Clinical trialPhase 3Pancreatic cancer

Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer: A Randomized Clinical Trial

JAMA Oncol · 2022493 patients

Conroy T, Castan F, Lopez A, et al. JAMA Oncol. 2022. 8:1571-1578

Study type: Clinical trial
Study name: PRODIGE 24
Phase: Phase 3
Design: Open-label randomised trial (1:1 randomisation) at 77 hospitals in France and Canada; final 5-year results (data cutoff: 28 June 2021); EudraCT: 2011-002026-52
Sample size: 493 patients
Source: JAMA Oncol · 2022
Trial registration: NCT01526135

In plain words

This report followed the patients of the large PRODIGE 24 study, who had chemotherapy after surgery for pancreatic cancer, for about 6 years. Patients who had the three-drug FOLFIRINOX regimen lived about 18 months longer on average, and after 5 years about 43 in every 100 of them were alive, compared with about 31 in every 100 with gemcitabine alone. This regimen is stronger and has more side effects, so it suits patients who are in good general health after surgery; your doctor will choose the best option for your situation.

Key results

21.4 months vs 12.8 months

Median disease-free survival

HR 0.66; 95% CI 0.54-0.82; P < .001; median follow-up 69.7 months

26.1% vs 19.0%

5-year disease-free survival

mFOLFIRINOX vs gemcitabine

53.5 months vs 35.5 months

Median overall survival

HR 0.68; 95% CI 0.54-0.85; P = .001

43.2% vs 31.4%

5-year overall survival

mFOLFIRINOX vs gemcitabine

29.4 months vs 17.7 months

Median metastasis-free survival

HR 0.64; 95% CI 0.52-0.80; P < .001

54.7 months vs 36.3 months

Median cancer-specific survival

HR 0.65; 95% CI 0.51-0.82; P < .001

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

1Modified FOLFIRINOX (mFOLFIRINOX)

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, 30 minutes after the start of leucovorin); leucovorin 400 mg/m² (racemic; or 200 mg/m² of the L-form) over 2 hours; fluorouracil 2400 mg/m² continuous infusion over 46 hours (1200 mg/m² per day), no 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: Abstract of the paper and the original PRODIGE 24 paper (NEJM 2018); number of cycles, infusion durations and absence of a fluorouracil bolus from ClinicalTrials.gov NCT01526135

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 aged 18 to 79 with histologically confirmed pancreatic ductal adenocarcinoma who had undergone macroscopically complete resection (R0/R1) 3 to 12 weeks before randomisation. Enrolment from 16 April 2012 to 3 October 2016. 216 (43.8%) women; mean age 62.0 years (SD 8.9).

Endpoints

Primary outcome: disease-free survival. Secondary outcomes: overall survival, metastasis-free survival and cancer-specific survival. Prognostic factors for overall survival were also determined.

Safety and side effects

No new safety data are presented in this 5-year report. In the original trial report (NEJM 2018), grade 3 or 4 adverse events occurred in 75.9% of patients in the mFOLFIRINOX group and 52.9% in the gemcitabine group.

Clinical significance and place in guidelines

These mature data confirmed the overall survival superiority of modified FOLFIRINOX over gemcitabine with long follow-up (median 69.7 months) and established mFOLFIRINOX as the standard adjuvant therapy for patients in good general condition after resection of pancreatic ductal adenocarcinoma. The finding that higher-volume centres were a favourable prognostic factor underlines the importance of treatment at experienced centres.

Limitations

Open-label trial; strict eligibility criteria (age 18 to 79 and adequate recovery after surgery) limit generalisation to older or frailer patients. The prognostic factor analysis is exploratory. Safety data are not presented in the abstract of this report.

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.