapy was associated with a significant Chase Cancer Center, only 69.5% of patients actually received improvement in survival only in patients who did not undergo systemic therapy after surgery.194 The most common reason in this complete metastasectomy, highlighting the importance of surgery study for patients not to receive systemic therapy was rapid disease in the treatment of metastatic/recurrent RCC.200 progression, which occurred in 30% of patients. Also, there were In patients treated with immunotherapy, there are multiple eight perioperative deaths, accounting for 19% of patients who did retrospective series demonstrating that patients who underwent not receive systemic treatment.194 metastasectomy had better outcomes than those who did not un- In summary, CN offers patients with metastatic RCC a survival dergo resection of metastatic sites. In these series, 24% to 100% advantage and the National Comprehensive Cancer Network of patients were disease free 1 to 4 years postsurgery.201–206 More Guidelines recommend a CN for patients with an Eastern Co- recent data in patients who have received targeted therapies has operative Oncology Group performance status <2 who have no shown similar results, albeit in small patient cohorts. In a retro- evidence of brain metastasis.180 Despite these recommendations, spective, multi-institutional study, only 22 patients with metastatic recent data has shown that surgical risk associated with CN is not RCC who underwent metastasectomy after targeted therapy were insignificant, especially in the elderly and comorbid, and should identified. At a median follow-up of 42 weeks after surgery, 50% of be weighed against the patient’s disease biology (presence of poor- patients had experienced a tumor recurrence; however, only one risk disease) before reflexively proceeding with surgery. patient died of RCC 105 weeks after surgery.207 Surgical management of recurrent and metastatic RCC plays an important role in the treatment paradigm of this group of pa- Surgical Management of Recurrent and tients and appears to confer a survival advantage in retrospective Metastatic Disease series. However, not all patients will ultimately be optimal surgical candidates and the ability to achieve a complete surgical Approximately one-third of patients initially diagnosed with RCC resection is paramount in helping to guide preoperative surgical will present with metastatic disease.179 An additional 40% of pa- decision making. tients that present with localized disease will ultimately develop metastatic disease.179,195 As these statistics illustrate, the biology of RCC is unique and variable and as such the treatment of patients SYSTEMIC THERAPY FOR ADVANCED with metastatic RCC is as well. In patients with diffuse metastatic RENAL CELL CARCINOMA disease, metastatectomy is not routinely used for therapeutic purposes. However, for the subset of patients who either present with or develop low-volume, radiographically solitary, or limited Prognostic Factors metastases, whether it be synchronous or metachronous, resection is often an integral part of the treatment paradigm and can Clinical characteristics have been extensively studied as poten- confer a survival advantage.180,196,197 Complete metastasectomy tial prognostic factors in metastatic RCC. Performance status is has been associated with a two-fold reduction in the risk of death a measure of overall well-being and is the most consistently re- from RCC.162 ported factor associated with survival in advanced RCC, while Of the approximately 30% of patients with RCC who present other demographic features, such as age, gender, and race, are with metastases, only 1.5% to 3.5% have a solitary metastasis.198 of limited value.208–211 Some studies have found the presence of 878 Practice of Oncology / Cancers of the Genitourinary System

visceral (i.e., lung, liver, and adrenal), bone, and brain metastases TABLE 63.7 to be associated with poor survival,208,211,212 whereas others have found no relationship between these sites and prognosis.210,213 A Prognostic System in Metastatic Renal Cell more reliable finding is the number of metastatic sites present, Carcinoma which provides a rough estimate of tumor burden. Most studies Schema Factors Comments have found that patients with higher number of metastatic sites (more than two) are independently associated with at least two- MSKCC215 ■ Low Karnofsky Developed from fold greater probability of death. Similarly, patients with a short performance status patients with interval from initial RCC diagnosis to metastases have been found ■ High lactate metastatic RCC to have a worse outcome, likely as a reflection of faster-growing dehydrogenase patients treated with disease.209,211,214,215 Those with synchronous metastases have out- ■ Low serum IFN-based therapy comes intermediate between those with metastases developing hemoglobin on clinical trials at within 1 year of diagnosis and those with asynchronous metasta- ■ High corrected serum MSKCC ses that develop later.216 Investigators have evaluated the effects calcium of several laboratory parameters in patients with advanced RCC. ■ Time from initial RCC Erythrocyte sedimentation rate, C-reactive protein, hemoglobin, diagnosis to start of white blood cell, and platelet parameters have been evaluated. therapy <1 y Elevated erythrocyte sedimentation rate and C-reactive pro- Heng et al.187 ■ Low Karnofsky Developed from tein were consistently found to be independent poor prognostic 64,214,217,218 performance status retrospective data for factors. Patients with thrombocytosis (defined as plate- ■ a global multicenter > μ Low serum let counts 400,000/ L), another potential marker of inflamma- hemoglobin consortium of patients tion, have been reported to have a negative impact on survival ■ High corrected serum receiving targeted mostly in patients with localized RCC. Studies overall have been calcium therapy for metastatic inconsistent in the metastatic setting, especially when other mark- ■ Time from initial RCC RCC ers of inflammation were considered. Anemia has also consistently diagnosis to start of been found to be an independent prognostic factor for an adverse therapy <1 y outcome. Patients with pretreatment hemoglobin below the lower ■ Elevated neutrophils limit of laboratory normal values were found to have twice the ■ Elevated platelets risk of death compared with patients with normal hemoglobin 210,211 in several large studies. The mechanism of effect of such MSKCC, Memorial Sloan-Kettering Cancer Center; RCC, renal cell carcinoma; blood parameters is unknown—whether these markers reflect an IFN, interferon. underlying inflammatory disease and/or somehow contribute to the disease process itself is unclear. Other biochemical factors that have been implicated in RCC prognosis include pretreatment serum LDH and calcium (corrected for albumin), while serum has occurred to identify additional prognostic factors. VHL gene alkaline phosphatase, creatinine, gamma glutamyltransefrease, status has been investigated for an association with clinical out- and triglycerides have not been found to have prognostic value. come. Over multiple retrospective series and prospective trials, Corrected serum calcium >10 mg/dL and LDH >1.5 times the VHL status (and other VHL pathway elements, such as hypoxia- upper limit of normal have been associated with a two- to three- inducible factor expression) has not been consistently associated fold higher risk of death, respectively.210,211,214 with response to vascular endothelial growth factor (VEGF)-targeted agents.220–222 CA-IX, a member of the carbonic anhydrase Prognostic Schema family, regulates pH during hypoxia and is a product of the hypoxia inducible transcription factor (HIF) complex overexpression. The vast majority of ccRCC tumor samples stain positive for CA-IX Using the previously identified variables, investigators have com- and high CA-IX staining (>85% staining by immunohistochemi- bined these variables to stratify patients into “risk groups” to predict cal analysis) was found to be an independent favorable prognostic outcome. Such schema serve to aid in individual patient coun- indicator of survival in patients with metastatic ccRCC.223 Ret- seling, stratify patients for randomized clinical trial entry, and aid rospective data initially suggested CA-IX to be potentially associ- in interpretation of nonrandomized clinical trials (Table 63.7). ated with response to high-dose interleukin (IL)-2.224 However, The most commonly employed schema from Memorial Sloan- the prospective SELECT trial failed to confirm this finding and Kettering Cancer Center was developed from patients treated with thus there remain no predictive biomarkers to identify the small IFN-based regimens.219 This schema uses Eastern Cooperative percentage of patients who will have a complete response to high- Oncology Group performance status, anemia, LDH, corrected dose IL-2.225 Single nucleotide polymorphisms, which are natural serum calcium, and time from diagnosis to metastatic disease to variations in tumor and/or germline DNA sequences, have also segregate patients into three risk groups. This schema is still widely been investigated in relation to targeted therapy efficacy and tox- used today despite the limited IFN use currently and has been icity in RCC.226–228 While several retrospective series have found shown to also segregate patients treated with newer agents. More associations between single nucleotide polymorphisms associated recent efforts have developed prognostic variables and risk groups with the VEGF pathway and/or drug metabolism with outcome, based on patients treated with targeted agents. This schema uses none have been consistent or robust enough to currently affect hemoglobin, corrected calcium, performance status, and time clinical practice. Finally, clinical markers, such as treatment- from diagnosis to treatment, but additionally neutrophil and plate- induced hypertension, have been explored. Several retrospective let count.187 Both Memorial Sloan-Kettering Cancer Center and data sets have identified a strong association of treatment-induced Heng criteria are used to describe patient populations treated in hypertension and clinical outcome in response to VEGF-targeting the targeted therapy era. agents.229,230 This has been identified across mechanism of agent and including non-RCC diseases.231 The precise biologic mecha- Predictive Markers nism underlying this observation remains to be elucidated. In addition, this observation requires treatment of all patients initially With the shift in systemic therapy for RCC to molecularly tar- and as a result does not spare ineffective therapy for patients who geted agents, looking at the molecular characteristics of tumors will not benefit.

