As reported in The Lancet Oncology by Thierry Conroy, MD, and colleagues, the French phase III UNICANCER-PRODIGE 23 trial has shown that intensification of preoperative therapy with FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, fluorouracil [5-FU]) prior to chemoradiotherapy resulted in improved disease-free survival in newly diagnosed locally advanced rectal cancer.

Study Details

In the open-label multicenter trial, 461 patients with stage cT3 or cT4 M0 rectal adenocarcinoma were randomly assigned between June 2012 and June 2017 to receive neoadjuvant FOLFIRINOX followed by chemoradiotherapy (n = 231) or preoperative chemoradiotherapy alone (n = 230), both followed by total mesorectal excision and 3 vs 6 months of adjuvant chemotherapy.

Thierry Conroy, MD

FOLFIRINOX consisted of oxaliplatin at 85 mg/m², irinotecan at 180 mg/m², leucovorin at 400 mg/m², and 5-FU at 2,400 mg/m² every 14 days for six cycles. Chemoradiotherapy consisted of 50 Gy for 5 weeks and 800 mg/m² of concurrent oral capecitabine twice daily for 5 days per week.

Adjuvant chemotherapy was given for 3 months in the FOLFIRINOX group vs 6 months in the control group and consisted of modified FOLFOX6 (oxaliplatin at 85 mg/m² and leucovorin at 400 mg/m², followed by 400 mg/m² of 5-FU bolus and then continuous infusion of 2,400 mg/m² over 46 hours every 14 days) or capecitabine at 1,250 mg/m² orally twice daily on days 1 to 14 every 21 days. The primary endpoint was disease-free survival at 3 years in the intention-to-treat population.

Disease-Free Survival

Surgery was performed in 92% of patients in the FOLFIRINOX group vs 95% of the control group (P = .26). A total of 408 patients were eligible for adjuvant chemotherapy; of these, 160 (77%) of 207 patients in the FOLFIRINOX group and 158 (79%) of 201 in the control group received treatment.

Median follow-up was 46.5 months (interquartile range = 35.4–61.6 months). Rates of 3-year disease-free survival were 76% (95% confidence interval [CI] = 69%–81%) in the FOLFIRINOX group vs 69% (95% CI = 62%–74%) in the control group (stratified hazard ratio [HR] = 0.69, 95% CI = 0.49–0.97, P = .034). Subgroup analyses showed no evidence of heterogeneity of treatment effect size according to baseline characteristics.

Most recurrences were due to distant metastasis, occurring in 17% of the FOLFIRINOX group vs 25% of the control group. Metastasis-free survival at 3 years was 79% (95% CI = 73%–84%) vs 72% (95% CI = 65%–77%; stratified HR = 0.64, 95% CI = 0.44–0.93, P = .017). No difference between groups was observed for locoregional relapse (4% vs 6%, stratified HR = 0.78, 95% CI = 0.34–1.79, P = .56). Overall survival at 3 years was 91% (95% CI = 86%–94%) in the FOLFIRINOX group vs 88% (95% CI = 83%–91%) in the control group (stratified HR = 0.65, 95% CI = 0.40–1.05, P = .0773).

Adverse Events

During neoadjuvant FOLFIRINOX, grade ≥ 3 adverse events occurred in 47% of patients, with the most common being neutropenia (17%) and diarrhea (11%), and serious adverse events occurred in 20%. During chemoradiotherapy, the most common grade ≥ 3 adverse event was lymphopenia (28% vs 30%). During adjuvant chemotherapy, grade ≥ 3 adverse events occurred in 45% vs 76% of patients, with the most common being lymphopenia (11% vs 27%), neutropenia (6% vs 18%), and peripheral sensory neuropathy (12% vs 21%).

Serious adverse events occurred in 11% vs 23% of patients. Treatment-related death occurred in one patient in the FOLFIRINOX group (< 1%; due to sudden death) and two patients in the control group (1%; due to sudden death and myocardial infarction).

The investigators concluded, “Intensification of chemotherapy using FOLFIRINOX before preoperative chemoradiotherapy significantly improved outcomes compared with preoperative chemoradiotherapy in patients with cT3 or cT4 M0 rectal cancer. The significantly improved disease-free survival in the neoadjuvant chemotherapy group and the decreased neurotoxicity indicates that the perioperative approach is more efficient and better tolerated than adjuvant chemotherapy. Therefore, the PRODIGE 23 results might change clinical practice.”

Dr. Conroy, of the Department of Medical Oncology, Institut de Cancérologie de Lorraine, is the corresponding author for The Lancet Oncology article.  

Disclosure: The study was funded by the Institut National du Cancer, Ligue Nationale Contre le Cancer, and R&D Unicancer. For full disclosures of the study authors, visit thelancet.com.