Radiation Oncology/Bile duct/Unresectable Disease

Patients are typically managed with bile duct stent placement to resolve/prevent malignant obstruction and jaundice. Role of radiotherapy is palliative, and involves both EBRT as well as brachytherapy. There are no prospective randomized studies to show benefit, but a number of single institution retrospective studies suggest palliative advantage. Similarly, the role of combined modality therapy is still under investigation. Photodynamic therapy appears to offer survival advantage over supportive care. Some long-term survival (20% at 4-years) with chemoradiotherapy (intraarterial 5-FU).

External Beam RT
The role of external beam RT in this setting is not clear. There are no randomized studies; most reports are single institution retrospective analyses. Some studies show some benefit (symptom relief and survival), while other do not. Some studies also show benefit for higher dose (>45 Gy).

For EBRT literature review, please see the Unresectable Disease/EBRT page.

3D-CRT / IMRT

 * U Chicago PMID 15145161 -- Intensity-modulated radiotherapy in treatment of pancreatic and bile duct malignancies: toxicity and clinical outcome. (2004 Milano MT, Int J Radiat Oncol Biol Phys. 2004 Jun 1;59(2):445-53.)
 * 25 patients (21 pancreas, 3 bile duct, 1 pancreatic neuroectodermal); median follow-up 10.2 months
 * Conclusion : "In this hypothesis-generating analysis, the acute and chronic toxicity profile with IMRT in the treatment of pancreatic and bile duct cancer was encouraging. Local control was not compromised, despite efforts to increase conformality and avoid doses to normal structures. Distant failure remains a major obstacle in pancreatic cancer."


 * Sikoku Japan PMID 15553012 -- Impact of pretreatment cholinesterase level on survival of inoperable intrahepatic or hepatic-hilar carcinomas treated with three-dimensional conformal radiotherapy (2004 Hamamoto Y, Radiat Med. 2004 Sep-Oct;22(5):316-23.)
 * Retrospective. 35 patients with HCC, intrahepatic cholangio and hilar cholangio treated with 3D-CRT (mean 51.5 Gy); mean follow-up 11 months
 * 2-year OS: HCC 19% vs. intrahepatic 26% vs. hilar 39%
 * Pre-treatment cholinesterase value only multivariate prognostic variable (p<0.01)
 * Conclusion : "Pre-3DCRT cholinesterase value was a significant independent prognostic indicator for survival. Benefit of dose escalation above 60 Gy could not be demonstrated."


 * MD Anderson 2000-03 PMID 15234062 -- Daily ultrasound-based image-guided targeting for radiotherapy of upper abdominal malignancies. (2004 Fuss M, Int J Radiat Oncol Biol Phys. 2004 Jul 15;59(4):1245-56.)
 * Retrospective. 62 patients with upper abdominal CA treated with IMRT (10 cholangio/GB)
 * Daily BAT U/S measurements in 1337 patient setups, mean setup time 4.6 min
 * Mean shift from skin mark position: 4.9, 6.0, and 6.0 mm (x, y, z)
 * Proportion alignments corrected by >10, >15, >20 mm: 49%, 25%, 13%
 * Conclusion : "Daily US-guided BAT targeting for patients with upper abdominal tumors was feasible in the vast majority of attempted setups. This method of US-based image-guided tumor targeting has been successfully implemented in clinical routine. The observed improved daily repositioning accuracy might allow for individualized reduction of safety margins and optional dose escalation. Compared with the established application of the BAT device for prostate radiotherapy, in which the target can be directly visualized, the TV in the present study was predominantly positioned relative to guidance vascular structures in close anatomic relation. We perceived an enormous potential in improved and individualized patient positioning for fractionated radiotherapy and also for stereotactic extracranial radiotherapy and radiosurgery, especially for tumors of the liver and pancreas."


 * Erlangen Germany PMID 15592694 -- Chemoradiation May Prolong Survival of Patients with Non-Bulky Unresectable Extrahepatic Biliary CarcinomaA Retrospective Analysis. (2004 Brunner TB, Strahlenther Onkol. 2004 Dec;180(12):751-757.)
 * Retrospective. 98 pts treated with stenting alone or chemoradiation (3D-CRT 50.8 Gy + 5-FU/Gemcitabine)
 * Median survival: overall 11.8 months, stenting alone 9.3 months, chemoradiation 16.5 months (p=NS)
 * Chemoradiation median survival: <40mm tumor 21.4 months vs. >40mm tumor 8.7 months (p=0.01). Toxicity reasonable.
 * Conclusion: "Inclusion criteria for future CRT trials should be based on tumor size at diagnosis: patients otherwise eligible for CRT should only be included with an inoperable tumor </= 40 mm, while patients with larger tumors may only benefit from palliation by stenting."


