Modified FOLFIRINOX is superior to gemcitabine as adjuvant therapy for resected pancreatic cancer: The PRODIGE 24/CCTG PA6 Trial

Pancreatic cancer (PC) treatment continues to prove challenging. Most patients present with metastases, and even in patients with localized disease, relapse is frequent and overall survival rates are low. The European Study Group for Pancreatic Cancer (ESPAC)-1 and CONKO-001 randomized trials clearly demonstrated that surgery alone, even in resectable disease, was insufficient treatment for PC. ESPAC-1 showed a significant survival benefit in patients with resected nonmetastatic PC who received adjuvant 5 fluorouracil (5FU) plus folinic acid (leucovorin) over those who had surgery alone.¹

Similarly, in the CONKO-001 trial, adjuvant gemcitabine was found to prolong survival and decrease tumor recurrence at five years when compared with curative pancreatectomy only.^2,3 A subsequent comparison trial of adjuvant 5FU plus folinic acid versus gemcitabine in resected PC would show equivalent survival outcomes, but less toxicity was found in the gemcitabine arm.⁴ The addition of capecitabine to gemcitabine in the ESPAC-4 trial showed incremental improved survival when compared with gemcitabine alone.⁵ These data established gemcitabine-based treatments as the standard of care adjuvant therapy in patients with resected PC for more than a decade. However, contemporary cytotoxic combination therapies—particularly fluorouracil, leucovorin, oxaliplatin, and irinotecan (FOLFIRINOX)—have demonstrated improved efficacy over gemcitabine in metastatic PC and increased response rates in the neoadjuvant treatment of locally advanced and borderline resectable PC.^6,7 Based on these data, the PRODIGE (Partenariat de Recherche en Oncologie Digestive) intergroup and the Canadian Cancer Trials Group evaluated modified (m) adjuvant FOLFIRINOX in patients who underwent curative-resection of PC and established this regimen as the new gold standard adjuvant therapy for resected PC.⁸

Study design and findings

Conroy and colleagues randomized 493 patients after R0 or R1 resection of nonmetastatic PC from 77 hospitals in France and Canada to mFOLFIRINOX versus gemcitabine for 24 weeks. Randomization was stratified by trial center, lymph node status, serum CA 19-9 levels, and final margin status. Patients enrolled in the study had to be within three months of operation. Researchers used a modified FOLFIRINOX regimen without bolus 5FU to decrease toxicity. The primary outcome was disease-free survival (DFS); secondary outcomes included overall survival (OS), toxicity, and disease-specific survival (DSS).

At a median follow-up of 33.6 months, median DFS was longer in the mFOLFIRINOX group when compared with gemcitabine (21.6 versus 12.8 months, p <0.001) with a three-year DFS rate of 39.7 percent versus 21.4 percent. Median OS also significantly improved in the mFOLFIRINOX arm (54.4 versus 35.0 months) (see Figure 1). mFOLFIRINOX extended time to development of distant metastases (median 30.4 months versus 17.0 months for gemcitabine). More patients experienced grade 3/4 toxicity in the mFOLFIRINOX arm, and although these side effects were manageable, only 66.4 percent of patients completed all intended therapies in the mFOLFIRINOX arm versus 79 percent in the gemcitabine arm. However, it has yet to be determined whether the inability to complete therapy led to different outcomes. Regardless, on intention-to-treat analysis, median disease-free survival was 21.6 months in the modified-FOLFIRINOX group versus 12.8 months in the gemcitabine group, establishing mFOLFIRINOX as the new standard of care in adjuvant therapy for resected PC.

Figure 1. Kaplan–Meier estimates of DFS and OS in the intention-to-treat population, according to treatment group

The median disease-free survival was 21.6 months in the modified-FOLFIRINOX group versus 12.8 months in the gemcitabine group (Panel A). The median overall survival was 54.4 months in the modified-FOLFIRINOX group versus 35.0 months in the gemcitabine group (Panel B).

The study shows a striking median of OS of 54.4 months, significantly better than the previously reported median OS of 28 months seen with gemcitabine and capecitabine.^5,8 The major limitations of this trial included the inability to capture the number of patients who were unable to recover adequately from the operation to receive adjuvant therapy and the inability to widely apply this effective but toxic regimen to all PC patients because the study was highly selective.

Future directions

Given the challenges of delivering adequate postoperative therapy with mFOLFIRINOX and the reported benefit of upfront treatment, many centers now use neoadjuvant therapy for PC to maximize receipt of all intended therapies and select patients with aggressive biology who will derive no benefit from surgical resection. To test this approach, the Alliance 021806 trial, Perioperative Versus Adjuvant Chemotherapy for Resectable Pancreatic Cancer, was designed with the schema outlined in Figure 2 and will be opening shortly. This clinical trial will determine the optimal chemotherapy sequencing strategy for resectable PC, and the results will be eagerly awaited.

Figure 2. Alliance 021806 trial schema

For more information on the Alliance trial, contact Cristina Ferrone, MD, FACS, at cferrone@mgh.harvard.edu.

References

1. Neoptolemos JP, Stocken DD, Friess H, et al. A randomized trial of chemoradiotherapy and chemotherapy after resection of pancreatic cancer. N Engl J Med. 2004;350(12):1200-1210.
2. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs observation in patients undergoing curative-intent resection of pancreatic cancer: A randomized controlled trial. JAMA. 2007;297(3):267-277.
3. Oettle H, Neuhaus P, Hochhaus A, et al. Adjuvant chemotherapy with gemcitabine and long-term outcomes among patients with resected pancreatic cancer: The CONKO-001 randomized trial. JAMA. 2013;310(14):1473-1481.
4. Neoptolemos JP, Stocken DD, Bassi C, et al. Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: A randomized controlled trial. JAMA. 2010;304(10):1073-1081.
5. 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. 2017;389(10073):1011-1024.
6. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med. 2011;364(19):1817-1825.
7. Ferrone CR, Marchegiani G, Hong TS, et al. Radiological and surgical implications of neoadjuvant treatment with FOLFIRINOX for locally advanced and borderline resectable pancreatic cancer. Ann Surg. 2015;261(1):12-17.
8. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379(25):2395-2406.