Sanne B. Schagen

International Cognition and Cancer Task Force recommendations to harmonise studies of cognitive function in patients with cancer.

It has become increasingly apparent that cytotoxic drugs given systemically for non-CNS tumours might have cognitive side-effects, but many fundamental questions require further elucidation, and large samples from several institutions are needed. Two working groups brought together by the International Cognition and Cancer Task Force (ICCTF) developed recommendations for a core set of neuropsychological tests, common criterion for defining cognitive impairment and cognitive changes, and common approaches to improve the homogeneity of study methods. These recommendations will improve research design and facilitate study combinations, between-study comparisons, and meta-analyses, which will allow more accurate estimates of incidence, severity, individual risk factors, and causes of cognitive problems associated with chemotherapy for non-CNS tumours.

Cerebral Hyporesponsiveness and Cognitive Impairment 10 Years After Chemotherapy for Breast Cancer

Chemotherapy is associated with cognitive impairment in a subgroup of breast cancer survivors, but the neural circuitry underlying this side effect is largely unknown. Moreover, long‐term impairment has not been studied well. In the present study, functional magnetic resonance imaging (fMRI) and neuropsychological testing were performed in breast cancer survivors almost 10 years after high‐dose adjuvant chemotherapy (chemo group, n = 19) and in breast cancer survivors for whom chemotherapy had not been indicated (control group, n = 15). BOLD activation and performance were measured during an executive function task involving planning abilities (Tower of London) and a paired associates task for assessment of episodic memory. For the chemo group versus the control group, we found hyporesponsiveness of dorsolateral prefrontal cortex in the Tower of London, and of parahippocampal gyrus in the paired associates task. Also, the chemo group showed significantly impaired planning performance and borderline significantly impaired recognition memory as compared to findings in the control group. Whole‐brain analyses demonstrated hyporesponsiveness of the chemo versus the control group in very similar regions of bilateral posterior parietal cortex during both the Tower of London and the paired associates task. Neuropsychological testing showed a relatively stable pattern of cognitive impairment in the chemo group over time. These results indicate that high‐dose adjuvant chemotherapy is associated with long‐term cognitive impairments. These impairments are underpinned by (a) task‐specific hyporesponsiveness of dorsolateral prefrontal cortex and parahippocampal gyrus, and (b) a generalized hyporesponsiveness of lateral posterior parietal cortex encompassing attentional processing. Hum Brain Mapp, 2011.

Chemotherapy-Related Cognitive Dysfunction

Many cancer patients develop treatment-related cognitive dysfunction that affects their quality of life and can result in diminished functional independence. There is an emerging body of transdisciplinary research demonstrating that chemotherapeutic agents can produce neurobiological changes within the brain, which are associated with a constellation of cognitive changes that can result in decreased quality of life and functional independence. The increased incidence of cancer, coupled with longer survival times, has resulted in larger numbers of cancer survivors who are struggling with this neurotoxicity. This review summarizes the neuropsychological findings in patients with breast and brain cancer who receive systemic chemotherapy as well as the recent animal and imaging research elucidating the mechanisms by which these therapies impact brain structure, function, and consequent behavior.

Effects of Tamoxifen and Exemestane on Cognitive Functioning of Postmenopausal Patients With Breast Cancer: Results From the Neuropsychological Side Study of the Tamoxifen and Exemestane Adjuvant Multinational Trial

PURPOSE To evaluate the influence of adjuvant tamoxifen and exemestane on cognitive functioning in postmenopausal patients with breast cancer (BC). PATIENTS AND METHODS Neuropsychological assessments were performed before the start (T1) and after 1 year of adjuvant endocrine treatment (T2) in Dutch postmenopausal patients with BC, who did not receive chemotherapy. Patients participated in the international Tamoxifen and Exemestane Adjuvant Multinational trial, a prospective randomized study investigating tamoxifen versus exemestane as adjuvant therapy for hormone-sensitive BC. RESULTS Participants included 80 tamoxifen users (mean age, 68.7 years; range 51 to 84), 99 exemestane users (mean age, 68.3 years; range, 50 to 82), and 120 healthy controls (mean age, 66.2 years; range, 49 to 86). At T2, after adjustment for T1 performance, exemestane users did not perform statistically significantly worse than healthy controls on any cognitive domain. In contrast, tamoxifen users performed statistically significantly worse than healthy controls on verbal memory (P < .01; Cohens d = .43) and executive functioning (P = .01; Cohens d = .40), and statistically significantly worse than exemestane users on information processing speed (P = .02; Cohens d = .36). With respect to visual memory, working memory, verbal fluency, reaction speed, and motor speed, no significant differences between the three groups were found. CONCLUSION After 1 year of adjuvant therapy, tamoxifen use is associated with statistically significant lower functioning in verbal memory and executive functioning, whereas exemestane use is not associated with statistically significant lower cognitive functioning in postmenopausal patients with BC. Our results accentuate the need to include assessments of cognitive effects of adjuvant endocrine treatment in long-term safety studies.

