McAllister TW, Ahles TA, Saykin AJ, Ferguson RJ, McDonald BC, Lewis LD, Flashman LA, Rhodes CH.
Cognitive effects of cytotoxic cancer chemotherapy: predisposing risk factors and potential treatments. 

Curr Psychiatry Rep. 2004 Oct;6(5):364-71. Review. PMID: 15355759 [PubMed – indexed for MEDLINE]

Increasing evidence suggests that systemic cancer chemotherapy can have significant long-term effects on cognition, particularly on verbal learning, memory, attention, and speed of information processing. These deficits can be a source of significant distress to survivors. There is much less known about the mechanisms, predisposing vulnerabilities, and treatment of these deficits. We will summarize current knowledge of chemotherapy-associated cognitive deficits. Emerging theories about the role of selected genetic polymorphisms in heightening the vulnerability to chemotherapy-induced cognitive decline will be described.

bulletDepartment of Psychiatry, Dartmouth Medical School and Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA. thomas.w.mcallister@dartmouth.edu
Castellon SA, Ganz PA, Bower JE, Petersen L, Abraham L, Greendale GA.
Neurocognitive performance in breast cancer survivors exposed to adjuvant chemotherapy and tamoxifen.

J Clin Exp Neuropsychol. 2004 Oct;26(7):955-69.
PMID: 15742545 [PubMed – indexed for MEDLINE]

The primary aim of the current study was to examine whether neurocognitive functioning among breast cancer survivors (BCS) exposed to systemic adjuvant chemotherapy differs from that seen among BCS who did not receive chemotherapy. The performance of each of these BCS groups was compared to a demographically matched comparison group without history of breast cancer, a group not included in the majority of previous cognitive functioning studies. We also sought to explore whether usage of the anti-estrogen drug tamoxifen, a common component of breast cancer treatment, was related to neurocognitive functioning. Finally, we wished to examine the relationship between subjective report of cognitive functioning and objective performance on neurocognitive measures among BCS. Fifty-three survivors of breast cancer (all between 2-5 years after diagnosis and initial surgical removal of cancerous tissue) and 19 healthy non-BCS comparison subjects were administered a comprehensive neurocognitive battery, and measures of mood, energy level, and self-reported cognitive functioning. Those BCS who received adjuvant chemotherapy performed significantly worse in the domains of verbal learning, visuospatial functioning, and visual memory than BCS treated with surgery only. Those who received both chemotherapy and tamoxifen showed the greatest compromise. Although patients who received chemotherapy (with and without tamoxifen) performed worse than those treated with surgery only on several domains, neither group was significantly different from demographically matched comparison subjects without a history of breast cancer. Finally, we found no relationship between subjective cognitive complaints and objective performance, although cognitive complaints were associated with measures of psychological distress and fatigue. We highlight ways in which these data converge with other recent studies to suggest that systemic chemotherapy, especially in combination with tamoxifen, can have adverse yet subtle effects on cognitive functioning.

bulletDepartment of Psychiatry & Biobehavioral Sciences, UCLA School of Medicine, Los Angeles, CA, USA. scastell@ucla.edu
Weuve J, Kang JH, Manson JE, Breteler MM, Ware JH, Grodstein F.
Physical activity, including walking, and cognitive function in older women.


JAMA. 2004 Sep 22;292(12):1454-61.
PMID: 15383516 [PubMed – indexed for MEDLINE]

CONTEXT: Physical activity may help maintain cognitive function in older adults. OBJECTIVE: To examine the relation of long-term regular physical activity, including walking, to cognitive function. DESIGN: Women reported participation in leisure-time physical activities on biennial mailed questionnaires beginning in 1986. We assessed long-term activity by averaging energy expenditures from questionnaires in 1986 through participants’ baseline cognitive assessments (1995 to 2001). We used linear regression to estimate adjusted mean differences in baseline cognitive performance and cognitive decline over 2 years, across levels of physical activity and walking. SETTING AND PARTICIPANTS: Nurses’ Health Study, including 18 766 US women aged 70 to 81 years. MAIN OUTCOME MEASURE: Validated telephone assessments of cognition administered twice approximately 2 years apart (1995 to 2001 and 1997 to 2003), including tests of general cognition, verbal memory, category fluency, and attention. RESULTS: Higher levels of activity were associated with better cognitive performance. On a global score combining results of all 6 tests, women in the second through fifth quintiles of energy expenditure scored an average of 0.06, 0.06, 0.09, and 0.10 standard units higher than women in the lowest quintile (P for trend <.001). Compared with women in the lowest physical activity quintile, we found a 20% lower risk of cognitive impairment for women in the highest quintile of activity. Among women performing the equivalent of walking at an easy pace for at least 1.5 h/wk, mean global scores were 0.06 to 0.07 units higher compared with walking less than 40 min/wk (P< or =.003). We also observed less cognitive decline among women who were more active, especially those in the 2 highest quintiles of energy expenditure. Women in the fourth and fifth quintiles had mean changes in global scores that were 0.04 (95% confidence interval, 0.02-0.10) and 0.06 (95% confidence interval, 0.02-0.11) standard units better than those in the lowest quintile. CONCLUSION: Long-term regular physical activity, including walking, is associated with significantly better cognitive function and less cognitive decline in older women.

