Five-Year Outcomes of FOLFIRINOX vs Gemcitabine as Adjuvant Therapy for Pancreatic Cancer

Author(s): Thierry Conroy, MD¹; Florence Castan, MSc²; Anthony Lopez, MD³; Anthony Turpin, MD, PhD⁴; Meher Ben Abdelghani, MD⁵; Alice C. Wei, MD, CM⁶; Emmanuel Mitry, MD, PhD⁷; James J. Biagi, MD⁸; Ludovic Evesque, MD⁹; Pascal Artru, MD¹⁰; Thierry Lecomte, MD, PhD¹¹; Eric Assenat, MD, PhD¹²; Lucile Bauguion, MD¹³; Marc Ychou, MD, PhD¹⁴; Olivier Bouché, MD, PhD¹⁵; Laure Monard, PharmD¹⁶; Aurélien Lambert, MD¹; Pascal Hammel, MD, PhD¹⁷; for the Canadian Cancer Trials Group and the Unicancer-GI–PRODIGE Group

Source: JAMA Oncol. 2022;8(11):1571-1578. doi:10.1001/jamaoncol.2022.3829

Dr. Anjan Patel's Thoughts

Long-term results on adjuvant FOLFIRINOX vs Gem in adjuvant pancreatic cancer. Although the survival benefit is quite significant (OS 53.5 vs 35.5 months respectively), I think the tell-tale numbers are the 5 year DFS being 26.1 vs 19%. The modest 7% curative benefit of triplet vs single-agent chemotherapy highlights the difficulty in managing this disease and the continued need for investment in GI clinical trials.

IMPORTANCE

Early results at 3 years from the PRODIGE 24/Canadian Cancer Trials Group PA6 randomized clinical trial showed survival benefits with adjuvant treatment with modified FOLFIRINOX vs gemcitabine in patients with resected pancreatic ductal adenocarcinoma; mature data are now available.

OBJECTIVE

To report 5-year outcomes and explore prognostic factors for overall survival.

DESIGN, SETTING, AND PARTICIPANTS

This open-label, phase 3 randomized clinical trial was conducted at 77 hospitals in France and Canada and included patients aged 18 to 79 years with histologically confirmed pancreatic ductal adenocarcinoma who had undergone complete macroscopic (R0/R1) resection within 3 to 12 weeks before randomization. Patients were included from April 16, 2012, through October 3, 2016. The cutoff date for this analysis was June 28, 2021.

INTERVENTIONS

A total of 493 patients were randomized (1:1) to receive treatment with modified FOLFIRINOX (oxaliplatin, 85 mg/m² of body surface area; irinotecan, 150-180 mg/m²; leucovorin, 400 mg/m²; and fluorouracil, 2400 mg/m², every 2 weeks) or gemcitabine (1000 mg/m², days 1, 8, and 15, every 4 weeks) as adjuvant therapy for 24 weeks.

MAIN OUTCOMES AND MEASURES

Primary end point was disease-free survival. Secondary end points included overall survival, metastasis-free survival, and cancer-specific survival. Prognostic factors for overall survival were determined.

RESULTS

Of the 493 patients, 216 (43.8%) were women, and the mean (SD) age was 62.0 (8.9) years. At a median of 69.7 months’ follow-up, 367 disease-free survival events were observed. In patients receiving chemotherapy with modified FOLFIRINOX vs gemcitabine, median disease-free survival was 21.4 months (95% CI, 17.5-26.7) vs 12.8 months (95% CI, 11.6-15.2) (hazard ratio [HR], 0.66; 95% CI, 0.54-0.82; P < .001) and 5-year disease-free survival was 26.1% vs 19.0%; median overall survival was 53.5 months (95% CI, 43.5-58.4) vs 35.5 months (95% CI, 30.1-40.3) (HR, 0.68; 95% CI, 0.54-0.85; P = .001), and 5-year overall survival was 43.2% vs 31.4%; median metastasis-free survival was 29.4 months (95% CI, 21.4-40.1) vs 17.7 months (95% CI, 14.0-21.2) (HR, 0.64; 95% CI, 0.52-0.80; P < .001); and median cancer-specific survival was 54.7 months (95% CI, 45.8-68.4) vs 36.3 months (95% CI, 30.5–43.9) (HR, 0.65; 95% CI, 0.51-0.82; P < .001). Multivariable analysis identified modified FOLFIRINOX, age, tumor grade, tumor staging, and larger-volume center as significant favorable prognostic factors for overall survival. Shorter relapse delay was an adverse prognostic factor.

