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.

BACKGROUND

Treatment of locally advanced rectal cancer with chemoradiotherapy, surgery, and adjuvant chemotherapy controls local disease, but distant metastases remain common. We aimed to assess whether administering neoadjuvant chemotherapy before preoperative chemoradiotherapy could reduce the risk of distant recurrences.

METHODS

We did a phase 3, open-label, multicentre, randomised trial at 35 hospitals in France. Eligible patients were adults aged 18-75 years and had newly diagnosed, biopsy-proven, rectal adenocarcinoma staged cT3 or cT4 M0, with a WHO performance status of 0-1. Patients were randomly assigned (1:1) to either the neoadjuvant chemotherapy group or standard-of-care group, using an independent web-based system by minimisation method stratified by centre, extramural extension of the tumour into perirectal fat according to MRI, tumour location, and stage. Investigators and participants were not masked to treatment allocation. The neoadjuvant chemotherapy group received neoadjuvant chemotherapy with FOLFIRINOX (oxaliplatin 85 mg/m

FINDINGS

Between June 5, 2012, and June 26, 2017, 461 patients were randomly assigned to either the neoadjuvant chemotherapy group (n=231) or the standard-of-care group (n=230). At a median follow-up of 46·5 months (IQR 35·4-61·6), 3-year disease-free survival rates were 76% (95% CI 69-81) in the neoadjuvant chemotherapy group and 69% (62-74) in the standard-of-care group (stratified hazard ratio 0·69, 95% CI 0·49-0·97; p=0·034). During neoadjuvant chemotherapy, the most common grade 3-4 adverse events were neutropenia (38 [17%] of 225 patients) and diarrhoea (25 [11%] of 226). During chemoradiotherapy, the most common grade 3-4 adverse event was lymphopenia (59 [28%] of 212 in the neoadjuvant chemotherapy group vs 67 [30%] of 226 patients in the standard-of-care group). During adjuvant chemotherapy, the most common grade 3-4 adverse events were lymphopenia (18 [11%] of 161 in the neoadjuvant chemotherapy group vs 42 [27%] of 155 in the standard-of-care group), neutropenia (nine [6%] of 161 vs 28 [18%] of 155), and peripheral sensory neuropathy (19 [12%] of 162 vs 32 [21%] of 155). Serious adverse events occurred in 63 (27%) of 231 participants in the neoadjuvant chemotherapy group and 50 (22%) of 230 patients in the standard-of-care group (p=0·167), during the whole treatment period. During adjuvant therapy, serious adverse events occurred in 18 (11%) of 163 participants in the neoadjuvant chemotherapy group and 36 (23%) of 158 patients in the standard-of-care group (p=0·0049). Treatment-related deaths occurred in one (<1%) of 226 patients in the neoadjuvant chemotherapy group (sudden death) and two (1%) of 227 patients in the standard-of-care group (one sudden death and one myocardial infarction).

INTERPRETATION

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.

FUNDING

Institut National du Cancer, Ligue Nationale Contre le Cancer, and R&D Unicancer.

Informations de copyright

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Déclaration de conflit d'intérêts

Declaration of interests P-LE reports grants and non-financial support from Bristol Myers Squibb; and non-financial support from Amgen, Ipsen, Novartis, Roche, Sanofi, and Servier, outside the submitted work. OB reports personal fees from Amgen, Bayer, Bristol Myers Squibb, Grunenthal, Merck, Pierre Fabre, Roche, and Servier, outside the submitted work, and has been invited to congresses by Roche and Servier. VB reports grants from Merck Serono; personal fees from Merck Serono, Bayer, Bristol Myers Squibb, Sanofi, Eisai, Ipsen, Merck Sharpe and Dohme, and Prestizia; and non-financial support from Merck Serono, Bayer, Sanofi, and Roche, outside the submitted work. CL reports personal fees from Amgen, Celgene, Halozyme, Merck Sharpe and Dohme, and Roche, outside the submitted work. CdlF reports personal fees from Eisai, Amgen, Bayer, Pierre Fabre Oncologie, Roche, and Servier; and non-financial support from Amgen, Bayer, Pierre Fabre Oncologie, Roche, Servier, and Bristol Myers Squibb, outside the submitted work. CB reports grants from Roche; and personal fees from Servier, Pierre Fabre, and Merck Sharpe and Dohme, outside the submitted work. All other authors declare no competing interests.