ArticlesDefinitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial
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.
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Study design and patients
We undertook a multicentre, randomised, open-label, parallel-group, phase 2 trial—with extension to phase 3 if our specific phase 2 objectives were achieved—to compare definitive chemoradiotherapy with FOLFOX, or with fluorouracil and cisplatin in patients with oesophageal cancer. The phase 2 objectives of fast accrual rate (at least 88 patients enrolled in 18 months or fewer), completion of full treatment in 60% of patients in the FOLFOX group, and significantly more patients achieving an
Results
Between Oct 15, 2004, and Aug 25, 2011, 267 patients from 24 hospitals in France were randomly assigned to the two treatment groups: 134 to FOLFOX and 133 to fluorouracil and cisplatin. These patients constituted the intention-to-treat population (figure 1). Patients who did not receive any chemotherapy were not included in the safety population, which comprised 131 patients in the FOLFOX group and 128 in the fluorouracil–cisplatin group. Table 1 shows the baseline characteristics of the
Discussion
Definitive chemoradiotherapy with FOLFOX did not improve progression-free survival compared with chemoradiotherapy with fluorouracil and cisplatin in patients with oesophageal cancer unsuitable for surgery. Additionally, the full chemotherapy completion rate, proportion of patients achieving endoscopic complete responses, and overall survival (HR 0·94, 95% CI 0·68–1·29; p=0·70) were similar between the two treatment groups. In the RTOG 85-01 trial,1 all cycles of chemotherapy could be
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