Clinical impact of neutropenia and febrile neutropenia in metastatic colorectal cancer patients treated with FOLFOXIRI/bevacizumab: a pooled analysis of TRIBE and TRIBE2 studies by GONO

S Caponnetto,B Borelli,V Conca,A Antonuzzo,A Zaniboni,A Sbrana,F Daniel,A Boccaccino,A Falcone,A Raimondi,C Cremolini,G Tomasello,F Pietrantonio,G Masi,D Santini,A Buonadonna,F Marmorino,S Lonardi,D Rossini

doi:10.1016/j.esmoop.2021.100293

Abstract

BackgroundTRIBE and TRIBE-2 studies demonstrated higher benefit from FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan)/bevacizumab compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX/bevacizumab as an upfront option for metastatic colorectal cancer patients, with more toxicities. We focused on the incidence and longitudinal dynamics of neutropenia and febrile neutropenia (FN) in the two studies, to evaluate their clinical relevance, the magnitude of impact of FOLFOXIRI/bevacizumab, and the role of risk factors in predicting their occurrence.MethodsThe overall incidence of grade 3-4 (G3-4) neutropenia and FN, the time to their onset, the use of granulocyte colony-stimulating factor, and the association with risk factors were evaluated in the overall population and according to treatment arm. FN episodes were assessed by Multinational Association for Supportive Care in Cancer (MASCC) score.ResultsAmong 1155 patients, 568 (49%) received FOLFOXIRI/bevacizumab. Overall, 410 (35%) experienced G3-4 neutropenia and 70 (6%) FN, 21 (2%) at high risk. FOLFOXIRI/bevacizumab was associated with higher incidence of neutropenia (51% versus 21%, P < 0.001), FN (8% versus 4%, P = 0.02), and high-risk FN [18 (3%) versus 3 (1%), P = 0.015]. No related deaths were observed. The first episode of G3-4 neutropenia and FN occurred mainly in the first 2 months in both arms. Longitudinal analysis showed different patterns of evolution over cycles between the arms (P < 0.001) G3-4 neutropenia being more frequent in the first cycles with FOLFOXIRI/bevacizumab. Older patients (P = 0.01) and females (P < 0.001) had a significantly higher risk of G3-4 neutropenia. No significant interaction effect between arm and analysed risk factors in terms of risk of G3-4 neutropenia or FN was observed. The incidence of FN among older females receiving FOLFOXIRI/bevacizumab was 12%. Neither G3-4 neutropenia nor FN impaired efficacy in terms of overall response rate, progression-free survival, and overall survival.ConclusionsFOLFOXIRI/bevacizumab has a higher risk of G3-4 neutropenia and FN than doublets/bevacizumab. FN occurred in <10% of patients, mostly as low-risk episodes. A closer monitoring during the first 2 months is recommended; prophylactic use of granulocyte colony-stimulating factor may be considered for older females.

Highlights

The phase III TRIBE trial firstly proved the efficacy of this regimen compared with the doublet FOLFIRI plus bevacizumab as first-line therapy,[1,2] while the phase III TRIBE2 trial subsequently demonstrated that the upfront exposure to FOLFOXIRI plus bevacizumab followed by the reintroduction of the same agents after disease progression provided long-term benefit when compared with the sequential exposure to modified FOLFOX plus bevacizumab followed by FOLFIRI plus bevacizumab after disease progression.[3]
410 (35%) patients experienced grade 3-4 (G3-4) neutropenia, with a higher incidence in the FOLFOXIRI/bevacizumab group compared with the doublets/bevacizumab group (51% versus 21%; Odds ratios (ORs) 3.9, 95% confidence interval (CI) 3.03-5.1, P < 0.001)
febrile neutropenia (FN) was observed more frequently in the FOLFOXIRI/bevacizumab group compared with the doublets/bevacizumab group (8% versus 4%, OR 1.81, 95% CI 1.1-2.98, P 1⁄4 0.02) (Table 1)

Summary

Introduction

A recent individual patient data-based meta-analysis of five randomized trials of FOLFOXIRI plus bevacizumab versus doublets (FOLFOX or FOLFIRI) plus bevacizumab confirmed a statistically significant and clinically relevant survival advantage for the upfront intensified treatment that was obviously associated with a higher incidence of chemotherapy-related adverse events.[4]. TRIBE and TRIBE-2 studies demonstrated higher benefit from FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan)/bevacizumab compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) or FOLFOX/bevacizumab as an upfront option for metastatic colorectal cancer patients, with more toxicities. Methods: The overall incidence of grade 3-4 (G3-4) neutropenia and FN, the time to their onset, the use of granulocyte colony-stimulating factor, and the association with risk factors were evaluated in the overall population and according to treatment arm.

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Results

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Conclusion