 * MD Anderson Cancer Center PMID 30152073 -- Dose escalation of radiotherapy in unresectable extrahepatic cholangiocarcinoma. (2018 Elganainy D, Cancer Med. 2018;00:1–13.)
 * Retrospective. 80 patients treated with standard doses or escalated doses of radiation therapy.
 * Median overall survival for all patients was 18.7 months. No significant difference in overall survival between patients who received standard doses vs patients who received escalated doses.
 * Toxicity: Generally treatment was well tolerated. Rate of Grade 3+ acute GI toxicities was 11%.
 * Conclusion: RT dose escalation does not appear to benefit patients with unresectable non-metastatic extrahepatic cholangiocarcinoma probably due to anatomic constraints.


 * Guangzhou China PMID 14625193 -- [Therapeutic effect of three-dimensional conformal radiotherapy on hilar cholangiocarcinoma] - [Article in Chinese] (2003 Wu DH, Di Yi Jun Yi Da Xue Xue Bao. 2003 Nov;23(11):1217-8.)
 * Retrospective. 21 patients treated with 3D-CRT
 * 52% achieved CR or PR, 3-year OS: 14%
 * Complications: 8 (38%) duodenal ulcer, 4 (19%) died of GI bleeding
 * Conclusion : "3D-CRT can be considered as a valuable palliative approach for unresectabe hilar cholangiocarcinoma, and effective management of the late complications of radiotherapy play a key role in increasing survival rates of the patients."


 * Bordeaux France PMID 11899677 -- [Conformal therapy of locally advanced cholangiocarcinoma of the main bile ducts] - [Article in French] (2002 Bouras N, Cancer Radiother. 2002 Feb;6(1):22-9.)
 * Retrospective. 23 patients, 8 after radical resection (R0 but LN+), 7 after microscopic margins (R1), 7 not resected. Dose 45-50 Gy, followed by boost up to 60 Gy; concomittant chemo in 15 cases
 * Late toxicity: stenosis of duodenum, stenosis of biliary anastamosis, 2 cholangitis deaths
 * Median survival (5-year OS): 16.5 months (7%); similar among subgroups
 * Conclusion : "Conformal radiochemotherapy delivering 60 Gy represents a valuable palliative approach in locally advanced biliary carcinoma."


 * Hokkaido Japan PMID 10974464 -- High-speed magnetic resonance imaging for four-dimensional treatment planning of conformal radiotherapy of moving body tumors. (2000 Shimizu S, Int J Radiat Oncol Biol Phys. 2000 Sep 1;48(2):471-4.)
 * High speed MRI to look at movement of implanted fiduciary markers during normal breathing
 * Movement: average 10.6mm CC, 5.2 mm lateral, 4.6 mm AP
 * If PTV determined during exhalation +10mm margin, CTV not covered in 19% of images
 * If PTV determined during inhalation +10mm margin, CTV not covered in 36% of images
 * Conclusion : "Four-dimensional treatment planning using high speed MRI, and integrating time and spatial information, has the potential to determine the planning target volume of moving body tumors more precisely than does conventional CT planning."


 * Review PMID 10436827 -- Conformal irradiation for hepatobiliary malignancies. (1999 Gunderson LL, Ann Oncol. 1999;10 Suppl 4:221-5.)
 * Data presented from U Michigan. Conformal high dose EBRT (48-72.6 Gy) for (HCC) and intrahepatic cholangiocarcinoma (IHCC) to potentially increase local control and survival, over what would be expected with lower dose EBRT.


