Stent Placement As a Bridge to Surgery in Malignant Biliary Obstruction (Pancreatic Cancer, Distal Bile Duct Cancer, and Hilar Tumors)

Gastrointest Interv 2015; -:1–6

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Gastrointestinal Intervention

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Invited Review Article Stent placement as a bridge to surgery in malignant biliary obstruction (pancreatic cancer, distal bile duct cancer, and hilar tumors)

Mario Rodarte-Shade, Michel Kahaleh* abstract

Preoperative biliary drainage (PBD) has been a matter of controversy for years. It was initially aimed to improve the clinical status of patients with malignant obstructive jaundice prior to surgery. However, its efﬁcacy and safety have not been proven by randomized controlled trials. Most drawbacks of PBD are related to the increase in procedure-related adverse events and inappropriate biliary decompression. Current trends in PBD show that using self- expanding metallic stents (SEMSs) may reduce the high incidence of stent-related complications with improved outcomes. The aim of this study was to review the current literature regarding PBD in patients with resectable distal pancreaticobiliary and hilar tumors. Copyright Ó 2015, Society of Gastrointestinal Intervention. Published by Elsevier. All rights reserved.

Keywords: distal bile duct cancer, hilar tumor, malignant biliary obstruction, pancreatic cancer, preoperative biliary drainage

Introduction review the existing literature concerning the use of PBD in patients with resectable distal pancreaticobiliary malignancies. Preopera- Malignant biliary obstruction encompasses a group of neo- tive biliary drainage in hilar tumor is also discussed separately. plasms that compromise bile duct flow and clinically presents with obstructive jaundice. Obstruction can be anatomically classified as Pathophysiology of biliary obstruction “distal” or “proximal.” Proximal bile duct obstruction refers to hilar bile duct cholangiocarcinomas (i.e., Klatskin tumors), whereas Biliary obstruction and cholestasis has several deleterious distal bile duct obstruction refers to periampullary tumors. Peri- effects on patient homeostasis. Most evidence comes from exper- ampullary tumors are defined as neoplasms arising from the head imental studies in animals that received bile duct ligation. Gut of the pancreas, the distal bile duct, the ampulla of Vater, or the functions are severely impaired in different ways. Jaundiced rats second portion of the duodenum. Because of the broad range of indicate that intestinal barrier function is compromised.7 Such tumors, pancreatic cancer by far remains the most common ma- impairment has been related to a decreased number and function lignancy in Western countries. During 2014 in the United States, of gut mucosal T lymphocytes,8,9 decreased Kupffer cell function,10 46,420 patients were expected to be diagnosed with pancreatic increased intestinal permeability,11 impaired cell-mediated im- cancer. It is also the fourth most common cause of cancer-related munity,12 impaired reticuloendothelial function,13 and altered death among men (after lung cancer, prostate cancer, and colo- mucosal immunity.14 In addition, these gut barrier dysfunctions rectal cancer) and among women (after lung cancer, breast cancer, have been associated with significant bacterial translocation that and colorectal cancer).1 At the time of diagnosis, approximately may be related to endotoxemia that adversely affects patients with only 20% of patients can receive curative surgery.2,3 Hence, most biliary obstruction.11,15 Other experimental studies in animals and patients will require palliative decompression. clinical observations in jaundiced patients have demonstrated a Preoperative biliary drainage (PBD) is an old concept that was high concentration of tumor necrosis factor (TNF) and interleukin- first described in 1935 by Allen O. Whipple.4 Preoperative biliary 6, which may also contribute to the high morbidity rate of jaun- drainage emerged as a treatment to counteract the deleterious ef- diced patients.11,16 In addition to these experimental observations, fects of biliary obstruction. Literature suggests that performing obstructive jaundice has been associated with deleterious effects – surgical resection (i.e., pancreatoduodenectomy) in the setting of on the cardiovascular system and on renal function.17 19 Other hyperbilirubinemia is associated with higher perioperative mor- detrimental consequences of cholestasis include direct hepatic tality.5,6 However, conflicting data has been published regarding injury with altered hepatic protein synthesis20,21 that, in conjunc- the efficacy and safety of routine PBD. The aim of this article was to tion with deficient vitamin K absorption, produce coagulation

