PracticeUpdate Oncology February 2019

EDITOR’S PICKS 9

FOLFIRINOX Adjuvant Therapy Increases Survival in Pancreatic Cancer The New England Journal of Medicine Take-home message • This study compared the efficacy and safety of a modified FOLFIRINOX regimen with gemcitabine as adjuvant therapy in 493 patients with resected pancreatic cancer. • Adjuvant therapy with the FOLFIRINOX regimen led to significantly longer survival (DFS, 21.6 months; OS, 54.4 months) than gemcitabine (12.8 months; 35.0 months) among patients with resected pancreatic cancer, at the expense of a higher inci- dence of toxic effects. Jeffrey Wiisanen MD

COMMENT By Axel Grothey MD T he use of FOLFIRINOX as adju- vant treatment in pancreas cancer has rightfully been called practice-changing. The difference in disease-free and overall survival compared with gemcitabine is quite remarkable and has established a new standard of care (SOC) for patients who can tolerate this chemo triplet. The results of the adjuvant gemcit- abine/nab-paclitaxel trial are pending, but they will have a high bar to meet. Still, I believe that gem/nab-paclitaxel is somewhat better tolerated than FOLFIRINOX (even with the dose mod- ification – see below) and could open the door for more patients receiving active adjuvant therapy – if the data are as we expect them to be. The FOLFIRINOX regimen used in the adjuvant study for most of the patients had two modifications compared with the initial regimen used in the meta- static setting: no bolus 5-FU and a lower dose of irinotecan (150 vs 180 mg/m 2 every 2 weeks). In my practice, I have changed FOLFIRINOX to reflect these modifications and would like to use this modified regimen for the adjuvant and palliative setting. The rationale is that if a regimen is the SOC in a curative set- ting, it would make no real sense to use anything but the more tolerable version in a palliative setting. Even with the very remarkable adjuvant FOLFIRINOX data, the trend in resectable pancreas cancer rightfully goes toward using a neoad- juvant approach. The tolerability of an aggressive chemo regimen is likely better pre- than post-op, the tumor biology can be observed, and cancers can declare themselves beyond cura- tive surgery during the neoadjuvant phase, and the combination of chemo plus radiation therapy (SBRT vs chemo- rads) conceivably allows for a higher rate of R0 resections. " In my practice, I have changed FOLFIRINOX to reflect these modifications and would like to use this modified regimen for the adjuvant and palliative setting. "

Abstract BACKGROUND Among patients with metastatic pancreatic cancer, combination chemother- apy with fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) leads to longer overall survival than gemcitabine therapy. We compared the efficacy and safety of a modi- fied FOLFIRINOX regimen with gemcitabine as adjuvant therapy in patients with resected pan- creatic cancer. METHODS We randomly assigned 493 patients with resected pancreatic ductal adenocarci- noma to receive amodified FOLFIRINOX regimen (oxaliplatin [85 mg per square meter of body-sur- face area], irinotecan [180 mg per square meter, reduced to 150 mg per square meter after a pro- tocol-specified safety analysis], leucovorin [400 mg per square meter], and fluorouracil [2400 mg per square meter] every 2 weeks) or gemcitabine (1000 mg per square meter on days 1, 8, and 15 every 4 weeks) for 24 weeks. The primary end point was disease-free survival. Secondary end points included overall survival and safety. RESULTS At a median follow-up of 33.6 months, themedian disease-free survival was 21.6months in the modified-FOLFIRINOX group and 12.8 months in the gemcitabine group (stratified haz- ard ratio for cancer-related event, second cancer,

or death, 0.58; 95% confidence interval [CI], 0.46 to 0.73; P<0.001). The disease-free survival rate at 3 years was 39.7% in the modified-FOLFIRINOX group and 21.4% in the gemcitabine group. The median overall survival was 54.4 months in the modified-FOLFIRINOX group and 35.0 months in the gemcitabine group (stratified hazard ratio for death, 0.64; 95% CI, 0.48 to 0.86; P=0.003). The overall survival rate at 3 years was 63.4% in the modified-FOLFIRINOX group and 48.6% in the gemcitabine group. Adverse events of grade 3 or 4 occurred in 75.9% of the patients in the mod- ified-FOLFIRINOX group and in 52.9% of those in the gemcitabine group. One patient in the gem- citabine group died from toxic effects (interstitial pneumonitis). CONCLUSIONS Adjuvant therapy with a modified FOLFIRINOX regimen led to significantly longer survival than gemcitabine among patients with resected pancreatic cancer, at the expense of a higher incidence of toxic effects. FOLFIRINOX or Gemcitabine as Adjuvant Ther- apy for Pancreatic Cancer. N Engl J Med 2018 Dec 20;379(25)2417-2428, T Conroy, P Hammel, M Hebbar, et al. www.practiceupdate.com/c/77688

VOL. 3 • NO. 1 • 2019