Cancer therapy-related cognitive impairment, part 2: from bench to bedside-and back: why candidate therapies for cancer therapy-related cognitive impairment fail to translate.

Abstract

Although numerous pharmacological and nonpharmacological strategies have been proposed for the prevention or treatment of cancer therapy-related cognitive impairment (CRCI), only a few have achieved robust clinical translation. This review, the second part of a two-part series, first critically summarizes current candidate pharmacological and nonpharmacological interventions for CRCI, discussing their biological rationale, mechanisms of action, and the available preclinical and clinical evidence. It then reports why many of these promising approaches fail to translate into effective clinical therapies. We critically analyse the methodological gaps between preclinical models and cancer survivorship, including the use of non-tumour-bearing animals, inadequate modelling of age, sex, and hormonal status, mismatched behavioural and clinical endpoints, poor biomarker alignment, and insufficient assessment of potential interactions between neuroprotective agents and anticancer efficacy. Finally, we propose a translational roadmap for developing mechanism-informed, clinically predictive, and oncologically safe interventions for CRCI and explain why the preclinical efficacy of many candidate therapies has not yet translated into robust clinical benefit.