Pretreatment cancer-related cognitive impairment—mechanisms and outlook

Cognitive changes are common in patients with active cancer and during its remission. This has largely been blamed on therapy-related toxicities and diagnosis-related stress, with little attention paid to the biological impact of cancer itself. A plethora of clinical studies demonstrates that cancer patients experience cognitive impairment during and after treatment. However, recent studies show that a significant portion of patients with non-central nervous system (CNS) tumors experience cognitive decline prior to treatment, suggesting a role for tumor-derived factors in modulating cognition and behavior. Cancer-related cognitive impairment (CRCI) negatively impacts a patient’s quality of life, reduces occupational and social functioning, and increases morbidity and mortality. Furthermore, patients with cancer cachexia frequently experience a stark neurocognitive decline, suggesting peripheral tumors exert an enduring toll on the brain during this chronic paraneoplastic syndrome. However, the scarcity of research on cognitive impairment in non-CNS cancers makes it difficult to isolate psychosocial, genetic, behavioral, and pathophysiological factors in CRCI. Furthermore, clinical models of CRCI are frequently confounded by complicated drug regimens that inherently affect neurocognitive processes. The severity of CRCI varies considerably amongst patients and highlights its multifactorial nature. Untangling the biological aspects of CRCI from genetic, psychosocial, and behavioral factors is non-trivial, yet vital in understanding the pathogenesis of CRCI and discovering means for therapeutic intervention. Recent evidence demonstrating the ability of peripheral tumors to alter CNS pathways in murine models is compelling, and it allows researchers to isolate the underlying biological mechanisms from the confounding psychosocial stressors found in the clinic. This review summarizes the state of the science of CRCI independent of treatment and focuses on biological mechanisms in which peripheral cancers modulate the CNS.