Gemox versus surveillance following surgery of localized biliary tract cancer: Results of the PRODIGE 12-ACCORD 18 (UNICANCER GI) phase III trial.

Abstract

225 Background: No standard post-surgery adjuvant treatment is currently recommended in localized biliary tract cancer (BTC). Gemcitabine combined with platinum is the standard chemotherapy for advanced BTC. The aim of this phase III randomized trial was to assess whether GEMOX would increase relapse-free survival (RFS) while maintaining health-related quality of life (HrQoL). Methods: We performed a multicenter randomized phase III trial. Patients were randomized, within 3 months of R0 or R1 resection of a localized BTC (intra-hepatic, perihilar, extra-hepatic cholangiocarcinoma or gallbladder cancer), to receive either GEMOX 85 for 12 cycles (Experimental Arm A) or surveillance (Standard Arm B). Co-primary objectives were RFS and HrQoL. 190 patients and 126 RFS events were required to show an increase of median RFS from 18 to 30 months. Results: Between July 2009 and February 2014, 196 patients were included in 33 French centers. Baseline characteristics were balanced, with similar primary sites, R0 resection rates were 86.2% (Arm A) vs 87.9% (Arm B), lymph node invasion present in 37.2% vs 36.4%. In Arm A, a median of 12 cycles was delivered (mean: 9.3, range: 0-12). Maximal grade of adverse events were grade 3 in 57.5% vs 22.2%, and grade 4 in 17.0% vs 9.1%. During treatment one patient died in each arm. The main grade ≥ 3 adverse events in the year following inclusion were peripheral neuropathy (50.0% vs 1.1%), and neutropenia (22.3% vs 0%). Median follow-up was 44.3 months, with 54 and 64 RFS events in arms A vs B. There was no significant difference in RFS between the arms (log-rank p = 0.31), with a hazard ratio of 0.83 [95% CI: 0.58-1.19], p = 0.31 (futility boundaries were crossed). Median RFS was 30.4 [95% CI: 15.4-45.8] vs 22.0 months [95%CI: 13.6-38.3] in arms A & B respectively, and 4-years RFS was 39.3% [95%CI: 28.4%-50.0%] vs 33.2% [95%CI: 23.1-43.7%]. Global Health HrQoL scores were not different at 12 months (70.8 vs 83.3, p = 0.18) and at 24 months (75.0 vs 83.3, p = 0.50). Conclusions: Adjuvant chemotherapy in BTC with GEMOX was feasible and associated with expected toxicities and no deterioration of HrQoL. There was no significant difference in RFS between GEMOX and surveillance. Clinical trial information: NCT01313377.

Cholangiocarcinoma — evolving concepts and therapeutic strategies

“…Results of a phase III trial conducted in France, however, demonstrated that adjuvant chemotherapy with gemcitabine and oxaliplatin (GEMOX), initiated 3 months after R0 or R1 resection of biliary tract cancer, did not significantly improve recurrence-free survival compared with placebo (HR 0.83, 95% CI 0.58–1.19; P = 0.31) 74 . More evidence is needed to clarify the role of adjuvant chemotherapy in the treatment of cholangiocarcinoma.…”

New Horizons for Precision Medicine in Biliary Tract Cancers

“…Two randomized phase III clinical trials exploring adjuvant chemotherapy were reported in 2017. Firstly, the results from the PRODIGE-12/ACCORD-18 clinical trial assessing the benefit of adjuvant combination chemotherapy compared with observation alone were reported in January 2017 (22). This multicenter phase III trial randomized 196 patients within 3 months of resection of a localized BTC (intra-hepatic, perihilar, extra-hepatic cholangiocarcinoma or gallbladder cancer), to receive either adjuvant gemcitabine and oxaliplatin or surveillance; there was no significant difference in relapse-free survival between the arms (hazard ratio of 0.83 (95%-CI 0.58–1.19); p-value 0.31).…”

The role of surgery and adjuvant therapy in lymph node–positive cancers of the gallbladder and intrahepatic bile ducts

“…Furthermore, the generalizability of results from the only previous phase 3 trial evaluating adjuvant therapy for BTCs is unclear because of the high rate of margin‐positive resection (R+) and because the chemotherapy regimen and schedule evaluated in this study are uncommonly used in contemporary practice . Additional prospective, randomized trials of adjuvant therapy for localized BTCs are either ongoing or have recently finished accrual …”

“…Given existing uncertainty regarding the optimal management of BTC and the dearth of data about the benefits of both resection and adjuvant therapy for lymph node–positive disease, we used a national cancer registry to ascertain treatment patterns for patients with lymph node–positive BTC. Although we recognize the disparate nature of IHC, GBC, and extrahepatic cholangiocarcinoma (EHC), we believed it was important to attempt to study each, because they are included in all major randomized trials of adjuvant therapy for BTC and because the results generated herein could provide novel and potentially useful information for the treatment of these rare malignancies. The main objectives of this study were to understand the value of surgical resection in patients with lymph node–positive BTC and to evaluate any survival benefit associated with the receipt of adjuvant therapy.…”