Peer reviewer: Yu Katayose, Professor, Integrated Surgery and Oncology, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai 9808574, Japan
S- Editor Gou SX L- Editor A E- Editor Xiong L
Biliary tract cancer is a rare malignant tumor. There is limited knowledge about biology and natural history of this disease and considerable uncertainty remains regarding its optimal diagnostic and therapeutic management. The role of adjuvant therapy is object of debate and controversy. Although resection is identified as the most effective and the only potentially curative treatment, there is no consensus on the impact of adjuvant chemotherapy and/or radiotherapy on the high incidence of disease recurrence and on survival. This is mainly due to the rarity of this disease and the consequent difficulty in performing randomized trials. The only two prospectively controlled trials concluded that adjuvant chemotherapy did not improve survival. Most of the retrospective trials, which had limited sample size and included heterogeneous patients population and non-standardized therapies, suggested a marginal benefit of chemoradiotherapy in reducing locoregional recurrence and an uncertain impact on survival. Well-designed multi-institutional randomized trials are necessary to clarify the role of adjuvant therapy. Two ongoing phase III trials may provide relevant information.
Biliary tract cancer (BTC) is a rare tumor accounting for approximately 4% of all malignant neoplasms of the gastrointestinal tract. Marked gender, ethnical and geographical variations exist and, in certain regions of the world, like Chile or North India, BTC is one of the most common causes of cancer mortality. The median age at presentation is the seventh decade of life with a male to female ratio of 1.5[1-5].
Surgical resection is the only potentially curative treatment for BTC. However, the resectability rate has been reported to range between 30% and 70%, with large variability based on tumor location (70% for ampullary cancer, 40%-50% for gallbladder, intrahepatic and distal extrahepatic cancer and 30% for hilar BTC)[6,7]. The type of resection and prognosis vary with anatomical location with a 5-year overall survival (OS) rate of 20%-40% for intrahepatic adenocarcinoma, 50%-70% for ampullary cancer, 25%-50% for distal cholangiocarcinoma and for gallbladder cancer and 15%-35% for hilar BTC.
Due to the rarity of this disease, in which patients with curatively resected tumors are in the minority, prospective trials have been rarely performed and, sometimes, eligibility criteria allowed the enrolment of both patients with pancreatic cancer and BTC, thus hampering the interpretation of results. Accordingly, information with a high level of evidence is lacking and wide areas of debate and controversy on optimal adjuvant therapeutic management exist.
The 5-year OS rate with surgery alone is disappointing, ranging from 15% to 70%. Complete surgical resection with histologically negative (R0) surgical margins has been reported to be the most important prognostic factor. Since prognosis varies also with anatomical location, the heterogeneity of patient population of the reported studies may affect the interpretation of the data. Other prognostic factors such as tumor stage, nodal status, vascular and perineural invasion, elevated baseline CA 19-9 level and histologic grade have been identified in many reports[10-13]. Among those, the prognostic relevance of tumor stage, nodal status, histologic grade and resection margin is almost universally accepted and should be taken into account for the stratification of the patients in prospective trials and for the interpretation of the results in non-randomized series; while the prognostic role of elevated baseline CA 19-9 level and vascular and perineural invasion is still controversial[14-45].
Most patients with BTC are not suitable for curative surgery at diagnosis, and the rate of microscopically positive resection margins (R1) has been reported to be up to 74%. In addition, locoregional failure occurs in more than half of the patients, even after R0 resection[9,10]. Isolated locoregional disease was reported in approximately 15% of patients with gallbladder cancer, 20% with periampullary cancer and 60% with hilar cholangiocarcinoma. In contrast, systemic disease, with or without concomitant locoregional recurrence, occurred in 85% of patients with gallbladder cancer, 75% with periampullary cancer and 41% with hilar cholangiocarcinoma[10,11]. Because of poor survival after curative resection due to frequent local relapse and distant metastases[9-11,36], the role of adjuvant therapy has been widely explored[16,32,38,41-56].
