Fractionated brain X-irradiation profoundly reduces hippocampal immature neuron numbers without affecting spontaneous behavior in mice.

Whole brain radiotherapy (WBRT) is used to improve tumor control in patients with primary brain tumors, or brain metastasis from various primary tumors to improve tumor control. However, WBRT can lead to cognitive decline in patients. We assessed whether fractionated WBRT (fWBRT) affects spontaneous behavior of mice in automated home cages and cognition (spatial memory) using the Barnes maze. Male C57Bl/6j mice received bi-lateral fWBRT at a dosage of 4 Gy/day on 5 consecutive days. In line with previous reports, immunohistochemical analysis of doublecortin positive cells in the dentate gyrus showed a profound reduction in immature neurons 4 weeks after fWBRT. Surprisingly, spontaneous behavior as measured in automated home cages was not affected. Moreover, learning and memory measured with Barnes maze, was also not affected 4-6 weeks after fWBRT. At 10-11 weeks after fWBRT a significant difference in escape latency during the learning phase, but not in the probe test of the Barnes maze was observed. In conclusion, although we confirmed the serious adverse effect of fWBRT on neurogenesis 4 weeks after fWBRT, we did not find similar profound effects on spontaneous behavior in the automated home cage nor on learning abilities as measured by the Barnes maze. The relationship between the neurobiological effects of fWBRT and cognition seems more complex than often assumed and the choice of animal model, cognitive tasks, neurobiological parameters, and experimental set-up might be important factors in these types of experiments.

The prevalence of mild cognitive impairment in breast cancer patients receiving chemotherapy according to the criteria of the National Institute on Aging-Alzheimer's Association (NIA-AA).

PURPOSE: Breast cancer patients receiving chemotherapy can develop cognitive impairment. There is no gold standard for defining cognitive impairment. We applied the National Institute on Aging-Alzheimer's Association (NIA-AA) criteria for mild cognitive impairment (MCI) to determine its prevalence in breast cancer patients receiving adjuvant chemotherapy and examine differences between patients with and without MCI. METHODS: We used pre-existing cognitive data on 5 neuropsychological test outcomes (verbal memory, processing speed, executive functioning, and verbal fluency) gathered from 240 breast cancer patients who received adjuvant conventional (n = 154) or high-dose chemotherapy (n = 86). Assessments occurred 6 or 12 months post-chemotherapy and results were compared with data from 66 women without cancer. MCI was defined by the following: (i) presence of concern regarding a change in cognition, (ii) impairment in one or more cognitive tests (1.5 standard deviation below a normative mean), (iii) preservation of independence in functional abilities, and (iv) the absence of dementia. RESULTS: Twenty percent (n = 49) of breast cancer patients who received chemotherapy (conventional therapy n = 29 (12%), high-dose therapy = 20 (8.3%)) met the criteria for MCI, compared with 7.6% (n = 5) of controls. Prevalence was significantly different between patients and controls (P = 0.020, and corrected for IQ P < 0.001). Patients with MCI had significant lower education levels (P < 0.002) and premorbid IQ (P = 0.001) compared with patients without MCI. CONCLUSIONS: Twenty percent of breast cancer patients treated with chemotherapy met NIA-AA criteria for MCI, compared with 7.6% of the controls. IMPLICATIONS FOR CANCER SURVIVORS: These criteria, which include formal test performance as well as a person's symptoms and functional status, can be useful in clinical practice and scientific research.

Artificial and natural interventions for chemotherapy- and / or radiotherapy-induced cognitive impairment: A systematic review of animal studies.

BACKGROUND: Cancer survivors frequently experience cognitive impairments. This systematic review assessed animal literature to identify artificial (pharmaceutical) or natural interventions (plant/endogenously-derived) to reduce treatment-related cognitive impairments. METHODS: PubMed, EMBASE, PsycINFO, Web of Science, and Scopus were searched and SYRCLE's tool was used for risk of bias assessment of the 134 included articles. RESULTS: High variability was observed and risk of bias analysis showed overall poor quality of reporting. Results generally showed positive effects in the intervention group versus cancer-therapy only group (67% of 156 cognitive measures), with only 15 (7%) measures reporting cognitive impairment despite intervention. Both artificial (61%) and natural (75%) interventions prevented cognitive impairment. Artificial interventions involving GSK3B inhibitors, PLX5622, and NMDA receptor antagonists, and natural interventions utilizing melatonin, curcumin, and N-acetylcysteine, showed most consistent outcomes. CONCLUSIONS: Both artificial and natural interventions may prevent cognitive impairment in rodents, which merit consideration in future clinical trials. Greater consistency in design is needed to enhance the generalizability across studies, including timing of cognitive tests and description of treatments and interventions.

