New Advances in the Management of Biliary Tract Cancer

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REVIEW ARTICLE

New advances in the management of biliary tract cancer

JOHN BRIDGEWATER1 & CHARLES IMBER2

1Oncology, Royal Free and University College Medical School, London & 2Surgery, University College Hospital, London, UK

Abstract Biliary tract cancers are uncommon malignancies arising from biliary epithelium intrahepatically (peripheral cholangiocarcinoma), in the extrahepatic bile duct, the gall bladder and the ampulla of Vater. Treatment has been challenging because of late presentation, complex surgery, complex biliary obstruction with jaundice and a paucity of high quality data on which to establish standard care. With improvements in imaging, biliary stenting, surgical management and the establishment of a national investigational programme we hope to define the modern management of biliary tract cancers and enable a platform for further research.

Key Words: biliary tract cancer, surgery, photodynamic therapy, chemotherapy, clinical trials

Introduction factors fall primarily into two groups: genetic and inflammatory (Table I). Biliary tract malignancy comprises adenocarcinomas The incidence of BTC in the western world is of biliary epithelium. These are geographically dis- primarily related to gallstones and primary sclerosing tinct, arising from biliary epithelium within hepatic cholangitis (PSC), whereas that in the Far East is substance, known as peripheral cholangiocarcinomas, related to infective causes. The incidence worldwide is at the hilum of the biliary tree, where they are known rising and appears to be independent of an associated as hilar cholangiocarcinomas, in the distal bile duct increase in PSC (Figure 2) [2]. The rise is not and in the gall bladder (gall bladder carcinoma, GBC) associated with any changes in the proportion of (Figure 1). It follows that biliary tract carcinomas are patients with unstaged cancer, localized cancer, his- anatomically and aetiologically distinct from pancrea- tological confirmation, tumour size or overall survival. tic or small bowel adenocarcinomas, although histori- These data suggest that this is a true increase related cally they are often managed similarly. to an environmental factor as yet unknown. The management of biliary tract cancer (BTC) has The presentation of BTC is dependent on the site changed dramatically in the last 20 years. The of the tumour. These symptoms would clearly be obstacles to progress have been the poor performance guided by predisposing factors such as PSC but in status of these patients at the time of presentation and general, intrahepatic tumours present with systemic the lack of conclusive histological diagnosis. Improve- and advanced features whereas biliary and distal ments in biliary drainage have rendered patients tumours present with obstructive jaundice (Table II) sufficiently fit to allow more sophisticated imaging [3]. and histological diagnosis followed by consideration of novel innovative treatments such as photodynamic Pathology therapy. Cholangiocarcinoma is often associated with inactiva- tion of tumour suppressor genes, for example, p53, Incidence and aetiology APC, Smad-4, bcl-2 and p16 [46]. Mutations in Biliary tract cancers are uncommon, the incidence oncogenes have also been described, for example, being approximately 1500 cases per year [1]. The risk K-ras,c-myc, c-erbB-2 and c-neu. These data place

Correspondence: John Bridgewater, Oncology, Royal Free and University College Medical School, 91 Riding House Street, London W1W 7BS. E-mail: [email protected]

(Received 13 December 2006; accepted 11 January 2007) ISSN 1365-182X print/ISSN 1477-2574 online # 2007 Taylor & Francis DOI: 10.1080/13651820701216216 New advances in the management of biliary tract cancer 105 Table II. Presentation of biliary tract cancer.

Symptom Intrahepatic Perihilar Distal Total (%) (n18) (n196) (n80) (n294)

Jaundice 0* 91 87 84 Abdominal 61$ 36 27 35 pain Weight loss 11 36 30 33 Fever 6 14 2 10

From Nakeeb et al. [3]. *pB0.01 vs others. $pB0.05 vs others.

