The evolving landscape of cancer cachexia prevention: A review of metronomic chemotherapy and drug repurposing strategies.

Cancer cachexia, a multifactorial debilitating syndrome, highly impacts the quality of life, treatment tolerance, and survival among the cancer patients. Mainly characterized by progressive weight loss, skeletal muscle atrophy, and metabolic dysregulation, it is essentially an unmet medical need. This review explores the roles of metronomic chemotherapy (mCT) and drug repurposing as innovative strategies for cachexia prevention and management. Metronomic chemotherapy, a low-dose chemotherapeutic drug administration, shows reduced toxicity, anti-angiogenic, and immunomodulatory effects over Maximum Tolerated Dose (MTD), potentially mitigates chemotherapy-induced cachexia, and improves treatment tolerability. Drug repurposing, in which an existing drug is utilized for a new indication, has the advantages of rapid development, reduced costs, and established safety profiles. It provides targeted interventions against the complex inflammatory and metabolic pathways underlying cachexia. A good number of preclinical and early clinical studies have shown evidence for both approaches, particularly for Ponsegromab, a Growth Differentiation Factor-15 (GDF-15) inhibitor. Due to the multifactorial nature of cachexia, a multimodal, integrated intervention is a good substitute for the maximum tolerated dose, which can be effective against it. Future directions in cancer therapy should emphasize the development of robust clinical trial designs with cachexia-specific endpoints to advance precision prevention strategies.