Effect of physical exercise on the hippocampus and global grey matter volume in breast cancer patients: A randomized controlled trial (PAM study).

BACKGROUND: Physical exercise in cancer patients is a promising intervention to improve cognition and increase brain volume, including hippocampal volume. We investigated whether a 6-month exercise intervention primarily impacts total hippocampal volume and additionally hippocampal subfield volumes, cortical thickness and grey matter volume in previously physically inactive breast cancer patients. Furthermore, we evaluated associations with verbal memory. METHODS: Chemotherapy-exposed breast cancer patients (stage I-III, 2-4 years post diagnosis) with cognitive problems were included and randomized in an exercise intervention (n = 70, age = 52.5 ± 9.0 years) or control group (n = 72, age = 53.2 ± 8.6 years). The intervention consisted of 2x1 hours/week of supervised aerobic and strength training and 2x1 hours/week Nordic or power walking. At baseline and at 6-month follow-up, volumetric brain measures were derived from 3D T1-weighted 3T magnetic resonance imaging scans, including hippocampal (subfield) volume (FreeSurfer), cortical thickness (CAT12), and grey matter volume (voxel-based morphometry CAT12). Physical fitness was measured with a cardiopulmonary exercise test. Memory functioning was measured with the Hopkins Verbal Learning Test-Revised (HVLT-R total recall) and Wordlist Learning of an online cognitive test battery, the Amsterdam Cognition Scan (ACS Wordlist Learning). An explorative analysis was conducted in highly fatigued patients (score of ≥ 39 on the symptom scale 'fatigue' of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire), as previous research in this dataset has shown that the intervention improved cognition only in these patients. RESULTS: Multiple regression analyses and voxel-based morphometry revealed no significant intervention effects on brain volume, although at baseline increased physical fitness was significantly related to larger brain volume (e.g., total hippocampal volume: R = 0.32, B = 21.7 mm3, 95 % CI = 3.0 - 40.4). Subgroup analyses showed an intervention effect in highly fatigued patients. Unexpectedly, these patients had significant reductions in hippocampal volume, compared to the control group (e.g., total hippocampal volume: B = -52.3 mm3, 95 % CI = -100.3 - -4.4)), which was related to improved memory functioning (HVLT-R total recall: B = -0.022, 95 % CI = -0.039 - -0.005; ACS Wordlist Learning: B = -0.039, 95 % CI = -0.062 - -0.015). CONCLUSIONS: No exercise intervention effects were found on hippocampal volume, hippocampal subfield volumes, cortical thickness or grey matter volume for the entire intervention group. Contrary to what we expected, in highly fatigued patients a reduction in hippocampal volume was found after the intervention, which was related to improved memory functioning. These results suggest that physical fitness may benefit cognition in specific groups and stress the importance of further research into the biological basis of this finding.

Effect of physical exercise on cognitive function after chemotherapy in patients with breast cancer: a randomized controlled trial (PAM study).