Figure 1. Distribution of biliary tract malignancies. 1, peripheral Imaging cholangiocarcinoma; 2a and 2b, right and left hepatic ducts, respectively; 3, conﬂuence of right and left hepatic ducts (perihilar, Although the initial imaging investigation for patients Klatskin tumours); 4, common hepatic duct; 5, gall bladder; 6, with potential BTC is an ultrasound, patients nor- cystic duct; 7, common bile duct. mally proceed to magnetic resonance cholangiopan- creatography (MRCP) or endoscopic or percutaneous cholangio-pancreatography (ERCP-PTC). The latter Table I. Risk factors for biliary tract cancer. techniques allow for cytological sampling (positive in about 30%), allow stent insertion and in may cases . Age (65% greater than 65 years) will determine operability. Computed tomography . Smoking . Primary sclerosing cholangitis (PSC) (CT) and magnetic resonance (MR) scanning are . Chronic gallstones often used in parallel to define the intrahepatic extent . Bile duct adenoma and biliary papillomatosis of the tumour and there is little agreement as to a . Choledochal cysts (5% will transform) single optimal imaging investigation [7]. A key aim Liver flukes . of any imaging would be to identify appropriate . Chronic typhoid carriers lesions for biopsy and histological confirmation. Endoscopic ultrasound provides a useful guide for fine needle aspiration [8] and positron emission BTC in the family of gastrointestinal carcinomas tomography using fluorodeoxyglucose (FDG-PET) with a complex molecular profile and malignant can be helpful, particularly in upstaging potentially development. Molecular profiling may further define resectable disease [9]. the disposition of BTC among gastrointestinal carci- Hilar cholangiocarcinomas often infiltrate along nomas and provide insights into aetiology, mole- biliary epithelium, into lymphatics and perineu- cular pathogenesis and potential molecular interven- ral spaces making staging, particularly preoperative tions. staging, difficult. Endoscopic retrograde cholangio-

Figure 2. Incidence of biliary tract cancer. From Patel [2]. 106 J. Bridgewater & C. Imber

Figure 3. Imaging modalities. (a) Ultrasound. (b) Endoscopic cholangio-pancreatography (ERCP). (c) CT scan showing dilated biliary tree on the left side with parenchymal atrophy. (d) MRI scan demonstrating mass at the hilum. (e) PET scan demonstrating node and peritoneal disease. pancreatography (ERCP) and percutaneous trans- spread and can be used to calculate remnant tu- hepatic drainage (PTD) are recommended for the mour-free liver volumes for extended liver resections. added anatomical information they can provide. PTD MRCP offers a non-invasive method of defining the is better traversing tight malignant strictures [10]. extent of intrahepatic biliary involvement. Doppler Standard staging algorithms include CT of the ultrasound can define vascular involvement, although chest, abdomen and pelvis to exclude metastatic some clinicians still resort to invasive techniques such New advances in the management of biliary tract cancer 107 Table III. Procedures at surgery. Extended right hepatectomy (segments 48) with routine caudate lobe resection (segment 1) has been Site Operation shown to achieve the largest benefit with respect to resectability [12] (Table IV). Most tumours including Peripheral Lobectomy or