CHICAGO—A randomized, multicenter, phase III trial showed that patients with surgically resected pancreatic cancer lived a median of 20 months longer when treated with modified FOLFIRINOX in the adjuvant setting compared to single agent gemcitabine (Abstract LBA4001). The study findings were presented at the 2018 ASCO Annual Meeting.
“FOLFIRINOX should be now considered a new standard of care in patients with good performance status, at least in Western countries,” asserted study presenter Thierry Conroy, MD, a medical oncologist and Director of the Institut de Cancerologie de Lorraine in Nancy, one of the UNICANCER comprehensive cancer centers in France.
The PRODIGE 24/CCTG PA.6 trial (NCT01526135) enrolled patients with non-metastatic pancreatic ductal adenocarcinoma who achieved a complete resection after surgery and were able to receive chemotherapy within 12 weeks after surgery.
Study participants were randomized to receive either gemcitabine alone or a modified regimen of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (mFOLFIRINOX) for 6 months. The regimen was modified so that 5-fluorouracil was administered via continuous IV infusion instead of bolus to mitigate toxicity. The primary endpoint was disease-free survival (DFS); secondary endpoints included toxicity, overall survival (OS), cancer-specific survival, and metastasis-free survival (MFS).
A total of 493 patients were enrolled from centers in France and Canada and then randomized to one of the treatment arms. However, nine participants in the mFOLFIRINOX arm and three in the gemcitabine arm did not receive treatment for eligibility reasons and were therefore excluded from efficacy and safety analyses, leaving 238 patients in the mFOLFIRINOX arm and 243 in the gemcitabine arm.
Patient baseline characteristics were similar between both arms, except the gemcitabine arm had a higher rate of venous resection than the mFOLFIRINOX arm did (28% vs. 21%).
Longer Survival, But More Toxicity
The trial met its primary endpoint; the median DFS was nearly 9 months longer for the mFOLFIRINOX arm compared to the gemcitabine arm (21.6 months vs. 12.8 months; HR=0.58). Three-year DFS rate was nearly double for the mFOLFIRINOX arm compared to the gemcitabine arm (39.7% vs. 21.4%).
As for secondary endpoints, the trend of longer survival for the mFOLFIRINOX arm continued. MFS was 30.4 months for the mFOLFIRINOX arm and 17.7 months for the gemcitabine arm (HR=0.59). Median OS was 54.5 months for the mFOLFIRINOX arm and 35.0 months for the gemcitabine arm (HR=0.64).
Three-year OS rate was 63.4 percent for the mFOLFIRINOX arm and 48.6 percent for the gemcitabine arm. The 3-year cancer specific survival rate showed a 15 percent difference, with 66.2 percent for the mFOLFIRINOX arm and 51.2 percent for the gemcitabine arm.
Although the treatment arms had a 20-month median OS difference, Allyson Ocean, MD, gastrointestinal oncologist at Weill Cornell Medicine and NewYork-Presbyterian, pointed out that the comparator arm is not the standard of care in the U.S.
“We haven't really used gemcitabine alone, at least not since I've been practicing, in the adjuvant setting as a single agent after surgery,” said Ocean. “Usually gemcitabine is combined with capecitabine as a standard of care in the adjuvant setting, so it doesn't surprise me that the survival times were so good compared to gemcitabine alone.”
The safety analysis showed that there was no difference in anemia or neutropenia between the two arms. The gemcitabine arm had a higher rate of thrombocytopenia (4.5% vs. 1.3%). Conroy explained the lack of neutropenia difference was probably due to the large use of secondary prophylaxis with granulocyte colony-stimulating factor in the mFOLFIRINOX arm.
However, there was significantly more diarrhea in the mFOLFIRINOX arm than the gemcitabine arm (84.4% vs. 49%), with 18.6 percent of participants having grade 3 or 4 diarrhea. The mFOLFIRINOX arm also had more peripheral neuropathy, fatigue, vomiting, and mucositis. For the gemcitabine arm, there was significantly more headache, fever, and flu-like syndrome. There was one toxic death in the gemcitabine arm and none in the mFOLFIRINOX arm.
Treatment delay was more common in the mFOLFIRINOX arm than the gemcitabine arm (14.4% vs. 3.9%). Also, a higher portion of patients stopped therapy in the mFOLFIRINOX arm than the gemcitabine arm (33.6% vs. 21.0%).
“Early stop of treatment during the 6-month adjuvant chemotherapy was significantly more frequent in the FOLFIRINOX group due to patient decision or toxicity, but in the gemcitabine [group], the reason for early stop was relapse during the treatment,” explained Conroy.
“I feel that this was really practice-changing data because we haven't seen survival times that high in such an awful disease,” said Ocean. “It was actually surprising to me that this was not part of the plenary session at ASCO because of the significance of the data.”
Upon learning these trial results, Ocean said she went back and changed the chemotherapy regimen from gemcitabine plus capecitabine to mFOLFIRINOX for a pancreatic cancer patient who had undergone surgical resection and recovered well. She said the patient was “very excited,” “hopeful,” and “grateful” for the new data.
About the data, she added, “That's really good news for patients who are able to have surgery. Now we have a very active regimen, and we can hopefully improve on their survival.”
Although the data are potentially practice-changing for patients, they apply only to a small population of patients. Only about 15-20 percent of patients with pancreatic cancer have resectable disease (Int J Radiat Oncol Biol Phys 2018;100:1155-1174). Further, of those with resectable disease, some patients may not be healthy enough to undergo a chemotherapy regimen with so much toxicity.
“It's very hard to administer FOLFIRINOX to patients that have just gone through pancreatic cancer surgery. It's an intense regimen. Patients a lot of times have complications after surgery that delay the onset of chemotherapy, and then to give them a very intense regimen poses a challenge for a lot of patients,” said Ocean. “It can be done, absolutely, but it's going to be interesting to see how much it's adopted because of the fear of giving such an intense regimen to patients right after surgery.”
Because the study findings are limited to resectable disease, Ocean said, “Our efforts have to be more geared towards detecting this disease earlier so that patients can get surgery.
“It's very important that we get this out to the community,” she stressed. Not just academic centers, but community oncology practices too because many oncologists who treat pancreatic cancer are not experts in it. There's a sentiment of resignation among many physicians because pancreatic cancer is such an “awful” disease. “Now this gives us all hope that there are better treatments.”
Christina Bennett is a contributing writer.