# Radiation Oncology/Bile duct/Surgery

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| Bile Duct: Main Page | Resectable Disease | Adjuvant RT | Unresectable Disease | Clinical Trials | | |
Curative surgery (negative margins) is the only treatment modality shown to improve overall survival, and should be the first line therapy in operable patients. Unfortunately, only ~50% present with resectable disease, and only ~50% of these have negative margins. As a result, 5-year overall survival is around 30%.

## Primary Surgical Treatment

* Chang Gung Taiwan
** 1977-2001 PMID 15793863 -- Prognostic analysis of surgical treatment of peripheral cholangiocarcinoma: two decades of experience at Chang Gung Memorial Hospital. (2005 Jan YY, World J Gastroenterol. 2005 Mar 28;11(12):1779-84.)
*** Retrospective. 608 patients with bile duct CA, 373 patients with peripheral CCA (second order or more intrahepatic branches). Treatment 50% hepatectomy (36% curative resection), 28% choledochotomy with T-tube, 22% laparotomy with biopsy; median follow-up 7.2 months
*** Multivariate risk factors: mucobilia, tumor type, stage, type of operation, chemotherapy
*** Overall survival: 1-year 31%, 5-year 4%
*** Conclusion: "Favorable overall survival of PCC patients undergoing surgical treatment depends on early tumor stage, presence of mucobilia, papillary tumor type, hepatic resection, and post-operative chemotherapy"
** 1977-2000 PMID 15041513 -- Influence of age on surgical treatment of peripheral cholangiocarcinoma. (2004 Yeh CN, Am J Surg. 2004 Apr;187(4):559-63.)
*** Retrospective. 23 patients <40 years old compared with 284 patients >40 years old
*** Younger patients less mucobilia, less papillary, more advanced stage. Clinical presentation, PE similar, CEA, CA19-9, hepatolithiasis similar. Post-op adjuvant RT and CT more with older patients
*** 2-year OS: 0% in younger vs. 15% in older patients (p<0.001)
*** Conclusion: "Younger patients with PCC had a significantly worse survival rate than older patients with PCC. Hepatectomy is rational and may benefit younger patients with PCC."
* Seoul Korea 1986-97 PMID 15621994 -- Actual long-term outcome of extrahepatic bile duct cancer after surgical resection. (2005 Jang JY, Ann Surg. 2005 Jan;241(1):77-84.)
** Retrospective. 282 patients, 151 (54%) underwent resection
** 5-year OS: 32.5%, tumor histology and LN mets independent prognostic factors by multivariate analysis
** Conclusion: "In cases of extrahepatic bile duct cancer, resection should be considered and efforts should be made to obtain a tumor-free margin. An aggressive surgical approach will give some survival benefit to the patients with even advanced disease. Long-term follow up is needed before declaring "a cure," because late recurrence after 5 years is detected not infrequently. Adjuvant therapy, local and systemic, needs to be further developed."
* Ulsan Korea PMID 16096407 --The Number of Metastatic Lymph Nodes in Extrahepatic Bile Duct Carcinoma as a Prognostic Factor. (2005 Hong SM, Am J Surg Pathol. 2005 Sep;29(9):1177-1183.)
** Retrospective. 209 patients
** Conclusion: "The patients with 5 or more metastatic lymph nodes had significantly worse survival than those with 4 or less metastatic lymph nodes."
* Shanghai China 1997-2002 PMID 16083598 -- [Analysis of the relation between surgery and prognosis of hilar cholangiocarcinoma] - [Article in Chinese] (2005 Yi B, Zhonghua Wai Ke Za Zhi. 2005 Jul 1;43(13):842-5.)
