Clinical trialPhase 3Colorectal cancer

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 · 2024The same population as the original PRODIGE 23 trial (the number of patients is not stated in the abstract of this report)

Conroy T, Castan F, Etienne PL, et al. Ann Oncol. 2024. 35:873-881

Study type: Clinical trial
Study name: PRODIGE 23
Phase: Phase 3
Design: Long-term analysis of a multicentre, randomised, open-label phase 3 trial
Sample size: The same population as the original PRODIGE 23 trial (the number of patients is not stated in the abstract of this report)
Source: Ann Oncol · 2024
Trial registration: NCT01804790

In plain words

This report followed the patients of the French PRODIGE 23 study for about 7 years. Patients who had 3 months of strong chemotherapy (mFOLFIRINOX) before chemoradiotherapy and surgery not only had their disease come back or spread less often, they also lived longer: after 7 years about 82 in every 100 patients were alive, compared with 76 in the standard treatment group. This regimen is intensive and was tested in younger, fit patients; your doctor will decide whether it suits you.

Key results

81.9% vs 76.1%

7-year overall survival

RMST difference 4.37 months (95% CI 0.35-8.38); P = 0.033; median follow-up 82.2 months

67.6% vs 62.5%

7-year disease-free survival

RMST difference 5.73 months (95% CI 0.05-11.41); P = 0.048

79.2% vs 72.3%

7-year metastasis-free survival

RMST difference 6.1 months (95% CI 0.93-11.37); P = 0.021

Drugs in this study:Capecitabine (Xeloda)Fluorouracil (5-FU)Irinotecan (Camptosar)Oxaliplatin (Eloxatin)

Dose and schedule cards

mFOLFIRINOX followed by chemoradiotherapy (PRODIGE 23)

Rectal adenocarcinoma cT3 or cT4 M0; age 18 to 75 years; WHO performance status 0–1On the page “Colorectal cancer” · Locally advanced rectal cancer: total neoadjuvant therapy (TNT) and immunotherapy

Rectal adenocarcinoma cT3 or cT4 M0; age 18 to 75 years; WHO performance status 0–1

Drug	Dose	Route	Schedule
Phase 1: 6 cycles (every 14 days)
Oxaliplatin	85 mg/m²	IV	Day 1, every 14 days
Irinotecan	180 mg/m²	IV	Day 1, every 14 days
Leucovorin	400 mg/m²	IV	Day 1, every 14 days
Fluorouracil	2400 mg/m² (no bolus)	IV, continuous 46- to 48-h infusion	Days 1 and 2, every 14 days
Phase 2: chemoradiotherapy
Radiotherapy	50 Gy	Pelvis	Over 5 weeks
Concurrent capecitabine	800 mg/m² twice daily	Oral	5 days per week during radiotherapy
Phase 4: 3 months of adjuvant therapy after TME
mFOLFOX6 (6 cycles, every 14 days) or capecitabine	mFOLFOX6 at the standard doses above; or capecitabine 1250 mg/m² twice daily, days 1–14 every 21 days	IV / oral	mFOLFOX6 every 14 days (6 cycles); capecitabine days 1–14, every 21 days

Cycle length: mFOLFIRINOX induction every 14 days (6 cycles); chemoradiotherapy over 5 weeks; adjuvant therapy: mFOLFOX6 every 14 days or capecitabine every 21 days
Duration: 3 months of mFOLFIRINOX, chemoradiotherapy, TME (phase 3), then 3 months of adjuvant therapy

Doses from the original PRODIGE 23 publication; infusion durations (oxaliplatin and leucovorin over 2 hours, irinotecan over 90 minutes, fluorouracil 1200 mg/m² per day over 2 days without a bolus) from the trial registration.

On the page “Colorectal cancer” · Locally advanced rectal cancer: total neoadjuvant therapy (TNT) and immunotherapy

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Neoadjuvant mFOLFIRINOX chemotherapy (total neoadjuvant therapy)

Neoadjuvant mFOLFIRINOX, every 14 days for 6 cycles: oxaliplatin 85 mg/m² IV over 2 hours, irinotecan 180 mg/m² IV over 90 minutes, leucovorin 400 mg/m² IV and fluorouracil 2400 mg/m² continuous infusion over 46 to 48 hours (no bolus); then chemoradiotherapy 50 Gy over 5 weeks (2 Gy per fraction) with oral capecitabine 800 mg/m² twice daily, 5 days per week; then total mesorectal excision (TME) 6 to 8 weeks later; then 3 months of adjuvant chemotherapy: mFOLFOX6 (oxaliplatin 85 and leucovorin 400 mg/m², fluorouracil 400 mg/m² bolus and 2400 mg/m² over 46 hours; every 14 days, 6 cycles) or capecitabine 1250 mg/m² twice daily, days 1 to 14 every 21 days.

2Standard treatment

Chemoradiotherapy (50 Gy over 5 weeks with capecitabine 800 mg/m² twice daily, 5 days per week), TME and 6 months of adjuvant chemotherapy (12 cycles of mFOLFOX6 or 8 cycles of capecitabine at the same doses).

Source of the regimen details: Doses from the original PRODIGE 23 paper (Conroy et al, Lancet Oncol 2021; PMID 33862000) and ClinicalTrials.gov NCT01804790 (infusion durations); number of cycles from the abstract of this report

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

Patients with locally advanced rectal adenocarcinoma below the peritoneal reflection on MRI, stage cT3 or cT4.

Endpoints

Primary outcome: disease-free survival (reported previously).

Key secondary outcomes: overall survival, metastasis-free survival, and local and metastatic recurrence rates.

Safety and side effects

According to the abstract, the safety profile was unchanged from the previous analysis. Details are in the full text of the paper.

Clinical significance and place in guidelines

PRODIGE 23 is the first total neoadjuvant therapy (TNT) trial in rectal cancer to show an overall survival improvement, and it strengthened the place of TNT with mFOLFIRINOX as one of the best options for suitable patients. The ESMO guideline for localised rectal cancer (2025) recommends that, if irinotecan is used in TNT, it should be given according to the PRODIGE 23 protocol [I, A].

Limitations

Open-label design; the trial was conducted only in France and in patients aged 18 to 75 with good performance status; overall survival was a secondary outcome, and differences are reported as RMST differences (not hazard ratios) and are modest in absolute terms; the triplet regimen has considerable toxicity.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.