Previous studies, mainly focusing on adjuvant chemoradiation therapy (CRT) with a variety of regimens, led to conflicting results and the role of this therapeutic strategy remains controversial. No large randomized trial of adjuvant CRT has ever been performed. A small phase III European Organization for Research and Treatment of Cancer trial, including 92 eligible patients with periampullary adenocarcinoma, demonstrated no statistically significant difference in survival between adjuvant CRT following resection vs observation. However, since this trial included a limited number of patients and an outdated chemoradiation in terms of imaging, techniques, planning, dose and concomitant radiosensitizing chemotherapy, definitive conclusions on the role of modern chemoradiation are impossible to draw.
Conversely, a retrospective series of 73 patients with gallbladder cancer treated between 1985 and 2004 at Mayo Clinic suggested that adjuvant CRT may obtain a statistically significant improvement in OS only for patients with lymph node involvement. Similarly, two retrospective series of fluoropyrimidine-based post-operative chemoradiation from MD Anderson Cancer Center and from South Korea, including 96 patients affected by ampullary adenocarcinoma and 91 patients with extrahepatic bile duct cancer, respectively, suggested an improved OS only in patients with locally advanced tumor (T3/T4) or with R1 resection. A few other smaller retrospective series also reported a modest potential OS benefit with adjuvant CRT (Table 1)[38,39,41-45].
Apart from the controversial impact on OS, CRT may have a role in improving local control, especially in patients at higher risk of local failure, such as those with R1 margins and positive lymph nodes. In fact, 5-year local control rate raised from 40%-50% in patients with ampullary cancer treated with surgery alone to 65%-80% in those who received post-operative CRT[1,39-41,57].
Unfortunately, the retrospective nature of most of these studies, the small sample size, the lack of correction for multiple comparisons, patient selection bias; heterogeneity in terms of patients’ characteristics, treatment regimens, tumor site and stage; long-lasting accrual periods, different surgical, radiotherapy and radiological techniques in different historical periods and other confounding factors do not allow to draw any firm conclusion on the role of CRT. In fact, younger and healthier patients were more likely to be offered adjuvant CRT. On the other hand, patients with high risk features were more likely to receive adjuvant therapy than those with favorable features.
A few studies evaluated the role of adjuvant chemotherapy in BTC. A retrospective single centre analysis on 42 patients suggested that postoperative gemcitabine-based chemotherapy may be a promising strategy to improve OS after surgical resection for hilar cholangiocarcinoma. Consistently, the addition of fluorouracil-based chemotherapy to adjuvant CRT seemed to improve disease free survival (3-year DFS 45% vs 27%) and OS (3-year OS 63% vs 31%) compared to CRT alone in another retrospective series of 120 patients with radically resected extrahepatic BTC.
A phase III trial addressed the role of adjuvant chemotherapy with 5-fluorouracil and mitomycin-C in a series of 508 patients with surgically treated pancreaticobiliary malignancies including 335 patients with BTC. OS was significantly increased when compared to observation arm only in the unplanned subset analysis of 61 resected patients with macroscopically positive resection margins (R2) affected by gallbladder cancer. Similarly, a more recent phase III trial exploring the role of single agent adjuvant chemotherapy with either gemcitabine or 5-fluorouracil, in 304 patients with ampullary adenocarcinoma submitted to curative resection did not demonstrate a survival benefit for any of the adjuvant therapy arms when compared to surgery alone.
The National Comprehensive Cancer Network (NCCN) guidelines recommend only observation or adjuvant CRT with concomitant fluoropyrimidine for patients with R0 margins or negative lymph-nodes and adjuvant therapy with concurrent 5-fluorouracil-based CRT followed or not by additional fluoropyrimidine- or gemcitabine-based regimens in patients with R1 margins or metastatic lymph nodes. The use of chemotherapy is recommended due to the high incidence of systemic relapse and to the results observed in the therapeutic management of advanced disease[61,62]. The European Clinical Practice guidelines are more vague, only suggesting CRT as a possible therapeutic option after surgery for BTC. More restrictive indications derive from a modified and implemented version of NCCN guidelines proposed by a committee of specialists of the Middle East and North Africa Region, which recommend only observation or enrolment into a clinical trial after an R0 and/or a negative regional nodes resection, because of conflicting data regarding adjuvant CRT.