Long-lasting suppression of hippocampal cell proliferation and impaired cognitive performance by methotrexate in the rat

Methotrexate (MTX) is a cytostatic agent widely used in combination with other agents as adjuvant chemotherapy for breast cancer and is associated with cognitive impairment as a long-term side effect in some cancer patients. This paper aimed to identify a neurobiological mechanism possibly responsible for this cognitive impairment using an animal model. The first study explored the hypothesis that MTX reduces neuronal cell proliferation. A dose-dependent long-lasting decrease in hippocampal cell proliferation was shown with Ki-67 immunocytochemistry, following a single intravenous injection of MTX (37.5-300 mg/kg). Animals treated with MTX also showed a dose-dependent transient decrease in body weight gain. In the second study, the effect of MTX (250 mg/kg) on two spatial learning tasks was examined. Animals treated with MTX learned the Morris water maze task adequately; however, these animals showed a longer latency time to cross the platform location in the probe trial, reflecting an impairment of spatial memory function. In the novel object recognition task, animals treated with MTX failed to distinguish a novel object from a familiar one, indicating a decrease in the comparator function of the hippocampus. Our studies indicated that, in the rat, MTX has a dose-dependent negative effect on hippocampal cell proliferation, and on cognitive behavior. These findings suggest that adverse effects of certain cytotoxic agents on hippocampal cell proliferation may have a potential contributory role in cognitive impairment observed in humans after chemotherapy.

Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: converging results from multimodal magnetic resonance imaging.

The neural substrate underlying cognitive impairments after chemotherapy is largely unknown. Here, we investigated very late (>9 years) effects of adjuvant high‐dose chemotherapy on brain white and gray matter in primary breast cancer survivors (n = 17) with multimodal magnetic resonance imaging (MRI). A group of breast cancer survivors who did not receive chemotherapy was scanned for comparison (n = 15). Neuropsychological tests demonstrated cognitive impairments in the chemotherapy group. Diffusion tensor imaging (DTI) with tract‐based spatial statistics showed that chemotherapy was associated with focal changes in DTI values indicative for reduced white matter integrity. Single voxel proton MR spectroscopy (1H‐MRS) in the left centrum semiovale (white matter) showed a reduction of N‐acetylasparate/creatine indicative of axonal injury. Voxel‐based morphometry demonstrated a reduction of gray matter volume that overlapped with fMRI hypoactivation (as reported in a previous publication) in posterior parietal areas and colocalized with DTI abnormalities. Also, DTI correlated with 1H‐MRS only in the chemotherapy group. These results converge to suggest that high‐dose adjuvant chemotherapy for breast cancer is associated with long‐term injury to white matter, presumably reflecting a combination of axonal degeneration and demyelination, and damage to gray matter with associated functional deficits. Hormonal treatment with tamoxifen may also have contributed to the observed effects, although results from other studies indicate that it is unlikely that tamoxifen is solely or largely responsible. Using this multimodality approach we provide for the first time insight into the neural substrate underlying cognitive impairments following systemic administration of cytotoxic agents many years after treatment. Hum Brain Mapp, 2012.

Neurophysiological Evaluation of Late Effects of Adjuvant High-dose Chemotherapy on Cognitive Function