BACKGROUND: Up to 60% of breast cancer patients treated with chemotherapy is confronted with cognitive problems, which can have a significant impact on daily activities and quality of life (QoL). We investigated whether exercise training improves cognition in chemotherapy-exposed breast cancer patients 2-4 years after diagnosis. METHODS: Chemotherapy-exposed breast cancer patients, with both self-reported cognitive problems and lower than expected performance on neuropsychological tests, were randomized to an exercise or control group. The 6-month exercise intervention consisted of supervised aerobic and strength training (2 h/week), and Nordic/power walking (2 h/week). Our primary outcome was memory functioning (Hopkins Verbal Learning Test-Revised; HVLT-R). Secondary outcomes included online neuropsychological tests (Amsterdam Cognition Scan; ACS), self-reported cognition (MD Anderson Symptom Inventory for multiple myeloma; MDASI-MM), physical fitness (relative maximum oxygen uptake; VO2peak), fatigue (Multidimensional Fatigue Inventory), QoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire; EORTC QLQ C-30), depression (Patient Health Questionnaire-9, Hospital Anxiety and Depression Scale; HADS), and anxiety (HADS). HVLT-R total recall was analyzed with a Fisher exact test for clinically relevant improvement (≥ 5 words). Other outcomes were analyzed using multiple regression analyses adjusted for baseline and stratification factors. RESULTS: We randomized 181 patients to the exercise (n = 91) or control group (n = 90). Two-third of the patients attended ≥ 80% of the exercise sessions, and physical fitness significantly improved compared to control patients (B VO2peak 1.4 ml/min/kg, 95%CI:0.6;2.2). No difference in favor of the intervention group was seen on the primary outcome. Significant beneficial intervention effects were found for self-reported cognitive functioning [MDASI-MM severity (B-0.7, 95% CI - 1.2; - 0.1)], fatigue, QoL, and depression. A hypothesis-driven analysis in highly fatigued patients showed positive exercise effects on tested cognitive functioning [ACS Reaction Time (B-26.8, 95% CI - 52.9; - 0.6) and ACS Wordlist Learning (B4.4, 95% CI 0.5; 8.3)]. CONCLUSIONS: A 6-month exercise intervention improved self-reported cognitive functioning, physical fitness, fatigue, QoL, and depression in chemotherapy-exposed breast cancer patients with cognitive problems. Tested cognitive functioning was not affected. However, subgroup analysis indicated a positive effect of exercise on tested cognitive functioning in highly fatigued patients. Trial Registration Netherlands Trial Registry: Trial NL5924 (NTR6104). Registered 24 October 2016, https://www.trialregister.nl/trial/5924 .

Inter-observer variation of hippocampus delineation in hippocampal avoidance prophylactic cranial irradiation.

BACKGROUND: Hippocampal avoidance prophylactic cranial irradiation (HA-PCI) techniques have been developed to reduce radiation damage to the hippocampus. An inter-observer hippocampus delineation analysis was performed and the influence of the delineation variability on dose to the hippocampus was studied. MATERIALS AND METHODS: For five patients, seven observers delineated both hippocampi on brain MRI. The intra-class correlation (ICC) with absolute agreement and the generalized conformity index (CIgen) were computed. Median surfaces over all observers' delineations were created for each patient and regional outlining differences were analysed. HA-PCI dose plans were made from the median surfaces and we investigated whether dose constraints in the hippocampus could be met for all delineations. RESULTS: The ICC for the left and right hippocampus was 0.56 and 0.69, respectively, while the CIgen ranged from 0.55 to 0.70. The posterior and anterior-medial hippocampal regions had most variation with SDs ranging from approximately 1 to 2.5 mm. The mean dose (Dmean) constraint was met for all delineations, but for the dose received by 1% of the hippocampal volume (D1%) violations were observed. CONCLUSION: The relatively low ICC and CIgen indicate that delineation variability among observers for both left and right hippocampus was large. The posterior and anterior-medial border have the largest delineation inaccuracy. The hippocampus Dmean constraint was not violated.

Quantification of patient-reported outcome measures of radiation-induced skin reactions for use in clinical trial design.

PURPOSE: Skin toxicity is a common effect from radiotherapy, although difficult to predict on an individual basis, and there is little evidence-based management. This study aimed to quantify inter-patient variation in patient-reported outcome measures for radiation-induced skin reactions (RISR) to enable the determination of the number of patients required for adequate power in a comparative trial of RISR management strategies. METHODS: The study included 154 patients scheduled to receive breast cancer radiotherapy. Patients filled in a weekly questionnaire during and up to 4 weeks following the end of radiotherapy scoring five aspects of their experience of RISR: skin redness, and bother from redness like itching, burning sensation and tenderness/pain. RESULTS: Assessment of patients' reported experience of their RISR was shown to be feasible, with 91 % of patients returning at least two questionnaires. The mean score increase between weeks 1 and 4 was 25 points (p value <0.0001, 95 % CI 21-29), and the estimated standard deviation at 4 weeks was 18 (95 % CI 16-21). CONCLUSIONS: Patients' assessment of their reaction was not predicted on the basis of treatment and patient-related characteristics. Based on the observed variance in scores at 4 weeks, we could calculate the sample size required for a comparative study of two RISR management policies would be 200 patients to have statistical power to detect a clinically significant difference in patient-rated scores of their skin reactions. A trial employing this tool would help provide an evidence base to guide policy in advising patients how to manage their RISR.

