# Radiation Oncology/Bile duct/Adjuvant RT

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| Bile Duct: Main Page | Resectable Disease | Adjuvant RT | Unresectable Disease | Clinical Trials | | |
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.

## RT
### Intrahepatic (peripheral)

* 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"
* Paris VII France 1990-97 PMID 10398898 -- Resection of intrahepatic cholangiocarcinoma: a Western experience. (1999 Valverde A, J Hepatobiliary Pancreat Surg. 1999;6(2):122-7.)
** Retrospective. 42 patients, 30 curative resection
** Median survival: 28 months, 3 survivors > 5 years
** Adjuvant RT and/or CT had no impact on survival
** Conclusion: "Complete surgical resection may offer a chance for long-term survival in selected patients and may improve the quality of life of patients with more advanced disease."

### Perihilar

* UT MD Anderson 1984-2005 PMID 18754070 -- [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] (2008 Borghero,Y. 2008 Ann Surg Oncol Jul 15(11):3147-56.)
** Retrospective. 65 patients. Two groups compared, Surgery only n=23(had R0 and N0) and Surgery + Adjuvant CRT n=42 (had R1 and/or N1)
** Median (5-year) OS-5: S vs S-CRT 36% vs 42% p=NS LRR-5: 38% vs. 37%, P = .13
** Conclusion: "Our finding of a lack of a survival difference between the S and S-CRT groups suggests that for patients with extrahepatic bile duct adenocarcinoma at high risk for locoregional recurrence (i.e., R1 resection or pN1 disease), adjuvant chemoradiation provides an equivalent overall survival despite of these worse prognostic features."
* 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. Some treated with post-op RT (unclear)
** Post-op RT significant predictor of post-op survival (no numbers in abstract)
* Jefferson 1983-97 PMID 15685030 -- Positive microscopic margins alter outcome in lymph node-negative cholangiocarcinoma when resection is combined with adjuvant radiotherapy. (2005 Stein DE, Am J Clin Oncol. 2005 Feb;28(1):21-3.
** Retrospective. 16 patients treated post-op with RT (7 negative surgical margin, 9 positive surgical margin), average dose 53 Gy via both EBRT and BT; median follow-up 55 months
** Median (5-year) OS: margin (-) 21.5 months (18.4%) vs. margin (+) 26 months (15%), p=NS
** Conclusion: "Positive microscopic margins in lymph node-negative, resected hilar cholangiocarcinoma may not represent a negative prognostic factor when resection is combined with postoperative radiotherapy in this cohort."
* Miami 1985-97 PMID 11677948 -- Management of hilar bile duct carcinoma. (2001 Bathe OF, Hepatogastroenterology. 2001 Sep-Oct;48(41):1289-94.)
** Retrospective. 55 patients, 19 curative resection.
** 2-year survival longer in resection 47% vs. 18% (p=0.03)
** No benefit to RT (either postoperative RT or in unresectable disease)
** Conclusion: "Locoregional extent of disease is the greatest problem in cases of proximal bile duct cancers. Resection provides the best hope for long-term survival, but new adjuvant strategies are needed."
* 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 + EBRT 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."
* Amsterdam Netherlands PMID 9841770 -- Long-term survival after resection of proximal bile duct carcinoma (Klatskin tumors). (1999 Gerhards MF, World J Surg. 1999 Jan;23(1):91-6.)
** Retrospective. 12/79 surgically treated patients with >5 year survival evaluated
** No correlation with RT
** Conclusion: "Preoperative Bismuth classification of the tumor, absence of multifocality, diploid-type tumors, and negative proximal bile duct margins at histopathologic examination were the only significant prognostic factors for long-term survival"
* Hopkins 1988-93 PMID 7794082 -- Perihilar cholangiocarcinoma. Postoperative radiotherapy does not improve survival. (1995 Pitt HA, Ann Surg. 1995 Jun;221(6):788-97; discussion 797-8.)
** Prospective. 50 Pts w/ perihillar CA. Stratified by surgery (31 radical vs. 19 palliative) and RT (23 RT vs. 27 no RT)
** Resection improved the length (24.2 vs. 11.3 months, p < 0.05) and quality of survival.
** Radiation had *no* effect on the length (18.4 vs. 20.1 months) or quality of survival or on late toxicity.
** Conclusion: "This analysis suggests that in patients with localized perihilar cholangiocarcinoma, resection prolongs survival whereas radiation has no effect on either survival or late toxicity."
** Study insufficient to rule out post-op RT benefit in patients with complete surgical resection
* Amsterdam PMID 1648329 -- Does additive radiotherapy after hilar resection improve survival of cholangiocarcinoma? An analysis in sixty-four patients. (1991 Verbeek PC, Ann Chir. 1991;45(4):350-4.)
** Retrospective. 64 pts with Klatskin tumors, all had surgery. 29 post-op XRT, 22 resection only, and 13 postoperative deaths.
** Conclusion: Overall survival benefit for XRT (p<0.001)
* Hopkins PMID 1688486 -- Management of proximal cholangiocarcinomas by surgical resection and radiotherapy. (1990 Cameron JL, Am J Surg 1990; 159:91-7; discussion 97-8.)
** Retrospective. 96 patients, 55% resected (41% curative resection), 45% palliative stenting.
** 5-year OS: resected 8% vs. stented 0%
** RT given as EBRT 50-60Gy + some patients BT 2Gy boost: Adjuvant RT 72% (38/53), 51% BT boost;, palliative RT 58% (25/43), 10% BT boost
*** Adjuvant RT: 3-year OS 31% both groups (p=NS), but all long term survivors received RT
*** Palliative RT: 1-year OS 38% RT vs 9% no RT (p<0.05)
*** RT significantly extended survival in patients undergoing palliative stenting, but not in those undergoing resection.
** Conclusion: "We conclude that surgical resection of proximal cholangiocarcinomas can be performed safely and that it significantly prolongs survival."