AbstractObjectives: To evaluate late neurotoxicity of adjuvant high-dose (HD) chemotherapy versus standard-dose (SD) chemotherapy by event-related potentials (ERP) and quantitative electroencephalography (qEEG). Patients and methods: From a randomized study in high-risk breast cancer patients on the efficacy of high-dose versus standard-dose adjuvant chemotherapy, late effects on cognitive functioning were analyzed by neuropsychological tests. Cognitive impairment was found in 32% of the HD group, 17% of the SD group and in 9% of a control group of stage I breast cancer patients not treated with chemotherapy. In 17 consecutive patients in the HD group and 16 consecutive patients in the SD group neurophysiological tests were performed, consisting of P300 and qEEG. Results of patients treated with chemotherapy were compared with results of 14 control patients not treated with chemotherapy. All patients were tested two years after treatment. Results: Asymmetry of the alpha rhythm of ≥0.5 Hz was found in 7 HD patients, 2 SD patients and in none of the control patients (p = 0.01). No differences were found between the groups with regard to frequency of alpha rhythm, alpha blocking and latency of P300. No correlation was found between neurophysiological parameters and neuropsychological performance, except for an overall relation between the P300 latencies and the total number of deviant test scores. Conclusion: Although the neurophysiological differences are subtle and the relation with the cognitive functioning in individual patients as measured by the neuropsychological examination is equivocal, the results suggest that there is neurophysiological support for cognitive dysfunction as a late complication of high-dose systemic chemotherapy in breast cancer.

Clinical Characteristics, Pathophysiology, and Management of Noncentral Nervous System Cancer-Related Cognitive Impairment in Adults

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Neuropsychological functioning in postmenopausal breast cancer patients treated with tamoxifen or exemestane after AC-chemotherapy: Cross-sectional findings from the neuropsychological TEAM-side study

Background. Previous studies have indicated that a subset of cancer patients treated with chemotherapy show cognitive deficits and/or experience cognitive complaints, whereas literature about the influence of hormonal therapies on cognition is sparse. Because of the accumulating knowledge about the importance of estrogen for cognitive functioning, there is growing concern about adjuvant hormonal therapy for breast cancer (BC) affecting cognition. We examined the cognitive functioning of postmenopausal BC patients who were, following doxorubicin/cyclophosphamide (AC) chemotherapy, randomized to tamoxifen or exemestane, and compared their performance with that of non-cancer controls. Materials and methods. Thirty BC patients using tamoxifen and 50 patients using exemestane underwent interviews, questionnaires and cognitive tests, on average two years after completion of AC chemotherapy. Forty eight healthy controls were tested with similar measures. Results. Memory complaints were reported by 28% of AC/tamoxifen users, 24% of AC/exemestane users and 6% of healthy controls (p=0.02). Cognitive testing revealed no statistically significant differences between tamoxifen and exemestane users, but suggested that tamoxifen use is possibly related to worse verbal functioning, while exemestane use is possibly related to slower manual motor speed. Both patient groups performed significantly worse than healthy controls on verbal fluency and information processing speed. Discussion. Our findings show that sequential treatment of AC-chemotherapy and hormonal therapy in postmenopausal, primary BC is associated with lower test scores for certain cognitive functions, and provide indications for possibly distinctive associations for different types of hormonal treatment. Future research with larger groups is recommended to obtain a more definite picture.

Cognitive complaints and cognitive impairment following BEP chemotherapy in patients with testicular cancer

Introduction. There is growing concern that some cytotoxic regimens for cancer affect cognitive functioning. This study examined the prevalence of cognitive complaints and deficits in testicular cancer (TC) patients treated with the worldwide standard BEP (bleomycin, etoposide and cisplatin) chemotherapy. Materials and methods. Seventy TC patients treated with BEP chemotherapy after surgery (S+CT) were examined with interviews and neuropsychological tests. These patients were compared with 57 TC patients treated with radiotherapy after surgery (S+RT) and with 55 TC patients that received surgery only (S). Patients were examined a median of 3 years after completion of treatment. Results. Thirty two percent of the S+CT patients reported cognitive complaints compared with 32% of the S+RT patients and 27% of the S patients (p=0.85). No differences in mean cognitive test performance were observed between the groups. On individual impairment scores, more S+CT patients showed cognitive dysfunction compared with S patients, but not compared with S+RT patients (S+CT versus S [p=0.038, OR=4.6, CI=1.1–19.7], S+CT versus S+RT [p=0.70, OR=0.8, CI=0.3–2.4] and S+RT versus S [p=0.070, OR=3.7, CI=0.8–15.7). Cognitive complaints were not related to cognitive test performance, but to emotional distress and fatigue. Discussion. Cognitive complaints are common among TC patients, independent of treatment modality. These complaints are related to emotional distress and fatigue and not to formal cognitive deficits. The finding of a small group of TC patients treated with chemotherapy exhibiting cognitive deficits should be confirmed in a prospective study before we can decide on its cause and relevance.