Gallbladder toxicity and high-dose ablative-intent radiation for liver tumors: Should we constrain the dose?
OBJECTIVE
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
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.
Department of Radiation Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
Shyam K
SK
Tanguturi
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Andrzej
A
Niemierko
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Jennifer Y
JY
Wo
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Khanhnhat N
KN
Nguyen
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Hugh
H
Prichard
Department of Medicine, Division of Hematology/Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
Andrew X
AX
Zhu
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
John A
JA
Wolfgang
Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address: TSHong1@partners.org.
Theodore S
TS
Hong
D000368:Aged; D002764:Cholecystitis / Q000209:etiology / Q000517:prevention & control*; D002769:Cholelithiasis / Q000150:complications; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005500:Follow-Up Studies; D005704:Gallbladder / Q000528:radiation effects*; D006801:Humans; D008099:Liver / Q000473:pathology / Q000528:radiation effects; D008113:Liver Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011832:Radiation Injuries / Q000209:etiology / Q000517:prevention & control*; D016634:Radiosurgery / Q000009:adverse effects* / Q000379:methods; D011879:Radiotherapy Dosage; D012189:Retrospective Studies