Neoadjuvant chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) followed by chemoradiotherapy, surgery, and adjuvant chemotherapy significantly improved outcomes in patients with locally advanced rectal cancer compared with those who received standard chemoradiotherapy, surgery, and adjuvant chemotherapy, according to a study published in The Lancet Oncology.

The phase 3, open-label, randomized UNICANCER-PRODIGE 23 trial (ClinicalTrials.gov Identifier: NCT01804790) was conducted at 35 hospitals in France. Eligibility criteria included patients aged 18 to 75 years who had a pathologically confirmed rectal adenocarcinoma within 15 cm of the anal verge, a World Health Organization performance status of 0 or 1, and stage cT3 or cT4 disease. Disease-free survival at 3 years was the primary endpoint.

Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group (FOLFIRINOX, followed by chemoradiotherapy, surgery, and adjuvant chemotherapy) or the standard-of-care group (chemoradiotherapy, surgery, and adjuvant chemotherapy) within 14 days of enrollment from June 5, 2012 to June 26, 2017. Patients in the neoadjuvant chemotherapy group received FOLFIRINOX by continuous intravenous infusion for 46 hours every 14 days for 6 cycles.


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A total of 461 patients were included: 231 in the neoadjuvant chemotherapy group (median age, 61 years [interquartile range (IQR), 53-66]; 65% men) and 230 in the standard-of-care group (median age, 62 years [IQR, 55-66]; 68% men). The overall median follow-up was 46.5 months (IQR, 35.4-61.6).

The investigators found that 58 patients (25%) in the neoadjuvant chemotherapy group and 78 (34%) in the standard-of-care group reported disease-free survival rates. The 3-year disease-free survival rates were 76% (95% CI, 69-81) for patients in the neoadjuvant chemotherapy group and 69% (95% CI, 62-74) for those in the standard-of-care group (stratified hazard ratio, 0.69; 95% CI, 0.49-0.97; P =.034).

Among patients in the neoadjuvant chemotherapy group, 226 (98%) received FOLFIRINOX, of whom 207 (92%) completed 6 cycles, and grade 3/4 adverse events occurred in 105 (46%) of the study patients. The most frequent grade 3/4 events were neutropenia (38 [17%] of 225 patients) and diarrhea (25 [11%] of 226 patients). Serious adverse events (SAEs) were observed in 46 (20%) of 226 patients during neoadjuvant chemotherapy.

During chemoradiotherapy, lymphopenia (59 [28%] of 212 patients in the neoadjuvant chemotherapy group and 67 [30%] of 226 patients in the standard-of-care group) was the most common grade 3/4 adverse event (AE).

The most common grade 3/4 AEs during adjuvant chemotherapy were neutropenia (9 [6%] of 161 patients in the neoadjuvant chemotherapy group vs 28 [18%] of 155 patients in the standard-of-care group), lymphopenia (18 [11%] vs 42 [27%], respectively), and peripheral sensory neuropathy (19 [12%] of 162 patients vs 32 [21%] of 155 patients, respectively).

For the total treatment period, SAEs were observed in 27% of patients in the neoadjuvant chemotherapy group and 22% of those in the standard-of-care group (P =.167). In the standard-of-care group, 2 treatment-related cardiac deaths occurred, and 1 patient in the neoadjuvant chemotherapy group died from a treatment-related event.

The study authors noted limitations to their findings, including a lower accrual rate than initially planned, as well as the lack of extramural venous invasion reporting on preoperative magnetic resonance imaging.

“Neoadjuvant FOLFIRINOX can be considered part of the preoperative strategy for patients with locally advanced rectal cancer at risk of systemic recurrence and can be considered as one of the new standard-of-care treatment approaches in eligible patients,” the researchers concluded.

Disclosures: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Conroy T, Bosset J-F, Etienne P-L, et al. Neoadjuvant chemotherapy with FOLFIRINOX and preoperative chemoradiotherapy for patients with locally advanced rectal cancer (UNICANCER-PRODIGE 23): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. Published online April 13, 2021. doi:10.1016/S1470-2045(21)00079-6