Radiation Oncology/Bile duct/Resectable Disease

Surgery
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%, and as high as 50% in select series.

Resectability:
 * Intrahepatic: 30-50%
 * Perihilar: 25-79%
 * Distal bile duct: 56%

5-year survival:
 * Overall: 8-44%
 * Margin negative: 19-47%
 * Margin positive: 0-12%
 * Intrahepatic tumors: one series 60%
 * Perihilar tumors: as high as >50% but higher periop mortality (8-10%)
 * Distal tumors: 21-54% (but some series include periampullar tumors with better prognosis)

Liver transplantation no longer a treatment option outside research protocols due to high relapse rates. However, a protocol at Mayo (Rea 2005 below) appears promising for carefully selected patients.

Please see the Bile Duct/Surgery section for review of surgical literature.

Preoperative RT

 * Mayo 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."


 * 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."


 * Amsterdam Netherlands PMID 11016470 -- Prevention of implantation metastases after resection of proximal bile duct tumours with pre-operative low dose radiation therapy. (2000 Gerhards MF, Eur J Surg Oncol. 2000 Aug;26(5):480-5.)
 * Retrospective. 21 patients with proximal tumors given 3.5 Gy/fx x 3 fractions preop + biliary drainage, followed by resective surgery
 * No patients developed implantation mets (vs. 20% in previous study)
 * Conclusion : "The results of this study suggest that pre-operative radiotherapy in patients with a resectable proximal bile duct tumour who have undergone pre-operative drainage, decreases the risk of implantation metastases. To be certain about the role of pre-operative radiotherapy, a randomized study is required. Until then, we advocate standard low dose radiotherapy preceding resection in all patients with lesions suggestive of a proximal bile duct tumour who have undergone biliary drainage."


 * Utsunomiya Japan 1988-96 PMID 9537213 -- Preoperative radiotherapy for cancer of the extrahepatic bile duct. (1998 Hishinuma S, Am J Clin Oncol. 1998 Apr;21(2):203-8.)
 * Retrospective. 12 patients pre-op RT (40.6- 58.4 Gy), 11 surgery, 9 resection, 8 additional IORT
 * Complications: 4 patients, 3 post-op deaths
 * Conclusion : "The high complication rate requires modification of this strategy."


 * Louisville 1983-96 PMID 9409582 -- Neoadjuvant chemoradiation for extrahepatic cholangiocarcinoma. (1997 McMasters KM, Am J Surg. 1997 Dec;174(6):605-8; discussion 608-9.)
 * Retrospective. 91 patients, 40 resected (44%). Of these, 9 pre-op chemoradiation
 * Median survival: resected 22 months vs. palliative 10.7 months (p<0.0001)
 * Margin-negative resection: pre-op chemoradiation 100% vs. surgery alone 54% (p<0.01)
 * Conclusion : "These results suggest that preoperative chemoradiation for extrahepatic bile duct cancer can be performed safely, produces significant antitumor response, and may improve the ability to achieve tumor-free resection margins."


 * Amsterdam Netherlands PMID 9380186 -- [Pre- and postoperative irradiation in the treatment of resectable Klatskin tumours] - [Article in Dutch] (1997 van Gulik TM, Ned Tijdschr Geneeskd. 1997 Jul 5;141(27):1331-7.)
 * Retrospective. 71 patients, treated with 10.5 Gy pre-op RT, surgery, 48 post-op RT (55 Gy either EBRT or EBRT/BT) or 23 no post-op RT
 * RT statistically better survival (no numbers in abstract)
 * More complication from EBRT/BT therapy, but same survival
 * Conclusion : "Pre- and postoperative irradiation may contribute to the success of the treatment of the resectable Klatskin tumour."

Intraoperative RT

 * 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.


 * PMID 12210029 -- Treatment of nonresectable proximal bile duct carcinoma using intraoperative radiotherapy combined with hepatojejunostomy. (2002 Kaiser GM, J Surg Oncol. 2002 Sep;81(1):55-7.)
 * Case report. No abstract.


 * PMID 9263815 -- IORT of carcinoma of the extrahepatic bile ducts. (1997 Willborn K, Front Radiat Ther Oncol. 1997;31:173-6.)
 * No abstract.


 * Tsukuba Japan
 * PMID 10701737 -- Benefits of adjuvant radiotherapy after radical resection of locally advanced main hepatic duct carcinoma. (2000 Todoroki T, Int J Radiat Oncol Biol Phys. 2000 Feb 1;46(3):581-7.)
 * Retrospective. 63 pts with Klatskin IVA (T4, N0-1, M0) treated by radical resection.
 * 47 pts had microscopic + margins (R1). 28 of those received XRT (17 IORT + postop RT; 6 IORT only; 4 postop only)), 19 surgery only.
 * 5-year OS: surgery 13.5% vs. RT 33.9% (IORT + PORT 39.2%).
 * Locoregional control: surgery 31.2% vs. RT 79.2%
 * Conclusion : "Our data clearly suggest the improved prognosis of patients with locally advanced Klatskin tumor by integrated adjuvant radiotherapy with IORT and PORT to complete gross tumor resection with acceptable treatment mortality and morbidity."


