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

Abstract

PURPOSEGBC usually presents in advanced stage. First-line CT is the standard of care and there is no other option for responders than to wait for disease progression. We conducted a randomised study of consolidation 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. MATERIALS & METHODSResponders to first line CT (partial response, stable disease) were randomised to CTRT versus observation after 4 cycles. CTRT was delivered by 3DCRT (along-with concurrent capecitabine at 1250 mg/m2) to a dose of 45Gy 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 RTOG criteria. Dose volume data were correlated with the radiation induced side effects. RESULTSAmong 135 patients enrolled both arms are well balanced demographically and 58% patients had T4 tumours, 42% had N2 and 15% had paraaortic LN (PALN), 27% underwent upfront stenting. Grade 3 adverse events like anaemia, dyspepsia, hepatotoxicity (Child Pugh B), GI bleed due to CTRT was observed in 9%,1.5%,13% and 5.8% respectively. Age >58 years(p=0.02), PTV1volume (>919cc, p=0.02), PTV2 volume (>380cc, p=0.01), mean liver dose (>28 Gy, p=0.07), Liver V40 (>50%, p=0.02) predicted radiation induced liver disease (RILD). An ROC analysis revealed a cut-off value of PTV1volume of 800 cc (sensitivity and specificity of 75% and 54%) and PTV2volume of 300 cc (sensitivity and specificity of 81% and 65%) for prediction of hepatotoxicity. Duodenum V45 >45% (p=0.02) predicted grade 3 anaemia. Numerically high V15 duodenum (98%, p=0.11), large PTV2 volume >484cc (p=0.06) and prior stenting had predilection for GI bleed. CONCLUSIONConsolidation CTRT is tolerable in those with PTV1 volume less than 800 cc, PTV 2 volume less than 300 cc, Liver V40 <50%, Duodenum V45<45%.