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Systemic Therapy for metastatic RCC, although in practice many oncologists use bevacizumab monotherapy as the IFN likely adds some benefit, Although several active agents now exist for metastatic RCC (as but significantly more toxicity. Multiple attempts over many de- discussed subsequently), they are considered noncurative for cades to improve on the modest effects of IL-2 and IFN, including the majority of patients and thus require chronic therapy. Thus, combinations of cytokines, combinations with chemotherapy, and benefits must be weighed against the toxicity, time commitment, cytokine sequencing, have failed.249–252 and cost. There exists a subset of patients with metastatic RCC with low-volume slow-growing disease in which withholding sys- Investigational Immunotherapy temic therapy until radiographic progression has occurred may be a reasonable approach. Further investigation into this strategy is RCC has long been considered responsive to immune manipu- ongoing. lation due to the modest response to cytokines noted previously. Historically, progestational agents such as medroxyproges- Additional efforts are ongoing to expand the application of immu- terone acetate were investigated in metastatic RCC.232,233 These notherapy. Specifically, IMA901, a vaccine composed of multiple reports documented some tumor regression and symptom reduc- tumor-associated peptides, has been found to be safe and to induce tion, largely applied to a very advanced, symptomatic population antitumor immunity in patients with metastatic RCC.253 Based in of RCC patients. Multicenter randomized trials demonstrate uni- part on data that sunitinib may favorably modulate the immune formly low response rates.234 In the current era, progestational repertoire,254 a phase 3 trial that randomized patients with meta- agents may be useful for symptom palliation, but do not appear to static RCC to sunitinib alone or sunitinib in combination with have any significant antitumor effects. IMA901 has completed accrual. In addition, an autologous den- Due to success in other solid tumors, chemotherapy for ad- dritic cell vaccine derived from primary patient tumor-specific vanced RCC has been extensively studied during the last four antigens demonstrated favorable results in phase 2 studies and is decades. A summary of clinical trials from 1983 to 1993 noted a currently in phase 3 testing.255 6% overall response rate in 4,093 patients with advanced RCC.235 In addition, checkpoint inhibitors, agents that stimulate an- Another report of 51 published phase 2 clinical trials (n = 1,347) titumor immunity by releasing the natural “brake” of the im- involving 33 chemotherapeutic agents noted an overall response mune system, have entered clinical testing in metastatic RCC rate of 5.5%.236 Combinations of 5-fluorouracial and analogues with promising initial results.256,257 Nivolumab, which binds to with gemcitabine have produced modestly higher response rates, programmed death receptor 1 is one such checkpoint inhibitor. on the order of 10% to 15%.237,238 Similarly, the addition of chemo- A phase I expansion RCC cohort reported a 30% ORR associated therapy to cytokine regimens has not resulted in significant benefit with durable responses even after therapy was stopped. Additional over cytokines alone when investigated in phase 3 trials.239,240 A phase II trials and a phase III registration trial are ongoing. In report of 18 metastatic RCC patients with sarcomatoid histologic addition, several anti–programmed death receptor 1 agents and features and/or rapidly progressing disease treated with doxorubi- OF ONCOLOGY PRACTICE antibodies against its ligand, PD-L1, are being investigated in cin and gemcitabine noted a 28% objective response rate (ORR), metastatic RCC. potentially identifying a subset of patients with RCC where che- 241 motherapy may have some utility. Overall, chemotherapy cur- Vascular Endothelial Growth Factor–Targeted rently has little to no role in the treatment of metastatic RCC pending further study of novel chemotherapeutic agents or com- Therapy binations, or perhaps through additional patient selection efforts. RCC presents a unique clinical setting for the application of antiangiogenic approaches. Through mutations in the VHL gene and/or other genetic events that result in the deregulated expres- Immunotherapy sion of the hypoxia inducible transcription factors, HIF-1α and/ or HIF-2α, a large cohort of hypoxia-responsive genes is induced, IL-2 and IFN had been the standard of care for patients with