Barton D, Loprinzi C.
Novel approaches to preventing chemotherapy-induced cognitive dysfunction in breast cancer: the art of the possible.

Clin Breast Cancer. 2002 Dec;3 Suppl 3:S121-7. Review.
PMID: 12533273 [PubMed – indexed for MEDLINE]

Chemotherapy-induced cognitive dysfunction in women with breast cancer has become an increasingly important clinical issue. To date, little is known about its incidence, exact characteristics, and exact pathophysiology. Likewise, no treatments have been shown to prevent or decrease cognitive changes thought to result from chemotherapy. However, ongoing scientific research might help us understand the mechanisms that will help patients maintain maximal cognitive function. Changes in cognition due to chemotherapy might result from indirect chemical toxicity and oxidative damage, direct injury to neurons, inflammation, or a type of autoimmune response. Based on these potential causes, and based on interventions that have been tested in dementia and Alzheimer’s disease, there are a number of potential, novel interventions that could be tested in clinical trials as treatments for chemotherapy-induced cognitive dysfunction. Possible anecdotal strategies to consider include hormonal interventions, antioxidants, monoamine oxidase inhibitors, growth factors, dopamine agonists, cholinesterase inhibitors, antiinflammatory agents, and behavioral interventions

bulletMayo Clinic, Division of Medical Oncology, Rochester, MN 55905, USA.
O’Shaughnessy JA.
Effects of epoetin alfa on cognitive function, mood, asthenia, and quality of life in women with breast cancer undergoing adjuvant chemotherapy.

Clin Breast Cancer. 2002 Dec;3 Suppl 3:S116-20. Review.
PMID: 12533272 [PubMed – indexed for MEDLINE]

Several recently published studies describe moderate to severe cognitive dysfunction in breast cancer survivors who were treated with adjuvant chemotherapy 1-5 years before undergoing extensive neuropsychological testing. While these studies are hypothesis-generating and preliminary given their small size and retrospective nature, they consistently suggest that between approximately 15% and 25% of chemotherapy-treated breast cancer patients will have evidence of cognitive dysfunction some years after chemotherapy, compared to about 10% of breast cancer survivors who did not receive chemotherapy. Recent preclinical data strongly suggest that erythropoetin is a potent, endogenous neuroprotective agent that prevents neuronal apoptosis from a variety of insults including hypoxia, trauma, subarachnoidal hemorrhage, and encephalitis. Erythropoietin also appears to enhance learning in a mouse spatial learning maze model. We have conducted a pilot study of epoetin alfa versus placebo in early-stage breast cancer patients who received standard adjuvant anthracycline-based chemotherapy to determine the feasibility of administering standardized neurocognitive assessment tests in the oncology practice setting in order to understand whether the Executive Interview 25 test can detect the subtle cognitive impairment in verbal fluency, attention, and short-term memory observed with chemotherapy, and to assess whether epoetin alfa-treated patients have less evidence of cognitive dysfunction during and 6 months after chemotherapy compared with control-treated patients. We report here the preliminary results of this pilot clinical trial.

bulletBaylor Sammons Cancer Center, US Oncology, Dallas, Texas 75246, USA. Joyce.O’
Schagen SB, Muller MJ, Boogerd W, Van Dam FS.
Cognitive dysfunction and chemotherapy: neuropsychological findings in perspective.

Clin Breast Cancer. 2002 Dec;3 Suppl 3:S100-8. Review.
PMID: 12533270 [PubMed – indexed for MEDLINE]

Currently, the interest in cognitive functioning following chemotherapy is rapidly expanding as is reflected in a growing number of published studies on this topic. Although most studies are indicative of cognitive deficits after chemotherapy, definite conclusions on the role of chemotherapy on cognitive function can often not be drawn due to methodological problems. On the basis of the studies on cognitive functioning after chemotherapy that are conducted in The Netherlands Cancer Institute, the current article describes a number of such methodological topics that obscure straightforward interpretation of neuropsychological findings in toxicity research. Measurement issues that diverge from usual assessment issues encountered in psychosocial oncology will be described, and factors that might play a role in the cause of cognitive impairment will be evaluated. Also, future developments necessary to gain more insight into the prevalence, the pattern, and the impact of cognitive problems following chemotherapy are discussed

bulletDepartment of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam.
Freeman JR, Broshek DK.
Assessing cognitive dysfunction in breast cancer: what are the tools?