Division of Gastroenterology and Hepatology, Weill Cornell Medical College, New York, NY, USA Received 13 November 2014; Revised 5 February 2015; Accepted 7 February 2015 * Corresponding author. Division of Gastroenterology and Hepatology, Weill Cornell Medical College, 1305 York Avenue, 4th Floor, New York, NY 10021, USA. E-mail address: [email protected] (M. Kahaleh).

Table 1 The Adverse Effects of Biliary Obstruction reviews of prospectively collected consecutive series at major – pancreaticobiliary centers.34 39 Research has found that PBD in- Impaired intestinal barrier function creases the risk of positive intraoperative bile cultures, which also Decreased number and function of gut mucosal T lymphocytes Decreased Kupffer cell function has been associated with postoperative infectious complications 34 Increased intestinal permeability and a similar microorganism profile. Experience with 240 con- Impaired cell-mediated immunity secutives cases of pancreatoduodenectomy performed at the Me- Impaired reticuloendothelial function morial Sloan Kettering Cancer Center (New York, NY, USA) revealed Altered mucosal immunity Bacterial translocation that PBD (performed in 175 patients) was associated with a high rate Endotoxemia (high TNF and IL-6 levels) of complications, infectious complications, intra-abdominal ab- Cardiovascular dysfunction scess, and postoperative death.35 A subsequent study from the same Renal dysfunction group, which involved 340 consecutive patients who underwent Direct hepatic injury pancreatoduodenectomy, showed that PBD was associated with a Coagulation abnormalities stent-related complication rate of 23% and a two-fold increase in IL-6, interleukin-6; TNF, tumor necrosis factor. postpancreatectomy infectious complications.36 A retrospective analysis of 567 patients who underwent pancreatoduodenectomy at the John Hopkins University School of Medicine (Baltimore, MD, abnormalities.22 Animal models have demonstrated most benefits USA) found that 408 (72%) of patients underwent PBD. The authors of PBD; however, the clinical benefits of PBD have not been clearly of this analysis found that preoperative biliary stenting did not in- established. Table 1 lists the adverse effects of biliary obstruction, crease the overall complication rate or mortality rate in patients based on animal models and clinical observations. who underwent pancreatoduodenectomy; however, stenting did appear to increase the rate of pancreatic fistula, wound infection, Preoperative biliary drainage versus early surgery and bile contamination.37 Another research group found that PBD was associated with increased operative time, intraoperative blood Routine PBD in patients with pancreaticobiliary malignancies loss, and higher incidence of wound infection; however, it did not has been a matter of controversy for years. Early studies primarily increase major morbidity and mortality.38 A group at the University included patients who underwent percutaneous biliary drainage. of Texas MD Anderson Cancer Center (Houston, TX, USA) evaluated These studies were mostly represented by retrospective and small perioperative morbidity and mortality in 300 consecutive patients case series with methodological flaws and contradictory results. who underwent pancreatoduodenectomy.39 The group found that Percutaneous transhepatic biliary decompression was initially PBD (performed in 172 patients) did increase the risk of post- described as a safe and potentially helpful procedure that allowed operative wound infection; however, there was no increase in the normalization of hepatic function and theoretically resulted in a risk of major postoperative complications or death. lower operative morbidity in treated patients than in jaundiced Several recent meta-analyses have been published regarding the – patients.23 Some studies also report that PBD is associated with controversy of