Thierry Conroy, MD
Colin D. Weekes, MD, PhD
Adjuvant treatment with modified FOLFIRINOX resulted in the longest overall survival yet reported for patients with resected pancreatic cancer, according to the results of the phase III Unicancer GI PRODIGE 24/CCTG PA.6 trial, presented at the 2018 ASCO Annual Meeting.1 With adjuvant modified FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin), median overall survival was 54.4 months, compared with 35.0 months with gemcitabine, the study’s comparator, reported Thierry Conroy, MD, of the Institut de Cancérologie de Lorraine in Vandoeuvre-lès-Nancy, France.
FOLFIRINOX basically doubled the median overall survival over what we previously thought was possible. No other regimen has come close to this.— Colin D. Weekes, MD, PhD
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“We saw almost a doubling in the disease-free survival rate at 3 years and an improvement in median survival for patients treated with modified FOLFIRINOX. Its superiority was observed in all predefined patient subgroups,” Prof. Conroy reported.
In an interview with The ASCO Post, the study’s formal discussant, Colin D. Weekes, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, called the findings “a game changer,” noting that “the magnitude of effect with modified FOLFIRINOX is beyond what we have ever seen in pancreatic cancer.”
PRODIGE Details
PRODIGE 24/CCTG PA.6 was a phase III multicenter French-based study involving 493 patients with potentially resectable pancreatic cancers. The study aimed to evaluate modified -FOLFIRINOX vs gemcitabine. FOLFIRINOX has already proven to be more effective than gemcitabine as first-line treatment in metastatic disease among patients with a good performance status. The trial used single-agent gemcitabine as a comparator rather than gemcitabine plus capecitabine, which has become the standard of care, since it was designed prior to the publication of the ESPAC-4 trial, which showed an 18% reduction in mortality with the combination,2 Dr. Conroy noted.
We saw almost a doubling in the disease-free survival rate at 3 years and an improvement in median survival for patients treated with modified FOLFIRINOX. Its superiority was observed in all predefined patient subgroups.— Thierry Conroy, MD
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The control arm received 6 cycles, every 28 days, of gemcitabine on days 1, 8, and 15. The experimental arm received modified FOLFIRINOX (oxaliplatin at 85 mg/m2, leucovorin at 400 mg/m2, irinotecan at 150 mg/m2 on day 1, plus 5-FU at 2.4 g/m2 over 46 hours) given every 14 days for 12 cycles. The primary endpoint was disease-free survival.
After 91.5% of the required number of events had occurred, the data safety and monitoring committee advised an early intent-to-treat analysis for ethical reasons.
Improvement in Overall Survival
After a median follow-up of 30.5 months, multiple outcomes were significantly improved with modified -FOLFIRINOX vs gemcitabine (Table 1). Median disease-free survival was 12.8 months in the gemcitabine arm vs 21.6 months in the modified FOLFIRINOX arm, and median overall survival was 35.0 months vs 54.4 months, respectively.
“The median survival with modified FOLFIRINOX is the best ever achieved,” despite the fact that single-agent gemcitabine resulted in outcomes that were better than observed in previous studies, he said. The use of modified FOLFIRINOX resulted in an additional 15% of patients being alive without pancreatic cancer after 3 years, he noted.
More Toxicity, as Expected
The downside to these excellent results is toxicity. Grade 3/4 adverse events were reported for 51.5% of the gemcitabine arm vs 75.5% of the modified FOLFIRINOX arm, including grade 4 events in 12% of each arm, with 1 toxic death in the gemcitabine arm. The most common grade 3/4 toxicities included diarrhea (18.6% vs 3.7%; P < .001), fatigue (11.0% vs 4.6%; P = .014), sensory peripheral neuropathy (9.3% vs 0%; P < .001), vomiting (5.0% vs 1.2%; P = .039), and mucositis (2.5% vs 0%; P = .014). The gemcitabine arm experienced more grade 3/4 febrile neutropenia (3.7% vs 2.9%; P = .65) and thrombocytopenia (4.5% vs 1.3%; P = .03).
KEY FINDINGS OF PRODIGE 24 TRIAL
- The phase III Unicancer GI PRODIGE 24/CCTG PA.6 trial compared adjuvant modified FOLFIRINOX with single-agent gemcitabine after resection of pancreatic adenocarcinoma.
- Treatment with modified FOLFIRINOX resulted in the longest overall survival reported yet in pancreatic cancer following resection: 54.4 months, vs 35.0 months with gemcitabine (HR = 0.64; P = .003).
- Median disease-free survival was 21.6 months vs 12.8 months (HR = 0.58; P < .0001), respectively.
- Toxicity, however, was much higher with modified FOLFIRINOX. Grade 3/4 adverse events occurred in 75.75% of this arm, vs 51.5% with gemcitabine arm.
- This study regimen should be considered only for patients who are fit enough to tolerate it.
“Regrettably, one toxic death occurred in the gemcitabine arm. Patients treated with gemcitabine also had significantly more grade 1/4 headache, fever, flu-like symptoms, lymphopenia, and increases in transaminases,” he said. “Modified FOLFIRINOX is more toxic than gemcitabine, but it is a safe regimen with manageable toxicities,” he commented. ■
DISCLOSURE: Dr. Conroy has received travel expenses from Roche. Dr. Weekes reported no conflicts of interest.
REFERENCES
1. Conroy T, Hammel P, Hebbar M, et al: Unicancer GI PRODIGE 24/CCTG PA.6 trial: A multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine in patients with resected pancreatic ductal adenocarcinomas. 2018 ASCO Annual Meeting. Abstract LBA4001. Presented June 4, 2018.
2. Neoptolemos JP, Palmer DH, Ghaneh P, et al: Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): A multicentre, open-label, randomised, phase 3 trial. Lancet 389:1011-1024, 2017.
