Neoadjuvant Modified FOLFOX6 With or Without Radiation Versus Fluorouracil Plus Radiation for Locally Advanced Rectal Cancer: Final Results of the Chinese FOWARC Trial

Abstract

Purpose: In the multicenter, open-label, phase III FOWARC trial, modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) plus radiotherapy resulted in a higher pathologic complete response rate than fluorouracil plus radiotherapy in Chinese patients with locally advanced rectal cancer. Here, we report the final results.

Methods: Adults ages 18 to 75 years with stage II/III rectal cancer were randomly assigned (1:1:1) to five cycles of infusional fluorouracil (leucovorin 400 mg/m², fluorouracil 400 mg/m², and fluorouracil 2.4 g/m² over 48 hours) plus radiotherapy (46.0 to 50.4 Gy delivered in 23 to 25 fractions during cycles 2 to 4) followed by surgery and seven cycles of infusional fluorouracil, the same treatment plus intravenous oxaliplatin 85 mg/m² on day 1 of each cycle (mFOLFOX6), or four to six cycles of mFOLFOX6 followed by surgery and six to eight cycles of mFOLFOX6. The primary end point was 3-year disease-free survival (DFS).

Results: In total, 495 patients were randomly assigned to treatment. After a median follow-up of 45.2 months, DFS events were reported in 46, 39, and 46 patients in the fluorouracil plus radiotherapy, mFOLFOX6 plus radiotherapy, and mFOLFOX6 arms. In each arm, the probability of 3-year DFS was 72.9%, 77.2%, and 73.5% (P = .709 by the log-rank test), the 3-year probability of local recurrence after R0/1 resection was 8.0%, 7.0%, and 8.3% (P = .873 by the log-rank test), and the 3-year overall survival rate was 91.3%, 89.1%, and 90.7% (P = .971 by log-rank test), respectively.

Conclusion: mFOLFOX6, with or without radiation, did not significantly improve 3-year DFS versus fluorouracil with radiation in patients with locally advanced rectal cancer. No significant difference in outcomes was found between mFOLFOX6 without radiotherapy and fluorouracil with radiotherapy, which requires additional investigation of the role of radiotherapy in these regimens.

Trial registration: ClinicalTrials.gov NCT01211210.

FIG 1.

Trial profile. mFOLFOX6, modified infusional fluorouracil, leucovorin, and oxaliplatin; PP, per protocol. (*) excluded from PP analysis. (†) 8 patients received radiation.

FIG 2.

Kaplan-Meier estimates of (A) disease-free survival (DFS), (B) locoregional recurrence after R0/1 resection, and (C) overall survival (OS) in the intention-to-treat population. FU, fluorouracil; HR, hazard ratio; mFOLFOX6, modified infusional fluorouracil, leucovorin, and oxaliplatin; RT, radiotherapy.

FIG 3.

Multivariable analysis of the effects of prognostic factors on (A) 3-year disease-free survival and (B) locoregional recurrence. CEA, carcinoembryonic antigen; FU, fluorouracil; mFOLFOX6, modified infusional fluorouracil, leucovorin, and oxaliplatin; OR, odds ratio; RT, radiotherapy.

FIG A1.

Kaplan-Meier estimates of disease-free survival (DFS) in the per-protocol population, which included 445 patients who underwent surgery. FU, fluorouracil; HR, hazard ratio; mFOLFOX6, modified infusional fluorouracil, leucovorin, and oxaliplatin; RT, radiotherapy; SD, standard deviation.

FIG A2.

Kaplan-Meier estimates of locoregional recurrence in the per-protocol population, which included 445 patients who underwent surgery. FU, fluorouracil; HR, hazard ratio; mFOLFOX6, modified infusional fluorouracil, leucovorin, and oxaliplatin; RT, radiotherapy; SD, standard deviation.

FIG A3.

Kaplan-Meier estimates of overall survival (OS) in the per-protocol population, which included 445 patients who underwent surgery. FU, fluorouracil; HR, hazard ratio; mFOLFOX6, modified infusional fluorouracil, leucovorin, and oxaliplatin; RT, radiotherapy; SD, standard deviation.