Todoroki et al. [2] published a retrospective analysis of 63 patients who underwent resection of Klatskin tumors between 1976 and 1999. Forty-nine patients had R0 or R1 resections, of which 29 were treated adjuvantly with IORT, EBRT, or a combination. The 5-year survival was 33.9 % in the cohort that was treated with adjuvant radiation and 13.5 % in those who were observed (p < 0.01). Patients who had a combination of EBRT and IORT had better survival than those treated with either modality alone. Locoregional failure was diminished in the group that received adjuvant radiation: 20 % compared to 69 %. Initially, high toxicity rates were seen in the IORT group thought to be related to large single electron doses. These toxicities diminished after dose adjustment.

Likewise, a 2003 study by Gerhards et al. [3] suggested a survival benefit with adjuvant radiation. Ninety-one patients underwent mostly margin-positive surgical resection (86 %) for hilar cholangiocarcinoma, of which 71 received EBRT, intraluminal radiation, or a combination. The median survival for those that received radiation was 24 months, compared to 8 months in those observed (p < 0.01).

Most recently, Kim et al. [4] reported on 168 patients with extrahepatic biliary tract cancer who underwent resection between 2001 and 2009, of which approximately 70 % were margin negative. Postoperative chemoradiation with EBRT and concurrent 5-fluorouracil-based chemotherapy was administered to 115 of 168 patients. After a median follow-up of 33.8 months, the median survival was 36.4 months in the adjuvant treatment group, versus 27.9 months in the observation group, which was statistically significant on univariate analysis (p = 0.049) and multivariate analysis (p = 0.005). Likewise, locoregional failure was lower in the adjuvant treatment group on univariate analysis (41.5 vs. 55.6 %, p = 0.007) and multivariate analysis (p = 0.001). Other significant poor prognostic indicators on multivariate analysis included perineural invasion, vascular invasion, poor differentiation on histology, and positive resection margin.

Other series, however, were more equivocal in regard to benefit of adjuvant radiation therapy. Sagawa et al. [5], who reported on patients with hilar cholangiocarcinoma who underwent surgical resection, did not reveal an overall survival benefit in a subset that received adjuvant radiation. Of the 69 patients reported, approximately 50 % had R0 resections. Thirty-nine patients received EBRT with or without brachytherapy, and the others were observed. After a median follow-up of 32 months, 3-year survival was 40.9 % in the adjuvant therapy group compared to 33.3 % with surgery alone (p = 0.554).

Population studies have not demonstrated a clear benefit from adjuvant radiotherapy. In a Surveillance, Epidemiology and End Results (SEER) analysis by Shinohara et al. [6], 4,758 patients with extrahepatic cholangiocarcinomas treated with surgery or radiation between 1998 and 2003 were assessed for overall survival. Of these patients, 28.8 % underwent surgery alone, and 14.7 % underwent surgery and radiation therapy. Although the median survival was 16 months in the surgery and radiation group compared to 9 months with surgery alone (p < 0.0001), this did not hold after adjusting for potential confounders. A similar SEER analysis of patients with resected extrahepatic cholangiocarcinoma, which excluded patients with less than 3 months of follow-up, demonstrated no benefit from adjuvant radiation in local or locally advanced disease [7].

Gallbladder Cancer In the case of gallbladder cancer, there are fewer studies of adjuvant radiotherapy (Table 2). Like studies in extrahepatic cholangiocarcinoma, median survival in the majority of studies was approximately 2 years. Balachandran et al. [8] published a report on 117 patients with gallbladder cancer, of which only 37 underwent extended resections. Of the 117 patients, 73 received adjuvant chemoradiotherapy. Although no details were given regarding adjuvant chemoradiotherapy, the median survival for the adjuvant treatment group was 24 months compared to 11 months in the surgery-alone group (p = 0.001). Those patients who did not have extended surgical resections or had node-positive or T3 disease appeared to benefit more from adjuvant chemoradiotherapy.

A more recent study by Gold et al. [9] of 73 patients with stage I and II gallbladder cancer who underwent R0 resection reported a median survival approaching 5 years. In the 25 patients that received adjuvant chemoradiotherapy, which involved 50.4 Gy in 1.8 Gy per fraction with concurrent bolus 5-FU, the median survival was 4.8 years (vs. 4.2 years for surgery alone). Although not significant on univariate analysis (p = 0.56), overall survival was statistically improved with adjuvant chemoradiation on multivariate analysis, adjusting for T and N stages as well as pathologic diagnosis.

In 2008, Wang et al. [10] described a prediction model for gallbladder cancer using SEER data of 4,180 patients with resected disease, of whom 18 % received adjuvant radiation. In addition to factors such as age, histology, and stage of disease, adjuvant radiation was associated with a significant survival benefit on multivariate analysis. The median survival of those who received radiation therapy was 15 months, versus 8 months in those who did not. In the prediction model, the greatest benefit from adjuvant radiation therapy occurs in patients with T2 or node-positive disease.