FOLFIRINOX for the Treatment of Advanced Gastroesophageal Cancers

Abstract

IMPORTANCE Standard first-line regimens for patients with metastatic gastroesophageal adenocarcinomas have an approximate 40% objective response rate (ORR). The combination of leucovorin, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) has been efficacious as first-line therapy for other gastrointestinal cancers, such as pancreatic and colon cancers.OBJECTIVE To evaluate the clinical activity and safety of FOLFIRINOX as first-line treatment for patients with advanced gastroesophageal adenocarcinoma. DESIGN, SETTING, AND PARTICIPANTSThis is an open-label, single-arm phase 2 study of first-line FOLFIRINOX in patients with advanced gastroesophageal adenocarcinoma. Estimated sample size included 41 patients with ERBB2-negative disease with 90% power to detect an ORR of 60% or greater with α of .10. No enrollment goal was planned for ERBB2-positive patients, but they were allowed to receive trastuzumab in combination with FOLFIRINOX.INTERVENTIONS Starting doses were fluorouracil, 400 mg/m 2 bolus, followed by 2400 mg/m 2 over 46 hours; leucovorin, 400 mg/m 2 ; irinotecan, 180 mg/m 2 ; and oxaliplatin, 85 mg/m 2 . Trastuzumab was administered as a 6 mg/kg loading dose, followed by 4 mg/kg every 14 days in patients with ERBB2-positive disease. MAIN OUTCOMES AND MEASURESThe primary end point was ORR by the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary end points included safety profile, progression-free survival (PFS), overall survival (OS), and duration of response. RESULTSFrom November 2013 to May 2018, 67 patients were enrolled (median [range] age, 59.0 [34-78] years; including 56 [84%] men), and 26 of 67 (39%) had ERBB2-positive disease. Median follow-up was 17.4 months. The ORR was 61%(95% CI, 44.5%-75.8%) (25 of 41) in the ERBB2-negative group and 85% (95% CI, 65.1%-95.6%) (22 of 26) in the ERBB2-positive group, including 1 patient with complete response. For ERBB2-negative patients, median PFS was 8.4 months and median OS was 15.5 months; for ERBB2-positive patients, median PFS was 13.8 months and median OS was 19.6 months. Fifty-six patients (84%) had dose modifications or treatment delays. The most common toxic effects were neutropenia (91%, n = 61), diarrhea (63%, n = 42), peripheral sensory neuropathy (61%, n = 41), and nausea (48%, n = 32), with no unexpected toxic effects. CONCLUSIONS AND RELEVANCEThe FOLFIRINOX regimen with or without trastuzumab was associated with improved ORR and PFS in patients with advanced gastroesophageal adenocarcinoma in the first-line setting. This regimen may be a reasonable therapeutic option for patients with preserved performance status.

Stroma-targeting strategies in pancreatic cancer: Past lessons, challenges and prospects

“…The objective response rate (ORR) to FOLFOXIRI in these patients was 60%[ 5 ]. A phase II trial of FOLFIRINOX in patients with advanced gastroesophageal cancer showed an ORR of 61%[ 6 ]. This is in contrast to a response rate of only 31.6% in patients with metastatic PDAC receiving FOLFIRINOX[ 7 ].…”

Fortnightly or fractionated weekly docetaxel–cisplatin–5‐FU as first‐line treatment in advanced gastric and gastroesophageal junction adenocarcinoma: The randomized phase II DoGE study

“…FLOT is now a standard of care peri‐operative treatment for gastric and gastroesophageal junction adenocarcinoma, and is increasingly used in patients with advanced disease 2,21 . Promising efficacy data have also been reported with the repurposing of FOLFIRINOX in the metastatic setting of gastroesophageal cancer 22 . As a result, the interest for modified DCF regimens has gradually reduced, this being further mitigated by the negative results of recent trials comparing DCF‐like regimens with standard doublet chemotherapy 23 …”

“… 2 , 21 Promising efficacy data have also been reported with the repurposing of FOLFIRINOX in the metastatic setting of gastroesophageal cancer. 22 As a result, the interest for modified DCF regimens has gradually reduced, this being further mitigated by the negative results of recent trials comparing DCF‐like regimens with standard doublet chemotherapy. 23 …”

Results and Molecular Correlates from a Pilot Study of Neoadjuvant Induction FOLFIRINOX Followed by Chemoradiation and Surgery for Gastroesophageal Adenocarcinomas

“…In a recently published phase II trial of advanced GEA, among ERBB2-negative patients treated with FOLFIRINOX alone, the ORR was 61%, with a median overall survival of 15.5 months. Among ERBB2-positive patients treated with FOLFIRINOX and trastuzumab, the ORR was 85%, with a median OS 19.6 months 16 . Additionally, a multi-institutional phase II trial of 36 patients with locally advanced GEA evaluated pharmacogenomically dosed perioperative FOLFIRINOX and reported R0 resection rate of 92% and a pathologic complete response (pCR) rate of 23% 17 .…”

“…Outside of GEA, FOLFIRINOX has emerged as a standard of care for pancreatic cancer in both the resectable and metastatic setting 13,14 . Additionally, there is a growing body of literature evaluating the e cacy of this regimen in gastroesophageal and gastric cancers [15][16][17] . A pooled analysis of two ongoing Phase II trials of FOLFIRINOX in the rst line metastatic setting for GE junction cancers demonstrated an overall response rate (ORR) of 62.5% 15 .…”