High therapeutic efficacy of triplet therapy in unresectable or metastatic colorectal cancer and its optimal application strategies

Systemic chemotherapy for unresectable or metastatic colorectal cancer (mCRC) has improved clinical outcomes through substantial therapeutic advances. Triplet chemotherapy based on FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) has achieved high response rates and deep tumor shrinkage. In combination with molecularly targeted agents, triplet therapy plus bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, has demonstrated superior efficacy compared with doublet chemotherapy plus bevacizumab. In patients with RAS/BRAF wild-type tumors, combination therapy with anti-epidermal growth factor receptor (EGFR) monoclonal antibodies such as cetuximab and panitumumab has also shown improved survival outcomes, although toxicity remains a major concern. Although intensified treatment is associated with increased gastrointestinal and hematologic toxicity, improved supportive care and optimized dose-adjustment strategies have enhanced the feasibility of triplet therapy in routine clinical practice. This review outlines the historical development of triplet therapy in mCRC, summarizes the major clinical trials investigating triplet chemotherapy combined with molecularly targeted agents, and discusses direct comparisons between anti-VEGF- and anti-EGFR-based strategies. Particular emphasis is placed on practical considerations for clinical implementation, including toxicity management, dose optimization, and multidisciplinary supportive care.