PBD.40 45 Major drawbacks of these meta-analyses – reduced mortality, less morbidity, and shorter hospital stays.24 27 are the inclusion of retrospective series, methodological flaws, By contrast, further early trials showed that routine PBD by and the inclusion of patients who underwent percutaneous PBD or percutaneous methods did not offer any advantage in comparison endoscopic PBD. Table 2 shows the results of the most recent meta- to surgery without drainage.28 Furthermore, some publications analyses. report that patients who undergo preoperative percutaneous transhepatic biliary drainage have an increased rate of complica- DRainage vs OPeration (DROP-trial) tions resulting from the procedure and do not benefit from preoperative drainage.29 The preoperative percutaneous biliary A recent multicenter controlled trial randomized patients with drainage was also associated with increased hospital cost related to resectable cancer of the pancreatic head to undergo PBD for 4–6 the procedure and without any clear benefit in operative risk.30 weeks, followed by surgery, or to undergo surgery alone within 1 More recent publications include a greater number of patients week after diagnosis.46,47 This Dutch study enrolled 202 patients. It who underwent internal drainage by endoscopic retrograde chol- was conceived to compare the outcome of both strategies. The angiopancreatography (ERCP), and report that patients who un- primary outcome studied in the trial was the rate of serious com- derwent PBD did not have any difference in outcomes in comparison plications. The rate of overall serious complications were signifi- – to patients who went directly to surgery.31 33 A retrospective cantly higher in patients who underwent PBD (74% vs. 39%, analysis of 257 patients who underwent pancreatoduodenectomy P < 0.001). However, there was not a significantly increased rate of showed that a subgroup of 99 patients who had PBD did not have surgery-related complications (47% vs. 37%, P ¼ 0.14). In addition, any difference in morbidity, infectious complications, reoperation the mortality and length of stay did not differ between the two rate, mortality, or long-term survival.31 Another retrospective groups. Based on these results, the authors concluded that routine cohort reported the outcomes of 311 patients who were submitted PBD in patients undergoing surgery for pancreatic cancer increases to pancreatoduodenectomy.32 Of these, 232 patients received pre- the rate of serious complications. operative internal biliary drainage. They were compared to the Despite the adequate methodology used in this study, there are patients who underwent immediate surgery (n ¼ 58). The authors some major drawbacks that need to be considered and have been found that PBD did not influence the incidence of postoperative previously noted.48 The DROP-trial, which included low-volume complications. A retrospective review of 184 patients of 241 ERCP centers, reports a high number of serious complications in consecutive patients who underwent surgery showed no significant the PBD group that were mostly related to the drainage procedure. incidence of postoperative complications between patients who Endoscopic retrograde cholangiopancreatography is a technically had preoperative drainage and patients who did not.33 demanding and potentially high-risk procedure that needs to be Several studies have not associated PBD with an increased rate of performed in tertiary centers by experienced therapeutic endo- complications; however, there are other authors with contradictory scopists. In the best scenario, there is a consistently expected failure results that claim an increased risk of adverse eventsdprimarily, rate of up to 10%.49 However, the DROP-trial shows a failure rate of infectious complications. Most results come from retrospective 25% in patients who subsequently required a second drainage

