June’s paper of the month looks at the PRODIGE-23 trial, a randomised phase 3 clinical trial which sought to determine whether total neoadjuvant chemotherapy (TNT) before surgery improved disease-free survival (DFS) compared with standard preoperative chemoradiotherapy (CRT) in patients with locally advanced rectal cancer.

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

Thierry Conroy, Jean-François Bosset, Pierre-Luc Etienne, Emmanuel Rio, Éric François, Nathalie Mesgouez-Nebout, Véronique Vendrely, Xavier Artignan, Olivier Bouché, Dany Gargot, Valérie Boige, Nathalie Bonichon-Lamichhane, Christophe Louvet, Clotilde Morand, Christelle de la Fouchardière, Najib Lamfichekh, Béata Juzyna, Claire Jouffroy-Zeller, Eric Rullier, Frédéric Marchal, Sophie Gourgou, Florence Castan, Christophe Borg, Unicancer Gastrointestinal Group and Partenariat de Recherche en Oncologie Digestive (PRODIGE) Group

The Lancet Oncology, Volume 22, Issue 5, May 2021

What is known about the subject?

Previous TNT studies (RAPIDO, OPRA, CAO/AIO-12) have shown better compliance with chemotherapy for patients receiving neoadjuvant treatment compared to adjuvant; benefits of TNT with FOLFOX or CAPOX have also been shown in terms of DFS. The OPRA trial also showed higher rates of organ-preservation with long-course CRT followed by consolidation chemotherapy, similarly to the CAO/AIO-12 study; however, the use of induction vs. consolidation and long- vs. short-course radiotherapy is still under discussion.

What the study adds?

This study randomized 231 patients diagnosed with locally advanced rectal cancer (T3/T4, any N, M0) to TNT vs. standard of care (n=230). TNT consisted of induction chemotherapy with FOLFIRINOX, CRT, total mesorectal excision, and adjuvant chemotherapy. The authors chose FOLFIRINOX as it had previously shown better disease control rates in metastatic disease. This strategy with induction chemotherapy does not seem to increase postoperative morbidity.

At median follow-up of 46.5 months, 3-year DFS were significantly higher in the study group (76% vs. 69% in the standard-of-care group, p=0.034). The rate of disease progression was 1% for the TNT compared to 5% with the standard of care and there were no differences in 3-year overall survival (OS).

Implications for colorectal practice

The current standard of care for locally advanced rectal cancer management provides excellent control of local disease, but does not reduce risk of distant metastasis. There is growing evidence from some well-designed randomized trials that investigated the benefits of TNT in reducing local and distant recurrence, while increasing the percentage of organ-preservation. In the current study, the upfront use of FOLFIRINOX compared to standard of care CRT has shown to increase 3y-DFS and metastasis-free survival, suggesting a positive impact in DFS at 3-yrs of follow-up. FOLFIRINOX was also shown to increase the rate of pathological complete response, so a new algorithm including non-operative management and organ-preserving strategies should be proposed.

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