### Distal bile duct

* Shanghai China 1996-2002 PMID 15196364 -- [Prognostic analysis of patients suffering from distal bile duct cancer] - [Article in Chinese] (2004 Sun LC, Zhonghua Wai Ke Za Zhi. 2004 May 7;42(9):528-31.)
** Retrospective. 173 of distal bile duct CA.
** Significant impact: surgical procedure, LN mets, and pathological grade
** No impact: transfusion, invasion of pancreas, postoperative radiotherapy and chemotherapy, ERCP, diameter of tumour, serum level of CA-19-9, preoperative total serum bilirubin level (TBIL), ratio of albumin to globulin (A/G), sex and age
** Conclusion: "Radical resection is only curative treatment modality. Aggressive treatment and prevention on postoperative liver metastasis is a important strategy to improve the survival for distal bile duct cancer."
* Tsukuba Japan PMID 11260100 -- Treatment strategy for patients with middle and lower third bile duct cancer. (2001 Todoroki T, Br J Surg. 2001 Mar;88(3):364-70.)
** 67 patients with middle/lower BDCA
** 5-year OS: 63% R0 vs. 16% R1 vs. 0% R2 vs. 0% no resection. R2 median survival longer (11.4 months) then no resection (3.5 months)
** RT improved 5-year OS in R1 patients (8% vs. 0%) but p=NS
** R0 relapse: 1 locoregional, 6 distant mets, 5 both. Liver most frequent mets
** Conclusion: "Curative (R0) resection is only one step in curing cancer, and radiotherapy may play a beneficial role in controlling locoregional residual tumour."

