Adjuvant chemotherapy or chemo-radiation in gallbladder cancer: A phase III randomized controlled study (ACCELERATE trial).

Abstract

519 Background: Role of adjuvant therapy in gallbladder cancer is still evolving and no prospective trial has compared chemotherapy (ChT) alone to combination of chemotherapy and chemo-radiation (CRT). We designed this trial to answer whether adding CRT to ChT improves relapse free survival. Methods: In this open-label, multicentric, phase 3, non-inferiority academic trial, operated gallbladder cancers (R0 or R1) patients were randomized to physicians choice of ChT alone (either 6 cycles of mGemOx- Gemcitabine 900 mg/m2 and oxaliplatin 80 mg/m2 IVI days 1 and 8 every 3 weeks or GemCis- Gemcitabine 1000 mg/m2 and cisplatin 25 mg/m2 1 and 8 every 3 weeks) or 3 cycles of physicians choice of ChT (as above) followed by CRT (radiation 45Gyin 25 fractions in 5 weeks with concurrent oral capecitabine in the dose of 825 mg/m2 twice a day on days of radiation and further 2-3 cycles of mGemOx or GemCis. The primary endpoint was the relapse free survival. Planned sample size was 100 subjects in each arm. Results: Between April 2018 and January 2021, 137 patients were screened, and 94 eligible patients were randomized, 49 (52.1%) in chemotherapy alone arm (standard-arm1) and 45 (47.9%) in chemotherapy plus chemo-radiation arm (experimental-arm 2). Slow accrual led to premature closure of trial. COVID pandemic might have contributed to that. Baseline characteristics were well balanced (like, sex, presenting symptoms, ECOG PS, duration of symptoms, comorbidities, location of tumour in GB, presence of gallstone disease, and tumour markers were well balance in both groups) except that a greater number of patients had deranged baseline LFTs in arm1 and there was a trend towards higher numbers of stage IIA in arm 1. The median age was 55 years (range 27-73 years). Females constituted 32 in each group. 43 and 45 patients had ECOG PS of 0-1 in arm 1 and arm 2 respectively. One patient in arm 1 was ineligible. All had R0 resection. Incidences of dose reductions and dose delays were similar. A greater number of patients in arm 1 experienced diarrheal episodes (p=0.021) and peripheral neuropathy (0.001). 42 (85.7%) patients in arm 1 and 28 (62.2%) patients in arm completed 5-6 cycles. 18 (36.73%) and 23 (51.11%) died till last follow up. 14 (28.57%) and 20(44.44%) died because of disease progression. One patient in each arm died of toxicity. The primary end point of study, relapse free survival was not estimable in arm 1 and was 34.39 months in arm 2 (p=0.202). Median overall survival was not estimable in arm 1 and was 34.56 months in arm 2 (p=0.123). Mean RFS was 51.96 Vs 43.99 months in arm 1 and arm 2 respectively. Conclusions: This trial suggests that addition of CRT to ChT doesn’t improve outcome in resected gallbladder cancer compared to ChT alone. A larger trial is needed to address this issue. Clinical trial information: CTRI/2018/04/013218.