meta- including VEGF as one of the classic transcriptional targets.258 static RCC until the development of targeted therapy. These agents There is a direct link between VHL mutation and upregulation are nonspecific cytokines that presumably have an antitumor ef- of angiogenesis-promoting proteins, including VEGF and platelet- fect through stimulation of an antitumor immune response that is derived growth factor (PDGF). Thus, increased expression of these not adequate in the patient prior to therapy. Specific insights into proteins and the consequences of that increased expression are mechanism(s) of action are still lacking after decades of use and fur- central events in the development of most RCC tumors. VEGF is ther clinical and/or molecular markers to predict benefit are lacking. the major factor responsible for tumor angiogenesis. Several treat- Bolus high-dose intravenous IL-2 treatment, as initially de- ment strategies have thus been investigated in metastatic RCC to scribed many years ago, leads to sustained responses in a small 242 block components of the angiogenic signaling pathway compo- subset of patients. However, later randomizied trials failed to nents, such as VEGF. demonstrate a benefit over lower-dose cytokine regimens for the entire cohort, likely reflecting the small number of patients ben- Sunitinib efitting.243,244 The durable complete remissions that occur in 5% to 7% of patients, however, served as the basis for US Food and Drug Sunitinib (Sutent, Pfizer Inc., New York, NY) is an oral drug with Administration (FDA) approval of high-dose IL-2 in the United in vitro and cellular inhibitory activity against several related pro- States in 1992.245–247 Thus, given the noncurative nature of tar- tein tyrosine kinase receptors, including PDGF-receptor-beta, geted therapy and considering only a small fraction of patients are stem cell factor receptor (KIT), and Fms-like tyrosine kinase-3 eligible for this toxic treatment, IL-2 remains a viable treatment (FLT-3), as well as VEGF receptors 1, 2, and 3.259,260 Sunitinib option for patients with ccRCC and a good performance status. was initially studied in metastatic RCC in two sequential phase 2 IFN (given only in low doses in RCC) has also been employed. trials in cytokine-refractory patients that demonstrated an ORR of While never approved by the FDA specifically for this indication, approximately 40% with a combined median PFS of 8.2 months two large randomized trials demonstrated that IFN improved OS (Table 63.8).261,262 The most common adverse events with suni- compared with medroxyprogesterone234 or vinblastine.248 IFN thus tinib are fatigue, diarrhea, mucositis, hand-foot syndrome, and was a community standard for metastatic RCC prior to targeted hypertension. A phase 3 randomized trial of first-line sunitinib therapy and served as the comparator arm in many trials. Single- versus IFN-alfa in 750 patients with metastatic ccRCC showed agent IFN is generally no longer used. As noted in the following, statistically significant improvements in ORR and PFS with IFN combined with bevacizumab is a currently approved regimen sunitinib compared with IFN. Median PFS as assessed by an 880 Practice of Oncology / Cancers of the Genitourinary System

TABLE 63.8 Summary of Target Agents in Metastatic Renal Cell Carcinoma

Treatment Response Rate Progression-Free Survival Overall Survival VEGF Receptor Inhibitors Sunitinib 30% to 47% 9.5 to 11 mo in treatment-naïve patients 29.3 mo in untreated patients 8.4 mo in cytokine refractory patients Pazopanib 30% 8.4 to 9.2 mo 28.4 mo in untreated patients (11.1 mo in treatment-naïve patients) Sorafenib 2% to 10% 5.7 to 9 mo in treatment-naïve patients 17.8 to 19.2 mo in treatment- 5.5 mo in treatment-refractory patients refractory patients Axitinib 19% 6.7 mo (second-line) 20.1 mo in treatment- refractory patients VEGF Ligand-Binding Agents Bevacizumab 10% to 13% as monotherapy 8.5 mo in treatment-naïve patients as 18.3 to 23.3 mo 26% to 31% in combination monotherapy with IFNA 8.5 to 10.2 mo in treatment-naïve patients in combination with IFNA 4.8 mo in cytokine-refractory patients mTOR-Inhibiting Agents Temsirolimus 7% to 9% 3.7 mo (vs. 1.9 mo for IFNA monotherapy; 10.9 mo (vs. 7.3 mo for IFNA; p = 0.0001) in treatment-naïve patients p = 0.008) 5.8 mo in treatment-refractory patients Everolimus 1% 4.9 mo (vs. 1.9 mo for placebo-treated 14.8 mo (vs. 14.4 mo for patients) in refractory patients placebo-treated patients; p = 0.177)

VEGF, vascular endothelial growth factor; IFNA, interferon-alfa; mTOR, mammalian target of rapamycin.