 * PMID 2830731 -- The role of intraoperative radiation therapy in the treatment of bile duct cancer. (1988 Iwasaki, World J Surg. 1988 Feb;12(1):91-8.)
 * 81 patients. 50 resected (33 surgery, 14 +IORT, 3 +PORT). 31 not resected (6 +IORT, 4 +EBRT)
 * IORT (20 Gy) not used in curative resection (1 pt), only with incomplete resection (13 pts) or PTCD (6 pts)
 * 2-year OS: Non-curative resection + IORT 17.1% vs. resection alone 9.0%


 * PMID 3704902 -- Surgical treatment for carcinoma at the confluence of the major hepatic ducts. (1986 Iwasaki Y, Surg Gynecol Obstet. 1986 May;162(5):457-64.)
 * Retrospective. 46 pts, 22% curative resection, 24% palliative resection, 22% palliative resection + IORT, 32% bile duct drainage


 * PMID 7427860 -- Intraoperative radiotherapy for advanced carcinoma of the biliary system. (1980 Todoroki T, Cancer. 1980 Nov 15;46(10):2179-84.)
 * Case report 5 pts. IORT (25-30 Gy) for unresectable patients
 * Conclusion : "Intraoperative radiotherapy increased the effectiveness and length of palliation for the unresectable lesion."


 * Tokyo Japan 1976-96 PMID 10524416 -- Intraoperative radiotherapy for resectable extrahepatic bile duct cancer. (1999 Kurosaki H, Int J Radiat Oncol Biol Phys. 1999 Oct 1;45(3):635-8.)
 * Retrospective. 35 patients received IORT (15-30 Gy); 16 patients PORT (average 40.4 Gy)
 * Median survival (5-year OS): 19 months (19%)
 * Conclusion : "The combination of IORT and EBRT is useful for patients with bile duct cancer who undergo noncurative resection or who have lymph node metastasis."
 * RTOG PMID 1514529 -- Intraoperative radiation therapy of extrahepatic biliary carcinoma: a report of RTOG-8506. (1992 Wolkov HB, Am J Clin Oncol. 1992 Aug;15(4):323-7.)
 * Phase I/II. 23 patients entered, 16 patient eligible, 8 patients completed IORT protocol
 * No early Grade 3/4 toxicity, 1 late Grade 4 (perforated viscus) toxicity
 * No conclusions presented


 * Deaconess Boston PMID 2727900 -- Intraoperative radiation therapy for biliary tract carcinoma: results of a 5-year experience. (1989 Busse PM, Surgery. 1989 Jun;105(6):724-33.)
 * 15 patients with IORT (5-20 Gy), resected 2 patients, unresected 10 patients, recurrent 3 patients
 * Median survival: 14 months, operative mortality 13%
 * Conclusion : "This aggressive approach in the therapy for advanced disease has an acceptable level of morbidity and may warrant the use of IORT as part of the management of biliary tract cancer."

Adjuvant RT
There are no prospective randomized trials evaluating efficacy of adjuvant RT. Single institution retrospective studies seem to suggest some benefit to RT, particularly with higher doses (>45 Gy) and with microscopically positive margins (R1). The role of brachytherapy is similarly unclear.

Intrahepatic

 * 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. 373 patients with peripheral CCA (second order or more intrahepatic branches), 50% hepatectomy (36% curative resection). Please see more detail in surgical section
 * RT 63 patients vs. no RT 249 (not further discussed in text)
 * Median survival, 3-year OS, 5-year OS: RT 11.7 mo (16.6%, 6.6%) vs. no RT 6.2 mo (9.6%, 7.2%) (p=0.02)
 * 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"


 * Please see the Bile Duct/Adjuvant RT section for literature review.
 * Please see the Liver Cancer section for constraints on RT delivery

Combined modality therapy

 * Duke; 2009 (1992-2006) PMID 18805651 -- "Concurrent chemoradiotherapy in resected extrahepatic cholangiocarcinoma." (Nelson JW, Int J Radiat Oncol Biol Phys. 2009 Jan 1;73(1):148-53. Epub 2008 Sep 19.)
 * Retrospective. 45 patients, extrahepatic cholangio, curative resection. RT (median 50.4 Gy) + concurrent 5-FU based chemo. Neoadjuvant 12 patients felt to be borderline unresectable, adjuvant 33 patients. Brachy boost (mean 29 Gy) in 4 patients. R0 resection 80%, R1 13%, R2 7%. N0 75%. Median F/U 2.5 years
 * Outcome: 5-year LC 78%, DFS 37%, OS 33%. Median OS 2.8 years. Distal failure main problem. Neoadjuvant treatment potentially better (5-year OS 53% vs. 23%, p=0.16). No significant predictors of survival, though brachytherapy inferior outcome
 * Toxicity: Fatigue 80%, nausea 65%, anorexia 50%, abdominal pain 30%. No deaths
 * Conclusion: Possible local control benefit from combined chemo-RT and surgery. Preop CRT might be better