Increased cognitive problem reporting after information about chemotherapy-induced cognitive decline: The moderating role of stigma consciousness.

OBJECTIVE: Information about treatment side effects can increase their occurrence; breast cancer (BC) patients showed increased cognitive problem reporting (CPR) and decreased memory performance after information about cognitive side effects. The current study extends previous research on adverse information effects (AIE) by investigating (a) risk factors, (b) underlying mechanisms and (c) an intervention to reduce AIE. DESIGN: In an online experiment, 175 female BC patients were randomly assigned to one of three conditions. In the two experimental groups, patients were informed about the possible occurrence of cognitive problems after chemotherapy with (intervention group) or without (experimental group) reassuring information that 'there are still patients who score well on memory tests'. In the control group, no reference to chemotherapy-related cognitive problems was made. MAIN OUTCOME MEASURES: Main dependent measure was CPR. Four moderating and five mediating processes were examined. RESULTS: CPR increased with higher levels of stigma consciousness in the two experimental groups, but not in the no-information control group. CONCLUSION: Merely informing patients about cognitive side effects may increase their occurrence, especially among individuals vulnerable to patient stereotypes. Adding reassuring information is not sufficient to reduce AIE.

Neurobiological changes by cytotoxic agents in mice.

Cognitive deficit is a frequently reported side-effect of adjuvant chemotherapy. A large number of animal studies has been performed to examine the neurobiological mechanisms underlying this phenomenon, however, definite conclusions from these studies are restricted due to differences in experimental set-up. We systematically investigated the effects of 6 cytotoxic agents on various neurobiological parameters. C57Bl/6J mice were treated with cyclophosphamide, docetaxel, doxorubicin, 5-fluorouracil, methotrexate, or topotecan. The animals were sacrificed 3 or 15 weeks after treatment and the effect on neurogenesis, blood vessel density, and neuroinflammation was analyzed using immunohistochemistry. None of the cytostatic agents tested affected neurogenesis (cell survival or cell proliferation). Blood vessel density was increased in the hippocampus and prefrontal cortex 3 weeks after treatment with docetaxel and doxorubicin compared with control animals. A decrease in the number of microglial cells was observed in the prefrontal cortex after treatment with cyclophosphamide, docetaxel, 5-FU, and topotecan compared with control mice. The observed decrease in microglia cells is indicative of inflammation that occurred after treatment. Overall, the magnitude of the effects was relatively modest. Therefore, we conducted a similar study with topotecan in Abcg2;Abcb1a/b knock out and wildtype FVB mice. Animals were sacrificed 3 weeks after treatment and no notable effect was seen in hippocampal cell differentiation (DCX), microglia activation, or blood vessel density. Perhaps the FVB strain is more resistant to the neurotoxic effects of topotecan which makes this not the correct model to study the mechanism of chemotherapy-induced cognitive impairment.

Cognitive impact of cytotoxic agents in mice.

RATIONALE AND OBJECTIVES: Adjuvant chemotherapy is associated with changes in cognition in a subgroup of cancer patients. Chemotherapy is generally given as a combination of cytotoxic agents, which makes it hard to define the agent responsible for these observed changes. Literature on animal experiments has been difficult to interpret due to variance in experimental setup. METHODS: We examined the effects of cytotoxic agents administered separately on various cognitive measures in a standardized animal model. Male C57Bl/6 mice received cyclophosphamide, docetaxel, doxorubicin, 5-fluorouracil, methotrexate, or topotecan. These agents represent different compound classes based on their working mechanism and are frequently prescribed in the clinic. A control group received saline. Behavioral testing started 2 or 15 weeks after treatment and included testing general measures of behavior and cognitive task performance: spontaneous behavior in an automated home cage, open field, novel location recognition (NLR), novel object recognition (NOR), Barnes maze, contextual fear conditioning, and a simple choice reaction time task (SCRTT). RESULTS: Cyclophosphamide, docetaxel, and doxorubicin administration affected spontaneous activity in the automated home cage. All cytotoxic agents affected memory (NLR and/or NOR). Spatial memory measured in the Barnes maze was affected after administration with doxorubicin, 5-fluorouracil, and topotecan. Decreased inhibition in the SCRTT was observed after treatment with cyclophosphamide, docetaxel, and topotecan. CONCLUSIONS: Our data show that, in mice, a single treatment with a cytotoxic agent causes cognitive impairment. Not all cytotoxic agents affected the same cognitive domains, which might be explained by differences in working mechanisms of the various agents.