 * U Michigan PMID 9392548 -- A phase I trial of hepatic arterial bromodeoxyuridine and conformal radiation therapy for patients with primary hepatobiliary cancers or colorectal liver metastases. (1997 Robertson JM, Int J Radiat Oncol Biol Phys. 1997 Dec 1;39(5):1087-92.)
 * Phase I conformal EBRT with dose escalation of BrDU. Unresectable primary hepatobiliary CA or liver mets. RT dose (24, 48, 66) determined by fractionated volume of liver irradiated. 41 patients (18 CRC liver mets, 16 cholangiocarcinoma and 7 hepatoma)
 * Response rates were not improved compared to our previous experience.
 * Conclusion : "The appropriate dose of HA BrdU for Phase II evaluation is 25 mg/kg/day. Neither the hepatic parenchyma nor the gastrointestinal mucosa appeared to be sensitized by this method of BrdU administration. It is anticipated that these, or still newer methods of therapy, can improve treatment results in the near future."


 * U Michigan PMID 8742902 -- 3-D conformal radiation therapy in upper gastrointestinal cancer. The University of Michigan experience. (1996 Lawrence TS, Front Radiat Ther Oncol. 1996;29:221-8.)
 * No Abstract


 * U Michigan PMID 8391066 -- Treatment of primary hepatobiliary cancers with conformal radiation therapy and regional chemotherapy. (1993 Robertson JM, J Clin Oncol. 1993 Jul;11(7):1286-93.)
 * Retrospective. 26 patients treated with concurrent intraarterial FdUrd and conformal RT (1.5-1.65 Gy/fx bid, dose 48-72.6 Gy), 6 diffuse HCC, 11 localized HCC, 9 cholangiocarcinoma
 * Median survival for localized disease: 19 months
 * Conclusion : "These findings suggest that three-dimensional planned focal liver radiation and IAH FdUrd can produce a high, durable response rate and an encouraging median survival duration in patients with nondiffuse, unresectable primary hepatobiliary cancer."

Stereotactic radiosurgery

 * Stanford ASTRO Abstract Phase I Dose Escalation Study of CyberKnife Stereotactic Radiosurgery for Liver Malignancies (2005 Lieskovsky YC, ASTRO 2005 #2089)
 * Phase I. 6 patients/7 tumors (1 IH-CCA, 7 mets). Tumors <5cm. Treatment delivered with motion tracking of implanted fiducials
 * Dose escalation: 3 tumors with 18 Gy, 4 tumors with 22 Gy. MTD not reached. Toxicity: 1 GI Grade 1
 * Response: 4 PR
 * Conclusion : "Results thus far indicate that single fractions of 18 and 22 Gy are safe to administer to liver tumors with the CyberKnife. We have not yet reached the MTD at 22 Gy. We plan to dose-escalate to 30 Gy."


 * Freiburg Germany PMID 16097074 -- Klatskin tumor treated by inter-disciplinary therapies including stereotactic radiotherapy: a case report. (2005 Becker G, World J Gastroenterol. 2005 Aug 21;11(31):4923-6.)
 * Case report. 1 patient with Stage III unresectable Klatskin tumor
 * Total dose 48 Gy (3X4 Gy/wk), therapy was well tolerated.
 * Conclusion : "In the context of inter-disciplinary treatment concepts, this radiotherapy technique is a promising choice of treatment for patients with hilar CCC."

Brachytherapy
Literature review is available at the Unresectable Disease/Brachytherapy page. There are several dozen retrospective single-institution studies. Overall, the trend is toward BT having some benefit in terms of obstruction, and even survival. Howerver, randomized trials are lacking.

Please also see the Malignant Biliary Obstruction section.

Intraoperative RT

 * Mayo PMID 1341262 -- Intraoperative radiotherapy for unresectable cholangiocarcinoma--the Mayo Clinic experience. (1992 Monson JR, Surg Oncol. 1992 Aug;1(4):283-90.)
 * Retrospective. 13 patients treated with EBRT + IORT + stenting
 * Local failure in 50%; morbidity related to biliary sepsis and GI complications
 * Median survival: 16.5 months
 * Conclusion : "Although the median survival of 16.5 months seemed to be an improvement over our previous results for ERT alone or ERT with 5-fluorouracil, the survival data are still discouraging."


 * Tsukuba Japan 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%


 * Tsukuba Japan 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
 * Mean survival: 10.9 months (2 patients living 16+ and 18+ months)
 * Conclusion : "Intraoperative radiotherapy increased the effectiveness and length of palliation for the unresectable lesion."