** Retrospective. 198 patients treated, 61% resected, 30% radical resection.
** Significant predictors of outcome: occupation, preop maximum total bilirubin, operative procedure and postop adjuvant radiation
** Conclusion: "Operative procedure was the most important prognosic factor of hilar cholangiocarcinoma, radical resection still was the primary measure to cure and long term survival. For irresectable hilar cholangiocarcinoma, the effect of ERBD or EMBE could not be considered to be worse than that of open operative treatment."
* Mayo 1979-97 PMID 15136352 -- Major hepatic resection for hilar cholangiocarcinoma: analysis of 46 patients. (2004 Rea DJ, Arch Surg. 2004 May;139(5):514-23; discussion 523-5.)
** Retrospective. 46 patients treated with major hepatic resection; R0 in 80%
** Actual 5-year OS: 26%
** Tumor recurrence predominantly local and regional
** Conclusion: "The actual 5-year survival rate of 26% justifies major partial hepatectomy, bile duct resection, and regional lymphadenectomy for hilar cholangiocarcinoma. The high frequency of local and regional recurrence warrants investigation of adjuvant therapy."
* MSKCC 1990-2001 PMID 14534886 -- Patterns of initial disease recurrence after resection of gallbladder carcinoma and hilar cholangiocarcinoma: implications for adjuvant therapeutic strategies. (Jarnagin WR, Cancer. 2003 Oct 15;98(8):1689-700.)
** Retrospective. 80 GB and 76 hilar CCA reviewed
** Recurrence: 66% GB vs. 68% CCA at 2 years; median time to recurrence GB 11.5 months vs. CCA 20.3 months (p=0.007)
** Site of recurrence: isolated locoregional GB 15% vs. 59% CCA; distal (with or without concomitant locoregional) GB 85% vs. 41% CCA. Site of recurrence no apparent impact on survival
** Conclusion: "After resection, recurrent GBCA is much more likely than recurrent HCCA to involve a distant site. GBCA is also associated with a much shorter time to recurrence and a shorter survival period after recurrence. The results demonstrated significant differences in the clinical behavior of these tumors and suggested that an adjuvant therapeutic strategy targeting locoregional disease, such as radiotherapy, is unlikely to have a significant impact in the overall management of GBCA. Conversely, there is at least some rationale for such an approach in patients with HCCA based on the pattern of initial recurrence."
* MSKCC 1991-2000 PMID 11573044 -- Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. (2001 Jarnagin WR, Ann Surg. 2001 Oct;234(4):507-17; discussion 517-9.)
** Prospective. 225 patients, 36% underwent resection (28% negative margins)
** Pre-operative staging system developed
** All 9 actual 5-year survivors had negative margins and concomitant hepatic resection
** Conclusion: "By taking full account of local tumor extent, the proposed staging system for hilar cholangiocarcinoma accurately predicts resectability, the likelihood of metastatic disease, and survival. Complete resection remains the only therapy that offers the possibility of long-term survival, and hepatic resection is a critical component of the surgical approach."
* Hopkins PMID 10982602 -- Surgery for hilar cholangiocarcinoma: the Johns Hopkins approach. (2000 Lillemoe KD, J Hepatobiliary Pancreat Surg. 2000;7(2):115-21.)
** Retrospective. 109 patients
** Median survival (5-year OS): 19 months (11%)
* Barcelona 1989-99 PMID 11084070 -- Changing strategies in diagnosis and management of hilar cholangiocarcinoma. (2000 Figueras J, Liver Transpl. 2000 Nov;6(6):786-94.)
** Retrospective. 76 patients, 37% surgery (resection or liver transplant)
** Mean survival: surgery 35 months vs. palliation 6 months. Liver transplant > resection
** No benefit to chemoradiation over RT (as reported by Anderson 2004)
* Nagoya Japan 1977-97 PMID 10982608 -- Aggressive preoperative management and extended surgery for hilar cholangiocarcinoma: Nagoya experience. (2000 Nimura Y, J Hepatobiliary Pancreat Surg. 2000;7(2):155-62)