bulletDepartment of Epidemiology, Harvard School of Public Health, Boston, Mass 02215, USA. jweuve@hsph.harvard.edu
Wefel JS, Lenzi R, Theriault R, Buzdar AU, Cruickshank S, Meyers CA.
Chemobrain’ in breast carcinoma?: a prologue.

Cancer. 2004 Aug 1;101(3):466-75.PMID: 15274059 [PubMed – indexed for MEDLINE]

BACKGROUND: Chemotherapy-induced cognitive dysfunction in patients with breast carcinoma has been described previously. However, those studies only assessed patients’ postchemotherapy cognitive functioning and were not able to determine the relation between cognitive function and other treatments, such as surgery and radiotherapy, that often precede systemic chemotherapy. METHODS: Eighty-four women with breast carcinoma underwent a comprehensive neuropsychologic evaluation before receiving adjuvant therapy for nonmetastatic primary breast carcinoma. RESULTS: Before the start of systemic therapy, 35% of women in the current cohort exhibited cognitive impairment. Verbal learning (18%) and memory function (25%) were impaired significantly more frequently relative to normative expectations. Although the impairments were not significant in the women who were examined, nonverbal memory (17%), psychomotor processing speed and attention (13%), confrontational naming (13%), visuoconstruction (13%), and upper-extremity fine motor dexterity (12%) were impaired more frequently than was expected. Affective distress was related significantly to cognitive impairment (Pearson chi-square = 9.90; P = 0.002). Given the conservative statistical approach employed, extent of surgery, hormone replacement therapy history, and current menopausal status failed to achieve statistical significance, but these variables did exhibit provocative trends with respect to cognitive impairment. CONCLUSIONS: Cognitive impairment frequently is observed before the administration of systemic chemotherapy. Thus, investigations purporting to measure chemotherapy-induced cognitive dysfunction must employ study designs that incorporate prechemotherapy baseline assessments to accurately detect changes in cognitive function that are attributable to chemotherapy.

bulletDepartment of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Wefel JS, Lenzi R, Theriault RL, Davis RN, Meyers CA.
The cognitive sequelae of standard-dose adjuvant chemotherapy in women with breast carcinoma: results of a prospective, randomized, longitudinal trial.

Cancer. 2004 Jun 1;100(11):2292-9.
PMID: 15160331 [PubMed – indexed for MEDLINE]

BACKGROUND: Retrospective trials have reported that chemotherapy-induced cognitive dysfunction was experienced by a subset of patients with breast carcinoma. However, recent evidence indicated that a subset also exhibited impaired cognitive function at baseline, before the start of chemotherapy. A prospective, longitudinal trial that incorporates baseline neuropsychologic evaluations is necessary to determine to what extent cognitive dysfunction is attributable to chemotherapy in this population. METHODS: Eighteen women with breast carcinoma underwent a comprehensive neuropsychologic evaluation before treatment and at short-term and long-term intervals after chemotherapy. The incidence, nature, severity, and chronicity of cognitive dysfunction developing in patients with breast carcinoma treated with a standard dose of adjuvant chemotherapy were assessed. RESULTS: Before the start of systemic therapy, 33% of women in the current cohort exhibited cognitive impairment. At the short-term postchemotherapy time point, 61% of the cohort exhibited a decline relative to baseline in 1 or more domains of cognitive functioning and reported greater difficulty in maintaining their ability to work. The most common domains of cognitive dysfunction were related to attention, learning, and processing speed. At the long-term postchemotherapy time point, approximately 50% of patients who experienced declines in cognitive function demonstrated improvement, whereas 50% remained stable. Self-reported ability to perform work-related activities also improved over this interval. Neither impairment at baseline nor subsequent treatment-related cognitive decline exhibited any statistically significant correlation with affective well-being or with demographic or clinical characteristics. CONCLUSIONS: The current study is the first longitudinal trial to report evidence of an association between cognitive dysfunction and chemotherapy in a subgroup of women with nonmetastatic breast carcinoma. The importance of using prospective research designs, appropriate cognitive measures, and statistical methods to evaluate subgroup effects was discussed. Identification of mechanisms associated with cognitive dysfunction and of risk factors contributing to subgroup vulnerability is necessary. Copyright 2004 by the American Cancer Society.