extended lobectomy [13] with lymphadenectomy [14] Bismuth types IIIa/b (extension into right/left hepatic Hilar Type 1: Extrahepatic bile duct resection with Roux ducts) and IV (both ducts) can be managed with this loop reconstruction Types 24: Hepatectomy procedure, as long as adequate segment II/III remnant (extended with caudate lobe resection) and Roux volumes have been achieved with right portal vein loop reconstruction Distal Pylorus-preserving pancreatoduodenectomy embolization and biliary decompression of the left Any Transplantation [15] liver. This represents a major resection with an associated high postoperative morbidity/mortality rate for which patients need to have been assessed to as angioportography. CT has a low sensitivity for ensure adequate physiological reserve by an experi- peritoneal disease and therefore preoperative laparo- enced anaesthetist and they need to be well counselled scopy is usually included (Figure 3c). on the potential risk. Postoperative liver insufficiency can be avoided by ensuring remnant volumes of at Therapeutic options least 25% of the total volume and therefore portal vein embolization is a useful adjunct to cause atrophy of The current therapeutic options are biliary stenting, the ipsilateral resection side and hypertrophy of the surgery, radiotherapy (RT), photodynamic therapy planned remnant liver. (PDT) and chemotherapy. This review will not An understanding of hilar anatomy establishes consider biliary stenting. right-sided resections as preferable to left for two reasons. First, the confluence of the hepatic ducts lies posterior to the right side of the hepatoduodenal Surgery (Table III) ligament, increasing the potential for right hepatic Radical surgical resection offers the only chance of artery involvement. Second, the length of the extra- long-term survival in the treatment of BTC but hepatic left hepatic duct proximal to second-order segmental tributaries compared with the relatively unfortunatelyB20% of presenting patients are suita- short right duct increases the likelihood of an R0 ble for surgery. The aim of any proposed surgical resection if this is the intended anastomotic site. An procedure is to achieve complete tumour removal extended right resection is also a technically easier together with clear resection margins (R0) [11]. procedure with a natural transaction line provided by Peripheral cholangiocarcinoma can be adequately the falciform ligament. removed by segmental liver resection and lower third The 5-year survival varies between 29% and 100% bile duct cholangiocarcinoma (Figure 1) by pancrea- for those patients with completely resected disease, ticoduodenectomy. Hilar cholangiocarcinoma repre- suggesting that there is significant variability both in sents a formidable challenge both in terms of defining surgical technique and methodology of reporting preoperatively the extent of tumour extension within (Figures 4 and 5, Table V). Neuhaus and colleagues the intrahepatic biliary tree and as a technical [13] have achieved R0 5-year survival rates of 65%, challenge to achieve adequate surgical clearance. advocating more radical resections to increase the The anatomy of the biliary tract makes this a particular challenge. Table IV. Extent of resection of patients with hilar cholangiocarcinoma who underwent surgical resection.

