Background
Phase III RCT (UNICANCER PRODIGE 23) in 461 patients with cT3 or cT4, M0 rectal adenocarcinoma <15 cm from the anal verge, comparing total neoadjuvant therapy with induction FOLFIRINOX versus standard preoperative chemoradiotherapy.
Interventions and follow up
Arm A: Neoadjuvant FOLFIRINOX (oxaliplatin 85, irinotecan 180, leucovorin 400, 5-FU 2400 mg/m² Q14D) x6 cycles >> CRT (50 Gy + capecitabine 800 mg/m² BID) >> TME >> adjuvant mFOLFOX6/CAPOX x3 mo
Arm B: CRT >> TME >> adjuvant chemotherapy x6 mo
Primary endpoint: 3-year disease-free survival
Median follow up: 46.5 mo
Arm B: CRT >> TME >> adjuvant chemotherapy x6 mo
Primary endpoint: 3-year disease-free survival
Median follow up: 46.5 mo
Results
3-yr DFS: 76% vs 69%, HR 0.69, 95% CI 0.49-0.97, P=.034 (Arm A vs B)
3-yr OS: 91% vs 88%, HR 0.65, 95% CI 0.40-1.05, P=.0773
pCR: 28% vs 12%
3-yr metastasis-free survival: Favored the FOLFIRINOX arm
3-yr OS: 91% vs 88%, HR 0.65, 95% CI 0.40-1.05, P=.0773
pCR: 28% vs 12%
3-yr metastasis-free survival: Favored the FOLFIRINOX arm
Adverse events
During neoadjuvant therapy (grade 3-4, Arm A): Neutropenia 17%, diarrhea 11%
During adjuvant therapy (Arm A vs B): Lymphopenia 11% vs 27%, neutropenia 6% vs 18%, peripheral sensory neuropathy 12% vs 21%
Serious adverse events: 27% vs 22%
During adjuvant therapy (Arm A vs B): Lymphopenia 11% vs 27%, neutropenia 6% vs 18%, peripheral sensory neuropathy 12% vs 21%
Serious adverse events: 27% vs 22%
Conclusions
Neoadjuvant FOLFIRINOX followed by chemoradiotherapy improved 3-year disease-free survival and pathologic complete response versus standard preoperative chemoradiotherapy in locally advanced rectal cancer, supporting total neoadjuvant therapy. Overall survival was not significantly improved.
Key Limitations
No statistically significant overall survival benefit. Intensive FOLFIRINOX regimen with substantial neoadjuvant toxicity. Despite cat3 labeling as colon-perioperative, this is a rectal cancer trial. Generalizability of FOLFIRINOX intensity to broader populations is uncertain.
Clinical Context
PRODIGE 23, alongside RAPIDO, established total neoadjuvant therapy as a standard for locally advanced rectal cancer, as endorsed by ESMO. Induction FOLFIRINOX-based TNT is an option for high-risk disease. No new drug approval arises from this trial.
References
Conroy et al, Lancet Onc, 2021, PMID: 33862000
RAPIDO: Bahadoer RR et al, Lancet Oncol, 2021, PMID: 33301740
RAPIDO: Bahadoer RR et al, Lancet Oncol, 2021, PMID: 33301740