NEW YORK—Going beyond single-agent gemcitabine for first-line metastatic pancreatic cancer treatment, oncologists can choose between at least two combination regimens: FOLFIRINOX (folinic acid [leucovorin], fluorouracil [5-FU], irinotecan, and oxaliplatin), and gemcitabine-Abraxane (gemcitabine and nab-paclitaxel).
After years of negative clinical studies in pancreatic cancer, the two regimens are considered major treatment advances.
Two experts offered divergent views on which should be the preferred regimen, in a presentation here at the Chemotherapy Foundation Symposium, sponsored by the Mount Sinai School of Medicine. But with overall survival time in metastatic pancreatic cancer still so short, neither speaker thought either regimen was a “winner.”
“We are nowhere near ‘winning’ anything in this disease,” said Jordan D. Berlin, MD, Professor of Cancer Research and Medicine and Clinical Director of the GI Oncology Program at Vanderbilt-Ingram Cancer Center. “If we are going to sit here and concede that either one is a winner, we're wrong—both regimens are losers. One might be a slightly better loser than the other, but the bottom line is that we're still not where we want to be.”
‘Superior Survival with FOLFIRINOX’
Within that context, though, Howard S. Hochster, MD, Associate Director of Yale Cancer Center and Professor of Medicine at Yale School of Medicine, advocated the use FOLFIRINOX: “The survival and response achieved with FOLFIRINOX are unprecedented and appear better than gemcitabine-Abraxane,” he said.
He cited the French PRODIGE trial, sponsored by the French Ministry of Health, with 342 patients with metastatic pancreatic cancer, which showed almost a doubling in progression-free survival for FOLFIRINOX compared with single-agent gemcitabine (6.4 months versus 3.3 months) and improved median survival (11 versus 8.5 months). Objective response rates were 31.6 percent versus 9.4 percent. (Conroy et al: NEJM 2011;19:1817-1825).
“So for everything we can see, FOLFIRINOX really is superior,” Hochster said.
He noted, though, that many U.S. oncologists were hesitant at first about FOLFIRINOX because of the toxicity profile. “We knew FOLFOX isn't that bad, and FOLFIRI isn't that bad, but giving three [chemotherapy] drugs might be a big problem. But in the meantime, people have become a lot more comfortable with FOLFIRINOX.”
The regimen does have a relative disadvantage in toxicities, he said, including diarrhea and febrile neutropenia—“but despite substantial toxicities, patients feel better longer on FOLFIRINOX,” Hochster said, calling it “the standard of care for ‘fit patients’ with advanced pancreatic cancer.”
“Fit” is not as restrictive a term as it might seem, he added.
“In our experience at Yale, with our modified FOLFIRINOX, we have been able to treat patients with performance status of 1 and even 2, and even some people in their 70s and 80s.” Hochster said a study at Yale used a modified regimen, reducing the 5-FU bolus and the irinotecan by 25 percent, and added pegfilgrastim to make the regimen more tolerable.
“For good performance-status patients FOLFIRINOX is the better option, and even for people who are borderline, it is doable with some modifications.”
Hochster concluded his talk saying the real question for him is what will be the best platform for combining new drugs and biologics: “We don't have enough data to know that, but I don't believe in my experience that gemcitabine-Abraxane is that much more tolerated. It may vary, though, and for a biologic that has a lot of side effects like diarrhea, [combining with] a drug like FORLFIRINOX would be less preferable.”
Berlin was tasked with arguing the relative merits of gemcitabine-nabpaclitaxel, but he said that until the last minute he thought he was to take the side of FOLFIRINOX, because he has a potential conflict of interest, related to a relationship with Abraxane's manufacturer, Celgene.
“I take boatloads of money from Celgene and I enjoy it,” he said jocularly. “Let's face it, I might have a conflict here.”
Nevertheless, Berlin said there is evidence from two clinical studies of synergy between gemcitabine and nab-paclitaxel, although they point to two different mechanisms.
To support the regimen's efficacy, he cited the Phase III MPACT trial, sponsored by Celgene, with 863 patients, comparing gemcitabine plus nab-paclitaxel versus gemcitabine alone. The study showed superior overall survival, progression-free survival, and response with the combination regimen, although the rates of peripheral neuropathy and myelosuppression were increased (Von Hoff et al: NEJM 2013;18:1691-1703).
Berlin pointed out that the gemcitabine-nab-paclitaxel response rate of 29 percent by investigator review in MPACT was very close to the 31 percent response rate by investigator review for FOLFIRINOX in the PRODIGE study. The two studies are comparable, he said, as there were many similarities between the patient cohorts, including median age, gender, and stage, and all patients had stage IV disease.
There were also differences: MPACT allowed performance scores of 2, although that was less than 10 percent of the study; allowed patients over age 75; and was worldwide, while PRODIGE was conducted only in France.
But there was no clear difference in toxicities, Berlin said. “People have this mythological belief that there's a difference in the toxicity favoring gemcitabine-nabpaclitaxel and that therefore it's easier to combine, and we automatically think it's easier to give three drugs than four. But just as modifications in FOLFIRINOX can happen, modifications in gemcitabine-nabpaclitaxel might have to happen.”
Berlin lamented the fact that researchers tend to rationalize decisions about combination regimens made in advance rather than actually using the science: “They'll say ‘this drug synergizes with platinum, and therefore we should use it with FOLFIRINOX,’ or, ‘this drug synergizes with irinotecan, so therefore we should use it.’
“That's what happened in the past,” Berlin explained in a follow-up interview. “Everybody just combined their drugs with gemcitabine, with or without data, and we did a lot of ‘gemcitabine-plus-your drug here’ studies that were negative. And this includes me.”
Researchers need to be cautious about picking the best chemotherapy platform when moving forward into combination regimens with targeted drugs and biologicals, he said. “We've actually not done the justification that we need to do for these randomized trials. We should be talking to our basic scientists working in the lab. They can explain things—for example, they might know more about negative trials that were presented but never got published.”
Berlin concluded by admitting that he could have taken either side in this debate. “It could be that FOLFIRINOX is a better regimen—certainly numerically it looks better, and honestly, I use FOLFIRINOX fairly regularly, a modified regimen FOLFIRINOX that's used by the Intergroup as standard in clinical trials in the U.S. and Europe.”
But if the patient's performance score is poor, he said, he would use gemcitabine-nabpaclitaxel, and it is questionable whether FOLFIRINOX should be used in patients over age 75 while there are no safety or efficacy data.
State-of-the-Art Health Care versus Not So Much
Berlin went out on a limb in his presentation talking about the relative merits of clinical trials held in countries where medical care is top notch versus those in countries where the standard of care is not as good. Patients in PRODIGE were all treated in France, he said, while MPACT patients were from North American, several countries in Europe, Australia, and—to make his point—Russian and the Ukraine.
“Russia contributed a large number of patients, and we know they don't have the same level of supportive care infrastructure that we've got in this country, or that France has. France is a modern country with an outstanding health care system and a ready availability of all supportive measures, while Russia is still developing. This is not an indictment of Russian physicians, but their resources are more limited and there's less availability of some of the supportive care measures, including growth factors that would allow you to not modify doses.”
He said after his presentation that the theoretical consequence in a trial of a drug with a higher toxicity profile could be that patients need more supportive measures, such as growth factors. And if that supportive care were not readily available more patients could go off study, more dose modifications could mean less drug exposure, and that could have an impact on outcomes.
On the other hand, a drug with a low-toxicity profile such as gemcitabine would require fewer supportive measures and there might be no effect or limited effect between countries, he said, cautioning: “There is no data to support what I just said. This is theoretical.”