198998 19992004 Extent of resection (n19) (n27)

Central resection only 1 0 Right hepatectomy 1 8 Right hepatectomy with extension 11 to segment 4 Right trisectionectomy 3 11 Left hepatectomy 5 5 Left hepatectomy with extension 02 to segment 4 Left trisectionectomy 1 0 Left lateral sectionectomy 1 0 Concomitant complete caudate 427 lobectomy Figure 4. Comparison of survival between resections with and Concomitant portal vein resection 3 8 without marginal involvement. A signiﬁcant difference was found (p0.0018). From Kitagawa et al. [16]. From Liu et al. [12]. 108 J. Bridgewater & C. Imber distant metastasis of 10-20% at presentation. Perito- neal and distant metastasis increases to 50% with serosal involvement of the gall bladder, thus careful preoperative evaluation of the extent of gall bladder involvement is critical. Those tumours limited to the mucosa of the gall bladder (T12 tumours) should be treated with cholecystectomy. Any more advanced tumours should be treated with aggressive lymphatic and nodule resection, although there are few randomized data to suggest this improves survival. There are only two major surgical series of GBC (Table VI). There is a single adjuvant study reporting an improvement in survival for GBC patients receiving Figure 5. Survival according to nodal status in 110 patients with a postoperative regimen of mitomycin C and fluor- hilar cholangiocarcinoma who underwent resection with regional ouracil; however, the numbers are small and the data and para-aortic lymphadenectomy (all deaths included). Group I, need confirmation with a more commonly accepted patients without lymph node metastasis; group II, patients with regimen [26]. The value of adjuvant therapy will be regional lymph node metastasis; group III, patients with para-aortic node metastasis. *Log-rank test. From Madariaga et al. [20]. examined in a UK National Cancer Research Institute study randomizing patients between surveillance and likelihood of complete tumour excision and negative adjuvant chemotherapy. margins. In certain circumstances therefore they have included removal of the portal vein confluence and Radiation therapy reconstruction of the left portal vein branch together with an extended right resection. This enables the All therapeutic modalities are hampered by poor data surgeon to employ a ‘no touch technique’, avoiding supporting their use and RT is no exception. The the tumour and its immediate surrounding tissue. published data describe series of patients (B40 in This has been achieved with acceptable perioperative number) treated with adjuvant [27] and palliative [28] mortality figures (8% 60-day death rate). Other radiation. The evidence would not support standard factors that independently affected outcome and use of either modality. There are similarly limited were significant on multivariate analysis included datasets describing the use of brachytherapy [29,30], perineural sheath infiltration, lymphangiosis carcino- intraoperative radiation [31] and chemoradiation matosa and histopathological grading. [32,33]. The conclusion is that RT should only be considered in the context of a clinical trial. Transplantation Outcomes are poorer after transplantation for cholan- Photodynamic therapy giocarcinoma than for any other diagnosis [10]. Single- Photodynamic therapy (PDT) is a two-stage treat- centre reports demonstrate that careful patient selec- ment. A photosensitizer is given systemically and tion of patients with early stage disease with the use of taken up preferentially by tumour. The exact mechan- neoadjuvant therapies including chemoradiotherapy ism of this preferential uptake is not completely may produce outcomes approaching those of other understood. Most photosensitizers are modified hae- diagnoses for which transplantation is used [15]. matoporphyrins that absorb light at a specified wavelength following tumour localization. Normal Gall Bladder Carcinoma tissue is unaffected as it does not take up photosensitizer nor is it subsequently exposed to light. The Surgery for GBC is guided by similar strategies. As for differential in terms of treatment effect is therefore cholangiocarcinoma, lymph node involvement is com- both biological and anatomical. There has been mon at approximately 50% and there is peritoneal and increasing use of PDT concurrent with improved photosensitizers. The technology required to deliver Table V. 5-year survival following surgery for cholangiocarcinoma. PDT is not sophisticated, requiring only standard ERCP equipment and a relatively cheap light source. 5-year Reference No. survival (%) R0 (%) Table VI. Outcome following surgery for GBC. Bartlett et al. 1996 [19] 23 58 100 Nakeeb et al. 1996 [3] 294 1144 5091 No. of 5-year Madariaga et al. 1998 [20] 62 835 2950 Study patients survival (%) R0 (%) Jarnagin et al. 2001 [21] 160 30 50 Huang et al. 2004 [22] 31 33 Tsukada et al. 1996 [24] 106 33 70 Rea et al. 2004 [23] 46 26 80 Puhalla et al. 2002 [25] 60 18 75 New advances in the management of biliary tract cancer 109 Table VII. Randomized studies using palliative chemotherapy in BTC.