attempt with all potential procedure-derived complications. Furthermore, most serious complications in the PBD group were stent-related (e.g., cholangitis, stent occlusion, and need of stent exchange). As other authors have reported,48 the high rate of stent-related complications can be attributed to the use of small plastic stents. There is increasing evidence that self-expanding metallic stents (SEMSs) are superior in durability, patency, recurrent biliary obstruction, and reintervention.50

Indications for PBD ts ﬁ Routine PBD has been a matter of controversy, although there are some clinical scenarios in which patients with resectable distal effect of PBD rate of bile cultures positivethe for probability bacteria of and wound infection mortality and morbidity any bene the postoperative mortality and complications of malignant obstructive jaundice with similar mortality but hasserious increased morbidity in comparison to no PBD 51 - There is no evidence of a positive or adverse - Preoperative biliary drainage increases the - No evidence that PBD directly increases - Preoperative biliary drainage does not offer - Most adverse events are PBD-related - Preoperative biliary drainage does not reduce - Preoperative biliary drainage is associated pancreaticobiliary tumors need to undergo biliary drainage. Un- less biliary cannulation cannot be achieved, endoscopic biliary drainage is always the preferred approach.52 Endoscopic biliary drainage through endoscopic retrograde cholangiopancreatography provides an internal drainage that avoids external drains, percutaneous transhepatic puncture (i.e., the risk of bleeding or bile leak), and the risk of tumor seeding at the puncture site. Tumor- associated cholangitis is an absolute indication for intervention and should be approached as a medical emergency that requires prompt biliary decompression and subsequent stent placement. Indications for PBD are shown in Table 3 and are discussed later.

Delayed surgery

The process by which a patient with malignant biliary obstruction goes can be long and complex because of logistics, health care services, waiting lists, referrals, and an extensive diagnostic protocol. Patients are usually seen at primary or secondary health care services where the initial evaluation with general laboratory and imaging are performed. The patient eventually is sent to a tertiary referral center with a clinical question of or diagnosis of pancreaticobiliary malignancy. The treatment of patients at high- volume referral centers is of major importance because expert advanced care at these institutions can achieve better outcomes two groups. surgery or delayed gastric emptying 53 - No difference in- the death The rate complication rate- was adversely Preoperative affected biliary by drainage PBD - was associated No with difference longer in hospital postoperative stays complications and mortality between the - Preoperative biliary drainage- had no Positive effect bile on culture mortality negatively and impacted morbidity mortality and morbidity after - The wound infection prevalence was higher in patients- with Serious PBD morbidity was- higher in No the difference PBD in group the length of the hospital stay when treating patients with pancreaticobiliary malignancies. Further workup may include other time-consuming imaging studies such as computed tomography (CT; for staging or pancreatic

) Resultsimaging protocol), magnetic Conclusion resonance imagining (MRI), and n endoscopic ultrasound. A pathologic diagnosis is not absolutely required before surgery; however, patients can undergo different biopsy protocols that may include CT-guided ﬁne-needle aspiration ﬁ 302 2853 749 (radical surgery) 1728 (radical and palliative surgery) 5133 - Preoperative biliary drainage increased the wound and bile infection rates biopsy, endoscopic ultrasound-guided ne-needle aspiration, ERCP-guided biopsy, ductal brushings, cholangioscopy-guided biopsy, or laparoscopic biopsy. Patients will eventually be seen by a multidisciplinary team that specializes in cancer management, and will subsequently undergo different consultations (e.g., medical

Table 3 Indications for Preoperative Biliary Drainage

Distal pancreaticobiliary malignancies Cholangitis Neoadjuvant treatment 5 RCT 18 comparative cohort studies 2 RCT 18 retrospective studies 36 studies (which include 6 RCTs and 3 meta-analysis studies) 14 retrospective cohort studies 18266 RCT - No difference in mortality, pancreatic/bile leak, abdominal abscess, 520Severe pruritus - No difference in mortality Delayed surgery

44,45 Routine preoperative biliary drainage (controversial)

40 Hilar tumors 42

41 Cholangitis

43 NeoVadjuvant treatment Severe pruritus Delayed surgery Right hepatectomy Portal vein embolization 2010, Garcea et al 2011, Qiu et al Year, Author Studies included Patients ( 2002, Sewnath et al 2002, Saleh et al 2012, 2013, Fang et al Routine preoperative biliary drainage (controversial) Table 2 Meta-analysis Comparing Preoperative Biliary Drainage and no Preoperative Biliary Drainage PBD, preoperative biliary drainage; RCT, randomized controlled trial.