bulletDepartment of Neuro-Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Tannock IF, Ahles TA, Ganz PA, Van Dam FS.
Cognitive impairment associated with chemotherapy for cancer: report of a workshop.

J Clin Oncol. 2004 Jun 1;22(11):2233-9. Review.
PMID: 15169812 [PubMed – indexed for MEDLINE]

Cognitive dysfunction may occur in some patients who receive chemotherapy. We provide a summary of an April 2003 workshop on this topic, that included medical oncologists, radiologists, clinical and experimental psychologists, and patient advocates. Current studies indicate that cognitive deficits are often subtle, although they are observed consistently in a proportion of patients, may be durable, and can be disabling. Deficits have been observed in a range of cognitive functions. Underlying mechanisms are unknown, although preliminary studies suggest there may be genetic predisposition and that cognitive impairment may be accompanied by changes in the brain detectable by neuroimaging. The following priorities were established for future research: (1) large-scale clinical studies that use both a longitudinal design and concurrent evaluation of patients with cancer who do not receive chemotherapy-such studies should address the probability and magnitude of cognitive deficits, factors that predict them, and underlying mechanisms; (2) exploration of discrepancies between subjective reports of cognitive dysfunction and the objective results of cognitive testing; (3) studies of cognitive function in patients receiving treatment for diseases other than breast cancer, and in both men and women, to address the hypothesis that underlying mechanisms relate to changes in serum levels of sex hormones and/or to chemotherapy-induced menopause; (4) development of interventions to alleviate these problems; and (5) development of animal models and the use of imaging techniques to address mechanisms that might cause cognitive impairment associated with chemotherapy.

bulletDepartment of Medical Oncology and Hematology, Princess Margaret Hospital, 610 University Ave, Toronto, ON M5G 2M9, Canada. ian.tannock@uhn.on.ca
Minisini A, Atalay G, Bottomley A, Puglisi F, Piccart M, Biganzoli L.
What is the effect of systemic anticancer treatment on cognitive function?

Lancet Oncol. 2004 May;5(5):273-82. Review.
PMID: 15120664 [PubMed – indexed for MEDLINE]

Treatment regimens for solid tumours have been extensively investigated for their physical toxic effects, but far less is known about the potential impairment of cognitive function by anticancer treatment regimens. Here, we review published studies that examined cognitive function in adult patients receiving systemic therapy for solid tumours. Our review suggests that patients can experience cognitive changes related to their treatment. However, several studies had methodological limitations, such as use of a limited sample size, lack of baseline assessment, and lack of control for potential confounding factors. Better designed clinical trials are required so that the difficulties patients face in terms of reduced cognitive function as a result of anticancer treatment can be fully elucidated. These trials should have sufficient statistical power and, importantly, should also be prospective.

bulletUnit of Medical Oncology, University of Udine, Italy.

 

Ahles TA.
Do systemic cancer treatments affect cognitive function?

Lancet Oncol. 2004 May;5(5):270-1. 
PMID: 15120662 [PubMed – indexed for MEDLINE]

In their review, published in this issue of The Lancet Oncology, Minisini and colleagues1 discuss the effect of systemic anticancer treatment on cognitive functioning. Unlike other reviews that have simply focused on breast cancer, these authors provide a thorough overview of the published work across different tumour types, including breast, lung, prostate, and ovarian carcinoma. In addition, rather than focusing exclusively on chemotherapy, the authors also review other systemic therapies, including endocrine and androgen therapy, biological response modifiers, and molecularly targeted therapies. The authors appropriately discuss the limitations of the published work, but conclude that there is sufficient evidence to support the hypothesis that systemic cancer treatments can have a detrimental effect on cognitive functioning in cancer survivors—a conclusion similar to that published in a meta-analysis by Anderson- Hanley and colleagues.2

The breadth of the review is a major strength by showing that cognitive problems secondary to cancer treatment are not restricted to survivors of breast cancer who have been treated with adjuvant chemotherapy. Indeed, systemic treatments for patients with lymphoma, lung, prostate, or ovarian cancer have also been reported to cause long-term cognitive problems.