Reference No. of patients Survival (months) Chemotherapy

Glimelius et al. [37] 37 6 vs 2.5 5FU/Etop vs BSC Takada et al. [38] 31 6 vs 3 5FU/Dox/MMC vs BSC Kornek et al. [39] 51 6.7 vs 9.3 MMC/Gem vs MMC/Capecitabine Ducreux et al. [40] 58 5 vs 8 5FU vs Cis/5FU Rao et al. [35] 50 12 vs 9 FELV vs ECF Valle et al. [41] 86 Gemcitabine vs Gemcitabine-Cis

BSC, best supportive care; Cis, cisplatin; Dox, doxorubicin; Etop, etoposide; 5-FU, 5-fluorouracil; MMC, mitomycin C.

There is a thermal cytotoxic effect resulting in tissue Palliative chemotherapy necrosis, the extent of which depends on the type of There is no standard palliative chemotherapy for BTC photosensitizer used [34]. as the data derive from small, mostly unrandomized The defining study on PDT in CCA was performed series treating mixed populations and reported in by Marian Ortner and colleagues [35]. Thirty-nine inconsistent formats. Many agents have been tried patients were randomized to receive stenting or and are reported extensively elsewhere [36] but most stenting with PDT. Many patients had advanced disease and a poor performance status that precluded studies have used fluoropyrimidine- or gemcitabine- based schedules. In a malignancy for which estimates standard palliation with chemotherapy. The study which originally planned to recruit 200 patients was of change in tumour size are challenging, overall terminated early by the data monitoring committee, survival in a randomized context is likely to be the as there was a dramatic difference in the observed most reliable endpoint to estimate efficacy. The low survival. PDT conferred a survival advantage of 10 incidence of BTC means that such trials are difficult to months (493 vs 98 days). In addition, there was a establish and to date studies have not been designed to group of 20 patients who received PDT despite being reliably report survival differences (Table VII). ineligible who had a similar survival to those treated All studies have accruedB60 patients and none with PDT, suggesting that this PDT effect was real. were powered for survival. In addition, the two The data have been criticized for the small numbers earlier studies by Glimelius et al. [37] and Takada as well as the poor survival of the control group (most et al. [38] included patients with pancreas cancer. were jaundiced and did not receive palliative treat- These data cannot recommend a standard palliative ments) and it is unlikely that clinical practice will be treatment for BTC. There are a plethora of non- changed by 20 patients. However, these are stimulat- randomized phase II studies that are difficult to ing data with impressive survival benefit achieved with interpret. This is highlighted by a dramatic difference minimum toxicity (mild photosentivity in 10%). In between the response rates (957%) yet a relatively addition, the patients have an improvement in their small difference in median survival (79 months) bilirubin, an improvement in their quality of life and [42]. However, it is clear that there is activity with reduction in subsequent life- threatening events, fluropyrimidine- and gemcitabine-based regimes and particularly cholangitis. The potential of PDT will the confirmation of their comparative benefit rather be examined in a UK National Cancer Research than the demonstration of the benefit of palliative Institute study randomizing patients between stenting chemotherapy over best supportive care should be alone and PDT with stenting. the aim of current research programmes.

Table VIII. Some recent studies in BTC.

Trial identifier Compounds Phase Details

SWOG-S0202 Gemcitabine and capecitabine II 57 patients Median survival 7 months CWRU-2299 Rebeccamycin analogue II 637 patients Indolocarbazole compounds Recruitment completed UCCRC-11045 BMS-247550 (Ixabepilone) II 2150 patients Novel epothilone Recruitment completed FCCC-03042 Bortezomib II 35 patients Proteasome inhibitor NYWCCC-NCI-6254 Triapine and gemcitabine II 78 patients Ribonucleotide reductase inhibitor SWS-SAKK-44/02 Capecitabine and gemcitabine II 1944 patients Recruitment completed NCCTG-N9943 Gemcitabine and pemetrexed II 85 patients OSI-904-202 OSI7904L versus 5-FU/LV RII 58 patients Liposome encapsulated Thymidylate synthase inhibitor Recruitment completed NCT00090025 XL119 (becatecarin) versus RIII 600 patients Topoisomerase II inhibitor Terminated early 5-fluorouracil (5-FU) because of 5-FU advantage 110 J. Bridgewater & C. Imber Table IX. The portfolio of National Cancer Research Institute Table IX describes the portfolio of National Cancer (UK) trials now available. Research Institute (UK) trials now available. All studies are powered for survival and this portfolio is Trial Acronym Numbers Phase Endpoint accompanied by a tissue collection module. It is Adjuvant BILCAP 300 3 Survival hoped that the studies will help define the twenty- chemotherapy first century management of BTC. Photodynamic PHOTOSTENT2 300 3 Survival therapy Palliative ABC-02 400 3 Survival chemotherapy References [1] http://www.statistics.gov.uk [2] Patel T. Increasing incidence and mortality of primary The largest study reported in abstract form in 2006 intrahepatic cholangiocarcinoma in the United States. Hepa- is that of Valle and colleagues [42]. Although there tology 2001;33:/ 1353/ 7. appeared to be an improvement in 6 month DFS [3] Nakeeb A, Pitt HA, Sohn TA, Coleman J, Abrams RA, (57% vs 48%) in favour of the combination of Piantadosi S, et al. Cholangiocarcinoma. A spectrum of gemcitabine and cisplatin vs gemcitabine, the study intrahepatic, perihilar, and distal tumors. Ann Surg 1996;/