** Retrospective. 177 patients, 61% curative resection
** 5-year OS: curative hepatectomy 26%, bile duct resection 16%. If LN+ 14%.
** Conclusion: "Curative resection after aggressive preoperative management is recommended as a reasonable surgical approach to hilar cholangiocarcinoma."
* MSKCC PMID 9742921 -- Hilar Cholangiocarcinoma: patterns of spread, the importance of hepatic resection for curative operation, and a presurgical clinical staging system. (1998 Burke EC, Ann Surg. 1998 Sep;228(3):385-94.)
** 90 patients, 30 (33%) resected, 25 (28%) negative SM. 60 (67%) unresectable (of these, mets 52%, locally advanced 28%)
** Conclusion: "In half the patients, unresectability is mainly the result of intraabdominal metastases. Presurgical imaging predicts unresectability based on local extension but is poor for assessing nodal metastases. In one third of patients, disease can be resected for cure with a long median survival. Curative resection depends on negative margins, and hepatic resection is necessary to achieve this."
* Hanover Germany 1971-95 PMID 8988723 -- What constitutes long-term survival after surgery for hilar cholangiocarcinoma? (1997 Klempnauer J, Cancer 1997; 79:26-34.)
** Retrospective. 339 patients, 49% resected (54% including liver transplant)
** 32 patients survived >5 years, prognostic factors low stage, negative LNs, and no residual tumor
** Conclusion: "Radical resection offers the best possibility of prolonged survival with a good quality of life for patients with hilar cholangiocarcinoma."
* Rotterdam PMID 8049311 -- Proximal cholangiocarcinoma: a multidisciplinary approach. (1994 van der Hul RL, Eur J Surg. 1994 Apr;160(4):213-8.)
** Retrospective. 66 pts with proximal cholangiocarcinoma, 24% resected, 56% stented. 42% received RT
** Median survival: resection 35.8 months vs. conservative Rx 10.8 months
** Conclusion: "A multidisciplinary approach is necessary and the tumour should be resected if possible."
* Multi-institutional Japan 1973-91 PMID 8165536 -- Extensive resection of the bile ducts combined with liver resection for cancer of the main hepatic duct junction: a cooperative study of the Keio Bile Duct Cancer Study Group. (1994 Sugiura Y, Surgery. 1994 Apr;115(4):445-51.)
** Retrospective. 6 Institutions. 158 patients, 53% resected, 8.4% post-op deaths
** 5-year OS: 20%, 3/12 doing well 10+ years out
** Conclusion: "It is clear that cancer of the main hepatic duct junction has become a curable disease. The operation is a valid procedure that can be widely practiced by competent surgeons."
* Italy PMID 7684913 -- Palliative treatment of extrahepatic bile ducts tumors. (1993 Cucchiara G, J Surg Oncol Suppl. 1993;3:154-7)
** Retrospective. 111 patients, 6% no treatment, 29% biliary drainage, 65% surgical exploration (22% radical surgery, remaining 43% palliative surgery)
** Conclusion: "Although EHBD tumor treatment results are generally poor, surgical exploration should be performed in all patients with acceptable surgical risk, and without evidence of disseminated disease."
* International PMID 1705417 -- Surgical management of 552 carcinomas of the extrahepatic bile ducts (gallbladder and periampullary tumors excluded). Results of the French Surgical Association Survey. (1991 Reding R, Ann Surg. 1991 Mar;213(3):236-41.)