Proton therapy

 * PSI; 2000 PMID 10924999 -- "The role of proton therapy in the treatment of large irradiation volumes: a comparative planning study of pancreatic and biliary tumors." (Zurlo A, Int J Radiat Oncol Biol Phys. 2000 Aug 1;48(1):277-88.)
 * Treatment planning. 4 patients (2 pancreatic, 2 biliary). IMRT vs PT vs IMPT. RT 50 Gy + 20 Gy boost
 * Outcome: Protons better dose conformality to PTV and better dose homogeneity, except in post-op case
 * Conclusion: Proton therapy superior dose distribution compared to IMRT

Combined Modality

 * Italy 1991-97
 * PMID 16242254 -- Chemoradiation and brachytherapy in biliary tract carcinoma: long-term results. (2005 Deodato F, Int J Radiat Oncol Biol Phys. 2005 Oct 18; [Epub ahead of print])
 * 22 patients (17 unresectable, 5 residual; 13 perihilar, 8 distal, 1 GB) treated with EBRT (39.6-50.4 Gy) + 5-FU; 12 also BT (30-50 Gy @ 1cm)
 * 45% Grade I/II GI toxicity; 2 with EBRT + BT developed duodenal ulceration
 * Median survival: unresectable tumors 13.0 months (EBRT+BT) or 22.0 (EBRT alone), p=NS
 * Conclusion : "This study confirmed the role of concurrent chemoradiation in advanced biliary carcinoma; the role of intraluminal brachytherapy boost remains to be further analyzed in larger clinical trials."
 * PMID 10705013 -- Combined modality treatment in unresectable extrahepatic biliary carcinoma. (2000 Morganti AG, Int J Radiat Oncol Biol Phys 2000; 46:913-9.)
 * 20 patients with noncurative, nonmetastatic disease treated with EBRT (39.6-50.4 Gy), 19 also received 5-FU. 12 (60%) received ILRT (30-50 Gy) boost
 * Median survival: 21.2 months; distant mets in 50% of patients
 * 2 patients with EBRT + ILRT developed late duodenal ulceration
 * Conclusion : "Our data suggest that chemoradiation plus intraluminal brachytherapy was relatively well-tolerated, and resulted in reasonable local control and median survival."


 * Feldkirch Austria PMID 16101189 -- Radiotherapy and razoxane in advanced bile duct carcinomas. (2005 Rhomberg W, Anticancer Res. 2005 Sep-Oct;25(5):3613-8.
 * Prospective. 23 patients EBRT (median 48 Gy) + radiosensitization with razoxane
 * Overall response rate 64%, local control 75%.
 * Side effects: N/V Grade I/II in 61%, leukopenia Grade III/IV 9%
 * Conclusion : "Combined radiotherapy and razoxane led to local response rates which are superior to data from the literature when radiotherapy alone is used. Obstacles to the treatment were complications of the disease and frequent metastasis."


 * Washington University 1999-2002 PMID 15923794 -- A phase II study of alternating cycles of split course radiation therapy and gemcitabine chemotherapy for inoperable pancreatic or biliary tract carcinoma. (2005 Lin LL, Am J Clin Oncol. 2005 Jun;28(3):234-41.)
 * Phase II. 42 patients (40 pancreas, 1 GB, 1 CCA) treated with 3 6-wk courses: (gemcitabine x 2 weeks, 1 week break, RT 50.4 Gy x2 weeks, 1 week break) x 3 courses; followed by resection if response
 * Toxicity: 4 patients Grade 3/4 toxicity
 * 10 PRs, 6 underwent resection; Median survival: 9.5 months (2-32.5)
 * Conclusion : "Alternating cycles of split-course radiotherapy and gemcitabine chemotherapy permits the delivery of full doses of both modalities with acceptable tolerance."


 * Tokyo Japan PMID 16015690 -- Thermo-chemo-radiotherapy for advanced bile duct carcinoma. (2005 Kamisawa T, World J Gastroenterol. 2005 Jul 21;11(27):4206-9.)
 * Retrospective. 8 patients advanced disease and obstructive jaundice, treated with RT + RF heating to 42C + 5-FU+Cisplatin/MTX
 * Mean survival: 13.2 months, 4 patients >20 months. 3CR / 2PR / 3 no change
 * Conclusion : "Although the number of cases is rather small, TCRT in the treatment of locally advanced bile duct carcinoma is promising in raising local control and thus, long-term survival."


