Predictors of Toxicity in a Randomized Study of Consolidation Chemoradiation Versus Observation After First Line Chemotherapy in Advanced Gall Bladder Cancers

Abstract

Purpose: Gall bladder cancers (GBC) usually presents in advanced stage. First-line chemotherapy (CT) is the standard of care, and there is no other option for responders than to wait for disease progression. We conducted a randomized study of consolidation chemoradiation (CTRT) versus observation in responders to first line CT (NCT05493956), which showed an improvement in overall survival by 6 months and therefore is practice changing. We are reporting the toxicity and factors predicting toxicity due to CTRT so that it informs appropriate patient selection. Methods and Materials: Responders to first line CT (partial response, stable disease) were randomized to CTRT versus observation after 4 cycles. CTRT was delivered by 3D conformal radiotherapy (along-with concurrent capecitabine at 1250 mg/m2) to a dose of 45 Gy in 25 fractions to GBC and lymphatics followed by a boost of 9 Gy in 5 fractions to the GBC. Toxicities documented during CTRT were recorded using the Radiation Therapy Oncology Group criteria. Dose volume data were correlated with the radiation induced side effects. Results: Among 135 patients enrolled both arms are well balanced demographically, and 58% patients had T4 tumors, 42% had N2 and 15% had paraaortic lymph node, and 27% underwent upfront stenting. Grade 3 adverse events, such as anemia, dyspepsia, hepatotoxicity (Child Pugh B), and gastrointestinal bleed due to CTRT was observed in 9%, 1.5%, 13%, and 5.8%, respectively. Age >58 years (P = .02), planning target volume (PTV) 1 volume (>919 cc, P = .02), PTV2 volume (>380 cc, P = .01), mean liver dose (>28 Gy, P = .07), and liver V40 (>50%, P = .02) predicted radiation-induced liver disease. A receiver operating curve analysis revealed a cut-off value of PTV1 volume of 800 cc (sensitivity and specificity of 75% and 54%) and PTV2 volume of 300 cc (sensitivity and specificity of 81% and 65%) for prediction of hepatotoxicity. Duodenum V45 >45% (P = .02) predicted grade 3 anemia. Numerically high V15 duodenum (98%, P = .11), large PTV2 volume >484 cc (P = .06) and prior stenting had predilection for gastrointestinal bleed. Conclusions: Consolidation CTRT is tolerable in those with PTV1 volume less than 800 cc.