** Retrospective. 552 cases treated at 55 centers. Extrahepatic BD only, 56% upper third, 13% middle third, 18% lower thrid, 13% diffuse
** Resectability: 32% upper, 47% middle, 51% lower
** 1-year OS: 68% resection vs. 31% palliation (p<0.001)
** Conclusion: "The results of this study show that resection of extrahepatic bile duct carcinomas, particularly in an upper-third localization, often is associated with worthwhile long-term survival."
* U Illinois 1974-87 PMID 2011022 -- Carcinoma of the extrahepatic bile ducts. (1991 Chao TC, J Surg Oncol. 1991 Mar;46(3):145-50.)
** Retrospective. 37 patients, upper BD 38%, middle BD 43%, lower BD 19%.
** Mean OS: 11.2 months (upper 10.9 months, middle 9.4 months, lower 16.0 months)
* Hammersmith 1977-85 PMID 2162082 -- Outcome of radical surgery in hilar cholangiocarcinoma. (1990 Hadjis NS, Surgery. 1990 Jun;107(6):597-604.)
** Prospective local excision vs. partial liver excision. 27 patients with hilar CA
** Median survival: 29 months, no difference in type of surgery
* Hopkins PMID 2174191 -- Cholangiocarcinoma (1990 Yeo CJ, Surg Clin North Am 1990; 70:1429-47.)
** As many as half of all patients explored with curative intent will have a successful resection.
** The role of radiotherapy in the management of cholangiocarcinoma is uncertain. Our results, like those of many other retrospective analyses, suggest that radiotherapy prolongs survival after curative resection as well as after palliative stenting.
* Meta-analysis PMID 2204130 -- Research into the results of resection of hilar bile duct cancer. (1990 Boerma EJ, Surgery. 1990 Sep;108(3):572-80.)
** Meta-analysis. 581 patients reviewed, 499 since 1980.
** Operative mortality: overall 12%, perihilar 8%, major liver resections 15%
** 5-year OS: overall 13%, perihilar 7%, major liver resections 17%
** Conclusion: "Despite the best treatments available, present-day resection modalities are usually still not radical. Extension of resection in the retrohilar and hepatoduodenal direction might further improve the long-term surgical results."
* PMID 2449770 -- Extended right hepatic lobectomy, left hepatic lobectomy, and skeletonization resection for proximal bile duct cancer. (1988 Pinson CW, World J Surg. 1988 Feb;12(1):52-9.)
* Vanderbilt PMID 2420244 -- An aggressive surgical approach to bile duct cancer. (1986 Adkins RB, Am Surg. 1986 Mar;52(3):134-9.)
** 55 patients (1957-1985), 38% upper, 15% middle, 18% lower third
** Resection in 35%, decompression in 45%, no surgery 20%
** Median survival: 2.1 years resection, 7.7 months decompression, 4.6 months biopsy only
* Lahey PMID 3887621 -- Management of cancer of the bile duct. (1985 Rossi RL, Surg Clin North Am 1985; 65:59-78.)
** Resectability rate for bile duct tumor is currently 25 per cent. Resection is more frequently possible for tumor of the distal bile duct
** 5-year OS: proximal bile duct is anecdotal, distal bile duct is up to 30 per cent
* UCSF PMID 4049246 -- Carcinoma of the extrahepatic bile ducts: results of an aggressive surgical approach (1985 Langer JC, Surgery 1985; 98:752-9.)
** Retrospective, 90 patients (1969-1984)
** Resection 30% (22% proximal, 40% middle, 57% distal)
** RT used with resection and for palliation. Responses were observed, but the complication of radiation duodenitis has limited the dose.
** Conclusion: "An aggressive approach to resection of bile duct tumors is possible with a low operative mortality rate and offers the best opportunity for cure as well as good palliation. Internal bypass is preferable to chronic intubation. The role of radiation therapy in this disease is still not clear."
* PMID 7053662 -- Diagnosis and treatment of primary extrahepatic bile duct tumors. (1982 Chitwood, Am J Surg 1982; 143:99-106.
* PMID 4354116 -- Carcinoma of the extrahepatic biliary tract. (1973 Longmire WP, Ann Surg. 1973 Sep;178(3):333-45.)