independent review was 11 months in the sunitinib arm versus p <0.0001) and in cytokine-pretreated patients (7.4 months versus 5 months in the IFN arm, and ORR was 31% versus 6%, respec- 4.2 months; p <0.001). tively (p <0.000001; see Table 63.8).263 Median OS was 26.4 Pazopanib has been further studied in a noninferiority study months for sunitinib versus 21.8 months for IFN (p = 0.051).264 compared to sunitinib in the front-line treatment of metastatic The OS data are a reflection of not only sunitinib activity, but RCC (COMPARZ study).265 Over 1,100 patients with previously several other active drugs that patients received upon progression, untreated ccRCC were randomized to either pazopanib or suni- resulting in notably prolonged median survival times compared to tinib (1:1) in a noninferiority design. Median PFS was 9.5 months historical controls. Sunitinib was approved by the FDA as mono- with sunitinib and 8.4 months with pazopanib, with a hazard ratio therapy for advanced RCC in January 2006 and remains an initial of 1.047 (95% CI = 0.898 to 1.220). The upper bound of the con- standard of care in metastatic RCC. fidence interval was< 1.25, satisfying the predefined boundary for noninferiority. OS was approximately 29 months in both arms. Pazopanib Certain toxicities were more common with sunitinib including fatigue and hand-foot syndrome, while pazopanib produced greater Pazopanib is an oral multitargeted tyrosine kinase inhibitor that hepatic abnormalities. This trial demonstrated that both sunitinib targets VEGF receptors 1 to 3, PDGF receptor, and c-kit. A phase and pazopanib are appropriate front-line treatment options in 2 study initially designed as a randomized discontinuation study metastatic RCC and that a differing toxicity profile may allow the was revised to an open-label study based on the response rate of a physician to tailor therapy to each individual patient. planned interim analysis. This study evaluated 255 patients with metastatic RCC who received pazopanib 800 mg once daily; 69% Sorafenib had no prior treatment and 31% had received one prior treatment. The overall response rate was 35%, the median PFS was 52 weeks, Sorafenib (Nexavar, Bayer Pharmaceuticals and Onyx, Leverku- and the median duration of response was 68 weeks. The main sen, Germany) is an oral multikinase inhibitor that inhibits adverse effects were diarrhea and fatigue, and the most common VEGF receptors 1 to 3, PDGF-receptor-beta, and the serine grade 3-4 side effect was hypertension. Alanine transaminase and threonine kinase Raf-1, which acts through the RAF/MEK/ERK aspartate transaminase elevation occurred in 54% of patients. In signaling pathway and plays a role in cellular proliferation and October 2009, the FDA approved pazopanib for the treatment of tumorigenesis.266,267 In an initial sorafenib trial, metastatic RCC metastatic RCC, based on the results of a phase 3 trial. This study patients (n = 202) were treated with 12 weeks of continuous oral evaluated 435 patients with advanced ccRCC with either no previ- sorafenib 400 mg bid and patients with tumor burden increase ous treatment or with one prior cytokine treatment. Patients were or decrease within 25% of baseline were randomized to placebo randomized (2:1) to receive pazopanib 800 mg daily or placebo. or to continuation of sorafenib. A PFS advantage of 24 versus 6 The response rate for patients treated with pazopanib was 30% and weeks (p = 0.0087) was demonstrated in the randomized cohort the median duration of response was 58.7 weeks. Median PFS was of 65 patients at 12 weeks postrandomization.268 A subsequent 905 9.2 months in the pazopanib group and 4.2 months in the placebo patient, placebo-controlled, randomized trial of sorafenib 400 mg group (HR = 0.46; p <0.0001; see Table 63.8). PFS was prolonged bid in treatment-refractory, metastatic RCC reported a PFS ad- in both treatment naïve patients (11.1 months versus 2.8 months; vantage in the sorafenib arm of 5.5 months versus 2.8 months for

tahir99 - UnitedVRG Chapter 63 Cancer of the Kidney 881 placebo (p <0.000001; see Table 63.8). A 2% RECIST-defined Mammalian Target of Rapamycin–Targeted ORR was seen in the sorafenib arm, but 74% of patients overall Therapy had some degree of tumor burden shrinkage thus accounting for the PFS benefit. The median OS was 19.3 months for patients in Temsirolimus the sorafenib group and 15.9 months for patients in the placebo group (HR = 0.77; 95% CI = 0.63 to 0.95; p = 0.02), which did Temsirolimus is an inhibitor of mTOR, a molecule implicated not reach prespecified statistical boundaries for significance.269 in multiple tumor-promoting intracellular signaling pathways, Common toxicity in the sorafenib trials has included dermato- including regulation of transcription factors involved in VEGF