Monitoring and optimising cognitive function in cancer patients: Present knowledge and future directions.

The potentially detrimental effects of cancer and related treatments on cognitive functioning are emerging as a key focus of cancer survivorship research. Many patients with central nervous system (CNS) or non-CNS tumours develop cognitive problems during the course of their disease that can result in diminished functional independence. We review the state of knowledge on the cognitive functioning of patients with primary and secondary brain tumours at diagnosis, during and after therapy, and discuss current initiatives to diminish cognitive decline in these patients. Similarly, attention is paid to the cognitive sequelae of cancer and cancer therapies in patients without CNS disease. Disease and treatment effects on cognition are discussed, as well as current insights into the neural substrates and the mechanisms underlying cognitive dysfunction in these patients. In addition, rehabilitation strategies for patients with non-CNS disease confronted with cognitive dysfunction are described. Special attention is given to knowledge gaps in the area of cancer and cognition, in CNS and non-CNS diseases. Finally, we point to the important role for cooperative groups to include cognitive endpoints in clinical trials in order to accelerate our understanding and treatment of cognitive dysfunction related to cancer and cancer therapies.

Chemotherapy-related cognitive dysfunction: current animal studies and future directions.

Cognitive impairment is a potential long-term side effect of adjuvant chemotherapy that can have a major impact on the quality of life of cancer survivors. There is a growing number of preclinical studies addressing this issue, thereby extending our knowledge of the mechanisms underlying chemotherapy-induced neurotoxicity. In this review, we will summarize the recent advances and important findings presented in these studies. Emerging challenges, such as the development of neuroprotective strategies, and the role of the blood-brain barrier on cognitive impairment will be described and future directions in this field of investigation will be outlined.

Self-reported cognitive functioning in postmenopausal breast cancer patients before and during endocrine treatment: findings from the neuropsychological TEAM side-study.

OBJECTIVE: This study aimed to evaluate self-reported cognitive functioning of postmenopausal breast cancer patients before and during endocrine treatment compared with healthy female controls, and to investigate associations between self-reported cognitive functioning, cognitive test performance and anxiety/depression, fatigue, and menopausal complaints. METHODS: Self-reported cognitive functioning, anxiety/depression, fatigue, menopausal complaints, and cognitive tests performance were assessed before (T1) and after 1 year (T2) of adjuvant endocrine treatment in postmenopausal chemotherapy-naïve breast cancer patients. Self-reported cognitive functioning was assessed by the cognitive failures questionnaire and interview questions concerning cognitive complaints. Patients participated in the TEAM-trial, a prospective randomized study investigating tamoxifen versus exemestane as adjuvant therapy for hormone-sensitive breast cancer. Identical information was obtained from healthy postmenopausal volunteers. RESULTS: Two measures for self-reported cognitive functioning provided the distinctive results. At T1 and T2, healthy controls reported a higher frequency of cognitive failures than patients; change over time did not differ between groups. The prevalence of cognitive complaints did not differ between the groups at T1, but change over time regarding attention/concentration complaints differed between groups, due to an increased prevalence in tamoxifen users. Self-reported cognitive functioning showed moderate associations with anxiety/depression, fatigue, and menopausal complaints. Cognitive test performance was not associated with self-reported cognitive functioning, but weakly with anxiety/depression and fatigue. CONCLUSION: Adjuvant therapy with tamoxifen and exemestane did not influence the self-reported frequency of cognitive failures. Increased attention/concentration complaints were observed in tamoxifen users, but not in exemestane users. This latter finding should be confirmed with better validated instruments.