Given the lack of guidelines based on high level of evidence, it is not surprising that patients submitted to curative surgery for biliary tract tumors receive heterogeneous management around the world. A survey of therapeutic strategies recommended in the clinical practice in 2001-2002, reported that adjuvant CRT was widely adopted in the majority of American centers (71%), followed by Asian/Pacific centers (55%), but only by 29% of European institutions. This scenario may have changed in more recent years with a trend towards possibly increasing use of adjuvant treatment due to the numerous positive experiences reported in the literature in the last decade[9-11,38-42,44,45,55,57-59,66,67]. However, eighty-eight percent of the interviewed physicians recognized the unmet need for achieving higher levels of evidence from large prospective trials to support the routine use of adjuvant treatment.
Altogether, the available data do not allow to answer the question whether patients submitted to curative resection for BTC should receive an adjuvant therapy and which treatment strategy may provide the largest benefit.
In fact, neither adjuvant CRT nor adjuvant chemotherapy with either single agent or a 5-fluorouracil-mitomycin doublet improved OS when compared to observation alone in phase III trials[14,58,59], while only a modest benefit in loco-regional control rather than on OS was suggested with CRT by retrospective series that, in any case, suffer from previously mentioned methodological limitations[1,38,41-45,65-68].
The causes of this disappointing scenario and of the lack of a convincing answer are manifold. First, when compared to trials on advanced disease, trials on adjuvant therapy are more demanding, also due to the involvement of different specialists (surgeon, radiologist, oncologist and radiotherapist); more resource- and time-consuming, due to the longer patient’s life expectancy and to the inferior number of patients; and require a more selective choice of centers to be involved. Second, evidence-based information on the most active and effective chemotherapy regimen against unresectable or metastatic disease is limited as well. Accordingly, the selection of promising regimens that may have a relevant impact on disease natural history is challenging. Only recently, cisplatin and gemcitabine regimen became the new standard of treatment in advanced BTC providing a rational for investigating the role of this combination in the adjuvant setting. Additionally, two ongoing phase III trials are currently exploring the role of capecitabine (NCT00363584) and of GEMOX regimen (NCT01313377) in the adjuvant setting and may provide further information in the next future. Third, the rarity of disease limits the interest of pharmaceutical companies while investigator initiated trials are hindered by the restricted availability of agents already registered and authorized for the treatment of the disease. Fourth, the choice of the most promising therapeutic strategy is crucial in this disease that has a very high rate of both local and systemic recurrence. Systemic chemotherapy and CRT, rather than being taken as alternative therapies, should be combined taken into account in the design of post-operative management. However, the role of sequential therapy with CRT followed by systemic chemotherapy or the inverse sequence was rarely addressed in prospective trials. Fifth, the knowledge on tumor biology is limited and, at the moment, does not allow to identify new agents that may contribute to improve the outcome of the disease. Last but not least, the interpretation of trials result is often challenging due to the heterogeneity of enrolled patients population. Stratification based on tumor location, extent of resection, lymph node status and resection margin status will be crucial to the success of future studies.
A multi-institutional worldwide effort to conduct well designed phase III trial and to expand biological knowledge of the disease is necessary to clarify the role of adjuvant therapy in BTC.
