Cytokines as Mediators of Chemotherapy-Associated Cognitive Changes: Current Evidence, Limitations and Directions for Future Research

Objectives: While various clinical and pharmacological determinants for chemotherapy-associated cognitive impairment have been identified, conflicting evidence suggests that cytokines might play an intermediary role. The objective of this systematic review was to evaluate the current evidence pertaining to the associations among chemotherapy, cytokines induction and cognitive impairment in cancer patients. Methods: A literature search with PubMed and SciVerse Scopus was conducted in March 2013 to gather relevant articles and abstracts that fulfilled the inclusion and exclusion criteria. This review included studies that had performed objective and/or subjective cognitive assessments and cytokine measurements on defined populations of cancer patients who received chemotherapy. Results: High methodological heterogeneity existed among the selected studies which differed in cancer populations, subject characteristics, cognitive endpoints, types of cytokines tested and their measurement methods. Weak to moderate correlations were observed between IL-1 beta, IL-6, TNF-alpha levels, and different degrees of cognitive impairment. Different types of chemotherapy treatments might lead to varying presentations and severities of cytokine-induced cognitive impairment. Notably, the time concordance between the onset of cytokine induction and occurrence of cognitive impairment was not well elucidated. A number of confounding factors was identified to interfere with the expression levels of cytokines; these confounders included subjects' cancer types, ages, genders, genetics and psychosocial characteristics such as anxiety, depression and fatigue. Conclusion: Although existing studies observed cognitive impairment and cytokine dysregulation in patients who receive chemotherapy, our results suggest that the intermediary role of cytokines in post-chemotherapy cognitive impairment is still controversial and requires further evaluation. A list of methodological recommendations is proposed to harmonize future studies of this subject matter.