Clin Breast Cancer. 2002 Dec;3 Suppl 3:S91-9.
PMID: 12533269 [PubMed – indexed for MEDLINE]

The goal of adjuvant chemotherapy in the treatment of breast cancer is to reduce recurrence and mortality. With respect to quality of life and morbidity, however, such treatments come at a cost. Decreased cognitive functioning, development of fatigue, and mood alterations are common during chemotherapy and persist after its conclusion as evidenced by subjective self-reports and objective neurocognitive performance records. Few efforts, however, have used standardized neuropsychological measures, and no study has empirically selected those measures that best distinguish women in active chemotherapy from those who have previously completed it. Perhaps the most glaring deficit in the literature is that no study has used baseline data to track individual neurocognitive changes across treatment phases and after completion. This article provides an overview of the field of neuropsychology and the cognitive domains theorized to be affected by chemotherapy and the measures typically used, including validated computerized tests, which are tools for future studies; briefly summarizes existing research on the cognitive effects that chemotherapy has on breast cancer patients; compares data resulting from an ongoing pilot study of the cognitive performance of women actively undergoing anthracycline-containing chemotherapy with that of women 6-12 months post chemotherapy completion; and provides a preliminary analysis of the relationship between cognitive and emotional functioning. Future uses of these data to refine the ideal tools that efficiently, accurately, and validly detect short-term and persistent chemotherapy effects are proposed.

bulletDepartment of Psychiatric Medicine, University of Virginia School of Medicine, Charlottesville, USA.
Ahles TA, Saykin AJ.
Breast cancer chemotherapy-related cognitive dysfunction.

Clin Breast Cancer. 2002 Dec;3 Suppl 3:S84-90. Review.
PMID: 12533268 [PubMed – indexed for MEDLINE]

Cognitive side effects of systemic chemotherapy have become an increasing concern among breast cancer survivors, their families, and health care professionals. A growing body of research supports the hypothesis that chemotherapy can produce long-term cognitive changes in at least a subgroup of cancer survivors. We review evidence implicating systemic chemotherapy as the cause of cognitive changes; describe the limitations due to lack of longitudinal studies and gaps in knowledge (ie, no clear mechanism by which chemotherapy can produce cognitive changes has been proposed); discuss possible factors like age, intelligence quotient/education, and psychological, genetic, and hormonal factors that might increase risk for chemotherapy-induced cognitive changes; and outline future directions for research. Such future research includes large-scale, longitudinal studies of pretreatment neuropsychological assessments, use of imaging techniques and the development of animal models to study the mechanisms of chemotherapy-induced changes in cognitive functioning, and the development of interventions to prevent or reduce the negative cognitive effects of chemotherapy

bullet1 Department of Psychiatry and Center for Psycho-Oncology Research, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.

Schagen SB, Muller MJ, Boogerd W, Rosenbrand RM, van Rhijn D, Rodenhuis S, van Dam FS.
Late effects of adjuvant chemotherapy on cognitive function: a follow-up study in breast cancer patients.

Ann Oncol. 2002 Sep;13(9):1387-97.
PMID: 12196364 [PubMed – indexed for MEDLINE]

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.

bulletDepartment of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
Harder H, Cornelissen JJ, Van Gool AR, Duivenvoorden HJ, Eijkenboom WM, van den Bent MJ.
Cognitive functioning and quality of life in long-term adult survivors of bone marrow transplantation.

Cancer. 2002 Jul 1;95(1):183-92.
PMID: 12115332 [PubMed – indexed for MEDLINE]

BACKGROUND: The late neurotoxic effects of bone marrow transplantation (BMT) on cognitive functioning and quality of life (QOL) were investigated in a consecutively treated cohort of long-term adult survivors. METHODS: Progression-free patients treated with BMT or peripheral stem cell grafts for a hematologic malignancy at least 2 years before study participation were examined with a comprehensive battery of neuropsychological tests and questionnaires for QOL and mood states. The results of the neuropsychological tests were compared with healthy population norms. RESULTS: Forty patients were included, 87.5% of whom had undergone an allogeneic transplantation. All received total body irradiation up to 12 Gy (in two fractions). Assessment took place 22-82 months after BMT. Mild to moderate cognitive impairment was found in 24 patients (60%). Compared with healthy population norms, selective attention and executive function, information processing speed, verbal learning, and verbal and visual memory were most likely to be affected. The mean score for the total patient group revealed that these patients scored significantly lower on the information processing speed task compared with expected scores obtained from the normal population. The main predictors for poor neuropsychological performance were fatigue, global health, and educational level. Other correlations with moderate to severe cognitive impairment were subjective cognitive complaints, physical functioning, social functioning, overall mood states, and employment status. CONCLUSIONS: These data indicate that BMT may lead to cognitive complaints and late cognitive deficits in long-term adult survivors. Cognitive functioning should therefore be used as an outcome parameter in BMT studies. Copyright 2002 American Cancer Society.

bulletDepartment of Neuro-Oncology, University Hospital Rotterdam/Daniel den Hoed Cancer Center, Rotterdam, The Netherlands.