Peer reviewer: Yu Katayose, Professor, Integrated Surgery and Oncology, Tohoku University Graduate School of Medicine, 1-1 Seiryomachi, Aobaku, Sendai 9808574, Japan
S- Editor Gou SX L- Editor A E- Editor Xiong L
|1.||Aljiffry M, Walsh MJ, Molinari M. Advances in diagnosis, treatment and palliation of cholangiocarcinoma: 1990-2009. World J Gastroenterol. 2009;15:4240-4262. [PubMed] [DOI]|
|2.||de Groen PC, Gores GJ, LaRusso NF, Gunderson LL, Nagorney DM. Biliary tract cancers. N Engl J Med. 1999;341:1368-1378. [PubMed] [DOI]|
|3.||Andreotti G, Liu E, Gao YT, Safaeian M, Rashid A, Shen MC, Wang BS, Deng J, Han TQ, Zhang BH. Medical history and the risk of biliary tract cancers in Shanghai, China: implications for a role of inflammation. Cancer Causes Control. 2011;22:1289-1296. [PubMed] [DOI]|
|4.||von Hahn T, Ciesek S, Wegener G, Plentz RR, Weismüller TJ, Wedemeyer H, Manns MP, Greten TF, Malek NP. Epidemiological trends in incidence and mortality of hepatobiliary cancers in Germany. Scand J Gastroenterol. 2011;46:1092-1098. [PubMed] [DOI]|
|5.||Farges O, Fuks D, Le Treut YP, Azoulay D, Laurent A, Bachellier P, Nuzzo G, Belghiti J, Pruvot FR, Regimbeau JM. AJCC 7th edition of TNM staging accurately discriminates outcomes of patients with resectable intrahepatic cholangiocarcinoma: By the AFC-IHCC-2009 study group. Cancer. 2011;117:2170-2177. [PubMed] [DOI]|
|6.||Talamini MA, Moesinger RC, Pitt HA, Sohn TA, Hruban RH, Lillemoe KD, Yeo CJ, Cameron JL. Adenocarcinoma of the ampulla of Vater. A 28-year experience. Ann Surg. 1997;225:590-599; discussion 590-599. [PubMed] [DOI]|
|7.||Nagakawa T, Kayahara M, Ikeda S, Futakawa S, Kakita A, Kawarada H, Matsuno M, Takada T, Takasaki K, Tanimura H. Biliary tract cancer treatment: results from the Biliary Tract Cancer Statistics Registry in Japan. J Hepatobiliary Pancreat Surg. 2002;9:569-575. [PubMed] [DOI]|
|8.||Heron DE, Stein DE, Eschelman DJ, Topham AK, Waterman FM, Rosato EL, Alden M, Anne PR. Cholangiocarcinoma: the impact of tumor location and treatment strategy on outcome. Am J Clin Oncol. 2003;26:422-428. [PubMed]|
|9.||Jan YY, Yeh CN, Yeh TS, Chen TC. Prognostic analysis of surgical treatment of peripheral cholangiocarcinoma: two decades of experience at Chang Gung Memorial Hospital. World J Gastroenterol. 2005;11:1779-1784. [PubMed]|
|10.||Jarnagin WR, Ruo L, Little SA, Klimstra D, D'Angelica M, DeMatteo RP, Wagman R, Blumgart LH, Fong Y. Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. Cancer. 2003;98:1689-1700. [PubMed] [DOI]|
|11.||Smeenk HG, van Eijck CH, Hop WC, Erdmann J, Tran KC, Debois M, van Cutsem E, van Dekken H, Klinkenbijl JH, Jeekel J. Long-term survival and metastatic pattern of pancreatic and periampullary cancer after adjuvant chemoradiation or observation: long-term results of EORTC trial 40891. Ann Surg. 2007;246:734-740. [PubMed] [DOI]|
|12.||Iacono C, Verlato G, Zamboni G, Scarpa A, Montresor E, Capelli P, Bortolasi L, Serio G. Adenocarcinoma of the ampulla of Vater: T-stage, chromosome 17p allelic loss, and extended pancreaticoduodenectomy are relevant prognostic factors. J Gastrointest Surg. 2007;11:578-588. [PubMed] [DOI]|