### Any location

* Pittsburgh 1983-97 PMID 12902899 -- Cholangiocarcinoma: the impact of tumor location and treatment strategy on outcome. (2003 Heron, Am J Clin Oncol. 2003 Aug;26(4):422-8.)
** Retrospective. 118 patients, treated with surgery, RT (EBRT or ILRT), surgery + RT, chemo, palliation, and combinations
** Mean survival: overall 22 months, proximal tumors 17 months vs. distal tumors 47 months
** Improved survival for surgery + RT vs surgery alone for proximal and distal lesions.
** Poor prognosis (3.5 months) for palliation only.
* Florida 1962-93 PMID 9822171 -- Carcinoma of the extrahepatic biliary tract: surgery and radiotherapy for curative and palliative intent. (1998 Zlotecki RA, Radiat Oncol Investig 1998; 6:240-7.)
** Retrospective. 47 patients, 17 surgery alone, 20 surgery + EBRT, 10 EBRT alone
** 5-year OS: 15%, surgery alone 15% vs. surgery + EBRT or EBRT alone 14%
** 5-year OS: gross total resection alone 19% vs. gross total resection + EBRT 35% (p=0.07)
** Median survival after EBRT alone: 6.4 months
** Conclusion: " Postoperative adjuvant radiotherapy was well tolerated and may improve local-regional control after gross total resection."
* Hopkins 1971-94 PMID 8857851 -- Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors. (1996 Nakeeb A, Ann Surg. 1996 Oct;224(4):463-73; discussion 473-5.)
** Retrospective. 294 patients, 6% intrahepatic, 67% perihilar, 27% distal tumors
** Resectability rate: 50% intrahepatic, 56% perihilar, 91% distal
** Median survival (5-year survival): intrahepatic 26 months (44%), perihilar 19 months (11%), and distal 22 months (28%)
** Post-op RT did not improve survival
** Conclusion: "Cholangiocarcinoma is best classified into three broad categories. Resection remains the primary treatment, whereas postoperative adjuvant radiation has no influence on survival."
* Jefferson 1983-1992 PMID 7480704 -- Cholangiocarcinoma: clinical significance of tumor location along the extrahepatic bile duct. (1995 Alden ME, Radiology. 1995 Nov;197(2):511-6.)
** Retrospective. 81 pts, 56 proximal, 25 distal. Median follow-up 28 months
** 5-year OS: proximal 13% vs. distal 53% (p<0.01)
** Proximal CA (RT or resection + RT or palliation): median survival no RT 6 mo vs. RT 17 mo (p=0.01). No benefit for resection in presence of RT
** Distal CA (resection +/- RT): no benefit for RT after resection
** Conclusion: "Patients with proximal cancer should undergo primary RT, and expectations should be limited. Patients with distal cancer should undergo resection, and RT may not be needed."
* UCSF 1977-1987 PMID 8147607 -- Carcinoma of the extrahepatic bile ducts. The University of California at San Francisco experience. (1994 Schoenthaler R, Ann Surg 1994; 219:267-74.)
** Retrospective. 129 patients, min 5 year follow-up. 48% surgery alone, 35% surgery + RT, 17% charged particles (helium/neon)
** Median survival: entire group 6.5/11/14 months, curative intent 16/16/23 months
** Patients with microscopic residual disease had increased median survival times when they were treated with adjuvant RT, most markedly after CP (p = 0.0005) but also with conventional XRT (p = 0.0109).
** Patients with gross residual disease had a less marked but still statistically significant extended survival (p = 0.05 for S + X and p = 0.0423 for S + CP) after RT
** Conclusion: "The mainstay of bile duct carcinoma management was maximal surgical resection in these patients. Postoperative radiotherapy gave patients with positive microscopic margins a significant survival advantage and may be of value in selected patients with gross disease."
* Wash U PMID 8159005 -- Multidisciplinary treatment of biliary tract cancers. (1994 Kraybill WG, J Surg Oncol 1994; 55:239-45.)
