A Literature Review on Hypothalamic–Pituitary–Adrenal (HPA) Axis Dysregulation in Older Adults with Cancer: A Missing Link in Predicting Treatment Toxicity?

Older adults with cancer face disproportionately high rates of severe treatment-related toxicities, yet current prediction tools rarely incorporate biomarkers that capture physiological resilience. The hypothalamic–pituitary–adrenal (HPA) axis—central to stress adaptation, immune regulation, and tissue repair—undergoes pronounced age-related alterations, including elevated basal cortisol, reduced dehydroepiandrosterone (DHEA) and its sulphate form DHEAS, and an increased cortisol:DHEA(S) ratio. These changes may impair immune function, delay recovery, and exacerbate vulnerability to treatment toxicity. This narrative review synthesizes mechanistic and clinical evidence linking HPA-axis dysregulation to treatment tolerance in geriatric oncology. Common patterns include blunted diurnal cortisol slopes, elevated evening cortisol, and low DHEA(S), which are associated with fatigue, functional decline, and reduced survival across cancer types. However, their predictive value for acute treatment toxicities remains underexplored due to methodological heterogeneity, lack of age-specific reference ranges, and absence from existing geriatric toxicity models. This review proposes a translational roadmap that prioritizes (1) standardization of salivary cortisol/DHEA(S) protocols; (2) prospective, age-stratified validation studies using standardized toxicity endpoints; (3) interventional testing of behavioral or pharmacological strategies to modulate HPA function; and (4) integration into oncology workflows and electronic decision-support tools. Incorporating endocrine biomarkers into risk prediction could refine treatment stratification, enable targeted supportive care, and ultimately improve outcomes for older cancer patients.