|13.||Balachandran P, Agarwal S, Krishnani N, Pandey CM, Kumar A, Sikora SS, Saxena R, Kapoor VK. Predictors of long-term survival in patients with gallbladder cancer. J Gastrointest Surg. 2006;10:848-854. [PubMed] [DOI]|
|14.||Qiao QL, Zhang TP, Guo JC, Zhan HX, Zhao JX, Liu YC, Wan YL, Leng XS, Zhao YP. Prognostic factors after pancreatoduodenectomy for distal bile duct cancer. Am Surg. 2011;77:1445-1448. [PubMed]|
|15.||Ruys AT, Kate FJ, Busch OR, Engelbrecht MR, Gouma DJ, van Gulik TM. Metastatic lymph nodes in hilar cholangiocarcinoma: does size matter? HPB (Oxford). 2011;13:881-886. [PubMed] [DOI]|
|16.||Tugba Kos F, Aksoy S, Odabas H, Ozdemir N, Oksuzoglu B, Uncu D, Zengin N. Adjuvant therapy for gallbladder and bile duct cancers: retrospective comparative study. J BUON. 2011;16:464-468. [PubMed]|
|17.||Yao X, Zhou L, Han S, Chen Y. High expression of CXCR4 and CXCR7 predicts poor survival in gallbladder cancer. J Int Med Res. 2011;39:1253-1264. [PubMed]|
|18.||Sun XN, Cao WG, Wang X, Wang Q, Gu BX, Yang QC, Hu JB, Liu H, Zheng S. Prognostic impact of vascular endothelial growth factor-A expression in resected gallbladder carcinoma. Tumour Biol. 2011;32:1183-1190. [PubMed] [DOI]|
|19.||Clark CJ, Wood-Wentz CM, Reid-Lombardo KM, Kendrick ML, Huebner M, Que FG. Lymphadenectomy in the staging and treatment of intrahepatic cholangiocarcinoma: a population-based study using the National Cancer Institute SEER database. HPB (Oxford). 2011;13:612-620. [PubMed] [DOI]|
|20.||Patel SH, Kooby DA, Staley CA, Sarmiento JM, Maithel SK. The prognostic importance of lymphovascular invasion in cholangiocarcinoma above the cystic duct: a new selection criterion for adjuvant therapy? HPB (Oxford). 2011;13:605-611. [PubMed] [DOI]|
|21.||Du X, Wang S, Lu J, Cao Y, Song N, Yang T, Dong R, Zang L, Yang Y, Wu T. Correlation between MMP1-PAR1 axis and clinical outcome of primary gallbladder carcinoma. Jpn J Clin Oncol. 2011;41:1086-1093. [PubMed] [DOI]|
|22.||Qureshi A, Hassan U, Azam M. Morphology, TNM staging and survival with Pancreatico-duodenectomy specimens received at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Pakistan. Asian Pac J Cancer Prev. 2011;12:953-956. [PubMed]|
|23.||Kai K, Kohya N, Kitahara K, Masuda M, Miyoshi A, Ide T, Tokunaga O, Miyazaki K, Noshiro H. Tumor budding and dedifferentiation in gallbladder carcinoma: potential for the prognostic factors in T2 lesions. Virchows Arch. 2011;459:449-456. [PubMed] [DOI]|
|24.||Choi SB, Kim WB, Song TJ, Suh SO, Kim YC, Choi SY. Surgical outcomes and prognostic factors for ampulla of Vater cancer. Scand J Surg. 2011;100:92-98. [PubMed]|
|25.||de Jong MC, Nathan H, Sotiropoulos GC, Paul A, Alexandrescu S, Marques H, Pulitano C, Barroso E, Clary BM, Aldrighetti L. Intrahepatic cholangiocarcinoma: an international multi-institutional analysis of prognostic factors and lymph node assessment. J Clin Oncol. 2011;29:3140-3145. [PubMed] [DOI]|
|26.||Sakata J, Shirai Y, Wakai T, Ajioka Y, Akazawa K, Hatakeyama K. Assessment of the nodal status in ampullary carcinoma: the number of positive lymph nodes versus the lymph node ratio. World J Surg. 2011;35:2118-2124. [PubMed] [DOI]|
|27.||Miyamoto M, Ojima H, Iwasaki M, Shimizu H, Kokubu A, Hiraoka N, Kosuge T, Yoshikawa D, Kono T, Furukawa H. Prognostic significance of overexpression of c-Met oncoprotein in cholangiocarcinoma. Br J Cancer. 2011;105:131-138. [PubMed] [DOI]|
