Candidate mechanisms for chemotherapy-induced cognitive changes

Abstract

The mechanism(s) for chemotherapy-induced cognitive changes are largely unknown; however, several candidate mechanisms have been identified. We suggest that shared genetic risk factors for the development of cancer and cognitive problems, including low-efficiency efflux pumps, deficits in DNA-repair mechanisms and/or a deregulated immune response, coupled with the effect of chemotherapy on these systems, might contribute to cognitive decline in patients after chemotherapy. Furthermore, the genetically modulated reduction of capacity for neural repair and neurotransmitter activity, as well as reduced antioxidant capacity associated with treatmentinduced reduction in oestrogen and testosterone levels, might interact with these mechanisms and/ or have independent effects on cognitive function.Studies associating cognitive changes with cancer chemotherapy have been reported since the mid 1970s 1 ; however, systematic research on the cognitive side effects of chemotherapy did not appear until the 1990s. Over the past 10 years, neuropsychological studies of cancer survivors 2-8 and emerging data from longitudinal studies that include pretreatment neuropsychological assessments 9,10 have found evidence supporting the influence of chemotherapy on cognitive functioning, although negative studies have also been reported [11][12] . The cognitive changes associated with chemotherapy are typically subtle (functioning is reduced but often remains in the normal range), and occur across various domains of cognition, including working memory, executive function and processing speed [13][14][15][16] , but not the retrieval of remote memories (see BOX 1 for a description of the cognitive functions that can be affected by chemotherapy). Furthermore, although acute cognitive changes during chemotherapy are common 14,15 , long-term post-treatment cognitive changes seem to persist in only a subgroup (17-34%) of cancer survivors. Historically, cognitive changes in cancer patients were assumed to be related to psychological factors such as depression or anxiety, or other side effects of cancer treatments like fatigue. However, most of the studies cited above have found evidence for persistent post-chemotherapy cognitive changes after statistically controlling for © 2007 Nature Publishing Group Correspondence to T.A.A. ahlest@mskcc.org. Competing interests statementThe authors declare no competing financial interests. 17,18 . A reduction in the volume of brain structures important for cognitive functioning (such as the frontal cortex) and changes in the integrity of white-matter tracks that connect brain structures have been associated with changes in cognitive functioning, and have been seen using structural magnetic resonance imaging (MRI) on patients after chemotherapy. Recent data from a longitudinal study of breast cancer patients, who were evaluated with structural and functional MRI before treatment and 1 and 12 months after treatment, have suggested a pattern of reduced activation in frontal areas during a working memory...

Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy

“…Treatment of breast cancer with cytotoxic agents has been associated with structural and functional brain changes (Table 1) [1]. White-matter pathology has been observed within months up to 10 years post-treatment.…”

Effect of β-glucan Supplementation on Levels of IgM, IgA, IgG and Its Subclasses IgG1, IgG2, IgG3, and IgG4 in Cancer Patients

“…Briefly, these factors involve effects of treatment, depression, fatigue, fear, changes in coagulability of microvascular small blood vessels, induction of endogenous hormones and cytokines and also genetical disposition. One cannot forget depressed function of reflux pump (Pglycoprotein), deficit of DNA repair mechanisms and deregulation of immune functions [21] . Some authors even suggested possible correlation between clinical manifestation of insomnia and immune mechanisms [2,3,19] .…”

Bases biológicas del deterioro de la función cognitiva inducido por los tratamientos antineoplásicos

“…Con técnicas sofisticadas de medicina nuclear, se ha podido detectar la presencia de fármacos quimioterápicos radiomarcados en el SNC tras su administración sistémica (cisplatino, BCNU, paclitaxel…). Aunque sus concentraciones son demasiado bajas como para producir un efecto antineoplásico, no se puede descartar que alcancen el nivel necesario para deteriorar la FC (7) . La mayoría de los fármacos quimioterá-picos pueden causar daño celular y roturas de las cadenas de ADN, ya sea directamente (alquilantes, antimetabolitos) o bien indirectamente, a través de mecanismos oxidativos que incluyen, entre otros, la liberación de radicales libres (antraciclinas).…”