Patients with untreated metastatic colorectal cancer who received FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, irintotecan) plus bevacizumab (Avastin) had improved survival compared with patients who received FOLFIRI (folinic acid, fluorouracil, irintotecan) plus bevacizumab in a phase III randomized trial conducted at 34 Italian centers. “The median progression-free survival was prolonged by 2.4 months, reaching 12.1 months,” for patients treated with FOLFOXIRI plus bevacizumab, Fotios Loupakis, MD, PhD, of Azienda Ospedaliero–Universitaria Pisana and Università di Pisa, Italy, and colleagues reported in The New England Journal of Medicine. For patients treated with FOLFIRI plus bevacizumab, median progression-free survival was 9.7 months (hazard ratio [HR] for disease progression, 0.75; 95% confidence interval [CI], 0.62–0.90; P = .003).
“Moreover, an absolute increase of 12.0% in response rate was reported, and median overall survival was extended, but not significantly so, by 5.2 months, from 25.8 to 31.0” months in the FOLFOXIRI group, the researchers reported. The objective response rates were 65% with FOLFOXIRI vs 53% with FOLFIRI (P = .006).
“The intensification of the treatment was associated with a significant increase in the rates of grade 3 or 4 neurotoxicity, stomatitis, diarrhea, and neutropenia. However, no significant differences between treatment groups in the rates of febrile neutropenia, serious adverse events, or deaths due to treatment-related toxic effects were observed,” the investigators wrote. “In our opinion, early recognition and active management of adverse events are crucial.”
A total of 508 patients were randomly assigned to receive FOLFIRI plus bevacizumab (control group, 256 patients) or FOLFOXIRI plus bevacizumab (experimental group, 252 patients). “Up to 12 cycles of treatment were administered, followed by fluorouracil plus bevacizumab until disease progression,” the investigators stated. Patients had unresectable metastatic colorectal cancer and had not received chemotherapy or biologic therapy for metastatic disease, although 12.6% had received adjuvant chemotherapy earlier in their disease course.
“Demographic and baseline characteristics of the patients were similar in the two groups,” the investigators noted, “but a higher percentage of patients in the experimental group than in the control group had a primary tumor in the right colon (34.9% vs 23.8%, P = .02).” Among all patients, 79.3% had multiple sites of metastases and 20.7% had disease limited to he liver. The median age was 60 in the FOLFIRI group and 60.5 in the FOLFOXIRI group.
Grade 3/4 neutropenia occurred in 50% of patients receiving FOLFOXIRI vs 20.5% of patients receiving FOLFIRI. Higher rates with FOLFOXIRI vs FOLFIRI also occurred for several other grade 3/4 adverse events, including diarrhea (18.8% vs 10.6 %), febrile neutropenia (8.8% vs 6.3%), stomatitis (8.8% vs 4.3%), and peripheral neuropathy (5.2% vs 0%). The only grade 3/4 adverse event with a higher incidence reported for FOLFIRI was nausea, but the incidences were low and the differences slight.
“The incidence of serious adverse events was similar in the two groups (19.7% in the control group and 20.4% in the experimental group, P = .91),” the researchers stated. “A total of 142 (91.6%) of the deaths in the control group and 121 (92.4%) of the deaths in the experimental group were attributed to disease progression. In each group, a similar number of patients died as a result of adverse events (4 [1.6%] in the control group and 6 [2.4%] in the experimental group).” ■
Loupakis F, et al: N Engl J Med 371:1609-1618, 2014.