FOLFIRINOX Should Remain Adjuvant Standard for Resectable Pancreatic Cancer

Matthew H.G. Katz, MD, FACS

Systemic chemotherapy with FOLFIRINOX should be the backbone of treatment for patients with localized pancreatic cancer who have undergone surgical resection, said Matthew H.G. Katz, MD, FACS.

In results of the phase III PRODIGE 24/CCTG PA.6 trial presented at the 2018 ASCO Annual Meeting and subsequently published in the New England Journal of Medicine, adjuvant mFOLFIRINOX significantly improved overall survival (OS) and disease-free survival (DFS) compared with gemcitabine in patients with metastatic pancreatic cancer.¹

“If patients are treated with surgery as primary therapy, they should receive postoperative mFOLFIRINOX for 6 months if they can tolerate it,” said Katz, an associate professor in the Department of Surgical Oncology and the Division of Surgery at The University of Texas MD Anderson Cancer Center.

At a median follow-up of 30.5 months, median OS was 54.4 months in those who received mFOLFIRINOX compared with 34.8 months in patients treated with gemcitabine. Median DFS was 21.2 months versus 12.8 months in favor of mFOLFIRINOX.

The PREOPANC-1 trial also looked to further refine neoadjuvant and adjuvant treatments for these patients. The study showed that patients who received preoperative chemoradiation lived longer than those who received surgery alone. However, Katz said, an optimal chemoradiation regimen is still unclear, and community oncologists need more data to feel comfortable bringing this into routine practice.²

OncLive: Could you discuss the key takeaways from the PRODIGE 24/CCTG PA.6 trial?

In an interview at the 2019 OncLive^® State of the Science Summit™ on Gastrointestinal Cancers, Katz highlighted pivotal trials in pancreatic cancer and how these data are shifting the treatment paradigm for these patients.Katz: This was a very important study that randomized patients undergoing surgical resection for their cancer to either systemic chemotherapy with gemcitabine or systemic chemotherapy with mFOLFIRINOX. This is an important trial because the patients who received mFOLFIRINOX had the longest median OS that has been ever reported. Median OS was more than 50 months—significantly longer than patients who received gemcitabine, which was only about 35 months. Therefore, chemotherapy with mFOLFIRINOX is the standard of care for patients who undergo surgical resection for pancreatic cancer, as long as they can tolerate that therapy.

There are some issues in that regard because mFOLFIRINOX is a little bit harder to tolerate. Toxicity rates were higher in this study for the patients treated with mFOLFIRINOX, and these are factors that you need to take into account when selecting [the appropriate] postoperative chemotherapy for your patient. I would also add that the inclusion criteria for that study are very important. All the patients underwent surgery, but all of the patients also had a CA 19-9 level of <180. All patients had to completely recover from surgery and they could not have any symptomatic or cardiac issues. This is a pretty selected group when you look at patients who have undergone surgical resection.

Could you discuss the PREOPANC-1 study? What were the clinical implications of its findings?

What are the drawbacks to preoperative chemoradiation?

I would say that FOLFIRINOX is now the backbone of therapy for patients who have undergone surgical resection. You can add any experimental agent that you can imagine to that.This was a European study which looked at patients with resectable pancreatic cancer or borderline resectable disease. About half of those patients had more advanced cancers. It was essentially a study of 1 preoperative regimen: gemcitabine-based chemoradiation. Patients who were enrolled in this trial—and they had to have decent performance status—were randomized [to undergo either immediate surgery or preoperative chemoradiation, both followed by adjuvant chemotherapy]. That study showed that patients who were enrolled in the preoperative chemoradiation arm lived longer than those who underwent surgery first. This was one of the first studies to show a significant benefit to the addition of preoperative chemoradiation therapy [in these patients].For patients with localized cancer, we know that surgery is beneficial as long as the patient is healthy and can tolerate the operation. We know that for those who receive surgery, postoperative chemotherapy improves survival compared with surgery alone. What we do not completely understand is the role of radiation therapy. I believe there is some role to giving radiation, either preoperatively or postoperatively.

There is a study that examined the role of radiation in the postoperative setting—it showed a benefit to radiation in the preoperative setting, but it did not randomize patients to receive either radiation or chemotherapy. It randomized them to receive radiation or surgery de novo. I do not think it conclusively demonstrated that the benefits of that study were due to radiation. Chemoradiation seems to be beneficial in the preoperative setting, but we are not entirely sure that this is true. In general, [physicians] feel more comfortable giving chemotherapy preoperatively. For example, I would not feel comfortable giving a patient chemoradiation if they have subclinical metastatic disease or if the CA 19-9 level was astronomically high.

Were there any other trials recently presented that were critical in this space?

What is the biggest challenge that needs to be overcome in early or locally advanced pancreatic cancer?

At its nature, chemoradiation is a local treatment, but this is all experimental at this point, and there have not been any large phase III studies looking at surgery versus preoperative therapy. Until that is done, this is all just [decided by] bias and [data from] retrospective studies.To me, [the one with postoperative mFOLFIRINOX] is a practice-changing study that now defines the standard of care. If you get surgery for pancreatic cancer, recover completely, and can tolerate mFOLFIRINOX, you should probably be treated with it. That is the “home run” from the 2018 ASCO Annual Meeting.One of the biggest hurdles is the indiscriminate use of surgery for a disease that is systemic in most cases. We have an uphill battle treating systemic cancer with a local therapy like surgical resection. Our chemotherapy is getting better, but until it gets a lot better, we are going to struggle.

References

1. Conroy T, Hammel P, Hebbar M, et al. Unicancer GI PRODIGE 24/CCTG PA.6 trial: a multicenter international randomized phase III trial of adjuvant mFOLFIRINOX versus gemcitabine (gem) in patients with resected pancreatic ductal adenocarcinomas. J Clin Oncol. 2018;36 (suppl 8; abstr LBA4001). doi: 10.1200/JCO.2018.36.18_suppl.LBA4001.
2. Van Tienhoven G, Versteijne E, Suker M, et al. Preoperative chemotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer (PREOPANC-1): a randomized, controlled, multicenter phase III trial. J Clin Oncol. 2018;36 (suppl 18; abstr LBA4002). doi: 10.1200/JCO.2018.36.18.suppl.LBA4002.