 * Erlangen Germany PMID 15592694 -- Chemoradiation May Prolong Survival of Patients with Non-Bulky Unresectable Extrahepatic Biliary CarcinomaA Retrospective Analysis. (2004 Brunner TB, Strahlenther Onkol. 2004 Dec;180(12):751-757.)
 * Retrospective. 98 pts treated with stenting alone or chemoradiation (3D-CRT 50.8 Gy + 5-FU/Gemcitabine)
 * Median survival: overall 11.8 months, stenting alone 9.3 months, chemoradiation 16.5 months (p=NS)
 * Chemoradiation median survival: <40mm tumor 21.4 months vs. >40mm tumor 8.7 months (p=0.01). Toxicity reasonable.
 * Conclusion : "Inclusion criteria for future CRT trials should be based on tumor size at diagnosis: patients otherwise eligible for CRT should only be included with an inoperable tumor </= 40 mm, while patients with larger tumors may only benefit from palliation by stenting."


 * Oita Japan 1993-2002 PMID 15160347 -- Radiotherapy combined with transarterial infusion chemotherapy and concurrent infusion of a vasoconstrictor agent for nonresectable advanced hepatic hilar duct carcinoma. (2004 Matsumoto S, Cancer. 2004 Jun 1;100(11):2422-9.)
 * Retrospective. 23 patients treated with EBRT (mean 41.4 Gy) + transarterial infusion of epirubicin/mitomycin C/5-FU
 * Response rate 41%. OS 1 year (59%), 2 years (36%), and 3 years (18%)
 * Conclusion : "The combination of radiotherapy, transarterial infusion chemotherapy, and concurrent infusion of a vasoconstrictor can be delivered safely with good efficacy for patients with advanced hilar duct carcinoma."


 * Italy PMID 12972696 -- Concomitant gemcitabine (Gemzar) and extended nodes irradiation in the treatment of pancreatic and biliary carcinoma: a phase I study. (2003 Morganti AG, Onkologie. 2003 Aug;26(4):325-9.)
 * Phase I dose escalation. 15 patients (5 after radical resection). EBRT using 3F technique + gemcitabine short infusion once/week
 * No dose-limiting toxicity at gemcitabine 100-250mg/m2. 3 DLTs at 300 mg/m2
 * 6 patients stable disease, 4 patients progressive disease
 * Conclusion : "Based on this study, the recommended dose for weekly short infusional gemcitabine combined with radiation therapy to the tumor and lymph nodes is 250 mg/m(2). This value is suggestive of a correlation between acute toxicity and inclusion of lymph nodes in the irradiated volume."


 * MD Anderson 1957-2000 PMID 12095564 -- Limitations of conventional doses of chemoradiation for unresectable biliary cancer. (2002 Crane CH, Int J Radiat Oncol Biol Phys. 2002 Jul 15;53(4):969-74.
 * Retrospective. 52 patients treated with RT +/- chemo. Pts grouped by dose: 30 Gy (52%) vs. 36-50.4 Gy (27%) vs. 54-85 Gy (21%). Additionally, 73% received protracted venous 5-FU infusion
 * Median time to radiographic progression: 9 months vs. 11 months vs. 15 months (p=NS)
 * Median survival: 10 months
 * No variables (RT dose, chemo, grade, size) had influence on progression or OS
 * Conclusion : "The primary limitation of definitive chemoradiation was local progression. Although the small patient numbers limited the statistical power of this study, a suggestion of improved local control was found with the use of higher RT doses."


 * Mie Japan PMID 11788896 -- Clinical efficacy of brachytherapy combined with external-beam radiotherapy and repeated arterial infusion chemotherapy in patients with unresectable extrahepatic bile duct cancer. (2002 Nomura M, Int J Oncol. 2002 Feb;20(2):325-31.)
 * Retrospective. 17 patients treated with BT alone (5), BT+EBRT (12), HA infusion (1), or HA infusion+BT+EBRT (6)
 * Mean survival: BT alone 4.6 months vs. HA infusion+BT 16.2 months (p<0.01)
 * RT >50 Gy resulted in radiation gastritis
 * Conclusion : "Brachytherapy combined with external-beam radiotherapy and repeated hepatic arterial infusion chemotherapy increases survival compared with brachytherapy alone in patients with unresectable bile duct cancer."