### Review

PMID 12607583 -- Extent of resection and outcome after curative resection for intrahepatic cholangiocarcinoma. (2002 Kokudo, Surg Oncol Clin N Am. 2002 Oct;11(4):969-83.)

## Liver Transplantation

* Mayo
** 1993-2004 PMID 16135931 -- Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. (2005 Rea DJ, Ann Surg. 2005 Sep;242(3):451-8; discussion 458-61.)
*** Prospective. 71 patients on protocol (neoadjuvant RT, chemosensitization, orthotopic liver transplant), 38 patients underwent liver transplant. Compared with conventional resection 54 patients explored, 26 patients resected.
*** 5-year OS: liver transplant 82% vs. resection 21% (p=0.02)
*** Recurrenct: liver transplant 13% vs. resection 27%
*** Conclusion: "Liver transplantation with neoadjuvant chemoradiation achieved better survival with less recurrence than conventional resection and should be considered as an alternative to resection for patients with localized, node-negative hilar CCA."
** 1993-2003 PMID 15192792 -- Liver transplantation for unresectable perihilar cholangiocarcinoma. (2004 Heimbach JK, Semin Liver Dis. 2004 May;24(2):201-7.)
*** Prospective. 56 patients, Stage I/II perihilar CCA, treated with neoadjuvant EBRT + BT + 5-FU/capecitabine, followed by liver transplant
*** 4 died and 4 progression of disease prior to completion. 48 staged, 28 underwent transplant
*** 5-year actuarial survival: 54% for all patients, 64% for staged patients, 82% for transplant
*** Conclusion: "Neoadjuvant chemoradiotherapy with liver transplantation achieves excellent results for patients with localized, regional lymph node negative, hilar cholangiocarcinoma."
* Essen Germany PMID 15239635 -- 10-year tumor-free survival after intraoperative radiation therapy and secondary liver transplantation for hilar cholangiocarcinoma. (2004 Sotiropoulos GC, Transplantation. 2004 May 27;77(10):1625.)
** Case report. No abstract.
* Nebraska PMID 12243499 -- Radiochemotherapy and transplantation allow long-term survival for nonresectable hilar cholangiocarcinoma. (2002 Sudan D, Am J Transplant. 2002 Sep;2(8):774-9.)
** Prospective. 11 patients treated with 60 Gy BT + 5-FU, followed by transplantation
** 5/11 (45%) alive without recurrence with median follow-up 7.5 years (2.8-14.5)
** 6/11 (55%) died; 2 recurrence, 3 sepsis, 1 transplant rejection
** Conclusion: "Cholangiocarcinoma should not be considered an absolute exclusion criteria for orthotopic liver transplantation. Long-term, tumor-free survival was achieved in 45% of the transplanted patients. Complications of biliary catheter placement for brachytherapy were associated with poor outcome."
* Pittsburgh
** 1990-95 PMID 10219804 -- Radiotherapy and multimodality management of cholangiocarcinoma. (1999 Urego M, Int J Radiat Oncol Biol Phys 1999; 44:121-6.)
*** Retrospective. 61 patients, 38% resection +/- transplant, 62% palliative surgery/biopsy
*** All patients had RT (median dose 49.5 Gy), 50% received chemo (5-FU/Leucovorin/IFNalpha or taxol)
*** Median survival (5-year OS): 20 months (24%)
*** Only predictor of survival was complete resection
*** Conclusion: "Combined modality therapy that includes complete surgical resection with or without transplantation can be curative in the majority of patients with biliary duct carcinoma. Further study is needed to better define the roles of chemotherapy and radiotherapy in cholangiocarcinoma."
** 1981-96 PMID 9783781 -- Treatment of hilar cholangiocarcinoma (Klatskin tumors) with hepatic resection or transplantation. (1998 Iwatsuki S, J Am Coll Surg. 1998 Oct;187(4):358-64.)
*** Retrospective. 72 patients (34 hepatic resection, 38 resection)
*** 5-year OS: resection 9% vs. transplantation 25%
*** Prognostic factors: Stage 0-II, LN-, SM- (5-year OS 73%)
*** Conclusion: "Satisfactory longterm survivals can be obtained by curative surgery for hilar cholangiocarcinoma either with hepatic resection or liver transplantation. Redefining pTNM stage III and IV-A is proposed to better define prognosis."

## Palliative surgery

* Shanghai China 1997-2002 PMID 16083598 -- [Analysis of the relation between surgery and prognosis of hilar cholangiocarcinoma] - [Article in Chinese] (2005 Yi B, Zhonghua Wai Ke Za Zhi. 2005 Jul 1;43(13):842-5.)
* Retrospective. 198 patients treated, 61% resected, 30% radical resection.
* Conclusion: "For irresectable hilar cholangiocarcinoma, the effect of ERBD or EMBE could not be considered to be worse than that of open operative treatment."
* UCLA PMID 2434042 -- Proximal bile duct cancer. Quality of survival. (1987 Lai EC, Ann Surg. 1987 Feb;205(2):111-8.)
** Conclusion: "When noncurable disease is found on examination, operative intubation after dilatation is the preferred palliative measure" compared to palliative resection or bypass.

## Salvage

* Tsukuba Japan PMID 8325597 -- Long-term survivors after salvage surgery combined with radiotherapy for recurrence of stage IV main hepatic duct cancer--report of two cases. (1993 Todoroki T, Hepatogastroenterology. 1993 Jun;40(3):285-93.)
** Case report. Successful combined treatment with surgery + PORT or IORT+PORT
** Literature review of other cases