Quénet 2021 - PRODIGE 7 Trial

Full citation: Quénet F, Elias D, Roca L, Goéré D, Ghouti L, Pocard M, Facy O, Arvieux C, Lorimier G, Pezet D, et al., on behalf of the BIG Renape Group. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy versus cytoreductive surgery alone for colorectal peritoneal metastases (PRODIGE 7): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. 2021;22(2):256-266. ClinicalTrials.gov NCT00769405.

Raw PDF: raw/Quénet 2021 - PRODIGE 7 Trial.pdf

Study type / design

Multicenter (17 French centers), randomized, open-label, phase III trial. Eligible patients: age 18-70, histologically confirmed colorectal cancer with peritoneal metastases, Peritoneal Carcinomatosis Index (PCI) ≤25, WHO performance status 0-1, eligible for 6 months of systemic chemotherapy. Patients in whom complete macroscopic resection (or resection with <1mm residual tumor) was achieved were randomized 1:1 to:

• CRS + HIPEC: oxaliplatin-based HIPEC (open or closed technique; 360mg/m² closed or 460mg/m² open, with IV 5-FU/folinic acid given 20 min before HIPEC), 30-minute perfusion.
• CRS alone.

All patients received systemic chemotherapy (before, after, or both; investigators’ choice) with or without targeted therapy. 265 patients randomized (133 CRS+HIPEC, 132 CRS alone). Primary endpoint: overall survival.

Key findings

• No overall survival benefit from adding HIPEC: median OS 41.7 months (CRS+HIPEC, 95% CI 36.2-53.8) vs 41.2 months (CRS alone, 95% CI 35.1-49.7); HR 1.00 (95.37% CI 0.63-1.58), P=0.99. Essentially identical survival curves.
• No relapse-free survival benefit: median RFS 13.1 months (CRS+HIPEC) vs 11.1 months (CRS alone); HR 0.91 (95% CI 0.71-1.15), P=0.43. Peritoneal-free survival also did not differ significantly.
• More morbidity with HIPEC, specifically delayed: grade ≥3 complications at 30 days were similar between groups (42% vs 32%, P=0.083, not significant), but at 60 days were significantly more common with HIPEC (26% vs 15%, P=0.035) — intra-abdominal digestive fistulae and abscesses were the most common complications.
• Both groups achieved unexpectedly long median OS (~41 months) — longer than most prior retrospective series (35-40 months), likely reflecting a highly selected surgical population (radical resection was a trial-entry prerequisite) and improved systemic chemotherapy in both arms.
• Post-hoc subgroup signal (hypothesis-generating only, not confirmatory): patients with PCI 11-15 had numerically longer median OS and RFS with CRS+HIPEC than CRS alone — the authors flag this as a basis for future research, not a treatment recommendation.
• Authors’ conclusion: “cytoreductive surgery alone should be the cornerstone of therapeutic strategies with curative intent for colorectal peritoneal metastases” — i.e., routine addition of oxaliplatin-based HIPEC to CRS is not supported by this trial.

Limitations

• Highly selected population (complete/near-complete macroscopic resection required for randomization) — 118 of 396 preoperatively-assessed patients were not enrolled, mostly for PCI>25 or non-resectable disease; results may not generalize beyond expert high-volume centers capable of this degree of cytoreduction.
• Only one specific HIPEC regimen tested (oxaliplatin, 30-minute perfusion, open or closed technique pooled) — the trial explicitly does not rule out benefit from other HIPEC regimens (e.g. longer oxaliplatin exposure, mitomycin C-based protocols) or from HIPEC in non-colorectal peritoneal disease.
• 16 patients (12%) originally randomized to CRS-alone crossed over to receive HIPEC for isolated peritoneal relapse — excluded from per-protocol analysis but included in intention-to-treat; the authors note this could theoretically bias toward the null, though sensitivity analyses were consistent.
• No RAS/BRAF mutation data collected (not available early in the trial) — the discussion speculates that extensive pre-HIPEC oxaliplatin exposure could select for oxaliplatin-resistant clones, a hypothesis this trial cannot test directly.

Relevance

Directly closes the “no primary publications of PRODIGE 7 … ingested yet” open item on Cytoreductive Surgery and HIPEC — previously that page only had this trial’s findings secondhand via a review. This is the largest and most rigorous RCT specifically isolating HIPEC’s added value over CRS alone for colorectal peritoneal metastases, and its negative result (no OS/RFS benefit, more delayed morbidity) is a major reason CRS+HIPEC’s routine use for colorectal peritoneal disease has become more controversial since 2021 — contrast with the more encouraging retrospective literature this wiki’s Cytoreductive Surgery and HIPEC page was previously built from.