Cognitive functioning of postmenopausal breast cancer patients before adjuvant systemic therapy, and its association with medical and psychological factors.

PURPOSE: This study aimed to identify medical and psychological predictors for cognitive performance of breast cancer (BC) patients before the start of adjuvant systemic treatment and to compare cognitive performance between BC patients and healthy controls adjusting for medical and psychological variables. MATERIAL: 205 postmenopausal BC patients underwent pre-treatment neuropsychological tests and provided medical and psychological data. 124 healthy controls underwent the same assessment. RESULTS: 'Treatment for diabetes mellitus' and/or 'hypertension', 'less hours spent on cognitively stimulating activities', 'fewer days since surgery' and 'more reproductive years' were associated with worse cognitive performance in the BC patients, independent of age and IQ. Cognitive differences between BC patients and healthy controls could partly be explained by the evaluated variables. CONCLUSION: The results stress the need for adjustment for pre-treatment cognitive differences between study groups, and also indicate that further research into pre-treatment cognitive dysfunction is warranted.

[The effect of hormone therapy on cognitive function in patients with breast cancer]. / De invloed van hormonale therapie op het cognitieffunctioneren van patiënten met het mammacarcinoom.

Preclinical and clinical studies suggest that oestrogens have an important role in brain functioning and cognitive ability. Given that hormone therapies for breast cancer reduce oestrogen levels or block oestrogen receptors, it is conceivable that these agents also influence cognitive function. Several small studies have been conducted to address this issue, but many of them are methodologically insufficient. The negative effects of oophorectomy and luteinising hormone-releasing hormone (LHRH) analogues on verbal memory and working memory have been demonstrated the most consistently, albeit only in small studies. Anastrozole and tamoxifen also appear to exert some negative effect on cognition, but well-designed studies are lacking. No data are available on the influence of the aromatase inhibitors exemestane and letrozole on cognitive function. Raloxifene, a drug that has no obvious advantages over tamoxifen and will likely not be developed further for breast cancer treatment, has no negative influence on cognitive functioning. It remains unclear whether the observed effects are transient or permanent, and to what extent age, menopausal status and duration of therapy influence the severity of cognitive effects.

Cancer and cancer-therapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop.

A subset of survivors has cognitive impairment after cancer treatment. This is generally subtle, but may be sustained. In October 2006, the second international cognitive workshop was held in Venice. The workshop included neuropsychologists, clinical and experimental psychologists, medical oncologists, imaging experts, and patient advocates. The main developments since the first Cognitive Workshop in 2003 have been the following. (i) studies evaluating cognitive function in patients receiving chemotherapy for cancers other than breast cancer, and in patients receiving hormonal therapy for cancer. (ii) The publication of longitudinal prospective studies which have shown that some patients already exhibit cognitive impairment on neuropsychological testing before receiving chemotherapy, and some patients have deterioration in cognitive functioning from pre- to postchemotherapy. (iii) Studies of the underlying mechanisms of cognitive impairment both in patients and in animal models. (iv) Use of structural and functional imaging techniques to study changes in brain morphology and activation patterns associated with chemotherapy. (v) At present cognitive research in cancer is limited by methodological challenges and the lack of standardization in neuropsychological studies. The current workshop addressed many of these issues and established an international task force to provide guidelines for future research and information on how best to manage these symptoms.

Effects of hormonal therapy on cognitive functioning in breast cancer patients: a review of the literature.

(Pre)clinical research suggests that estrogens play a role in brain- and cognitive functioning. It is, among others, hypothesized that estrogens have a beneficial effect on neurotransmitters that are involved in cognitive processes, protect the brain by exerting anti-inflammatory actions after ischemic injury, promote survival of brain cells, and increase cerebral blood flow and glucose transport into the brain. Neuropsychological studies suggest that natural changes in estrogen levels are associated with (small) changes in cognitive functioning, for example during the menstrual cycle. In estrogen substitution studies, however, contradicting results are found, suggesting that substitution can have both beneficial and detrimental effects on cognitive functioning. Hormonal therapy for breast carcinoma lowers estrogen levels or blocks the growth-promoting effects of estrogens. The neuropsychological studies conducted so far give, though they vary highly in design, measures and participants, some indications for effects on cognition: ovariectomy, treatment with LHRH analogues, anastrozole and tamoxifen seem to be associated with (small) negative effects on some tests. It is unclear whether those effects are reversible, and whether time on therapy is associated with the seriousness of the effects. Raloxifene, currently under study for breast cancer prevention, does not seem to have detrimental effects on cognitive functioning. For the aromatase inhibitors letrozole and exemestane no data are available yet. Because the role of hormonal therapy in breast cancer treatment is increasing, the medical grounds for prescribing are expanding and physicians can make a choice from a broad spectrum of hormonal treatments, potential effects on cognitive functioning should be part of long-term drug safety evaluations.

