Oncologists who treat pancreatic cancer patients say the results of a new study published in TheNew England Journal of Medicine in December are practice-changing (2018;379:2395-2406).
In the multinational, randomized, phase III clinical trial, researchers from Canada and France—the Canadian Clinical Trials Group and the Unicancer-GI–PRODIGE Group—compared two chemotherapy regimens, one that's been a standard treatment for years with a multi-drug chemotherapy cocktail that's not typically used in patients after pancreatic surgery. They found that the combination drug leads to longer survival in patients who undergo adjuvant chemotherapy after surgery.
The researchers, who were primarily looking at disease-free survival, but also tracked overall survival and safety issues, compared gemcitabine with a modified FOLFIRINOX regimen (combination chemotherapy with fluorouracil, leucovorin, irinotecan, and oxaliplatin) in patients with resected pancreatic cancer.
“Gemcitabine was used for metastatic pancreatic cancer in the 1990s. In 2007, we started to use it in the adjuvant setting based on CONKO-001 (JAMA 2007;297(3):267-277). It became the standard for the next decade,” said Craig E. Devoe, MD, Chief of the Don Monti Division of Medical Oncology and Hematology at Northwell Health Cancer Institute, in Lake Success, N.Y.
Oncologists have treated cancer patients with metastatic disease with FOLFIRINOX, but generally they've steered away from its use in patients on the mend after surgery, thinking it would be too toxic, explained Devoe, who was not involved in the new study. It also hadn't been demonstrated to be better in this setting.
The international PRODIGE 24 trial involved 77 hospitals in France and Canada. In essence, the plan was for both groups to get 6 months of chemotherapy after surgery. Half of the study's 493 patients received a modified (slightly less toxic) FOLFIRINOX treatment for 6 months and the other half received gemcitabine for 6 months. The patients were between 18 and 79 years of age and had to be at least 3-12 weeks post-surgery and feel fully recovered from their operations.
After 3 years, the median disease-free survival was significantly longer in the modified FOLFIRINOX group—21.6 months among the study participants taking modified FOLFIRINOX compared with 12.8 months in those taking gemcitabine. The researchers also reported that 63.5 percent of patients who had received the modified FOLFIRINOX were still alive after 3 years compared with 48.6 percent of patients who received gemcitabine.
The new findings are heartening, said co-author Alice Wei, MD, who was a hepato-pancreato-biliary surgical oncologist at Princess Margaret Cancer Centre in Toronto at the time of the research and is now a surgical oncologist with Memorial Sloan Kettering in New York.
“Pancreatic cancer is a really lethal disease to treat and this study offers the most promising results we've seen in a generation for these resected patients. It's a huge advance in treating the disease in terms of disease-free survival and overall survival. Absolutely. This is going to be a practice-changing study,” Wei said.
Pancreatic cancer is the third-leading cause of death from cancer in the U.S. An estimated 44,330 people in the U.S. died from the disease in 2018, according to the NCI.
“Surgery offers the only chance of cure, but 5-year survival rates after surgical resection alone are low (approximately 10%),” the study authors wrote.
James Abbruzzese, MD, Chief of Medical Oncology and Associate Director for Clinical Research at the Duke Cancer Institute, said the results of the trial are “impressive.”
“I think many oncologists will quickly adopt this program,” he said, adding though, that not all pancreatic cancer patients will benefit. It's only for people who are fit enough to undergo surgery and who go on to recover well.
“I would say about 20 percent of patients struggle after surgery and may never get to the point where the oncologist and the surgeon feel comfortable giving adjuvant therapy,” Abbruzzese noted.
There's another trade-off. Patients who received modified FOLFIRINOX had more side effects—diarrhea, tingling, fatigue, and abdominal pain, among other issues—compared to patients who received gemcitabine, and they were less likely to complete all of their chemotherapy. Even so, the FOLFIRINOX group had better outcomes.
The study results were first presented as an abstract at the ASCO annual conference in June 2018.
“We've known about this result for a few months and many oncologists immediately adopted it as the new standard of care in pancreas cancer and this full manuscript gives more details on the statistical analysis and high quality of the study design. I think their data is extremely persuasive,” said Devoe, who added that that they've already started using the new modified-FOLFIRINOX treatment at Northwell.
The December 2018 NEJM study indicated that patients in the gemcitabine group might have been at a higher risk of relapse due to an increased number of cases that required venous vascular reconstruction, Devoe also noted.
“This could have led to an increased bias making the difference between the two regimens a little larger than it actually is; nevertheless, the results remain impressive,” he said.
Duke's Abbruzzese said future research looking at the sequencing of the modified chemotherapy regimen and surgery in relation to outcomes would be valuable information.
“A strategy that's been used at individual institutions, including MD Anderson where I spent 27 years, is switching around the sequence of therapy even for patients we ultimately thought would go to surgery. They get their chemotherapy first and sometimes some chemotherapy and radiation combined. Surgery became the last step instead of the first step and there are still a lot of institutions that pursue that strategy,” he said.
The new NEJM study is significant, Abbruzzese added. “With the publication of the modified-FOLFIRINOX paper, I've talked with my surgeons here and we're leaning much more toward doing surgery first in those patients with no blood vessel involvement because of the success of this trial.”
Mary Brophy Marcus is a contributing writer.