Several options are available for the upfront treatment of patients with metastatic colorectal cancer. On the basis of the results from the phase 3 TRIBE study1, 2 by the Gruppo Oncologico del Nord Ovest (GONO) and other phase 2 randomised trials,3, 4, 5, 6 the combination of the three-cytotoxic drug regimen FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) with the antiangiogenic bevacizumab is regarded as a valuable first-line option by most guidelines.7, 8
The previous TRIBE study2 showed significantly longer progression-free survival (the primary endpoint of the study; hazard ratio [HR] 0·77 [95% CI 0·65–0·93]; p=0·006), increased response rate (odds ratio [OR] 1·59 [95% CI 1·10–2·28]; p=0·013), and longer overall survival (HR 0·80 [95% CI 0·65–0·98]; p=0·030) with the triplet FOLFOXIRI plus bevacizumab compared with the doublet FOLFIRI (fluorouracil, leucovorin, irinotecan) plus bevacizumab; however, an increased incidence of specific grade 3 and 4 adverse events (diarrhoea, stomatitis, and neutropenia) was reported following FOLFOXIRI.1, 2 Notably, because the treatment used after progression was left to the investigators' choice and collected as post-study treatments in the TRIBE study,1, 2 the efficacy of the triplet compared with exposure to the same drugs in a sequential strategy of less toxic doublets was not shown.9 Furthermore, despite the significant improvement in overall survival with the intensified chemotherapy backbone, some concerns have been raised regarding the feasibility and efficacy of treatments after progression following the upfront exposure to the three cytotoxic drugs.
Research in context
Evidence before this study
A previous phase 3 trial (TRIBE study) by the Italian GONO Foundation suggested the superiority of the first-line triplet regimen FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) over the doublet FOLFIRI (fluorouracil, leucovorin, and irinotecan) when bevacizumab was added to both regimens in patients with unresectable metastatic colorectal cancer. On the basis of these results, FOLFOXIRI plus bevacizumab is supported by all major clinical guidelines as a valuable first-line option for patients with metastatic colorectal cancer patients, selected according to the pivotal TRIBE study criteria. However, some concerns have been raised about the use of FOLFOXIRI in daily practice, including the actual benefit of the exposure to all the three cytotoxic agents compared with the preplanned sequential administration of the same drugs in oxaliplatin-based doublets and irinotecan-based doublets, and the feasibility and the efficacy of treatments after progression. We searched PubMed from inception until July 30, 2019, with the terms “FOLFOXIRI”, “triplet”, “doublets”, “FOLFOX”, “XELOX”, “FOLFIRI”, “XELIRI”, “bevacizumab”, “reintroduction”, “second-line”, “strategy trial”. Only publications in English were considered. We found only a few reports that retrospectively described a favourable outcome of second-line therapies, including the reintroduction of the triplet, given following disease progression after first-line FOLFOXIRI in non-randomly assigned subgroups, and no trials that prospectively compared the efficacy of the upfront use of FOLFOXIRI versus a standard sequential strategy of oxaliplatin-based doublets and irinotecan-based doublets.
Added value of this study
We provide additional evidence of the effect of the upfront use of FOLFOXIRI plus bevacizumab on the survival of patients with unresectable metastatic colorectal cancer, showing its superiority compared with a sequential strategy of doublets plus bevacizumab. The efficacy of treatments after progression to FOLFOXIRI plus bevacizumab is clear, and the beneficial effect of the reintroduction of the triplet in selected patients is suggested, to our knowledge, for the first time.
Implications of all the available evidence
On the basis of these results, upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen in case of disease progression seems to be an optimal therapeutic option for patients with metastatic colorectal cancer who meet the study inclusion criteria.
Over the past few years, new recommendations were formulated on the basis of results from clinical trials of maintenance strategies and treatments after progression: following a 4–6 month first-line treatment with a combination chemotherapy regimen plus bevacizumab, maintenance with a fluoropyrimidine plus bevacizumab until disease progression is recommended,10, 11, 12, 13 and the continuation of angiogenesis inhibition beyond disease progression is a valuable option supported by evidence from phase 3 trials.14, 15
From these considerations, the TRIBE2 study was designed to verify whether the upfront exposure to the three cytotoxic drugs in the FOLFOXIRI regimen was superior to a preplanned sequence of doublets (first-line mFOLFOX6 [fluorouracil, leucovorin, and oxaliplatin], followed by FOLFIRI after disease progression), with a sustained inhibition of angiogenesis with bevacizumab in both groups. Therefore, upfront FOLFOXIRI plus bevacizumab is compared with an oxaliplatin-based doublet instead of an irinotecan-based doublet plus bevacizumab as done in the previous TRIBE study.1, 2