|28.||Wakai T, Shirai Y, Sakata J, Matsuda Y, Korita PV, Takamura M, Ajioka Y, Hatakeyama K. Prognostic significance of NQO1 expression in intrahepatic cholangiocarcinoma. Int J Clin Exp Pathol. 2011;4:363-370. [PubMed]|
|29.||Ito H, Ito K, D'Angelica M, Gonen M, Klimstra D, Allen P, DeMatteo RP, Fong Y, Blumgart LH, Jarnagin WR. Accurate staging for gallbladder cancer: implications for surgical therapy and pathological assessment. Ann Surg. 2011;254:320-325. [PubMed] [DOI]|
|30.||Murakami Y, Uemura K, Sudo T, Hashimoto Y, Nakashima A, Kondo N, Sakabe R, Kobayashi H, Sueda T. Prognostic factors of patients with advanced gallbladder carcinoma following aggressive surgical resection. J Gastrointest Surg. 2011;15:1007-1016. [PubMed] [DOI]|
|31.||Li H, Qin Y, Cui Y, Chen H, Hao X, Li Q. Analysis of the surgical outcome and prognostic factors for hilar cholangiocarcinoma: a Chinese experience. Dig Surg. 2011;28:226-231. [PubMed] [DOI]|
|32.||Showalter TN, Zhan T, Anne PR, Chervoneva I, Mitchell EP, Yeo CJ, Rosato EL, Kennedy EP, Berger AC. The influence of prognostic factors and adjuvant chemoradiation on survival after pancreaticoduodenectomy for ampullary carcinoma. J Gastrointest Surg. 2011;15:1411-1416. [PubMed] [DOI]|
|33.||Kawaguchi T, Ochiai T, Ikoma H, Inoue K, Morimura R, Murayama Y, Komatsu S, Shiozaki A, Kuriu Y, Nakanishi M. Prognostic impact of histological blood vessel invasion in patients with ampullary adenocarcinoma. Hepatogastroenterology. 2010;57:1347-1350. [PubMed]|
|34.||Guglielmi A, Ruzzenente A, Campagnaro T, Pachera S, Conci S, Valdegamberi A, Sandri M, Iacono C. Prognostic significance of lymph node ratio after resection of peri-hilar cholangiocarcinoma. HPB (Oxford). 2011;13:240-245. [PubMed] [DOI]|
|35.||Anderson C, Kim R. Adjuvant therapy for resected extrahepatic cholangiocarcinoma: a review of the literature and future directions. Cancer Treat Rev. 2009;35:322-327. [PubMed] [DOI]|
|36.||Murakami Y, Uemura K, Hayasidani Y, Sudo T, Hashimoto Y, Ohge H, Sueda T. Indication for postoperative adjuvant therapy in biliary carcinoma based on analysis of recurrence and survival after surgical resection. Dig Dis Sci. 2009;54:1360-1364. [PubMed] [DOI]|
|37.||Klinkenbijl JH, Jeekel J, Sahmoud T, van Pel R, Couvreur ML, Veenhof CH, Arnaud JP, Gonzalez DG, de Wit LT, Hennipman A. Adjuvant radiotherapy and 5-fluorouracil after curative resection of cancer of the pancreas and periampullary region: phase III trial of the EORTC gastrointestinal tract cancer cooperative group. Ann Surg. 1999;230:776-782; discussion 782-784. [PubMed] [DOI]|
|38.||Gold DG, Miller RC, Haddock MG, Gunderson LL, Quevedo F, Donohue JH, Bhatia S, Nagorney DM. Adjuvant therapy for gallbladder carcinoma: the Mayo Clinic Experience. Int J Radiat Oncol Biol Phys. 2009;75:150-155. [PubMed] [DOI]|
|39.||Krishnan S, Rana V, Evans DB, Varadhachary G, Das P, Bhatia S, Delclos ME, Janjan NA, Wolff RA, Crane CH. Role of adjuvant chemoradiation therapy in adenocarcinomas of the ampulla of vater. Int J Radiat Oncol Biol Phys. 2008;70:735-743. [PubMed] [DOI]|
