Modified FOLFIRINOX Versus CISGEM Chemotherapy for Patients With Advanced Biliary Tract Cancer (PRODIGE 38 AMEBICA): A Randomized Phase II Study

Abstract

PURPOSE Whether triplet chemotherapy is superior to doublet chemotherapy in advanced biliary tract cancer (BTC) is unknown. METHODS In this open-label, randomized phase II-III study, patients with locally advanced or metastatic BTC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were randomly assigned (1:1) to receive oxaliplatin, irinotecan, and infusional fluorouracil (mFOLFIRINOX), or cisplatin and gemcitabine (CISGEM) for a maximum of 6 months. We report the results of the phase II part, where the primary end point was the 6-month progression-free survival (PFS) rate among the patients who received at least one dose of treatment (modified intention-to-treat population) according to Response Evaluation Criteria in Solid Tumors version 1.1 (statistical assumptions: 6-month PFS rate ≥ 59%, 73% expected). RESULTS A total of 191 patients (modified intention-to-treat population, 185: mFOLFIRINOX, 92; CISGEM, 93) were randomly assigned in 43 French centers. After a median follow-up of 21 months, the 6-month PFS rate was 44.6% (90% CI, 35.7 to 53.7) in the mFOLFIRINOX arm and 47.3% (90% CI, 38.4 to 56.3) in the CISGEM arm. Median PFS was 6.2 months (95% CI, 5.5 to 7.8) in the mFOLFIRINOX arm and 7.4 months (95% CI, 5.6 to 8.7) in the CISGEM arm. Median overall survival was 11.7 months (95% CI, 9.5 to 14.2) in the mFOLFIRINOX arm and 13.8 months (95% CI, 10.9 to 16.1) in the CISGEM arm. Adverse events ≥ grade 3 occurred in 72.8% of patients in the mFOLFIRINOX arm and 72.0% of patients in the CISGEM arm (toxic deaths: mFOLFIRINOX arm, two; CISGEM arm, one). CONCLUSION mFOLFIRINOX triplet chemotherapy did not meet the primary study end point. CISGEM doublet chemotherapy remains the first-line standard in advanced BTC.

Reply to M. Salati et al

“…We agree with Drs Salati and Rizzo 1 that seemingly higher overall survival (OS) in the CISGEM arm in the PRODIGE 38 AMEBICA trial 2 compared with that in the ABC-02 trial (median, 13.8 v 11.7 months) 3 in the absence of any benefit in progression-free survival (PFS; median, 7.4 v 8.0 months) is likely due to patient selection bias—patients had to be fit enough for modified fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) triplet chemotherapy regimen—and its usual consequences: better performance status (performance status 2, 0% v 13.2%) and a higher proportion of patients who received second-line treatment (64.6% v 17%). The second-line rate in the PRODIGE-38 AMEBICA trial is even higher than in recent, expert-center studies (for instance, 45.7% in a series of 315 German patients 4 ).…”

The focus clinical research in intrahepatic cholangiocarcinoma

“…Moreover, GCS has better tolerability and convenience, while the combination of albumin-bound paclitaxel and conventional chemotherapy also achieved preliminary effect on patients with advanced ICC, and median PFS and OS reached similar or even better levels than the current first-line regimen [ 76 , 77 ]. Modified FOLFIRINOX had promising efficacy and favorable tolerance in patients with advanced ICC [ 78 ]. Phase III clinical trials of modified FOLFIRINOX is currently ongoing, which is expected to provide more first-line chemotherapy options for advanced ICC.…”

Evolving Role of Immunotherapy in Advanced Biliary Tract Cancers

“…More intensive triplet therapy regimens have also been investigated in the first-line setting for advanced BTC. Modified FOLFIRINOX (5-FU, irinotecan, oxaliplatin) failed to improve 6-month PFS compared to GEMCIS (44.6% vs. 47.3%) in the phase II/III PRODIGE 38 AMEBICA trial [ 32 ]. In Japan, GEMCIS plus S-1 improved survival outcomes compared to GEMCIS in 246 patients with advanced BTC, with a median OS of 13.5 months versus 12.6 months (HR 0.79, p = 0.046) [ 33 ].…”