Therapeutic Sequencing in Colorectal Cancer: Pharmacological Rationale for the Administration of Cytotoxic Agents and Monoclonal Antibodies

Abstract

The composition of therapeutic protocols used in the treatment of colorectal cancer is largely standardized. Despite this fact, the order of administration of the different agents within each cycle often remains determined by historical conventions, operational constraints, or incompletely characterized pharmacological rationale. This narrative review aimed to critically analyze the pharmacological, translational, and clinical evidence regarding the order of administration of cytotoxic agents and targeted therapies in protocols used for colorectal cancer. A narrative literature review was conducted focusing on currently used therapeutic protocols, including DeGramont, FOLFOX, FOLFIRI, FOLFOXIRI, and combinations with bevacizumab, cetuximab, and panitumumab. The available evidence suggests that the relevance of therapeutic sequencing is not uniform across protocols. In FOLFIRI and FOLFOXIRI regimens, the order of administration appears to be supported by a more consistent pharmacodynamic rationale, potentially influencing both efficacy and tolerability. In contrast, protocols such as DeGramont and FOLFOX seem to be additionally constrained by pharmaceutical and physicochemical compatibility factors. Among targeted therapies, sequential scheduling of bevacizumab and chemotherapy represents a pharmacologically plausible strategy, whereas evidence regarding anti-EGFR antibodies remains limited. The order of administration should be considered a potentially relevant variable in therapeutic optimization, depending not only on pharmacodynamic interactions but also on pharmaceutic limitations, infusion safety, and operational constraints. Dedicated prospective studies are needed to clarify the clinical impact of alternative sequencing strategies.

Keywords: therapeutic protocols in oncology, sequential administration, cytotoxic agents, monoclonal antibody, colorectal cancer.