Cognitive impairment after cytotoxic chemotherapy

Abstract

Background: Neurotoxicity is a frequent side effect of cytotoxic chemotherapy and affects a large number of patients. Despite the high medical need, few research efforts have addressed the impact of cytotoxic agents on cognition (ie, postchemotherapy cognitive impairment; PCCI). One unsolved question is whether individual cytotoxic drugs have differential effects on cognition. We thus examine the current state of research regarding PCCI. Neurological symptoms after targeted therapies and immunotherapies are not part of this review.

Methods: A literature search was conducted in the PubMed database, and 1215 articles were reviewed for predefined inclusion and exclusion criteria. Thirty articles were included in the systematic review.

Results: Twenty-five of the included studies report significant cognitive impairment. Of these, 21 studies investigated patients with breast cancer. Patients mainly received combinations of 5-fluorouracil, epirubicin, cyclophosphamide, doxorubicin, and taxanes (FEC/FEC-T). Five studies found no significant cognitive impairment in chemotherapy patients. Of these, 2 studies investigated patients with colon cancer receiving 5-fluorouracil and oxaliplatin (FOLFOX). Independent risk factors for PCCI were patient age, mood alterations, cognitive reserve, and the presence of apolipoprotein E e4 alleles.

Conclusions: There is evidence that certain chemotherapy regimens cause PCCI more frequently than others as evidenced by 21 out of 23 studies in breast cancer patients (mainly FEC-T), whereas 2 out of 3 studies with colon cancer patients (FOLFOX) did not observe significant changes. Further studies are needed defining patient cohorts by treatment protocol in addition to cancer type to elucidate the effects of individual cytotoxic drugs on cognitive functions.

Keywords: chemotherapy; cognition; cognitive decline; neurotoxicity.

Fig. 1

Overview of Screening and Elimination Process

Fig. 2

Summary of Molecular Effects Induced in Neuronal Precursor Cells by the Cytotoxic Drug Paclitaxel Binding of paclitaxel to NCS-1 stabilizes the Ca²⁺-bound conformation of this protein and thus causes an increased binding of NCS-1 to the InsP₃R. As a result, the InsP₃R is positively modulated, and an increased release of Ca²⁺ from the endoplasmic reticulum to the cytoplasm occurs. Ca²⁺ in turn, among other cellular processes, activates the Ca²⁺-dependent protease µ-calpain, which not only degrades NCS-1 in a negative feedback loop, but is also able to trigger a number of molecular pathways, including apoptosis. Interaction of NCS-1 with the InsP₃R can be inhibited with lithium ions. Ca²⁺ indicates calcium; InsP₃R, inositol-1,4,5-trisphosphate-receptor; NCS-1, neuronal calcium sensor 1-protein; PTX, paclitaxel. Figure adapted from Huehnchen et al.