Please cite this article in press as: Rodarte-Shade M, Kahaleh M, Stent placement as a bridge to surgery in malignant biliary obstruction (pancreatic cancer, distal bile duct cancer, and hilar tumors), Gastrointestinal Intervention (2015), http://dx.doi.org/10.1016/j.gii.2015.02.003 4 Gastrointestinal Intervention 2015 -(-), 1–6 oncologist, pancreaticobiliary surgeon, radiotherapy, and preoper- (n ¼ 11); endoscopic reintervention was required in 39% of the ative assessment). Depending on the clinical conditions, patients plastic stent group awaiting surgery, but no reintervention was will also need to undergo an extensive preoperative assessment required in the SEMS group.64 Furthermore, a multicenter ran- (e.g., cardiovascular/pulmonary clearance). Most patients will need domized controlled trial found that SEMS had an longer patency to improve their clinical condition prior to surgery (e.g., nutritional than plastic stents.65 This study was performed in palliative pa- status, coagulopathy, and treatment of comorbidities). Waiting lists tients. However, the time to stent failure was 385 52.5 days in the and other administrative issues may preclude prompt surgery. All of SEMS patients and 153.3 19.8 days in the plastic stent patients.65 these factors should be considered when deciding to perform PBD. Another advantage of PBD with SEMS is that no further interven- An expected delay in definitive treatment with surgery should be tion is required for patients who have unresectable disease (20% of an indication to perform PBD. the patients underwent curative-intent surgery).66 With regard to the individual costs of each stent type (i.e., plastic Neoadjuvant therapy vs. SEMS), the SEMS has a higher cost. However, several studies have assessed the cost-effective strategy of using SEMS in distal Most pancreaticobiliary malignancies are not resectable at the biliary obstruction without regard to surgical resectability. A study moment of diagnosis. However, there is increasing evidence that from our group reviewed 101 patients with biliary obstruction who neoadjuvant chemoradiation may be useful in patients with underwent SEMS placement.67 A model was developed to compare borderline or unresectable pancreatic adenocarcinoma (i.e., locally the costs of intervention with SEMS and plastic stents (e.g., poly- advanced disease). Several meta-analyses show that up to one- ethylene and double-layer stents). Because of the high rate of third of unresectable locally advanced tumors can be ultimately reintervention with plastic stents, the routine use of SEMS resulted resected after neoadjuvant treatment with comparable outcomes in a prolonged patency with less cost. Another study constructed a as patients with initially resectable tumors.54,55 Surgery can be Markov model to evaluate the cost and outcomes of four strategies delayed for several months when receiving preoperative chemo- regarding PBD: (1) an initial plastic stent, followed by a plastic radiation and in most instances, the administration of chemo- stent; (2) an initial plastic stent, followed by a SEMS; (3) an initial therapy requires normalization of liver function. Therefore, PBD is SEMS, followed by a plastic stent; and (4) SEMS, followed by a required in these patients prior to neoadjuvant treatment.56 SEMS. The authors concluded that an initial SEMS that was fol- A study evaluated the performance of plastic biliary stents in 49 lowed by SEMS (if needed) was the less expensive strategy when patients undergoing neoadjuvant chemoradiotherapy for pancre- approaching patients with pancreatic cancer and unknown surgical atic cancer.57 The median time from stent placement to surgery was status.68 Hence, the SEMS seems to be a promising option that 150 days (range, 71–227 days). The authors found that up to 55% of should be included in further randomized controlled trials to the patients required a repeat ERCP for stent dysfunction and ex- effectively assess the value of PBD. At this time, a multicenter change.57 Another prospective study assessed the efficacy and randomized trial comparing covered metal stents and plastic stents safety of SEMS in 55 patients with resectable or borderline for preoperative biliary decompression is under progress resectable pancreatic cancer receiving neoadjuvant therapy.56 This (ClinicalTrials.gov NCT01191814). study found that the mean time for neoadjuvant therapy before surgery was 104 days (range, 70–260 days) and that 88% of the Preoperative biliary drainage for hilar tumors SEMS remained patent at the end of the therapy. In the end, 49% of the