Gallbladder toxicity and high-dose ablative-intent radiation for liver tumors: Should we constrain the dose?

Abstract

Purpose: Little is known about the risk of gallbladder toxicity from hypofractionated (HFXRT) and stereotactic body radiation therapy (SBRT). We report on gallbladder toxicity and attribution to treatment in a prospective series of patients with primary and metastatic liver tumors receiving ablative-intent HFXRT and SBRT with protons.

Methods and materials: We evaluated 93 patients with intact gallbladders enrolled in either of 2 trials investigating proton HFXRT and SBRT for primary and metastatic liver tumors from 2009 to 2014. Patients received 45 to 67.5 GyE in 15 fractions for primary liver tumors (n = 45) and 30 to 50 GyE in 5 fractions for metastatic tumors (n = 48). No gallbladder dose constraints were used at treatment, and gallbladder volumes and dose-volume histograms were created retrospectively. Attributable toxicity was defined as cholecystitis or perforation without preexisting gallbladder disease. Baseline factors were evaluated using Fisher exact test and the nonparametric K-sample test.

Results: At baseline, 25 patients had preexisting cholelithiasis and 15 underwent biliary stenting before or after RT. Median follow-up after treatment was 11.8 months (range, 0.1-59.2 months). Despite maximum gallbladder doses >70 GyE in 41%, >80 GyE in 31%, and >90 GyE in 13% (equieffective dose at 2 Gy [EQD2], α/β = 3), there were no attributable cases of gallbladder toxicity. Two patients developed grade 3 and 4 cholecystitis 16 and 2 months after treatment, respectively, and both had a strong history of preexisting cholelithiasis and biliary stenting. These patients received relatively low gallbladder doses with mean doses of 0.02 GyE and 5.1 GyE (EQD2, α/β = 3), well below the 17.1 GyE mean for the remaining cohort (range, 0-81.1 GyE, EQD2).

Conclusions: We identified no relationship between gallbladder dose and toxicity and did not reach the maximum tolerated gallbladder dose in this cohort treated with high-dose radiation. We recommend not constraining dose to the gross tumor volume to protect the gallbladder during ablative HFXRT and SBRT.