1. Patients with metastatic colorectal cancer treated with a combination of bevacizumab and triple-drug chemotherapy including fluorouracil (plus leucovorin), irinotecan, and oxaliplatin had statistically significant, improved progression-free survival compared to patients treated with bevacizumab and two-drug therapy with fluorouracil (plus leucovorin) and irinotecan.
2. Patients treated with the triple-drug chemotherapy and bevacizumab had a significantly increased incidence of grade 3 and 4 adverse events including neurotoxicity and diarrhea.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Current treatment regimens for newly diagnosed metastatic colorectal carcinoma revolve around primary treatment with two-drug combinations of fluorouracil (plus leucovorin) and either irinotecan (FOLFIRI) or oxaliplatin (FOLFOX) plus bevacizumab, a monoclonal antibody targeting vascular epithelial growth factor (VEGF). This study aimed to compare this standard of care to 12 cycles of a novel triple-drug combination of fluorouracil (plus leucovorin), irinotecan, and oxaliplatin (FOLFOXIRI) plus bevacizumab. 508 patients with newly diagnosed metastatic colorectal cancer, approximately 90% of whom were asymptomatic, were randomized to receive bevacizumab plus either FOLFOXIRI or FOLFIRI. Following 12 cycles of each of these regimens, patients continued on maintenance therapy with fluorouracil plus bevacizumab.
Patients were followed for a median of 32.2 months (range, 24.7 to 40.6). In the primary analysis, patients receiving bevacizumab plus FOLFOXIRI fared significantly better, with a median progression-free survival of 12.1 months compared to 9.7 months with FOLFIRI, and median survival time 31 months compared to 25.8 months with FOLFIRI. However, the intensified therapy of FOLFOXIRI plus bevacizumab was also associated with a significantly increased incidence of grade 3 or 4 neurotoxicity, stomatitis, diarrhea, and neutropenia.
The results of this study suggest that there may be a benefit to pursuing triple therapy plus bevacizumab in patients with newly diagnosed metastatic colorectal cancer, particularly in patients who are relatively young, with less symptomatic disease, and who were not previously treated with adjuvant therapy. The study is strengthened by its randomized design; however, it was not blinded, and it did not capture patients’ subjective quality of life. Clinicians and patients must weigh the potential benefit of statistically significant increases in progression-free survival versus the increased risk of side effects.
Study Authors, Dr. Fotios Loupakis, MD, PhD and Dr. Alfredo Falcone, MD, talk to 2 Minute Medicine: Universitaria Pisana.
“The main findings are that the use of an initial more intensive therapy with a triplet of cytotoxics (FOLFOXIRI) plus bevacizumab versus a doublet (FOLFIRI) plus bevacizumab improves the outcome of metastatic colorectal cancer patients with unresectable metastases. These results, also compared to those reported in previous phase III studies in molecularly unselected patients, represent an important advance in the treatment of this disease.
Physicians should consider an initial intensive therapy with FOLFOXIRI plus bevacizumab, followed by maintenance with 5-FU/LV and bevacizumab, as a very good option for many metastatic colorectal cancer patients with a good ECOG Performance-status (0-1), no relevant comorbidities and age ≤ 70-75 years, independently from the molecular characteristics of the tumor.”
In-Depth [randomized controlled trial]: In this study, 508 patients with untreated metastatic colorectal cancer were randomly assigned to receive either FOLFIRI (control group) plus bevacizumab or FOLFOXIRI (experimental group) plus bevacizumab for 12 cycles in both arms. Patients above the age of 75 were excluded, and those between 70 and 75 were required to have asymptomatic disease. Patients were approximately 60 years of age on average, 79.3% had multiple sites of colorectal cancer metastases, and 20.7% had disease limited to the liver. 82% of patients in the control group continued maintenance therapy with fluorouracil plus bevacizumab, compared to 91.5% in the experimental group.
The primary end point was progression-free survival. The median progression-free survival was 9.7 months in the control group versus 12.1 months in the experimental group; the hazard ratio for progression was 0.75 (95%CI 0.62 to 0.90; P=0.003). When controlling for a number of potential confounding factors, this hazard ratio remained constant at 0.75. There was a significant interaction between exposure to a previous adjuvant treatment and progression-free survival (P=0.04), whereby patients who had received prior adjuvant treatment fared significantly worse. The median survival time was 31 months in the experimental group compared with 25.8 months in the control group, yielding a hazard ratio of 0.79 (95%CI 0.63 to 1.00; P=0.054).
In the safety analysis, there was a significantly increased incidence of treatment-related grade 3 or 4 neurotoxicity, stomatitis, diarrhea, and neutropenia in the FOLFOXIRI group; there were no significant differences in terms of severe adverse events or deaths due to treatment-related toxic effects.
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