patients underwent surgery and the presence of the SEMS did Tumors of the biliary confluence are also known as Klatskin not interfere with surgical resection. These results show that biliary tumors. As with distal pancreaticobiliary malignancies, obstructive drainage in patients undergoing neoadjuvant treatment should be jaundice is the presenting symptom; the only potential chance of durable to avoid repeat endoscopic procedures. It also suggests that long-term survival is by surgical resection. Hilar tumors deserve a the best stent for pancreaticobiliary malignancies is the SEMS separate discussion because to achieve complete surgical resection because of its high patency rate and low reintervention rate.58 most often requires bile duct and major liver resection (i.e., right or left hepatectomy). Performing liver resections in patients with Stent selection: Plastic versus metal obstructive jaundice can carry increased morbidity and mortality; thus, most major hepatobiliary centers usually offer patients PBD to Plastic stents have traditionally been used for temporary improve their clinical condition and outcomes.69 The value of PBD drainage in patients with potentially resectable pancreaticobiliary has been acknowledged as part of “preoperative liver optimization” malignancy. Plastic stents are inexpensive and can be easily placed in conjunction with portal vein embolization. These actions prevent endoscopically without sphincterotomy. The use of the SEMS in postoperative acute liver failure and improve postoperative out- surgical candidates was initially avoided because of the concern comes in patients with hilar tumors.70 that a metallic foreign body may preclude or have an impact on As with distal pancreaticobiliary malignancies, routine PBD for surgical resection.59 However, there is increasing evidence that hilar tumors is controversial. A recent systematic review of the short uncovered or fully covered SEMS can be safely placed in pa- literature included 10 studies with 442 patients who underwent – tients who will undergo surgery.60 63 routine PBD and 233 patients who did not have PBD. This meta- Self-expanding metallic stents represent a safe option in pa- analysis could not provide evidence of a clinical benefit of using tients undergoing PBD that may significantly decrease adverse routine PBD in obstructive jaundice secondary to hilar tumors.71 events such as stent dysfunction, cholangitis, and the need for However, there are some clinical scenarios in which PBD may be reintervention. However, most studies that claim a high rate of an acceptable approach. First, cholangitis is an absolute indication stent-related complications in PBD have used plastic stents.45,47 for PBD. Another indication for PBD includes patients who undergo Most endoscopic centers typically use 10-Fr plastic stents which right hepatectomy (for Bismuth type IIIA or IV hilar chol- offer an inside lumen diameter of 3.3 mm (0.131 inch). However, a angiocarcinoma). A recent European multicenter retrospective SEMS can provide an inside diameter of up to 10 mm (0.394 inch), analysis reviewed the outcomes of 366 patients with hilar chol- which is three times greater than the diameter of the plastic angiocarcinoma in whom 180 PBD procedures were performed.72,73 counterpart. A retrospective study compared the outcome of 29 The authors of this analysis found that PBD did not affect the overall patients who underwent PBD with plastic stents (n ¼ 18) or SEMS mortality in patients with hilar cholangiocarcinoma; however, PBD

Please cite this article in press as: Rodarte-Shade M, Kahaleh M, Stent placement as a bridge to surgery in malignant biliary obstruction (pancreatic cancer, distal bile duct cancer, and hilar tumors), Gastrointestinal Intervention (2015), http://dx.doi.org/10.1016/j.gii.2015.02.003 Mario Rodarte-Shade and Michel Kahaleh / Preoperative Biliary Drainage 5 was associated with a decreased mortality rate after right hepa- Conflicts of interest tectomy and an increased mortality rate after left hepatectomy. The data show that patients with PBD and hilar cholangiocarcinoma All authors declare no conflicts of interest. who underwent left hepatectomy had a higher rate of septic complications. By contrast, patients who underwent right hepatectomy had a lower rate of liver failure. These observations may be References related to the fact that the residual right liver in patients with left hepatectomy is larger than the smaller residual left liver after right 1. Siegel R, Ma J, Zou Z, Jemal A. 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