Priming the Brain Before Chemotherapy: Chronic Stress and HPA-Axis Dysregulation in Cancer-Related Cognitive Impairment

Cancer-related cognitive impairment (CRCI) is often attributed to chemotherapy, yet cognitive deficits are detectable in some patients before systemic treatment begins. This review examines a proposed two-hit framework in which cancer-related psychological and physiological stress contributes to pretreatment neural vulnerability, followed by superimposed chemotherapy-associated neurotoxicity. The review focuses on adults with non-central nervous system cancers. This narrative review synthesizes epidemiologic, neuroendocrine, neuroimaging, neuroimmune, autonomic, preclinical, and clinical evidence addressing chronic stress biology, pretreatment cognitive and brain changes, chemotherapy-related neurotoxicity, hypothalamic–pituitary–adrenal (HPA) axis interactions, and potential interventions. Pretreatment cognitive impairment has been reported in approximately one-quarter of patients, accompanied by elevated inflammatory cytokines, altered neurotrophic signaling, and changes in amygdala–hippocampal connectivity. The first hit may reflect interacting cancer- and host-related factors, including systemic inflammation, distress, sleep disruption, fatigue, pain, and HPA-axis/circadian dysregulation. The second hit occurs when chemotherapy inflicts superimposed neurotoxic injury, including white matter degradation, suppressed hippocampal neurogenesis, and blood–brain barrier disruption. The relationship may also be bidirectional: chemotherapy can perturb HPA-axis function, while glucocorticoid signaling may influence treatment response and antitumor immunity. Behavioral, autonomic, and circadian interventions are mechanistically promising, although neuroprotective efficacy remains uncertain. CRCI is likely multifactorial and may begin before chemotherapy. The two-hit framework integrates pretreatment stress-related vulnerability with treatment-associated neurotoxicity but remains hypothesis-generating rather than causally established. Prospective studies beginning at diagnosis and incorporating serial cognitive, psychological, endocrine, inflammatory, autonomic, and neuroimaging measures are needed to test this model and identify patients at greatest risk.