** Retrospective. 96 patients with GB or with biliary duct CA. Median survival 11 months
** Resection significantly (p=0.02) improved survival
** RT > 40Gy significantly (p=0.003) improved survival
* Hopkins 1973-89 PMID 1329453 -- Gastric and duodenal obstruction in patients with cholangiocarcinoma in the porta hepatis: increased prevalence after radiation therapy. (1992 Mogavero GT, AJR Am J Roentgenol. 1992 Nov;159(5):1001-3.)
** 96 patients resection or stenting, 66% received RT (49.6-72.2Gy)
** 7 patients developed gastric/duodenal obstruction, after evaluation presumed radiation fibrosis
** Conclusion: "Our experience suggests that radiation therapy increases the risk of postoperative gastric and duodenal obstruction in patients undergoing surgery for cholangiocarcinoma."
* Lyon Sud France 1980-88 PMID 1866463 -- Radiation therapy in extrahepatic bile duct carcinoma. (1991 Mahe M, Radiother Oncol. 1991 Jun;21(2):121-7.)
** Retrospective. 51 patients, 4 radical resection, 10 positive margins, 12 palliative resection, 10 biopsy, 15 no surgery
** RT curative (mean EBRT 45 Gy, ILRT 50-60 Gy) for radical/positive margin surgery, palliative (mean EBRT 35 Gy, ILRT 30 Gy)
** Median survival (3-year OS): 12 months (15%)
* 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
** Please see Radiation_Oncology/Bile_duct/Surgery for surgical details
** Adjuvant RT vs. surgery only no difference in survial
** However, total number of patients treated with RT in both adjuvant and palliative setting was 27
* Hyogo Japan PMID 1658858 -- Radiotherapy of postoperative residual tumor of bile duct carcinoma. (1991 Kurisu K, Radiat Med. 1991 Mar-Apr;9(2):82-4.)
** Case report of EBRT + HDR BT for residual tumor. Alive for ~3 years
** Conclusion: "HDRIBT following external irradiation is recommended for the treatment of postoperative small residual tumors of the bile duct."
* Pittsburgh 1976-88 PMID 2070327 -- Radiation therapy for primary carcinoma of the extrahepatic biliary system. An analysis of 63 cases. (1991 Flickinger JC, Cancer. 1991 Jul 15;68(2):289-94.)
** Retrospective. 63 (55 EHBD, 8 GB) patients treated with RT. 12 liver transplant, 13 chemo, 3 BT alone, 9 EBRT + BT
** Median survival: 7 months
** Conclusion: "Extrahepatic biliary duct cancers, the absence of metastases, increasing calendar year of treatment, and liver transplantation with postoperative radiation therapy were factors significantly associated with improved survival."
* Rotterdam PMID 2153649 -- The role of radiotherapy in the treatment of bile duct carcinoma. (1990 Veeze-Kuijpers B, Int J Radiat Oncol Biol Phys. 1990 Jan;18(1):63-7)
** Retrospective. 42 patients (11 microscopic positive margins after surgery, 31 unresectable) given EBRT + ILRT
** Median survival 10 months

