Patients with metastatic pancreatic adenocarcinoma who received FOLFIRI.3 chemotherapy alternating with fixed-dose rate gemcitabine demonstrated improved response and longer survival than those treated with fixed-dose rate gemcitabine alone, according to results of a randomized phase 2 study.
Fluorouracil- and irinotecan-based regimens, as well as gemcitabine-based regimens, are standards of care for first-line therapy for patients with metastatic pancreatic cancer. However, poor outcomes in this patient population demonstrate the need for new, effective treatment options to extend survival and improve quality of life.
Researchers in France conducted an open-label, multicenter study, to determine the safety and efficacy of the FIRGEM regimen, which entails alternating FOLFIRI.3 — which consists of irinotecan, leucovorin and fluorouracil — with gemcitabine.
The analysis included 98 patients with WHO performance status of 0-1 and bilirubin levels <1.5 upper limit of normal values.
Researchers assigned half of the patients to first-line treatment with FIRGEM, which consisted of FOLFIRI.3 alternating with fixed-dose rate gemcitabine in 2-month intervals. The other half of patients received fixed-dose rate gemcitabine alone.
The crude PFS rate at 6 months served as the primary outcome measure. Treatment continued until disease progression or limiting toxicity.
Researchers reported higher rates of objective response (37% vs. 10%) and 6-month PFS (43.5% vs. 26.1%) among patients assigned the FIRGEM regimen.
Results showed longer median PFS (5 months vs. 3.4 months; HR=0.59; 95% CI, 0.38-0.9) and OS (11 months vs. 8.2 months; HR=0.71; 95% CI, 0.46-1.1) in the FIRGEM arm.
Common grade 3 to grade 4 toxicities — all of which were more common in the FIRGEM arm — included neutropenia (49% vs. 24%), febrile neutropenia (4% vs. 0%), diarrhea (12% vs. 0%) and nausea/vomiting (8% vs. 4%). No toxicity-related deaths occurred.
Disclosure: See the study for a full list of the researchers’ relevant financial disclosures.
Malcolm J. Moore
This is an interesting study by Trouilloud and colleagues that compared fixed-dose rate gemcitabine alone with a strategy of fixed-dose rate gemcitabine alternating with FOLFIRI as first-line treatment in advanced pancreatic cancer. There was improvement in the primary endpoint of 6-month PFS (43% vs 26%), as well as in secondary endpoints of OS and response rate, all in favor of the alternating strategy.
Now that we have several agents that have some activity against pancreatic cancer, it does open up this idea of using alternating, potentially non-cross–resistant regimens. This might be of particular interest in pancreatic cancer, as it is known that if patients do not respond to first-line therapy, their survival is short and it is difficult to salvage them with second-line treatment. We also are now seeing cumulative neurotoxicity when patients are treated with a first-line regimen like FOLFIRINOX, so the idea of alternating with a non-neurotoxic regimen could be quite helpful. That said, the strategy of using alternate regimens in first-line therapy has not been a useful advance in most of the settings where it has been tested.
There are some limitations of the study. There was a major imbalance in second-line therapies, and a sample size of 98 is not sufficient to draw conclusions, so this study should be considered hypothesis generating. However, it does raise an interesting question about alternating first-line regimens that would be worthy of further study in an appropriately powered phase 3 study.