logic (hand-foot syndrome), fatigue, diarrhea, and hypertension. expression, such as HIF.280 A phase 2 trial in patients with treat- Sorafenib was approved by the FDA as monotherapy for advanced ment-refractory, metastatic RCC randomized 111 patients to tem- RCC in December 2005. A randomized phase 2 trial of sorafenib sirolimus at one of multiple dose levels (25 mg, 75 mg, or 250 mg versus IFN in untreated metastatic RCC failed to demonstrate intravenously weekly).281 The ORR was 7% with additional pa- a difference in median PFS between the two treatment arms.270 tients demonstrating minor responses (see Table 63.8). Retrospec- Sorafenib has thus assumed a small, salvage role in the treatment tive assignment of risk criteria to patients in this study identified a of metastatic RCC. poor-prognosis group with a median OS of 8.2 months compared to 4.9 months for historical IFN-treated patients.215 Loss of phos- Bevacizumab phatase and tensin homolog and/or activation of Akt (upstream regulators of the mTOR expression) may be more common in Bevacizumab (Avastin, Genentech, South San Francisco, CA) poor-risk patients and thereby potentially increase the relevance of is a monoclonal antibody that binds and neutralizes circulating mTOR-targeted therapy in this subgroup. VEGF protein.271 The activity of this agent in RCC was initially A subsequent randomized phase 3 trial was conducted in pa- identified by small randomized trials.272,273 Two phase 3 trials were tients with metastatic RCC (n = 626) and three or more adverse subsequently reported and led to FDA approval of bevacizumab risk features as defined by existing prognostic schema (see Table plus IFN for advanced RCC. One phase 3 trial randomized 649 63.7).211,215 Patients were randomized equally to receive IFN (18 untreated patients with metastatic RCC to treatment with IFN million units subcutaneously) three times a week, temsirolimus (Roferon, Roche, Basel, Switzerland) plus placebo infusion or 25 mg intravenously weekly, or temsirolimus 15 mg intravenously to IFN plus bevacizumab infusion 10 mg/kg every 2 weeks.274 A weekly and IFN (6 million units subcutaneously) three times significant advantage for bevacizumab plus IFN was observed for a week. The primary study endpoint was OS and the study was ORR (31% versus 13%, p <0.0001) and PFS (10.2 months ver- powered to compare each of the temsirolimus arms to the IFN sus 5.4 months, p <0.0001; see Table 63.8). A second multicenter arm. Both temsirolimus-containing arms demonstrated a PFS phase 3 trial, conducted in the United States and Canada through advantage versus IFN (3.7 months for each arm versus 1.9 months; the Cancer and Leukemia Group B, was nearly identical in de- p = 0.0001 for temsirolimus monotherapy and p = 0.0019 for tem- OF ONCOLOGY PRACTICE sign with the exception of lacking a placebo infusion and not re- sirolimus plus IFN). Patients treated with temsirolimus monother- quiring prior nephrectomy.275 In this trial, the median PFS was apy had a statistically longer survival than those treated with IFN 8.5 months in patients receiving bevacizumab plus IFN (95% alone (10.9 months versus 7.3 months, p = 0.0069). OS of patients CI = 7.5 to 9.7) versus 5.2 months (95% CI = 3.1 to 5.6) for IFN treated with IFN and temsirolimus + IFN were not statistically dif- monotherapy (p <0.0001; see Table 63.8). Also, among patients ferent (7.3 months versus 8.4 months, p = 0.6912). Even though with measurable disease, the ORR was higher in patients treated temsirolimus has demonstrated activity in poor-risk RCC, it is not with bevacizumab plus IFN (25.5%) than for IFN monotherapy clear that this agent has more activity than the VEGF-targeted (13.1%; p <0.0001). OS data are similar to the other agents with agents in this subset, as VEGF-targeted agents have shown activity, a numerical advantage in median survival not meeting statistical albeit in limited subsets, in poor-risk patients. significance, reflecting the large proportion of patents who receive subsequent active therapy. The contribution of IFN to the antitu- Everolimus mor effect of this regimen is unclear at present, although preliminary results indicate a longer PFS and higher response rate than Everolimus is an oral rapamycin analogue that inhibits mTOR. expected with bevacizumab monotherapy.272 Combination IFN A phase 3 study evaluated 410 patients previously treated with and bevacizumab therapy is more toxic than either as monother- sorafenib, sunitinib, or both who were randomized (2:1) to apy, notable for fatigue, anorexia, hypertension, and proteinuria. receive everolimus 10 mg once daily or placebo.282 PFS was Thus, the use of IFN with bevacizumab requires evaluation of the significantly longer in the everolimus group (HR= 0.30, 95% risk/benefit ratio for each patient. CI = 0.22 to 0.40; p <0.0001). Median PFS in the everolimus group was 4.9 months versus 1.9 months in the placebo group. Axitinib Partial response in the everolimus group occurred in 1% of the patients, and 63% (versus 32% in the placebo group) had disease Axitinib is a potent VEGF receptor family inhibitor studied in stabilization for at least 56 days. Most common adverse effects of several setting in metastatic RCC. Initial studies in cytokine- and everolimus were stomatitis, rash, fatigue, asthenia, and diarrhea. sorafenib-refractory patients demonstrated objective responses and Stomatitis, fatigue, infection, and pneumonitis were the most disease control, which prompted further development.276,277 The common grade 3/4 toxicities. On the basis of these results, everoli- phase 3 AXIS trial randomized 723 patients with metastatic RCC mus was approved for the treatment of metastatic RCC refractory (refractory to either sunitinib, cytokines, bevacizumab, or temsiro- to sunitinib and/or sorafenib. limus) to axitinib or sorafenib.278 The median PFS was 6.7 months A recent trial (RECORD-3) randomized 471 patients with pre- for axitinib versus 4.7 months for sorafenib (HR for disease progres- viously untreated metastatic RCC to either sunitinib or everolimus, sion or death of 0.665 [95% CI = 0.544 to 0.812]; p <0.0001). with crossover at progression.283 This trial, reported to date only in ORR was 19.4% versus 9.4% with axitinib and sorafenib, respec- abstract form, demonstrated an advantage to sunitinib in response tively. This trial resulted in FDA approval of axitinib for previously rate (27% versus 8%), PFS (10.7 months versus 7.9 months), and treated metastatic RCC. A separate trial examined axitinib versus OS (32 months versus 22 months). In addition, all subsets exam- sorafenib in the front-line setting.279 Despite a numerical ad- ined (non–clear cell, clear cell, and prognostic groups) favored vantage for PFS for axitinib, this trial did not meet its stringent sunitinib. These data support the use of everolimus only in a re- predefined efficacy endpoint, and thus axitinib is largely used in fractory setting and confirm a hypothesis that VEGF targeting is a the second-line setting in RCC. superior initial strategy for RCC therapy. 882 Practice of Oncology / Cancers of the Genitourinary System

Second-Line Therapy standard of care is an empiric sequence of targeted therapy monotherapy, notwithstanding the select patient who initially receives As noted previously, axitinib has been studied and FDA-approved high-dose IL-2. as second-line therapy in metastatic RCC with a PFS advantage over sorafenib. Still debated is the role of everolimus versus a VEGF agent in this setting. The INTORSECT trial randomized CONCLUSION AND FUTURE DIRECTIONS patients with metastatic RCC refractory to prior sunitinib to receive either temsirolimus or sorafenib.284 Although there was no The last 20 years have seen a tremendous increase in our under- significant difference in PFS (approximately 4 months in both standing of the tumor biology of the heterogeneous tumors within arms), an OS advantage to sorafenib was observed. These data the family of renal cancers. Insights beginning with the clinical lend support to the hypothesis that continued VEGF targeting observation of the hypervascularity of these tumors, continuing is of benefit in metastatic RCC, although no PFS advantage was with rigorous scientific investigation of familial cases of RCC, demonstrated and the mTOR inhibitor used in this trial had not and culminating in the development of treatments based on the been specifically shown to have benefits in this setting. VEGF pathway, have made the last decade a rich period of expansion in treatment options for RCC. With increasing availability of next generation sequencing, the potential for subsequent discov- Current Status of Systemic Therapy in eries to advance our understanding of and therapies for this often Metastatic Renal Cell Carcinoma lethal malignancy remains considerable. Through multidisciplinary explorations of these fascinating neoplasms, renal cancer Of note, several trials have been conducted attempting to com- can continue to pace oncologic discoveries for the next 20 years bine the targeted therapies discussed previously. None have dem- as well. onstrated an advantage over monotherapy, in large part due to excessive toxicity in the combination arms.285,286 Sunitinib and pazopanib are the most commonly used front-line agents based in ACKNOWLEDGMENTS large part on the COMPARZ efficacy data as well as their tolerability and oral formulation. There is no proven sequence of agents or The authors would like to thank Sabrina Noyes for administrative ability to predict response to any given agent, and thus the current support and technical editing.