 * Michigan PMID 9069303 -- Long-term results of hepatic artery fluorodeoxyuridine and conformal radiation therapy for primary hepatobiliary cancers. (1997 Robertson JM, Int J Radiat Oncol Biol Phys. 1997 Jan 15;37(2):325-30.)
 * Retrospective. 22 patients (11 HCC and 11 cholangio) with unresectable tumors, treated with concurrent HA FdUrd + conformal EBRT (48-66 Gy)
 * Median survival (4-year OS): 16 months (20%)
 * Conclusion : "Combined conformal RT and HA FdUrd can produce long-term freedom from hepatic progression and survival in patients with unresectable, nondiffuse primary hepatobiliary malignancies. There were no long-term liver complications observed."


 * Princess Margaret PMID 8567347 -- A phase I study of combined radiation therapy with 5-fluorouracil and low dose folinic acid in patients with locally advanced pancreatic or biliary carcinoma. (1996 Hsue V, Int J Radiat Oncol Biol Phys. 1996 Jan 15;34(2):445-50.)
 * Phase I. 27 patients (pancreas 19, BD 7, GB 1). EBRT split course 40 Gy (20 Gy in 10 fxs, 2 weeks, 20 Gy in 10 fxs) + 5-FU (300-375) + folinic acid.
 * Toxicity: 8 patients Grade 3/4, 4 did not complete treatment, 2 treatment deaths to septic neutropenia
 * Conclusion : "This protocol is poorly tolerated by elderly patients or those with poor performance status, and 350 mg/m2/day is our recommended dose for 5FU as given in this protocol."


 * Jefferson 1984-90 PMID 8138448 -- The impact of radiation dose in combined external beam and intraluminal Ir-192 brachytherapy for bile duct cancer. (1994 Alden ME, Int J Radiat Oncol Biol Phys. 1994 Mar 1;28(4):945-51)
 * Retrospective. 48 patients treated, 24 received RT (EBRT mean 46Gy + ILRT 192Ir mean 25 Gy) + CT (5FU +/- Adriamycin/Mitomycin)
 * Mean survival (2-year OS): no RT 5.5 mo (17%) vs. CMT 12 mo (30%) p=0.01
 * Mean survival (2-year OS): RT <55 Gy 6 mo (0%) vs. RT >55 Gy 24 mo (48%) p=0.003. Dose response suggested
 * Conclusion : "A dose response is shown with more than double the 2-year and median survival for doses > 55 Gy. A brachytherapy dose of 25 Gy, plus 44-46 Gy external beam is well tolerated. High dose combined brachytherapy and external beam radiation (60-75 Gy) appears to be the most effective modality for extrahepatic bile duct cancer."


 * Med Col Ohio PMID 3756765 -- 125I interstitial implant, precision high-dose external beam therapy, and 5-FU for unresectable adenocarcinoma of pancreas and extrahepatic biliary tree. (1986 Dobelbower RR, Cancer. 1986 Nov 15;58(10):2185-95.)
 * 14 patients (2 EHBD, 12 pancreas) treated with EBRT (48.6-63 Gy) + BT (median 140 Gy) + 5FU
 * Acute morbidity: 2 pancreatic fistula, 1 GIB, 1 PE, 1 cholangitis
 * Case presentation of 2 EHBD patients


 * PMID 4186452 -- Combined 5-fluorouracil and supervoltage radiation therapy of locally unresectable gastrointestinal cancer. (1969 Moertel CG, Lancet. 1969 Oct 25;2(7626):865-7.)

Targeted therapy

 * MSKCC PMID 16138120 -- Treatment of cholangiocarcinoma with oncolytic herpes simplex virus combined with external beam radiation therapy. (2005 Jarnagin WR, Cancer Gene Ther. 2005 Sep 2; [Epub ahead of print])
 * Cell lines.
 * Conclusion : "Combined XRT and oncolytic viral therapy is a potentially important treatment strategy that may enhance the therapeutic ratios of both individual therapies.)