One important implication of Minisini’s review is a recognition that there might be many interacting mechanisms by which systemic cancer therapies affect cognitive functioning. As noted by the authors, and others,3 chemotherapy can have both a direct effect on the central nervous system and cause cognitive problems by indirect effects, such as anaemia or a reduction in oestrogen concentrations associated with chemotherapy-induced menopause. In addition, the use of hormonal therapies for breast and prostate cancer can influence cognitive functioning by causing a reduction in oestrogen and testosterone concentration whereas biological response modifiers may exert their influence through an effect on the immune system.

Cognitive side-effects resulting from cancer treatment can also be increased by factors that normally confer increased vulnerability to cognitive dysfunction after any type of insult to the CNS. For instance, Minisini and coauthors propose that elderly patients are more vulnerable to cognitive problems after systemic treatments, especially those with advanced stage disease and multiple comorbidities. Clearly, elderly people are an important population to investigate because very little research has been done assessing the effect of cancer treatment on cognition within the setting of palliative care. Other factors that might increase vulnerability to cognitive side-effects induced by chemotherapy include, intelligence quotient (IQ) and educational status (it has been hypothesised that people with a higher IQ or level of education might have more a “cognitive reserve” protecting them from problems secondary to brain insult), a history of development disorders or learning disabilities, previous head trauma, or cooccurring neurological disorders.4,5

Genetic factors may also be important determinants of long-term cognitive problems in cancer survivors. The apolipoprotein E (APOE) gene is polymorphic and occurs in three common alleles, APOE , 3 and 4 which give rise to six different genotypes. The presence of APOE 4 has been associated with Alzheimer’s disease and cognitive deficits secondary to various types of brain injury.6 A preliminary study7 has reported that cancer survivors previously treated with chemotherapy who have the 4 allele score worse in several domains of cognitive functioning compared with patients who have other APOE alleles.Although more research is needed, genes associated with brain function, neural or vascular repair in the central nervous system, drug metabolism, or blood–brain transporter systems, might also be important for predicting which patients are more vulnerable to chemotherapy-induced changes in cognition.

Taken together, the current weight of evidence suggests that some cancer treatments, or combinations of treatments, have long-term negative effects on cognitive function in cancer survivors. Furthermore, specific factors might increase vulnerability to long-term cognitive side-effects. Minisini and colleagues conclude their review with a call for large scale, longitudinal studies that control for important confounding variables (such as age, IQ, menopausal status, haemoglobin concentration, anxiety, depression, fatigue, and concomitant drugs) and include appropriate comparison groups. In view of Minisini’s excellent review, it is clear that routine monitoring of cognition and other effects on the CNS, is now needed among patients who have been treated for cancer to understand the mechanisms of treatment-induced cognitive dysfunction and to develop interventions to prevent, or reduce, the potentially negative long-term effects of systemic therapy.

References

1. Minisini AM, Atalay G, Bottomley A, et al. What is the impact of systemic anticancer treatments on cognitive functioning?. Lancet Oncol 2004; 5: 273-282.

2 Anderson-Hanley C, Sherman ML, Riggs R, et al. Neuropsychological effects of treatments for adults with cancer: a meta-analysis and review of the literature. J Int Neuropsychol Soc 2003; 9: 967-982.

3 Saykin AJ, Ahles TA, McDonald BC. Mechanisms of chemotherapy-induced cognitive disorders: neuropsychological, pathophysiological, and neuroimaging perspectives. Semin Clin Neuropsychiatry 2003; 8: 201-216.

4. Rugo HS, Ahles TA. The impact of adjuvant therapy for breast cancer on cognitive function: current evidence and directions for research. Semin Oncol 2003; 30: 749-762. |

5 Ferguson RJ, Ahles TA. Chemotherapy associated cognitive impairment in patients with cancer and cancer survivors. Curr Neurol Neurosci Rep 2003; 3: 215-222.

6 Parasuraman R, Greenwood PM, Sunderland T. The apolipoprotein E gene, attention, and brain function. Neuropsychology 2002; 16: 254-274.

7 Ahles TA, Saykin AJ, Noll WW, et al. The relationship of APOE genotype to neuropsychological performance in longterm cancer survivors treated with standard dose chemotherapy. Psycho-oncology 2003; 12: 612-619.

bulletDepartment of Psychiatry and Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, NH.