Kingma A, Van Dommelen RI, Mooyaart EL, Wilmink JT, Deelman BG, Kamps WA.
No major cognitive impairment in young children with acute lymphoblastic leukemia using chemotherapy only: a prospective longitudinal study.

J Pediatr Hematol Oncol. 2002 Feb;24(2):106-14.
PMID: 11990695 [PubMed – indexed for MEDLINE]

PURPOSE: To study, using serial neuropsychological assessment and evaluation of school achievement, persistent neuropsychological late effects in children treated for acute lymphoblastic leukemia (ALL) at a young age with chemotherapy only. PATIENTS AND METHODS: Twenty consecutive patients underwent three evaluations, including 12 psychometric measures beside IQ. The authors applied strict methodology and a prospective-longitudinal design that started at diagnosis and extended to a median follow-up of 7 years. This report focuses on the outcome of the last evaluation. Test results were compared with healthy controls and to patients with ALL treated on a previous chemotherapy-only protocol. School achievement was evaluated in patients and their siblings. RESULTS: At the last evaluation, significantly lower test scores in patients compared with controls were found for only 2 of 14 cognitive measures (1 intelligence and 1 attention measure). No great differences were seen between school achievement of patients and siblings. Compared with the previous chemotherapy protocol, a better outcome was seen in the current study group on two measures (one memory and one attention measure). CONCLUSIONS: Children surviving ALL have no major cognitive impairment after chemotherapy, including intrathecal and high-dose intravenous methotrexate. The slightly better outcome in the current group may indicate possible adverse effects of more dexamethasone treatment in the previous group.

bulletDepartment of Pediatrics, University Hospital Groningen, The Netherlands.

Ahles TA, Saykin AJ, Furstenberg CT, Cole B, Mott LA, Skalla K, Whedon MB, Bivens S, Mitchell T, Greenberg ER, Silberfarb PM.
Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma.

J Clin Oncol. 2002 Jan 15;20(2):485-93.
PMID: 11786578 [PubMed – indexed for MEDLINE]

PURPOSE: The primary purpose of this study was to compare the neuropsychologic functioning of long-term survivors of breast cancer and lymphoma who had been treated with standard-dose systemic chemotherapy or local therapy only. PATIENTS AND METHODS: Long-term survivors (5 years postdiagnosis, not presently receiving cancer treatment, and disease-free) of breast cancer or lymphoma who had been treated with systemic chemotherapy (breast cancer: n = 35, age, 59.1 +/- 10.7 years; lymphoma: n = 36, age, 55.9 +/- 12.1 years) or local therapy only (breast cancer: n = 35, age, 60.6 +/- 10.5 years; lymphoma: n = 22, age, 48.7 +/- 11.7 years) completed a battery of neuropsychologic and psychologic tests (Center for Epidemiological Study-Depression, Spielberger State-Trait Anxiety Inventory, and Fatigue Symptom Inventory). RESULTS: Multivariate analysis of variance, controlling for age and education, revealed that survivors who had been treated with systemic chemotherapy scored significantly lower on the battery of neuropsychologic tests compared with those treated with local therapy only (P <.04), particularly in the domains of verbal memory (P <.01) and psychomotor functioning (P <.03). Survivors treated with systemic chemotherapy were also more likely to score in the lower quartile on the Neuropsychological Performance Index (39% v 14%, P <.01) and to self-report greater problems with working memory on the Squire Memory Self-Rating Questionnaire (P <.02). CONCLUSION: Data from this study support the hypothesis that systemic chemotherapy can have a negative impact on cognitive functioning as measured by standardized neuropsychologic tests and self-report of memory changes. However, analysis of the Neuropsychological Performance Index suggests that only a subgroup of survivors may experience long-term cognitive deficits associated with systemic chemotherapy.

bullet1 Department of Psychiatry and Center for Psycho-Oncology Research, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.