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tahir99 - UnitedVRG Molecular Biology of 64 Bladder Cancer

Margaret A. Knowles and Carolyn D. Hurst

INTRODUCTION tumors, are negative regulators of FGFR3 expression.7 Transcrip- tional regulation by the p53 family member p63 has also been dem- There has been rapid progress in elucidating the molecular changes onstrated.8 In cultured normal human urothelial cells (NHUC), that underlie bladder cancer development. A wealth of data is now expression of mutant FGFR3 leads to activation of the RAS-MAPK available that identifies several critical drivers of the malignant uro- pathway and PLCγ, leading to overgrowth of cells at confluence,9 thelial phenotype, some of which have clear potential for therapeu- and suggesting a possible contribution of FGFR3 activation to uro- tic targeting. Most studies have focused on urothelial carcinomas thelial hyperplasia in vivo. An alternative mechanism of FGFR3 (UC), which comprise the majority (>90%) of tumors diagnosed in activation in a subset of cases (2% to 5%) is chromosomal transloca- the Western world. This chapter will provide an overview of somatic tion to generate a fusion protein. All FGFR3 fusions identified to molecular features of UC identified by genomic, epigenomic, and date show loss of the final exon of FGFR3 and fusion in-frame to expression profiling. There is also much information about germ- TACC3 (transforming acid coiled-coil containing protein 3), or in line variants that confer increased risk of UC development and the one case to BAIAP2L1 (BAI1-associated protein 2-like 1) also known reader is referred to recent reviews on this topic.1,2 as IRTKS (insulin receptor tyrosine-kinase substrate).10 It is not yet At diagnosis, approximately 60% of UCs are noninvasive clear whether this activation mechanism is related to tumor grade or (stage Ta) papillary lesions. These commonly recur, but progression stage. These fusion proteins are highly activated and transforming to muscle invasion is infrequent (10% to 15%) and prognosis is good. oncogenes. FGF1 and FGF2 are expressed in UC tissues and cell In contrast, tumors that are muscle invasive at diagnosis (≥T2) have lines,11,12 FGF2 is detected in the urine of patients with bladder can- poor prognosis (<50% survival at 5 years). Stage T1 tumors, which cer,13 and expression has been detected in the urothelial stroma.14 have penetrated the epithelial basement membrane but not invaded Thus, it is also likely that both autocrine and paracrine FGF produc- OF ONCOLOGY PRACTICE muscle, represent a clinically challenging and molecularly hetero- tion contributes to FGFR3 activation in UC, particularly in those geneous group with features related to each of the two major groups. tumors with expression of wild-type protein (Fig. 64.1B). The distinction of the two major groups is supported by a wealth of Activation of the RAS-MAPK pathway in Ta tumors may also be molecular information, and a “two-pathway” model for UC patho- achieved by mutation of one of the RAS genes (most commonly genesis has long dominated thinking about this cancer type and its HRAS or KRAS2), and this is mutually exclusive with FGFR3 clinical management. Many genomic alterations and expression of mutation.15 More than 80% of noninvasive bladder tumors are specific genes relate directly to these groups and will be discussed in predicted to have RAS-MAPK pathway activation via these mecha- this context here. Global expression and epigenetic alterations show nisms (Fig. 64.2A). Compatible with this, urothelial expression of less direct relationships and will be discussed together. Importantly, an activated Ras transgene in mice leads to hyperplasia and papil- recent molecular information provides strong evidence for multi- lary tumors,16 suggesting an important role for activation of the ple molecular subgroups that are independent of tumor grade and RAS-MAPK pathway in the generation of urothelial hyperplasia. stage. This new molecular classification, which shows great promise In NMI UC, FGFR3 mutation is associated with favorable of clinical relevance, is described in a separate section. outcome.17–19 High FGFR3 expression, normal staining pattern for CK20, and low proliferative index in papillary urothelial neoplasms of low malignant potential 20 is reported to identify tumors KEY MOLECULAR ALTERATIONS IN STAGE that do not recur.21 Ta UROTHELIAL CARCINOMA FGFR3 is considered a good therapeutic target in superficial UC, though early clinical application is most likely in muscle invasive Low-grade stage Ta papillary UC (“superficial” UC) are genomi- rather than superficial UC (see the following). Several studies indi- cally stable, often with near-diploid karyotype. Common features cate that inhibition of mutant FGFR3 by knockdown or inhibition are activation of FGFR1, FGFR3, PIK3CA, and CCND1 genes by using small molecules or antibodies has a profound effect on UC cell mutation or upregulated expression and mutational inactivation of phenotype, including inhibition of xenograft growth in vivo.22 CDKN2A, STAG2, and TSC1. The most common event recorded Upregulated expression of the related receptor FGFR1 is also to date is mutation of the promoter region of telomerase reverse found in Ta tumors.23 No mutations have been detected, and there transcriptase (TERT). is infrequent gene amplification.24 Ectopic expression of FGFR1 in NHUC in the presence of FGF2 ligand, activates the RAS-MAPK γ 23 FGF Receptors pathway and PLC , and promotes cell survival. Currently, there is no information on the prognostic significance of these alterations. Activating point mutations in FGF receptor 3 (FGFR3) are present in ≥ 70% of cases.3 These are in hot-spot codons in exons 7, 10, and PIK3CA 15 (Fig. 64.1A) and are all predicted to constitutively activate the receptor.4 Mutations are also found in urothelial papilloma, a likely The phosphatidylinositol-3 kinase (PI3K) pathway plays a pivotal precursor of superficial UC.5 Increased expression of mutant FGFR3 role in signaling from receptor tyrosine kinases (Fig. 64.2A). Activat- is common in these tumors.6 MicroRNAs (miRNAs) miR-99a/100, ing mutations of the p110α catalytic subunit (PIK3CA) are found which are commonly downregulated in non–muscle-invasive (NMI) in UC, most commonly in low-grade, stage Ta tumors (∼25%).25–28 885