Late effects of adjuvant chemotherapy on cognitive function: a follow-up study in breast cancer patients.

BACKGROUND: Neuropsychological examinations have shown an elevated risk for cognitive impairment 2 years after therapy in breast cancer patients randomized to receive adjuvant high-dose cyclophosphamide, thiotepa, carboplatin (CTC) chemotherapy compared with a non-treated control group of stage I breast cancer patients. Patients randomized to receive standard-dose fluorouracil, epirubicin, cyclophosphamide (FEC) chemotherapy showed no elevated risk compared with controls. However, breast cancer patients treated with conventional cyclophosphamide, methotrexate, 5-fluorouracil (CMF) chemotherapy showed a higher risk of cognitive impairment. The present study was designed to obtain a greater insight into these long-term neuropsychological sequelae following chemotherapy and their course in time. PATIENTS AND METHODS: At 4 years post-therapy, 22 of the original 34 CTC patients, 23 of 36 FEC patients, 31 of 39 CMF patients and 27 of 34 control patients were re-examined with neuropsychological tests. RESULTS: Improvement in performance was observed in all chemotherapy groups, whereas in the control group there was a slight deterioration in test results. A differential attrition was observed among the groups, with a relatively high percentage of initially cognitively impaired patients from the CTC group dropping out due to factors related to disease progression. CONCLUSIONS: The results suggest that cognitive dysfunction following adjuvant chemotherapy in breast cancer patients may be transient. Additional studies are needed to investigate the differential attrition of patients with cognitive impairment.

Neurophysiological evaluation of late effects of adjuvant high-dose chemotherapy on cognitive function.

OBJECTIVES: 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 > or =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.

Cognitive deficits after postoperative adjuvant chemotherapy for breast carcinoma.

BACKGROUND: A number of patients who have undergone adjuvant (CMF) chemotherapy for operative primary breast carcinoma have reported impaired cognitive function, sometimes even years after completion of therapy. The possible role of cytostatic treatment as a causative factor has scarcely been investigated. The objective of the current study was to examine the late effects on neuropsychologic functioning of CMF adjuvant chemotherapy given to patients with breast carcinoma. METHODS: Thirty-nine breast carcinoma patients who had been treated with adjuvant CMF (6 courses) followed (n = 20) by 3 years of tamoxifen 20 mg daily or not (n = 19) were examined with neuropsychologic tests and interviews. The control group consisted of 34 age-matched axillary lymph node negative breast carcinoma patients who received the same surgical and radiation therapy but no systemic adjuvant treatment. The CMF patients were examined a median of 1.9 years after the sixth CMF course, and the controls a median of 2.4 years after surgery of the primary tumor. RESULTS: Patients treated with CMF reported significantly more problems with concentration (31% vs. 6%, P = 0.007) and with memory (21% vs. 3%, P = 0.022) than the control patients. No relation was found between reported complaints and results on the neuropsychologic tests. Impairment in cognitive function was found in 28% of the patients treated with chemotherapy compared with 12% of the patients in the control group (odds ratio 6.4 [95% confidence interval 1.5-27.6] P = 0.013). Hormonal therapy had no influence on patients' self-reports of symptoms or cognitive function. Cognitive impairment following chemotherapy was noticed in a broad domain of functioning, including attention, mental flexibility, speed of information processing, visual memory, and motor function. CONCLUSIONS: Breast carcinoma patients treated with adjuvant CMF chemotherapy have a significantly higher risk of late cognitive impairment than breast carcinoma patients not treated with chemotherapy (OR 6.4). This cognitive impairment is unaffected by anxiety, depression, fatigue, and time since treatment, and not related to the self-reported complaints of cognitive dysfunction.