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Expert Point of View: Colin D. Weekes, MD, PhD and Andrew Epstein, MD


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Colin D. Weekes, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, called the results of the PRODIGE trial “practice-changing.” Dr. Weekes was the invited discussant of the study and was interviewed by The ASCO Post.

“The magnitude of effect is beyond what we have ever seen in pancreatic cancer,” Dr. Weekes observed. “FOLFIRINOX basically doubled the median overall survival over what we previously thought was possible. No other regimen has come close to this.”

In a press briefing, ASCO spokesperson Andrew Epstein, MD, a gastrointestinal cancer specialist at Memorial Sloan Kettering Cancer Center, agreed on the importance of the findings. “We saw a significant improvement in overall survival for a notoriously aggressive disease. I agree that modified FOLFIRINOX represents a new standard of care for these patients,” he added.

Dr. Weekes explained that, until now, gemcitabine plus capecitabine has been considered the most effective adjuvant therapy, yielding a median overall survival of 28 months in ESPAC-4.1 In contrast, modified FOLFIRINOX achieved a 54-month survival in PRODIGE. Although gemcitabine/capecitabine would have been a better comparator than single-agent gemcitabine, the PRODIGE study was designed prior to the publication of these results. 

Reasons for Improved Outcomes

The fact that patients lived so long is no doubt also a result of subsequent lines of therapy for management of metastatic disease, according to Dr. Weekes. For the average patient, disease recurred at 21.6 months, leaving 33 months (after recurrence, before death) during which the patient may well have been treated with -FOLFIRINOX for a second time or another multimodality chemotherapy. “We don’t yet know what the subsequent treatments were in this study, but that will be important information, as we evaluate the true impact of this study,” he said. 

Better metastatic disease therapies, he added, may also be behind the improved overall survival of gemcitabine-treated patients, which was about 10 months longer than expected without any change in disease-free survival, based on historic studies. “This is not because gemcitabine is doing more; rather it suggests as we improve upon our metastatic disease therapy, patients are living longer,” he said.

Toxicity Concerns

The fly in the ointment with modified FOLFIRINOX, which was borne out in this study, is toxicity, the experts agreed. “That’s the major limitation of the application of these findings,” Dr. Weekes commented. Since many patients cannot tolerate modified FOLFIRINOX, subjects had to be very fit to be considered for enrollment in PRODIGE.

He predicted most oncologists will now want to use adjuvant modified FOLFIRINOX, “but we have to be cautious about applying these findings to all patients who had tumors resected,” warned Dr. Weekes. “Not every patient should, or can, receive this regimen after surgery for pancreatic adenocarcinoma.”

The temptation is to “push the envelope” when a chance for cure is within sight, but when doing so, clinicians and patients must accept the possibility of additional toxicity, they agreed. “Because modified FOLFIRINOX is a relatively challenging regimen, we need to make sure we recommend it only in appropriate patients who are healthy enough to withstand the rigor of it,” Dr. Epstein said. “With -FOLFIRINOX, if you don’t make the appropriate dose modifications at the appropriate time, then you may cure more patients, but you may permanently hurt them in the process,” Dr. Weekes cautioned.

Indeed, he added, with FOLFIRINOX, more patients can approach that brass ring, the findings suggest. “The improved 3-year disease-free survial hints to the possibility of a chance for cure in some patients,” he said.

The bottom line, the specialists said, is that FOLFIRINOX is proving to be beneficial across treatment settings and should be part of the management of patients who can tolerate it. ■

DISCLOSURE: Drs. Weekes and Epstein reported no conflicts of interest.

REFERENCE

1. 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 389:1011-1024, 2017.


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