 

Correa DD, DeAngelis LM, Shi W, Thaler H, Glass A, Abrey LE.
Cognitive functions in survivors of primary central nervous system lymphoma.

Neurology. 2004 Feb 24;62(4):548-55.
PMID: 14981169 [PubMed – indexed for MEDLINE]

BACKGROUND: The standard treatment for primary CNS lymphoma (PCNSL) involves high-dose methotrexate-based (MTX) chemotherapy and whole brain radiotherapy (WBRT). This combined regimen prolongs patient survival, but also carries a substantial risk for delayed neurotoxicity particularly in the elderly. However, cognitive outcome evaluations have not been included in most clinical trials. OBJECTIVE: To assess cognitive functioning and quality of life in PCNSL survivors treated either with WBRT +/- MTX-based chemotherapy or chemotherapy alone. METHODS: Twenty-eight PCNSL patients in disease remission received a post-treatment baseline neuropsychological evaluation, and a subset of patients were available for an 8-month follow-up evaluation. Assessment of quality of life and extent of white matter disease on MRI were also performed. RESULTS: Patients displayed mild to moderate impairments across several cognitive domains. These were of sufficient severity to reduce quality of life in half of the patient sample. Comparisons according to treatment type revealed more pronounced cognitive impairment, particularly in the memory and attention/executive domains, among patients treated with WBRT +/- chemotherapy. Extent of white matter disease correlated with attention/executive, memory, and language impairment. CONCLUSIONS: PCNSL survivors treated with WBRT +/- chemotherapy displayed more pronounced cognitive dysfunction than patients treated with MTX-based chemotherapy alone.

bulletDepartment of Neurology, Memorial Sloan-Kettering Cancer Center, New York 10021, USA. corread@mskcc.org
Poppelreuter M, Weis J, Kulz AK, Tucha O, Lange KW, Bartsch HH.
Cognitive dysfunction and subjective complaints of cancer patients. a cross-sectional study in a cancer rehabilitation centre.

Eur J Cancer. 2004 Jan;40(1):43-9.
PMID: 14687788 [PubMed – indexed for MEDLINE]

Although the neurotoxicity of many anticancer therapies is well documented, the impact of cancer treatment on cognitive functioning has been studied less frequently. The present study examines deficits in cognitive functioning and their correlation with medical data as well as with psychosocial variables. A standardised neuropsychological test battery and several questionnaires were administered to a random sample of 119 patients. 24% of our patients fulfilled our criterion for cognitive impairment. There were no significant associations between the results of the neuropsychological testing and the current affective status or self-reports of attentional deficits in daily life. Cognitive impairment occurs in a clinically relevant percentage of cancer patients and cannot be explained exclusively due to depression or anxiety. Since subjective and objective cognitive impairment data showed little correlation, neuropsychological evaluation should not only be based on subjectively-reported complaints, but also on objective measurements.

bulletTumor Biology Center, Breisacher Strasse 117, 79106 Freiburg, Germany. poppelreuter@tumorbio.uni-freiburg.de

 

Jenkins V, Shilling V, Fallowfield L, Howell A, Hutton S.
Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study.

Psychooncology. 2004 Jan;13(1):61-6.
PMID: 14745746 [PubMed – indexed for MEDLINE]

This pilot study examines whether hormone therapy for breast cancer affects cognition. Patients participating in a randomised trial of anastrozole, tamoxifen alone or combined (ATAC) (n=94) and a group of women without breast cancer (n=35) completed a battery of neuropsychological measures. Compared with the control group, the patients were impaired on a processing speed task (p=0.032) and on a measure of immediate verbal memory (p=0.026) after controlling for the use of hormone replacement therapy in both groups. Patient group performance was not significantly related to length of treatment or measures of psychological morbidity. The results showed specific impairments in processing speed and verbal memory in women receiving hormonal therapy for the treatment of breast cancer. Verbal memory may be especially sensitive to changes in oestrogen levels, a finding commonly reported in studies of hormone replacement therapy in healthy women. In view of the increased use of hormone therapies in an adjuvant and preventative setting their impact on cognitive functioning should be investigated more thoroughly. Copyright 2003 John Wiley & Sons, Ltd.

bulletCancer Research UK, Brighton and Sussex Medical School, University of Sussex, Brighton, UK. v.jenkins@biols.susx.ac.uk

 

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