|40.||Kim S, Kim SW, Bang YJ, Heo DS, Ha SW. Role of postoperative radiotherapy in the management of extrahepatic bile duct cancer. Int J Radiat Oncol Biol Phys. 2002;54:414-419. [PubMed] [DOI]|
|41.||Nakeeb A, Tran KQ, Black MJ, Erickson BA, Ritch PS, Quebbeman EJ, Wilson SD, Demeure MJ, Rilling WS, Dua KS. Improved survival in resected biliary malignancies. Surgery. 2002;132:555-563; discission 563-564. [PubMed] [DOI]|
|42.||Kim K, Chie EK, Jang JY, Kim SW, Han SW, Oh DY, Im SA, Kim TY, Bang YJ, Ha SW. Adjuvant Chemoradiotherapy After Curative Resection for Extrahepatic Bile Duct Cancer: A Long-term Single Center Experience. Am J Clin Oncol. 2012;35:136-140. [PubMed] [DOI]|
|43.||Serafini FM, Sachs D, Bloomston M, Carey LC, Karl RC, Murr MM, Rosemurgy AS. Location, not staging, of cholangiocarcinoma determines the role for adjuvant chemoradiation therapy. Am Surg. 2001;67:839-843; discussion 843-844. [PubMed]|
|44.||Bhatia S, Miller RC, Haddock MG, Donohue JH, Krishnan S. Adjuvant therapy for ampullary carcinomas: the Mayo Clinic experience. Int J Radiat Oncol Biol Phys. 2006;66:514-519. [PubMed] [DOI]|
|45.||Hughes MA, Frassica DA, Yeo CJ, Riall TS, Lillemoe KD, Cameron JL, Donehower RC, Laheru DA, Hruban RH, Abrams RA. Adjuvant concurrent chemoradiation for adenocarcinoma of the distal common bile duct. Int J Radiat Oncol Biol Phys. 2007;68:178-182. [PubMed] [DOI]|
|46.||Konishi M. Adjuvant chemotherapy for resectable biliary tract cancer: current status and future direction. J Hepatobiliary Pancreat Sci. 2012;[Epub ahead of print]. [PubMed] [DOI]|
|47.||Narang AK, Miller RC, Hsu CC, Bhatia S, Pawlik TM, Laheru D, Hruban RH, Zhou J, Winter JM, Haddock MG. Evaluation of adjuvant chemoradiation therapy for ampullary adenocarcinoma: the Johns Hopkins Hospital-Mayo Clinic collaborative study. Radiat Oncol. 2011;6:126. [PubMed] [DOI]|
|48.||González ME, Giannini OH, González P, Saldaña B. Adjuvant radio-chemotherapy after extended or simple cholecystectomy in gallbladder cancer. Clin Transl Oncol. 2011;13:480-484. [PubMed] [DOI]|
|49.||Bonet Beltrán M, Roth AD, Mentha G, Allal AS. Adjuvant radio-chemotherapy for extrahepatic biliary tract cancers. BMC Cancer. 2011;11:267. [PubMed] [DOI]|
|50.||Park HS, Lim JY, Yoon DS, Park JS, Lee DK, Lee SJ, Choi HJ, Song SY, Lee WJ, Cho JY. Outcome of adjuvant therapy for gallbladder cancer. Oncology. 2010;79:168-173. [PubMed] [DOI]|
|51.||Vern-Gross TZ, Shivnani AT, Chen K, Lee CM, Tward JD, MacDonald OK, Crane CH, Talamonti MS, Munoz LL, Small W. Survival outcomes in resected extrahepatic cholangiocarcinoma: effect of adjuvant radiotherapy in a surveillance, epidemiology, and end results analysis. Int J Radiat Oncol Biol Phys. 2011;81:189-198. [PubMed] [DOI]|
|52.||Cho SY, Kim SH, Park SJ, Han SS, Kim YK, Lee KW, Lee WJ, Woo SM, Kim TH. Adjuvant chemoradiation therapy in gallbladder cancer. J Surg Oncol. 2010;102:87-93. [PubMed] [DOI]|
|53.||Park JH, Choi EK, Ahn SD, Lee SW, Song SY, Yoon SM, Kim YS, Lee YS, Lee SG, Hwang S. Postoperative chemoradiotherapy for extrahepatic bile duct cancer. Int J Radiat Oncol Biol Phys. 2011;79:696-704. [PubMed] [DOI]|
|54.||Murakami Y, Uemura K, Sudo T, Hayashidani Y, Hashimoto Y, Nakamura H, Nakashima A, Sueda T. Adjuvant gemcitabine plus S-1 chemotherapy improves survival after aggressive surgical resection for advanced biliary carcinoma. Ann Surg. 2009;250:950-956. [PubMed] [DOI]|