## Brachytherapy

* Hokkaido Japan 1980-98 PMID 15976951 -- Effectiveness of radiation therapy after surgery for hilar cholangiocarcinoma. (2005 Sagawa N, Surg Today. 2005;35(7):548-52)
** Retrospective. 69 patients, 30 surgery alone vs. 39 surgery + adjuvant RT. Similar features in both groups.
** RT treatment: 31 EBRT (mean 37.2 Gy) + BT (mean 36.9 Gy) vs. 8 EBRT only (mean 37.5 Gy)
** 3-year survival: surgery + RT 41% vs. surgery alone 33% (p=NS)
** Subgroup analysis (by surgical margin, stage) no benefit to RT, except adjuvant RT with pStage III/IVa (p=0.04)
** 2 complications: stenosis of bile duct, venous bleeding from ostomy
** Conclusion: "Radiation therapy after surgery did not show any clinical benefits for patients with hilar cholangiocarcinoma. However, it may be effective as adjuvant therapy after curative resection in a small subgroup of patients with p-stage III or IVa disease."
* Amsterdam 1983-98 PMID 12616432 -- Results of postoperative radiotherapy for resectable hilar cholangiocarcinoma. (2003 Gerhards MF, World J Surg. 2003 Feb;27(2):173-9.)
** Retrospective. 112 patients underwent resection, 91 survived post-op. No RT in 20 patients, EBRT in 30 patients (median 46 Gy), 41 patients EBRT (median 42 Gy) + ILRT (median 10 Gy)
** 88% late complications; significantly more with RT
** Median survival: surgery only 8 months vs. surgery + RT 24 months, but no add'l benefit to ILRT
** Conclusion: "Additional radiotherapy after resection of hilar cholangiocarcinoma significantly improved survival and is recommended by giving external beam irradiation but not intraluminal brachytherapy."
* Maryland PMID 11202795 -- Postoperative endoscopic retrograde high dose-rate brachytherapy for cholangiocarcinoma. (2000 Ove R, Am J Clin Oncol. 2000 Dec;23(6):559-61.)
** Case report for nasobiliary route BT
* Amsterdam 1985-97 PMID 10436826 -- Role of radiotherapy, in particular intraluminal brachytherapy, in the treatment of proximal bile duct carcinoma. (1999 Gonzalez Gonzalez D, Ann Oncol. 1999;10 Suppl 4:215-20.)
** Retrospective. 109 patients received RT, 71 patients surgery + preop RT (19) or + post-op RT (52). Of these, 41 received 10 Gy ILRT boost. Median dose 50-55 Gy. 38 patients palliative RT, 19 received 22-25 ILRT Gy boost. Median dose 60-68 Gy.
** Median survival: surgery + RT 24 months vs. palliative 10.4 months
** Surgical patients: dose > 55 Gy had *lower* survival, and no benefit to brachytherapy
** Palliative patients: no benefit to brachytherapy
** Conclusion: "The role of radiotherapy either as adjuvant or as primary treatment remains to be demonstrated in prospective randomised studies. From our results, it seems that high radiation doses could be dangerous and could detriment prognosis. Brachytherapy boost was not superior to treatment with external beam irradiation alone."
* Hammersmith London PMID 8961369 -- External beam and intraluminal radiotherapy for locally advanced bile duct cancer: role and tolerability. (1996 Vallis KA, Radiother Oncol. 1996 Oct;41(1):61-6.)
** Prospective. 38 patients, various types of surgical treatment. Hyperfractionation schedule: 20 patients EBRT (6 patients 22.5 Gy 2.25 Gy/fx BID, 12 patients 45 Gy 2.25 Gy/fx BID, 1 patient EBRT 30 Gy conventional, 1 patient EBRT 50 Gy conventional). 14 patients EBRT (median 24 Gy) + BT (40 Gy). 4 patients BT alone (45 Gy @ 1cm)
** Toxicity: 1 patient acute Grade 3, 2 patients late GIB
** Conclusion: "Accelerated external beam radiotherapy with or without intraluminal radiotherapy is feasible and associated with acceptable toxicity when used in the management of advance cholangiocarcinoma."

## Charged particles

* UCSF PMID 8365945 -- Definitive postoperative irradiation of bile duct carcinoma with charged particles and/or photons. (1993 Schoenthaler R, Int J Radiat Oncol Biol Phys. 1993 Sep 1;27(1):75-82.)
** Retrospective. 62 patients, 77% treated post resection (62% XRT 54 Gy, 38% charged particles 60 Gy)
** Median survival (2-year OS): 12 months photons (18%) vs. 23 months particles (44%) p=0.048
** Conclusion: "Compared to conventional photon radiotherapy, treatment with post-operative charged particle irradiation at Lawrence Berkeley Laboratory appeared to offer a survival advantage in this non-randomized series."

## Late toxicity

* Sapporo Japan PMID 11148994 -- Biliary stricture as a possible late complication of radiation therapy. (2000 Nakakubo Y, Hepatogastroenterology. 2000 Nov-Dec;47(36):1531-2.)
** Case report. 11 years after resection with PORT, development of biliary stricture at site of RT