224:463/ 73. was not powered to provide a statistically meaningful [4] Abraham SC, Lee JH, Hruban RH, Argani P, Furth EE, Wu result and this benefit may be offset by a significant TT. Molecular and immunohistochemical analysis of intra- increase in fatigue (29% vs 9%). Patients received ductal papillary neoplasms of the biliary tract. Hum Pathol more treatment on the combination arm (23.1 vs 15.0 2003;34:/ 902/ 10. weeks), suggesting that there were fewer disease- [5] Kang YK, Kim WH, Jang JJ.. Expression of G1-S modulators (p53, p16, p27, cyclin D1, Rb) and Smad4/Dpc4 in intrahe- related treatment delays and reasons for stopping on

patic cholangiocarcinoma. Hum Pathol 2002;33:/ 877/ 83. the combination arm. The UK National Cancer [6] Ito Y, Takeda T, Sasaki Y, Sakon M, Monden M, Yamada T, et Research Institute has expanded this study to provide al. Bcl-2 expression in cholangiocellular carcinoma is inversely a statistically meaningful survival endpoint with correlated with biologically aggressive phenotypes. Oncology quality of life assessments. This will provide the 2000;59:/ 63/ 7. [7] Huppertz A, Haraida S, Kraus A, Zech CJ, Scheidler J, Breuer largest dataset in BTC research and define the J, et al. Enhancement of focal liver lesions at gadoxetic acid- palliative chemotherapy for BTC. enhanced MR imaging: correlation with histopathologic ﬁnd-

ings and spiral CT initial observations. Radiology 2005;234:/ / 46878. Current studies in advanced BTC [8] Fritscher-Ravens A, Broering DC, Knoefel WT, Rogiers X, Swain P, Thonke F, et al. EUS-guided ﬁne-needle aspiration Table VIII details some recent studies in BTC. of suspected hilar cholangiocarcinoma in potentially operable Increasingly BTC are being recognized as a tumour patients with negative brush cytology. Am J Gastroenterol

type in which novel agents may be used. 2004;99:/ 45/ 51. [9] Anderson CD, Rice MH, Pinson CW, Chapman WC, Chari RS, Delbeke D. Fluorodeoxyglucose PET imaging in the Key questions in the management of BTC evaluation of gallbladder carcinoma and cholangiocarcinoma.

J Gastrointest Surg 2004;8:/ 90/ 7. The key questions for the management of BTC are as [10] Nimura Y, Kamiya J, Kondo S, Nagino M, Uesaka K, Oda K, follows: et al. Aggressive preoperative management and extended surgery for hilar cholangiocarcinoma: Nagoya experience. J

1. Is more aggressive surgery justified? The non- Hepatobiliary Pancreat Surg 2000;7:/ 155/ 62. [11] Nimura Y, Kamiya J, Nagino M, Kanai M, Uesaka K, Kondo randomized data suggest that some patients are S, et al. Aggressive surgical treatment of hilar cholangiocarci- cured by more extensive hepatic and nodal noma. J Hepatobiliary Pancreat Surg 1998;5:/ 52/ 61. resection but this needs to be formally tested. [12] Liu CL, Fan ST, Lo CM, Tso WK, Lam CM, Wong J. 2. Does adjuvant chemotherapy improve survival Improved operative and survival outcomes of surgical treat-

following surgery? The data from Takada et al. ment for hilar cholangiocarcinoma. Br J Surg 2006;93:/ 1488/ 94. [38] suggest a benefit and benefits have been [13] Neuhaus P, Jonas S, Bechstein WO, Lohmann R, Radke C, demonstrated in all major tumour types. Kling N, et al. Extended resections for hilar cholangiocarci- 3. Does improved biliary drainage with PDT im- noma. Ann Surg 1999;230:80818; discussion 819. prove survival? The early data from Ortner need [14] Shimoda M, Farmer DG, Colquhoun SD, Rosove M, to be validated [35]. The feasibility of conduct- Ghobrial RM, Yersiz H, et al. Liver transplantation for cholangiocellular carcinoma: analysis of a single-center ex- ing PDT has been confirmed in a phase II NCRI

perience and review of the literature. Liver Transpl 2001;7:/ / study [43]. 102333. 4. What is the optimum chemotherapy schedule? [15] Sudan D, DeRoover A, Chinnakotla S, Fox I, Shaw B Jr, There is consensus among oncologists that McCashland T, et al. Radiochemotherapy and transplantation palliative chemotherapy is of benefit but the allow long-term survival for nonresectable hilar cholangiocar-