|55.||Lim KH, Oh DY, Chie EK, Jang JY, Im SA, Kim TY, Kim SW, Ha SW, Bang YJ. Adjuvant concurrent chemoradiation therapy (CCRT) alone versus CCRT followed by adjuvant chemotherapy: which is better in patients with radically resected extrahepatic biliary tract cancer?: a non-randomized, single center study. BMC Cancer. 2009;9:345. [PubMed] [DOI]|
|56.||Gwak HK, Kim WC, Kim HJ, Park JH. Extrahepatic bile duct cancers: surgery alone versus surgery plus postoperative radiation therapy. Int J Radiat Oncol Biol Phys. 2010;78:194-198. [PubMed] [DOI]|
|57.||Murakami Y, Uemura K, Sudo T, Hayashidani Y, Hashimoto Y, Nakamura H, Nakashima A, Sueda T. Gemcitabine-based adjuvant chemotherapy improves survival after aggressive surgery for hilar cholangiocarcinoma. J Gastrointest Surg. 2009;13:1470-1479. [PubMed] [DOI]|
|58.||Takada T, Amano H, Yasuda H, Nimura Y, Matsushiro T, Kato H, Nagakawa T, Nakayama T. Is postoperative adjuvant chemotherapy useful for gallbladder carcinoma? A phase III multicenter prospective randomized controlled trial in patients with resected pancreaticobiliary carcinoma. Cancer. 2002;95:1685-1695. [PubMed] [DOI]|
|59.||Neoptolemos JP, Moore MJ, Cox TF, Valle JW, Palmer DH, Mcdonald A, Carter R, Tebbutt NC, Dervenis C, Smith D. Ampullary cancer ESPAC-3 (v2) trial: A multicenter, international, open-label, randomized controlled phase III trial of adjuvant chemotherapy versus observation in patients with adenocarcinoma of the ampulla of vater. J Clin Oncol. 2011;29:abstr LBA4006.|
|60.||Available from: http: //www.nccn.org/professionals/physician_gls/f_guidelines.asp.|
|61.||Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, Madhusudan S, Iveson T, Hughes S, Pereira SP. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273-1281. [PubMed] [DOI]|
|62.||Glimelius B, Hoffman K, Sjödén PO, Jacobsson G, Sellström H, Enander LK, Linné T, Svensson C. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996;7:593-600. [PubMed]|
|63.||Eckel F, Brunner T, Jelic S. Biliary cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2010;21 Suppl 5:v65-v69. [PubMed] [DOI]|
|64.||Yusuf MA, Kapoor VK, Kamel RR, Kazmi A, Uddin N, Masood N, Al-Abdulkareem A. Modification and implementation of NCCN guidelines on hepatobiliary cancers in the Middle East and North Africa region. J Natl Compr Canc Netw. 2010;8 Suppl 3:S36-S40. [PubMed]|
|65.||Nakeeb A, Pitt HA. Radiation therapy, chemotherapy and chemoradiation in hilar cholangiocarcinoma. HPB (Oxford). 2005;7:278-282. [PubMed] [DOI]|
|66.||Borghero Y, Crane CH, Szklaruk J, Oyarzo M, Curley S, Pisters PW, Evans D, Abdalla EK, Thomas MB, Das P. Extrahepatic bile duct adenocarcinoma: patients at high-risk for local recurrence treated with surgery and adjuvant chemoradiation have an equivalent overall survival to patients with standard-risk treated with surgery alone. Ann Surg Oncol. 2008;15:3147-3156. [PubMed] [DOI]|
|67.||Wang SJ, Fuller CD, Kim JS, Sittig DF, Thomas CR, Ravdin PM. Prediction model for estimating the survival benefit of adjuvant radiotherapy for gallbladder cancer. J Clin Oncol. 2008;26:2112-2117. [PubMed] [DOI]|