Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial

Summary

Background

Definitive chemoradiotherapy is a curative treatment option for oesophageal carcinoma, especially in patients unsuitable for surgery. The PRODIGE5/ACCORD17 trial aimed to assess the efficacy and safety of the FOLFOX treatment regimen (fluorouracil plus leucovorin and oxaliplatin) versus fluorouracil and cisplatin as part of chemoradiotherapy in patients with localised oesophageal cancer.

Methods

We did a multicentre, randomised, open-label, parallel-group, phase 2/3 trial of patients aged 18 years or older enrolled from 24 centres in France between Oct 15, 2004, and Aug 25, 2011. Eligible participants had confirmed stage I–IVA oesophageal carcinoma (adenocarcinoma, squamous-cell, or adenosquamous), Eastern Cooperative Oncology Group (ECOG) status 0–2, sufficient caloric intake, adequate haematological, renal, and hepatic function, and had been selected to receive definitive chemoradiotherapy. Patients were randomly assigned (1:1) to receive either six cycles (three concomitant to radiotherapy) of oxaliplatin 85 mg/m², leucovorin 200 mg/m², bolus fluorouracil 400 mg/m², and infusional fluorouracil 1600 mg/m² (FOLFOX) over 46 h, or four cycles (two concomitant to radiotherapy) of fluorouracil 1000 mg/m² per day for 4 days and cisplatin 75 mg/m² on day 1. Both groups also received 50 Gy radiotherapy in 25 fractions (five fractions per week). Random allocation to treatment groups was done by a central computerised randomisation procedure by minimisation, stratified by centre, histology, weight loss, and ECOG status, and was achieved independently from the study investigators. The primary endpoint was progression-free survival. Data analysis was primarily done by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00861094.

Findings

134 participants were randomly allocated to the FOLFOX group and 133 to the fluorouracil and cisplatin group (intention-to-treat population), and 131 patients in the FOLFOX group and 128 in the fluorouracil and cisplatin group actually received the study drugs (safety population). Median follow-up was 25·3 months (IQR 15·9–36·4). Median progression-free survival was 9·7 months (95% CI 8·1–14·5) in the FOLFOX group and 9·4 months (8·1–10·6) in the fluorouracil and cisplatin group (HR 0·93, 95% CI 0·70–1·24; p=0·64). One toxic death occurred in the FOLFOX group and six in the fluorouracil–cisplatin group (p=0·066). No significant differences were recorded in the rates of most frequent grade 3 or 4 adverse events between the treatment groups. Of all-grade adverse events that occurred in 5% or more of patients, paraesthesia (61 [47%] events in 131 patients in the FOLFOX group vs three [2%] in 128 patients in the cisplatin–fluorouracil group, p<0·0001), sensory neuropathy (24 [18%] vs one [1%], p<0·0001), increases in aspartate aminotransferase concentrations (14 [11%] vs two [2%], p=0·002), and increases in alanine aminotransferase concentrations (11 [8%] vs two [2%], p=0·012) were more common in the FOLFOX group, whereas serum creatinine increases (four [3%] vs 15 [12%], p=0·007), mucositis (35 [27%] vs 41 [32%], p=0·011), and alopecia (two [2%] vs 12 [9%], p=0·005) were more common in the fluorouracil and cisplatin group.

Interpretation

Although chemoradiotherapy with FOLFOX did not increase progression-free survival compared with chemoradiotherapy with fluorouracil and cisplatin, FOLFOX might be a more convenient option for patients with localised oesophageal cancer unsuitable for surgery.

Funding

UNICANCER, French Health Ministry, Sanofi-Aventis, and National League Against Cancer.

Introduction

The Radiation Therapy Oncology Group (RTOG) 85-01 trial established the efficacy of definitive radiotherapy plus concurrent chemotherapy with fluorouracil and cisplatin for patients with localised oesophageal cancer; chemoradiotherapy improved survival significantly compared with radiotherapy alone.¹ A subsequent trial confirmed the efficacy and safety of this chemoradiotherapy regimen,² and established it as a standard of care for patients with oesophageal cancer unsuitable for surgery.3, 4 However, in the chemoradiotherapy group, 46% of patients had local failure, 20% of patients had life-threatening toxicities, including toxic deaths, and 41% of patients could not receive the chemoradiotherapy as planned.¹

Despite this therapeutic progress, the prognosis of patients with oesophageal cancer remains poor, and more effective treatment regimens are needed. Moreover, cisplatin is difficult to administer because prolonged intravenous hydration is necessary, and so more convenient and safer schedules should be investigated to improve outcome. The addition of leucovorin modulates the activity of fluorouracil, and treatment with fluorouracil and leucovorin has shown encouraging results in small studies of patients with oesophageal cancer.5, 6 In-vitro and in-vivo preclinical and clinical studies have shown oxaliplatin to be a potent radiosensitising drug that can overcome resistance to cisplatin.⁷ Oxaliplatin is also less emetogenic than cisplatin, does not need intravenous hydration, and is not nephrotoxic.8, 9, 10, 11

The combination of oxaliplatin and fluorouracil with leucovorin (FOLFOX) has shown promising efficacy in several phase 1 and 2 trials of patients with advanced or metastatic oesophageal cancer when combined with radiotherapy,8, 9, 10 or when given as chemotherapy alone.¹¹ We established the maximum tolerated dose of concurrent FOLFOX in a phase 1 study.¹² We then did a randomised phase 2/3 study comparing the efficacy and safety of concurrent radiotherapy with either FOLFOX or fluorouracil and cisplatin—the standard RTOG regimen—in patients with oesophageal cancer unsuitable for surgery. We have previously reported results for the phase 2 part of this trial.¹³ Here, we detail the efficacy and safety results for the phase 3 extension of this study, in which we aimed to compare progression-free survival of the two treatment regimens.