cinoma. Am J Transplant 2002;2:/ 774/ 9. optimum schedule needs to be formally identi- [16] Kitagawa Y, Nagino M, Kamiya J, Uesaka K, Sano T, fied. Yamamoto H, et al. Lymph node metastasis from hilar 5. Is radiation of value? cholangiocarcinoma: audit of 110 patients who underwent New advances in the management of biliary tract cancer 111

regional and paraaortic node dissection. Ann Surg 2001;233:/ / [31] Todoroki T, Iwasaki Y, Okamura T, Nagoshi K, Asakura H, 38592. Nakano M, et al. Intraoperative radiotherapy for advanced

[17] Kosuge T, Yamamoto J, Shimada K, Yamasaki S, Makuuchi carcinoma of the biliary system. Cancer 1980;46:/ 2179/ 84. M. Improved surgical results for hilar cholangiocarcinoma [32] Hsue V, Wong CS, Moore M, Erlichman C, Cummings BJ, with procedures including major hepatic resection. Ann Surg MacLeod M. A phase I study of combined radiation therapy with 5-ﬂuorouracil and low dose folinic acid in patients with 1999;230:/ 663/ 71. [18] Heimbach JK, Haddock MG, Alberts SR, Nyberg SL, Ishitani locally advanced pancreatic or biliary carcinoma. Int J Radiat

MB, Rosen CB, et al. Transplantation for hilar cholangiocar- Oncol Biol Phys 1996;34:/ 445/ 50. [33] Whittington R, Neuberg D, Tester WJ, Benson AB 3rd, Haller cinoma. Liver Transpl;10(10 Suppl 2004;2):/ S65/ 8. [19] Bartlett DL, Fong Y, Fortner JG, Brennan MF, Blumgart LH. DG. Protracted intravenous ﬂuorouracil infusion with radia- Long-term results after resection for gallbladder cancer. tion therapy in the management of localized pancreaticobiliary carcinoma: a phase I Eastern Cooperative Oncology Group

Implications for staging and management. Ann Surg 1996;/

Trial. J Clin Oncol 1995;13:/ 227/ 32.

224:639/ 46. [34] Ayaru L, Bown SG, Pereira SP. Photodynamic therapy for [20] Madariaga JR, Iwatsuki S, Todo S, Lee RG, Irish W, Starzl pancreatic and biliary tract carcinoma. Int J Gastrointest TE. Liver resection for hilar and peripheral cholangiocarcino-

Cancer 2005;35:/ 1/ 13.

mas: a study of 62 cases. Ann Surg 1998;227:/ 70/ 9. [35] Ortner ME, Caca K, Berr F, Liebetruth J, Mansmann U, [21] Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Huster D, et al. Successful photodynamic therapy for non- Bodniewicz BSJ, et al. Staging, resectability, and outcome in resectable cholangiocarcinoma: a randomized prospective

225 patients with hilar cholangiocarcinoma. Ann Surg 2001;/

study. Gastroenterology 2003;125:/ 1355/ 63.

234:507/ 17. [36] Armstrong A, Valle J. Investigation and management of biliary [22] Huang JL, Biehl TR, Lee FT, Zimmer PW, Ryan JA Jr. tract cancer. In: Cunningham D, Jankowski J, Miles A, editors. Outcomes after resection of cholangiocellular carcinoma. Am J The effective management of upper gastrointestinal malig-

Surg 2004;187:/ 612/ 7. nancies. London: Aesculapius Medical Press; 2005. [23] Rea DJ, Munoz-Juarez M, Farnell MB, Donohue JH, Que [37] Glimelius B, Hoffman K, Sjoden PO, Jacobsson G, Sellstrom FG, Crownhart B, et al. Major hepatic resection for hilar H, Enander LK, et al. Chemotherapy improves survival and

cholangiocarcinoma: analysis of 46 patients. Arch Surg 2004;/ quality of life in advanced pancreatic and biliary cancer. Ann