CONCLUSIONS AND RELEVANCE

The final 5-year results from the PRODIGE 24/Canadian Cancer Trials Group PA6 randomized clinical trial indicate that adjuvant treatment with modified FOLFIRINOX yields significantly longer survival than gemcitabine in patients with resected pancreatic ductal adenocarcinoma.

Author Affiliations

¹Medical Oncology department, Institut de cancérologie de Lorraine, Vandoeuvre-lès-Nancy, France and Université de Lorraine, APEMAC, équipe MICS, Nancy, France ²Biometry Department, ICM Regional Cancer Institute of Montpellier, Montpellier, France and Montpellier University, Montpellier, France ³Hepatogastroenterology department, University Hospital, Nancy, France ⁴Medical Oncology Department, University hospital, Lille, France and University of Lille, Lille, France ⁵Medical Oncology Department, ICANS, Strasbourg, France ⁶Surgery department, Princess Margaret Hospital, Toronto, Ontario, Canada ⁷Medical Oncology department, Institut Paoli-Calmettes, Marseille, France ⁸Department of Oncology, Queen’s University, Canada ⁹Medical oncology department, Centre Antoine-Lacassagne, Nice, France ¹⁰Hepatogastroenterology department, Hôpital Jean-Mermoz, Lyon, France ¹¹Hepatogastroenterology department, Hôpital Trousseau, Tours, France and INSERM UMR 6239, Tours University, Tours, France ¹²Medical oncology department, Centre Hospitalier Universitaire de Saint-Eloi, Montpellier, France ¹³Hepatogastroenterology department, Centre Hospitalier Départemental Vendée, La Roche-sur-Yon, France ¹⁴Oncology department, ICM Regional Cancer Institute of Montpellier, Montpellier, France and Montpellier University, Montpellier, France ¹⁵Digestive oncology department, Centre Hospitalier Universitaire Robert Debré, Reims, France ¹⁶R&D, Unicancer, Paris, France ¹⁷Digestive and Medical Oncology department, Hôpital Paul Brousse and University Paris-Saclay, Villejuif, France

Addition of Metastasis-Directed Therapy to Systemic Therapy for Oligometastatic Pancreatic Ductal Adenocarcinoma (EXTEND): A Multicenter, Randomized Phase II Trial

Interesting study using local therapy in metastatic pancreatic ductal adenocarcinoma (MPDAC) patients with <=5 metastatic sites. I would really like to see overall survival data here as I think progression-free survival (PFS) is a tricky endpoint to use in a trial like this. Most likely the study arm will take a lot longer to demonstrate progression if all lesions are ablated, but most important to me is the quality of life, survival and overall exposure to cytotoxic therapy; the last of which is likely much better with local therapy being utilized.

Safety and Efficacy of CT041 in Patients With Refractory Metastatic Pancreatic Cancer: A Pooled Analysis of Two Early-Phase Trials

CAR-T agent for refractory met-pancreas showing a median duration of response of 9.5 months. These treatments are far from widely available, but the proof of principle is nice to see in a disease that otherwise has not had responses to immunotherapy. Hopefully more agents to come.

Nimotuzumab Plus Gemcitabine for K-Ras Wild-Type Locally Advanced or Metastatic Pancreatic Cancer

Asian study of nimotuzumab (humanized EGFR-inhibitor) + gemcitabine (gem) vs. gem alone. The overall survival (OS) was 10.9 vs. 8.5 months in favor of the combination arm. While the OS difference is small, recall that the OS in the NALIRIFOX and FOLFIRINOX studies are similar. The safety profile of nimotuzumab + gemcitabine is superior to a triplet or double cytotoxic chemotherapy combination regimen. This drug is currently not available in the USA but is approved for nasopharyngeal carcinoma in China.

NALIRIFOX versus nab-paclitaxel and gemcitabine in treatment-naive patients with metastatic pancreatic ductal adenocarcinoma (NAPOLI 3): a randomised, open-label, phase 3 trial

You may have enrolled a patient in this trial, but it seems we may have a new first line regimen. Surprisingly toxicity simar in both arms, but there was improvement in PFS and OS (17% reduction in death) although it wasn’t statistically significant in OS.
More diarrhea with nalirifox, but more neutropenia with gem abraxane.

Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial

Somewhat disappointing as this was a negative study, however it is still an option for patients who are not candidates for mFOLFIRINOX.