The TRIBE and TRIBE-2 trials established that first-line treatment with FOLFOXIRI combined with bevacizumab yields superior efficacy over FOLFIRI or FOLFOX plus bevacizumab in metastatic colorectal cancer, though it is associated with increased toxicity. In the present study, we investigated the occurrence and temporal patterns of neutropenia and febrile neutropenia (FN) in these trials, with the aim of determining their clinical impact, quantifying the effects attributable to FOLFOXIRI/bevacizumab, and evaluating predictive factors for their development. We investigated how often severe neutropenia (grade 3–4) and febrile neutropenia (FN) occurred, when these events typically developed, and the patterns of granulocyte colony-stimulating factor use. Analyses were performed for the full study population and separately by treatment regimen. FN episodes were further categorized using the (MASCC) risk score to evaluate their clinical severity. Out of 1,155 patients, 568 (49%) received FOLFOXIRI in combination with bevacizumab. Overall, severe neutropenia (grade 3–4) occurred in 410 patients (35%), while febrile neutropenia (FN) was observed in 70 patients (6%), with 21 (2%) classified as high risk. The FOLFOXIRI/bevacizumab regimen showed a markedly higher rate of neutropenia (51% vs. 21%, P < 0.001), FN (8% vs. 4%, P = 0.02), and high-risk FN [18 (3%) vs. 3 (1%), P = 0.015] compared with the alternative regimens, though no treatment-related deaths were reported. The majority of first G3–4 neutropenia and FN events occurred within the initial two months of therapy across all treatment arms. Temporal analysis across cycles indicated distinct patterns, with early cycles being particularly prone to G3–4 neutropenia in patients receiving FOLFOXIRI/bevacizumab (P < 0.001). Advanced age (P = 0.01) and female sex (P < 0.001) emerged as significant predictors of severe neutropenia, yet no meaningful interaction was found between treatment arm and these risk factors in terms of G3–4 neutropenia or FN occurrence. Notably, FN affected 12% of older female patients treated with FOLFOXIRI/bevacizumab. Despite the higher hematologic toxicity, neither severe neutropenia nor FN negatively influenced treatment outcomes, including overall response rate, progression-free survival, or overall survival. Treatment with FOLFOXIRI combined with bevacizumab carries a greater risk of grade 3–4 neutropenia and febrile neutropenia (FN) compared with doublet chemotherapy plus bevacizumab. FN was observed in fewer than 10% of patients and was predominantly classified as low risk. Enhanced monitoring during the initial two months of therapy is advisable, and prophylactic administration of granulocyte colony-stimulating factor could be considered for older female patients.
