Clinical trialPhase 3Colorectal 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

Lancet Oncol · 2021461 patients (231 neoadjuvant chemotherapy, 230 standard treatment)

Conroy T, Bosset JF, Etienne PL, et al. Lancet Oncol. 2021. 22:702-715

A newer report of this study has been published: Total neoadjuvant therapy with mFOLFIRINOX versus preoperative chemoradiotherapy in patients with locally advanced rectal cancer: long-term results of the UNICANCER-PRODIGE 23 trial (2024)

Study type: Clinical trial
Study name: PRODIGE 23
Phase: Phase 3
Design: Randomised, open-label, multicentre trial (35 hospitals in France); 1:1 randomisation by minimisation
Sample size: 461 patients (231 neoadjuvant chemotherapy, 230 standard treatment)
Source: Lancet Oncol · 2021
Trial registration: NCT01804790

In plain words

This French study showed that in locally advanced rectal cancer, giving 3 months of strong chemotherapy (FOLFIRINOX) first, followed by chemoradiotherapy and surgery, increases the chance of being alive without the disease coming back at 3 years (76% vs 69%). Patients also needed shorter chemotherapy after surgery and had less nerve damage. This regimen is intensive and was tested in younger, fitter patients (aged 18 to 75).

Key results

76% vs 69%

3-year disease-free survival

Stratified HR 0.69 (95% CI 0.49–0.97); p=0.034; median follow-up 46.5 months

11% vs 23%

Serious adverse events during adjuvant therapy

p=0.0049

12% vs 21%

Grade 3–4 peripheral sensory neuropathy during adjuvant therapy

19 of 162 vs 32 of 155

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 FOLFIRINOX + chemoradiotherapy

FOLFIRINOX (oxaliplatin 85 mg/m², irinotecan 180 mg/m², leucovorin 400 mg/m² and fluorouracil 2400 mg/m², IV every 14 days for 6 cycles); then chemoradiotherapy (50 Gy over 5 weeks with oral capecitabine 800 mg/m² twice daily, 5 days per week); total mesorectal excision; and 3 months of adjuvant chemotherapy with mFOLFOX6 (oxaliplatin 85 and leucovorin 400 mg/m², then fluorouracil 400 mg/m² bolus and 2400 mg/m² over 46 hours, every 14 days for 6 cycles) or capecitabine (1250 mg/m² orally twice daily, days 1 to 14 every 21 days).

2Standard treatment

Chemoradiotherapy (the same regimen), total mesorectal excision and adjuvant chemotherapy for 6 months.

Source of the regimen details: Doses and schedules from the published abstract of the paper (Lancet Oncol 2021), which gives the regimens in full

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

Adults aged 18 to 75 with newly diagnosed, biopsy-confirmed rectal adenocarcinoma, stage cT3 or cT4 without metastases (M0) and WHO performance status 0 to 1.

Endpoints

Primary outcome: 3-year disease-free survival in the intention-to-treat population.

Other: safety (in treated patients).

Safety and side effects

During FOLFIRINOX, the most common grade 3–4 adverse events were neutropenia (17%) and diarrhoea (11%). During chemoradiotherapy, grade 3–4 lymphopenia (28% versus 30%). During adjuvant therapy, lymphopenia (11% versus 27%), neutropenia (6% versus 18%) and peripheral sensory neuropathy (12% versus 21%) were less frequent in the neoadjuvant group. Serious adverse events over the whole treatment period 27% versus 22% (p=0.167). Treatment-related deaths: one patient (less than 1%) versus two patients (1%).

Clinical significance and place in guidelines

PRODIGE 23, together with RAPIDO, is the main evidence base for total neoadjuvant therapy (TNT) in locally advanced rectal cancer. The ESMO guideline for localised rectal cancer (2025) recommends consolidation or induction chemotherapy (CAPOX or FOLFOX) for 3 to 4.5 months [I, A] and that "if irinotecan is used, it should be administered according to the PRODIGE 23 trial protocol" [I, A].

Limitations

Open-label design; only in France and in patients aged 75 or younger with good performance status; the duration of adjuvant chemotherapy differed between the two arms (3 versus 6 months); 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.