/ 139:51423. Oncol 1996;7:/ 593/ 600. [24] Tsukada K, Hatakeyama K, Kurosaki I, Uchida K, Shirai Y, [38] Takada T, Nimura Y, Katoh H, Nagakawa T, Nakayama T, Muto T, et al. Outcome of radical surgery for carcinoma of the Matsushiro T, et al. Prospective randomized trial of 5-

gallbladder according to the TNM stage. Surgery 1996;120:/ / ﬂuorouracil, doxorubicin, and mitomycin C for non-resectable 81621. pancreatic and biliary carcinoma: multicenter randomized

[25] Puhalla H, Wild T, Bareck E, Pokorny H, Ploner M, Soliman trial. Hepatogastroenterology 1998;45:/ 2020/ 6. T, et al. Long-term follow-up of surgically treated gallbladder [39] Kornek GV, Schuell B, Laengle F, Gruenberger T, Penz M, Karall K, et al. Mitomycin C in combination with capecitabine cancer patients. Eur J Surg Oncol 2002;28:/ 857/ 63. [26] Takada T, Amano H, Yasuda H, Nimura Y, Matsushiro T, or biweekly high-dose gemcitabine in patients with advanced Kato H, et al; Study Group of Surgical Adjuvant Therapy for biliary tract cancer: a randomised phase II trial. Ann Oncol

Carcinomas of the Pancreas and Biliary Tract. Is postoperative 2004;15:/ 478/ 83. adjuvant chemotherapy useful for gallbladder carcinoma? A [40] Ducreux M, Van Cutsem E, Van Laethem JL, Gress TM, phase III multicenter prospective randomized controlled trial Jeziorski K, Rougier P, et al; EORTC Gastro Intestinal Tract Cancer Group. A randomised phase II trial of weekly high- in patients with resected pancreaticobiliary carcinoma. Cancer dose 5-ﬂuorouracil with and without folinic acid and cisplatin

2002;95:/ 1685/ 95. in patients with advanced biliary tract carcinoma: results of the [27] Urego M, Flickinger JC, Carr BI. Radiotherapy and multi-

40955 EORTC trial. Eur J Cancer 2005;41:/ 398/ 403. modality management of cholangiocarcinoma. Int J Radiat [41] Rao S, Cunningham D, Hawkins RE, Hill ME, Smith D,

Oncol Biol Phys 1999;44:/ 121/ 6. Daniel F, et al. Phase III study of 5FU, etoposide and [28] Shiina T, Mikuriya S, Uno T, Toita T, Serizawa S, Itami J, et leucovorin (FELV) compared to epirubicin, cisplatin and al. Radiotherapy of cholangiocarcinoma: the roles for primary 5FU (ECF) in previously untreated patients with advanced and adjuvant therapies. Cancer Chemother Pharmacol

biliary cancer. Br J Cancer 2005;92:/ 1650/ 4. 1992;31 Suppl:S115S118. [42] Valle JW, Wasan H, Johnson P, Bridgewater J, Maraveyas A, [29] Flickinger JC, Epstein AH, Iwatsuki S, Carr BI, Starzl TE. Jones E, et al. Gemcitabine, alone or in combination with Radiation therapy for primary carcinoma of the extrahepatic cisplatin, in patients with advanced or metastatic cholangio-

biliary system. An analysis of 63 cases. Cancer 1991;68:/ 289/ carcinomas and other biliary tract tumours: a multicentre, 94. randomised phase II study. ASCO GI January 2006. [30] Lu JJ, Bains YS, Abdel-Wahab M, Brandon AH, Wolfson AH, [43] Pereira S, Ragunath K, Devlin J, Meadows H. Preliminary Raub WA, et al. High-dose-rate remote afterloading intraca- results of a phase 2 trial to examine the safety and efﬁcacy of vitary brachytherapy for the treatment of extrahepatic biliary porﬁmer sodium PDT in locally advanced BTC. ASCO

duct carcinoma. Cancer J 2002;8:/ 74/ 8. Proceedings 2005.