 * Hopkins PMID 1657845 -- Variable low dose rate irradiation (131I-anti-CEA) and integrated low dose chemotherapy in the treatment of nonresectable primary intrahepatic cholangiocarcinoma. (1991 Stillwagon GB, Int J Radiat Oncol Biol Phys. 1991 Nov;21(6):1601-5.)
 * 24 patients prospectively treated with induction (RT 21 Gy @ 3 Gy/fx + doxorubicin + 5-FU), followed one month later by doxorubicin + cisplatin + 131I anti-CEA), repeated q 2 months
 * Toxicity: Grade 4 thrombocytopenia (17%) and leukopenia (4%)
 * Median survival: 10.1 months (compared with prior protocol 6.5 months)


 * RTOG PMID 6085756 -- Comparative tumor dose from 131I-labeled polyclonal anti-ferritin, anti-AFP, and anti-CEA in primary liver cancers. (1984 Leichner PK, Cancer Drug Deliv. 1984 Fall;1(4):321-8.)
 * Dosimetric studies for 30 patients with HCC and 5 patients with hepatic CCA.
 * Hepatoma (30 mCi day 0, 20 mCi day 5): mean dose anti-ferritin 11 Gy, anti-AFP 3.5 Gy, combination anti-ferritin/anti-AFP 9.6 Gy
 * CCA (20 mCi day 0, 10 mCi day 5): mean dose 6.2 Gy
 * Total-body irradiation for these injection schedules ranged from 0.3 to 0.50 Gy

Chemotherapy

 * Yonsei Korea PMID 16294346 -- Capecitabine combined with gemcitabine (CapGem) as first-line treatment in patients with advanced/metastatic biliary tract carcinoma. (2005 Cho JY, Cancer. 2005 Nov 17; [Epub ahead of print])
 * Phase II. 44 patients. Oral capecitabine + gemcitabine (CapGem) as first line therapy.
 * Response: 32% PR, 34% SD. Median OS 14 months
 * Toxicity: No Grade 4, transient Grade 3 heme
 * Conclusion : "CapGem is an active and well tolerated first-line combination chemotherapy regimen for patients with advanced/metastatic biliary tract carcinoma that offers a convenient home-based therapy."


 * NCC Japan PMID 16142487 -- Phase II study of single-agent gemcitabine in patients with advanced biliary tract cancer. (2005 Okusaka T, Cancer Chemother Pharmacol. 2005 Sep 2;:1-7 [Epub ahead of print])
 * Phase II. 40 patients. Gemcitabine 1000mg/m2 over 30 min qw
 * Response: 7% PR, 37% SD, 42% PD. Median survival 7.6 months
 * Toxicity: Grade 3/4 30% neutropenia, 12% leukopenia, 10% anemia, 15% liver
 * Conclusion : "In single-agent therapy, gemcitabine demonstrated moderate efficacy with manageable toxicity in patients with advanced or metastatic biliary tract cancer. Further evaluations are warranted, including the exact impact of gemcitabine on the management of advanced or metastatic biliary tract cancer."


 * Munich Germany PMID 15949047 -- Phase II trial of weekly 24-hour infusion of gemcitabine in patients with advanced gallbladder and biliary tract carcinoma. (2005 von Delius S, BMC Cancer. 2005 Jun 12;5(1):61.)
 * Phase I. 19 patients. Gemcitabine 100mg/m2 24 hour infusion on day 1, 8, 15 q28 days until progression
 * Response: 6% PR, 61% SD. Median OS 7.5 months
 * Toxicity: moderate myelosuppression
 * Conclusion : "Weekly 24-hour gemcitabine at a dose of 100 mg/m2 is well tolerated. There was a relatively high rate of disease control for a median duration of 5.3 months (range 2.8-18.8 months). However, the objective response rate of this regimen in gallbladder and biliary tract carcinomas was limited."

Malignant Biliary Obstruction
Please see the Malignant Biliary Obstruction section.

Photodynamic Therapy

 * CHUV Switzerland PMID 14598251 -- Successful photodynamic therapy for nonresectable cholangiocarcinoma: a randomized prospective study. (2003 Ortner ME, Gastroenterology. 2003 Nov;125(5):1355-63.)
 * Prospective randomized open-label. 39 patients with unresectable CCA, 20 to stenting + PDT vs. 19 to stenting alone
 * Median survival: stent + PDT 16.4 months vs. stent alone 3.3 months (p<0.001); Also improvement in biliary drainage and quality of life
 * Conclusion : "PDT, given in addition to best supportive care, improves survival in patients with NCC. The study was terminated prematurely because PDT proved to be so superior to simple stenting treatment that further randomization was deemed unethical."