Clinical trialPhase 3Pancreatic cancer

FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer

N Engl J Med · 2018493 patients (247 mFOLFIRINOX, 246 gemcitabine)

Conroy T, Hammel P, Hebbar M, et al. N Engl J Med. 2018. 379:2395-2406

A newer report of this study has been published: Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial (2022)

Study type: Clinical trial
Study name: PRODIGE 24 / CCTG PA.6
Phase: Phase 3
Design: Randomised, open-label, multicentre trial in France and Canada (1:1 randomisation)
Sample size: 493 patients (247 mFOLFIRINOX, 246 gemcitabine)
Source: N Engl J Med · 2018
Trial registration: NCT01526135

In plain words

After surgery for pancreatic cancer, even when the tumour has been completely removed, the chance of the disease coming back is high, so about six months of extra chemotherapy is given. This study showed that patients in good general health who receive the four-drug mFOLFIRINOX regimen instead of gemcitabine alone stay free of the disease for much longer on average and live longer (median about 54 months vs 35 months). This regimen has more side effects, such as diarrhoea, tiredness and tingling in the hands and feet, so it suits patients who have recovered well after surgery.

Key results

21.6 vs 12.8 months

Median disease-free survival

HR 0.58 (95% CI 0.46–0.73); P<0.001; median follow-up 33.6 months

39.7% vs 21.4%

3-year disease-free survival

54.4 vs 35.0 months

Median overall survival

HR for death 0.64 (95% CI 0.48–0.86); P=0.003

63.4% vs 48.6%

3-year overall survival

43.2% vs 31.4%

5-year overall survival (final follow-up)

Median OS 53.5 vs 35.5 months; HR 0.68 (95% CI 0.54–0.85); P=.001; median follow-up 69.7 months — Conroy T et al, JAMA Oncol 2022;8:1571-1578 (doi:10.1001/jamaoncol.2022.3829)

75.9% vs 52.9%

Grade 3 or 4 adverse events

One toxic death (interstitial pneumonitis) in the gemcitabine group

Drugs in this study:Fluorouracil (5-FU)Gemcitabine (Gemzar)Irinotecan (Camptosar)Oxaliplatin (Eloxatin)

Dose and schedule cards

Adjuvant mFOLFIRINOX (PRODIGE 24)

Resected pancreatic ductal adenocarcinoma (R0 or R1); age 18 to 79 years; WHO performance status 0–1; postoperative CA19-9 at most 180 U/mL; start 21 to 84 days after surgeryCycle length: Every 14 daysOn the page “Pancreatic cancer” · Adjuvant (postoperative) and neoadjuvant (preoperative) therapy

Resected pancreatic ductal adenocarcinoma (R0 or R1); age 18 to 79 years; WHO performance status 0–1; postoperative CA19-9 at most 180 U/mL; start 21 to 84 days after surgery

Drug	Dose	Route	Schedule
Oxaliplatin	85 mg/m²	IV over 2 hours	Day 1
Irinotecan	150 mg/m²	IV over 90 minutes	Day 1
Leucovorin	400 mg/m²	IV over 2 hours	Day 1
Fluorouracil (infusion)	2400 mg/m² (no bolus)	IV, 46-hour continuous infusion	Starting Day 1

Cycle length: Every 14 days
Duration: 12 cycles (24 weeks)

Doses from the PRODIGE 24 publication (the irinotecan dose was reduced from 180 to 150 mg/m² after a protocol-specified safety analysis); infusion durations, the absence of a fluorouracil bolus and the eligibility criteria from the trial registration. Survival evidence: PRODIGE 24, 5-year follow-up.

On the page “Pancreatic cancer” · Adjuvant (postoperative) and neoadjuvant (preoperative) therapy

mFOLFIRINOX (adjuvant)

Pancreatic cancer after surgery, within 12 weeks of the operationCycle length: Every 14 daysOn the page “FOLFIRINOX and mFOLFIRINOX: dose and side effects”

Pancreatic cancer after surgery, within 12 weeks of the operation

Drug	Dose	Route	Schedule
Oxaliplatin	85 mg/m²	IV over 2 hours	Day 1
Leucovorin	400 mg/m²	IV over 2 hours	Day 1
Irinotecan	150 mg/m²	IV over 90 minutes	Day 1
Fluorouracil	2400 mg/m²	Continuous 46-hour infusion (no bolus)	Starting on day 1

Cycle length: Every 14 days
Duration: 12 cycles (6 months)

Doses as in the PRODIGE 24 study.

