Chemoradiotherapy for patients with locally advanced or unresectable extra-hepatic biliary cancer

Abstract

Background: Although surgical resection is the preferred curative-intent treatment option for patients with non-metastatic, extra-hepatic biliary cancer (EBC), radiotherapy (RT) or chemoradiotherapy (CRT) may be utilized in select cases when surgical resection is not feasible. The purpose of this study is to report the efficacy and adverse events (AEs) associated with CRT for patients with locally advanced and unresectable EBC. Methods: This was a retrospective cohort study of patients with EBC, including extra-hepatic cholangiocarcinoma or gallbladder cancer, deemed inoperable who received RT between 1998 and 2018. The median RT dose was 50.4 Gy in 28 fractions and 94% received concurrent 5-fluorouracil. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS) from the start of RT. The cumulative incidence of local progression (LP), locoregional progression (LRP), and distant metastasis (DM) were reported with death as a competing risk. Cox proportional hazards regression models were used to assess for correlation between patient and treatment characteristics and outcomes. Results: Forty-eight patients were included for analysis. The median OS was 12.0 months [95% confidence interval (CI): 2.3-73.2 months]. The 2-, 3-, and 5-year OS were 33% (95% CI: 22-50%), 20% (95% CI: 11-36%), and 7% (95% CI: 2-20%), respectively. The 2-year PFS, LP, LRP, and DM were 21% (95% CI: 12-36%), 27% (95% CI: 17-44%), 31% (95% CI: 20-48%), and 33% (95% CI: 22-50%), respectively. On univariate analysis, biologically effective dose (BED) >59.5 Gy 10 was associated with improved OS [hazard ratio (HR): 0.40, 95% CI: 0.18-0.92, P=0.03] and PFS (HR: 0.37, 95% CI: 0.16-0.84, P=0.02) and primary tumor size (per 1 cm increase) was associated with worsened PFS (HR: 1.29, 95% CI: 1.02-1.63, P=0.04). BED >59.5 Gy 10 remained associated with PFS on multivariate analysis (HR: 0.34, 95% CI: 0.15-0.78, P=0.01). Treatment-related grade 3+ acute and late gastrointestinal AEs occurred in 13% and 17% of patients, respectively. Conclusions: RT is associated with 3-and 5-year survival in a subset of patients with unresectable EBC.Further exploration of the role of RT as part of a multi-modality curative treatment strategy is warranted.

Clinical outcomes for hilar and extrahepatic cholangiocarcinoma with adjuvant, definitive, or liver transplant-based neoadjuvant chemoradiotherapy strategies: a single-center experience

“…It would be reasonable to conclude that dCRT with traditional radiotherapy dose techniques and fluorouracilbased chemosensitization is not truly curative but instead only palliative. However, studies have demonstrated more promising outcomes when radiation dose escalation can be achieved safely (25).…”

American Radium Society (ARS) Appropriate Use Criteria (AUC) for Extrahepatic Cholangiocarcinoma

“…An alternative regimen, particularly before OLT, is 40.5 to 45 Gy in 1.5 Gy twice-daily fractions, followed by ILBT to a dose of 9.3 Gy with HDR brachytherapy or 20 Gy delivered over 20 to 25 hours with low dose rate brachytherapy, each prescribed to 1 cm depth 51,52,54,55. For definitive RT, doses of 45 to 60 Gy in 1.8 to 2.0 Gy fractions have most commonly been used 101–103,122,120. Hypofractionated regimens of 45 to 67.5 Gy in 15 fractions and 66 to 72 Gy in 10 to 22 fractions have also been used 104,106.…”

“…100,101 A single institution retrospective cohort study of 48 patients with unresectable EHCC treated with CRT found the 2-, 3-, and 5-year OS rates to 33% (95% CI: 22%-50%), 20% (95% CI: 11% to 36%), and 7% (95% CI: 2% to 20%), respectively, with a median OS of 12 months. 102 On univariate analysis, biologically effective dose (BED) > 59.5 Gy10 was associated with improved OS (HR = 0.40; 95% CI = 0.18-0.92; P = 0.03) and PFS (HR = 0.37; 95% CI = 0.16-0.84; P = 0.02), and on multivariate analysis it remained associated with PFS (HR = 0.34; 95% CI = 0.15-0.78; P = 0.01), suggesting a benefit to dose escalation for this disease. However, another retrospective series of 80 patients with unresectable EHCC failed to show a benefit to dose escalation.…”

“…51,52,54,55 For definitive RT, doses of 45 to 60 Gy in 1.8 to 2.0 Gy fractions have most commonly been used. [101][102][103]122,120 Hypofractionated regimens of 45 to 67.5 Gy in 15 fractions and 66 to 72 Gy in 10 to 22 fractions have also been used. 104,106 The most commonly reported regimens for SBRT have included 30 to 60 Gy in 3 to 5 fractions.…”

Non-surgical treatment of hilar cholangiocarcinoma

“…A retrospective analysis of 48 patients with gallbladder carcinoma and cholangiocarcinoma treated between 1998 and 2018 and a median radiotherapy dose of 50.4 Gy, achieved a median OS of 12.0 mo with OS at 2, 3, and 5 years of 33%, 20%, and 7%, respectively. In the univariate analysis, biologically effective dose (BED) > 59.5 Gy 10 was associated with improved PFS and OS and primary tumor size was associated with worsening PFS[ 44 ].…”