French Phase III Trial Shows No Benefit of Neoadjuvant Chemoradiation in Stage I and II Esophageal Cancer
The effect of neoadjuvant chemoradiation therapy in early-stage esophageal cancer is not clear. In the phase III FFCD 9901 trial reported in the Journal of Clinical Oncology, Mariette et al found that neoadjuvant chemoradiation including fluorouracil (5-FU) and cisplatin did not improve R0 resection rate or overall survival and increased postoperative mortality compared with surgery alone in patients with stage I or II esophageal cancer.
Study Details
In the trial, 195 patients aged < 75 years from 30 French centers were randomly assigned between June 2000 and June 2009 to receive neoadjuvant chemoradiation plus surgery (n = 98) or surgery alone (n = 97). Chemoradiation consisted of radiation therapy at 45 Gy in 25 fractions over 5 weeks and two courses of concomitant chemotherapy with fluorouracil at 800 mg/m2 and cisplatin at 75 mg/m2. The primary endpoint was overall survival.
The neoadjuvant group and control group were generally balanced for age (median, 58 years in both), sex (89% and 83% male), histology (squamous in 68% and 72%, adenocarcinoma in 31% and 28%), tumor site (below carina in 92% and 90%), World Health Organization performance status (0 in 78% and 73%, 1 in 22% and 23%), weight loss (< 10% in 91% and 93%), cT classification (cT1 in 25% and 24%, cT2 in 59% and 54%, cT3 in 15% and 22%), cN classification (cN0 in 70% and 74%), and cTNM stage (I in 18% and 20%, IIa in 52% and 55%, IIb in 30% and 26%).
Interim analysis of overall survival performed in December 2009 after 55% of expected deaths had occurred showed the improbability of demonstrating superiority of either treatment (hazard ratio [HR] = 1.09, P =.66, for chemoradiation vs surgery alone). Study recruitment was stopped on the basis of anticipated futility. The current report reflects final analysis after long-term follow-up.
Increased Postoperative Mortality
Median follow-up was 93.6 months. The R0 resection rate was 93.8% in the chemoradiation group vs 92.1% (P = .749) in the surgery-alone group. Postoperative morbidity was similar in the 2 groups (55.6% vs 52.8%, P = .720), but in-hospital postoperative mortality was significantly higher in the chemoradiation group (11.1% vs 3.4%, P = .049).
Overall and Disease-Free Survival
Median overall survival was 31.8 vs 41.2 months and 3-year and 5-year overall survival were 47.5% vs 53.0% and 41.1% vs 33.8% (hazard ratio [HR] for overall survival = 0.99, P = .94). No overall survival benefit was found in any of the subgroups analyzed.
Recurrent disease was found in 28.6% vs 44.3% of patients (P = .02), including locoregional recurrence in 15.3% vs 28.9% (P = .02) and distant recurrence in 22.5% vs 28.9% (P = .31). Median disease-free survival was 27.8 vs 26.7 months and 5-year disease-free survival was 35.6% vs 27.7% (HR = 0.92, P =.648).
The investigators concluded, “Compared with surgery alone, [neoadjuvant chemoradiotherapy] with cisplatin plus fluorouracil does not improve R0 resection rate or survival but enhances postoperative mortality in patients with stage I or II [esophageal cancer]…. [T]his phase III randomized controlled trial suggests that [chemoradiotherapy] is not the appropriate neoadjuvant therapeutic strategy for stage I or II [esophageal cancer].”
Christophe Mariette, MD, PhD, of University Hospital Claude Huriez-Regional University Hospital Center, Lille, is the corresponding author for the Journal of Clinical Oncology article.
The study was supported by the French National Cancer Institute. Françoise Mornex, MD, PhD, reported a consultant or advisory role with Merck and honoraria from Merck.
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