On the page “FOLFIRINOX and mFOLFIRINOX: dose and side effects”

FOLFIRINOX and modified FOLFIRINOX

Metastatic pancreatic cancer (ECOG 0 to 1); adjuvant treatment after pancreatic resectionCycle length: Every 14 daysOn the page “Oxaliplatin (Eloxatin)” · Standard doses and combination regimens (FDA label and key trials)

Metastatic pancreatic cancer (ECOG 0 to 1); adjuvant treatment after pancreatic resection

Drug	Dose	Route	Schedule
Metastatic
Oxaliplatin / irinotecan / leucovorin	85 / 180 / 400 mg/m²	IV	Day 1
Fluorouracil	400 mg/m² bolus, then 2400 mg/m²	IV bolus, then continuous 46-hour infusion	Days 1 to 3
Adjuvant (modified)
Oxaliplatin / irinotecan / leucovorin	85 / 150 (initially 180) / 400 mg/m²	IV	Day 1
Fluorouracil	2400 mg/m², no bolus	Continuous IV infusion	Day 1

Cycle length: Every 14 days
Duration: Metastatic: 6 months recommended in responding patients; adjuvant: 24 weeks (12 cycles)

The regimens of the PRODIGE 4/ACCORD 11 and PRODIGE 24 trials; not in the FDA label for oxaliplatin. In PRODIGE 24 the irinotecan dose was reduced from 180 to 150 mg/m² after a pre-specified safety analysis.

On the page “Oxaliplatin (Eloxatin)” · Standard doses and combination regimens (FDA label and key trials)

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

1mFOLFIRINOX (modified)

Every 14 days, 12 cycles (24 weeks): oxaliplatin 85 mg/m² IV over 2 hours on day 1; irinotecan 180 mg/m² (reduced to 150 mg/m² after a safety analysis planned in the protocol) over 90 minutes; leucovorin 400 mg/m² over 2 hours; fluorouracil (5-FU) 2400 mg/m² continuous infusion over 46 hours. No 5-FU bolus.

2Gemcitabine (control group)

Gemcitabine 1000 mg/m² IV over 30 minutes on days 1, 8 and 15 every 4 weeks, 6 cycles (24 weeks).

Source of the regimen details: NEJM 2018 abstract (doses) and ClinicalTrials.gov NCT01526135 (infusion durations, 12 cycles, continuous 46-hour 5-FU, irinotecan 150 mg/m²)

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

Histologically confirmed pancreatic ductal adenocarcinoma with macroscopically complete resection (R0 or R1).
Age 18 to 79 years and WHO performance status 0 to 1.
No prior chemotherapy or radiotherapy; full recovery from surgery and start of treatment 21 to 84 days after the operation.
Adequate bone marrow, liver (bilirubin up to 1.5 times the upper limit of normal) and kidney function.

Endpoints

Primary outcome: disease-free survival (DFS).

Secondary outcomes: overall survival (OS), cancer-specific survival, metastasis-free survival and safety.

Safety and side effects

Grade 3 or 4 adverse events occurred in 75.9% of patients in the mFOLFIRINOX group and 52.9% in the gemcitabine group. One toxic death (interstitial pneumonitis) was reported in the gemcitabine group. The irinotecan dose was reduced from 180 to 150 mg/m² after a safety analysis planned in the protocol. The percentage for each adverse event is given in the full text of the paper.

Clinical significance and place in guidelines

PRODIGE 24 made mFOLFIRINOX the standard adjuvant therapy for suitable patients (good performance status) after surgery for pancreatic cancer. The ESMO 2023 guideline recommends adjuvant mFOLFIRINOX for patients with ECOG 0 to 1 with level of evidence [I, A], and the NCCN guideline (version 4.2026) considers mFOLFIRINOX a category 1 preferred option for adjuvant therapy in patients who did not receive neoadjuvant therapy. The final 5-year results (JAMA Oncol 2022, median follow-up 69.7 months) confirmed the survival advantage: 5-year overall survival 43.2% versus 31.4%.

Limitations

Only patients younger than 80 with very good performance status and full recovery after surgery were enrolled, so the results cannot be generalised to older or frail patients. The study was open-label (no blinding), and the comparator was gemcitabine alone, not gemcitabine + capecitabine (the ESPAC-4 regimen). The higher toxicity of the regimen and the need to reduce the irinotecan dose during the study must also be considered.

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.