 * Wisconsin; 2002 (1990-2001) PMID 12407338 -- "Improved survival in resected biliary malignancies." (Nakeeb A, Surgery 2002; 132:555-63; discission 563-4.)
 * Retrospective. 140 biliary (111 cholangiocarcinoma, 29 gallbladder); 61% underwent exploration, 31% ultimately resected. Chemoradiation used more frequently since 1998
 * Resected 1998-2001 (n=25): 3-year survival 70%, median survival 44+ months
 * Resected 1990-1997 (n=19): 3-year survival 21%, median survival 13 months (p<0.01)
 * Conclusion: Improved outcomes with time, possibly due to careful surgical selection and adjuvant chemo-RT


 * Seoul; 2002 PMID 12243816 -- "Role of postoperative radiotherapy in the management of extrahepatic bile duct cancer." (Kim S, Int J Radiat Oncol Biol Phys 2002; 54:414-9.)
 * Retrospective. 84 surgical patients, 86% gross resection (65% negative margin), 14% subtotal/palliative resection. Median F/U 2 years
 * All patients received >40 Gy of external beam RT after surgery. In patients who underwent radical resection, the target volume was designed to include regional lymph nodes (porta hepatis, pancreaticoduodenal, and celiac axis lymph nodes). In patients who had gross residual disease, the target volume included both the tumor and the regional lymph node area with a margin of 2.5–3.0 cm beyond ductal involvement as demonstrated on cholangiogram and/or CT. Concurrent 5-FU administered during external beam RT in 71 patients, and maintenance chemotherapy was performed in 61 patients after RT completion.
 * OS: 2-year 52%, and 5-year 31%. N-stage only significant multivariate predictor (p=0.02)
 * Conclusion: Long-term survival feasible in patients with radical surgery and postop chemo-RT


 * South Florida; 2001 (1988-99) PMID 11565760 -- "Location, not staging, of cholangiocarcinoma determines the role for adjuvant chemoradiation therapy." (Serafini FM, Am Surg. 2001 Sep;67(9):839-43; discussion 843-4.)
 * Retrospective. 192 pts treated, 92 (48%) surgically. Of these, 38 patients had adjuvant CT/XRT vs. 50 no further treatment
 * Mean survival: adjuvant CT/XRT 42 months vs. no treatment 29 months (p=0.07)
 * Distal tumors mean survival: adjuvant CT/XRT 41 months vs. 25 months (p=0.04)
 * Conclusion : "Adjuvant chemoradiation improves survival after resection for cholangiocarcinoma (P = 0.07) particularly in patients undergoing resection for distal tumors (P = 0.04)."


 * 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."


 * ECOG PMID 7799024 -- Protracted intravenous fluorouracil infusion with radiation therapy in the management of localized pancreaticobiliary carcinoma: a phase I Eastern Cooperative Oncology Group Trial. (1995 Whittington R, J Clin Oncol 1995; 13:227-32.)
 * Phase I trial to determine maximum tolerated dose of 5-FU as continuous infusion + 59.4 Gy EBRT
 * Conclusion : "Concurrent radiation with protracted 5-FU infusion at 250 mg/m2/d is well tolerated and shows evidence of activity against tumors of the pancreas and biliary system."


 * MSKCC PMID 1951179 -- Extrahepatic biliary system cancer: an update of a combined modality approach. (1991 Minsky BD, Am J Clin Oncol. 1991 Oct;14(5):433-7.)
 * Retrospective. 12 patiens (1985-1990), 2 GB, 5 Klatskin, 5 CBD
 * Laparotomy + 50 Gy to tumor bed/LN (+ some received 15 Gy tumor bed boost) + 5FU/Mytomicin
 * Median survival: 17 months
 * Conclusion : "Our data continue to show that this approach is feasible and may result in an improvement in survival."


 * Padova Italy 1982-89 PMID 2057604 -- [Neoplasms of the gallbladder and the extrahepatic bile ducts: radio-chemotherapeutic combined treatment. Results in 18 treated cases] - [Article in Italian] (1991 Loreggian Radiol Med (Torino). 1991 May;81(5):714-7.)
 * Retrospective. 18 patients treated with surgery + RT + 5-FU
 * Mean survival: 16 months


 * MSKCC 1985-88 PMID 2347722 -- Combined modality therapy of extrahepatic biliary system cancer. (1990 Minsky BD, Int J Radiat Oncol Biol Phys. 1990 May;18(5):1157-63.)
 * Please see Minsky 1991 above for update.


 * PMID 73534 -- The role of radiation therapy in cancer of the extra-hepatic biliary system: an analysis of thirteen patients and a review of the literature of the effectiveness of surgery, chemotherapy and radiotherapy. (1977 Kopelson G, Int J Radiat Oncol Biol Phys. 1977 Sep-Oct;2(9-10):883-94.)
 * Review. ~30% resectable, ~50% of these recur