Conroy 2024 — PRODIGE 23 Long-Term Results

Citation: Conroy T, Castan F, Etienne PL, et al. Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial. Ann Oncol. 2024;35(10):873-881. doi:10.1016/j.annonc.2024.06.019.

Note on what this paper is: this is the long-term (median 82.2-month) follow-up of the UNICANCER-PRODIGE 23 trial, reporting mature overall survival data. The original primary-endpoint publication (3-year DFS) is Conroy et al., Lancet Oncol 2021;22:702-715 — that paper is not separately ingested in this wiki; some 3-year-only details (e.g. exact chemotherapy compliance percentages, quality-of-life results) live only in the original paper and aren’t captured here.

Study design

• UNICANCER-PRODIGE 23 (EudraCT 2011-004406-25; NCT01804790) — investigator-driven, multicentre (35 French centres), randomised, open-label, phase III trial. 461 patients randomised 2012–2017 (231 experimental / 230 standard of care).
• Population: locally advanced rectal adenocarcinoma, cT3 (at risk of local recurrence, MDT-selected for CRT) or cT4, age <76, WHO performance status ≤1. A lower-risk population than RAPIDO (no cT4-only or EMVI/MRF-based enrichment criteria) but overlaps STELLAR’s eligibility.
• Experimental (TNT) arm: neoadjuvant mFOLFIRINOX (6 cycles) → chemoradiotherapy → surgery → adjuvant chemotherapy (6 cycles).
• Standard-of-care arm: chemoradiotherapy → surgery → adjuvant chemotherapy (12 cycles). (Total chemotherapy duration equalized between arms — this is a genuinely different design philosophy from RAPIDO/STELLAR, which compare SCRT+chemo against CRT+optional/reduced adjuvant.)
• Primary endpoint (original trial): 3-year DFS. Key secondary endpoints (this long-term paper): overall survival (OS), metastasis-free survival (MFS), locoregional/metastatic recurrence rates.
• Median follow-up 82.2 months (95% CI 79.8–83.5) — one of the longest follow-ups among rectal cancer TNT trials.

Key findings

Outcome (7-year)	Experimental (TNT)	Standard of care	RMST difference	p
Disease-free survival	67.6%	62.5%	5.73 months	.048
Metastasis-free survival	79.2%	72.3%	6.1 months	.021
Overall survival	81.9%	76.1%	4.37 months	.033
Cumulative local relapse	5.3%	8.1%	—	—
Post hoc disease-related treatment failure (DrTF, RAPIDO-equivalent definition)	25.0%	34.0%	6.3 months	.019

• First rectal-cancer TNT trial to demonstrate a real overall-survival benefit — the authors note this is the first neoadjuvant strategy since the 1997 Swedish Rectal Cancer Trial to improve OS in this population; earlier TNT trials (including RAPIDO) showed metastasis-reduction benefits without translating to OS.
• No increase in local relapse with TNT — in fact numerically lower (5.3% vs 8.1%) — this contrasts with RAPIDO, where locoregional failure was numerically (and reportedly, at 5-year follow-up) higher with TNT. The authors explicitly attribute the difference to trial design: in PRODIGE 23 all patients received the same chemoradiotherapy and surgery, with only the sequencing of chemotherapy varied (neoadjuvant vs adjuvant), whereas RAPIDO substituted short-course RT for full chemoradiotherapy.
• No “ATRESS phenomenon” (neoadjuvant-therapy-related shortening of survival after distant relapse) — unlike RAPIDO, median survival after metastatic relapse was similar between arms (36.5 vs 35.7 months). The authors specifically investigated this because RAPIDO’s failure to show an OS benefit despite a metastasis reduction was attributed partly to ATRESS.
• Second cancers were more frequent in the experimental arm (6.1% vs 2.2% at 7 years) — the authors discuss but cannot rule out a chemotherapy-related contribution, while noting their experimental- arm rate is comparable to background rates reported in other colorectal chemotherapy literature (4.3–7.8%).
• Exploratory analysis: patients achieving ypT0N0 had markedly better 5-year DFS (84.2% vs 67.8% for residual tumour); within ypT0N0, adjuvant chemotherapy omission did not appear to compromise DFS (84.8% with vs 82.6% without) — hypothesis-generating for future de-escalation trials (cited: NORAD01-GRECCAR16, GRECCAR 14, Alliance JANUS).
• Male sex and higher baseline TNM stage were independent poor prognostic factors for OS in multivariate analysis.

Limitations

• Enrollment capped at age <76 — excludes older patients disproportionately represented in real-world rectal cancer populations.
• No extramural venous invasion (EMVI) data collected — a known poor-prognosis marker used as an enrichment criterion in RAPIDO but not assessable here.
• Mismatch-repair/MSI status not available for all patients.
• This long-term paper reports a post hoc DrTF analysis (applying RAPIDO’s definition retrospectively) rather than a pre-specified endpoint — useful for cross-trial comparison but methodologically softer than RAPIDO’s own primary DrTF analysis.
• As noted above, the original 3-year primary publication is not independently ingested in this wiki — this source reflects only the long-term update’s content and framing.

Relevance

Closes the primary-literature gap flagged in Total Neoadjuvant Therapy (TNT) and Rectal Cancer’s Open items, and is the wiki’s strongest evidence yet for the once-only- theoretical claim that TNT can improve overall survival, not just DFS/MFS. Provides an important cross-trial contrast with Bahadoer 2021 - RAPIDO Trial: both are phase III rectal-cancer TNT trials, but PRODIGE 23’s chemotherapy-first, same-CRT-for-both-arms design showed a real OS benefit and no locoregional trade-off, whereas RAPIDO’s SCRT-substitution design showed a metastasis benefit without OS benefit and a (reported) locoregional trade-off. The wiki should not collapse these into one “TNT works” narrative — the two represent materially different treatment strategies with materially different risk/benefit profiles, and Jin 2022 - STELLAR Trial (SCRT-based, like RAPIDO, but without RAPIDO’s locoregional trade-off) further complicates any simple SCRT-vs- chemotherapy-first generalization.