CANCER / CA THERAPY NEUROPSYCH EFFECTS

Gray matter reduction on voxel-based morphemetry in chemotherapy –treated cancer survivors.

Saykin AJ, Ahles TA, Schoenfeld JD, Wishart HA, Petras CG, Furstenburg cT, McDonald BC, McAllister TW, & Mamourian AC.; saykin@dartmouth.edu

Journal of the International Neuropsychological Society, in press.

J Neuropsychiatry Clin Neurosci 16:185-191, May 2004

Cognitive Dysfunction and Depression During Treatment With Interferon-Alpha and Chemotherapy

Randall S. Scheibel, Ph.D., Alan D. Valentine, M.D., Susan O'Brien, M.D. and Christina A. Meyers, Ph.D.; cameyers@mail.mdanderson.org (E-mail).

Trials with interferon-alpha (IFN-) have provided contradictory findings regarding the presence of cognitive side effects. The development of depression in some patients also raises questions about whether cognitive dysfunction might be secondary to an organic, interferon-induced mood disorder. Thirty patients with chronic myelogenous leukemia were examined before and during treatment with IFN- alone or IFN- and chemotherapy. Increased depressive symptoms and declines in information processing and executive functions were observed, but depression alone could not account for cognitive dysfunction. There was some evidence suggesting that exposure to chemotherapy and higher cumulative IFN- dose may contribute to cognitive impairment.

A Critical Review of the Clinical Effects of Therapeutic Irradiation Damage to the Brain: The Roots of Controversy

Neuropsychology Review March 2004, vol. 14, no. 1, pp. 65-86(22)

Armstrong CL; Gyato K; Awadalla AW; Lustig R; Tochner ZA

We critically examined the damaging affects of therapeutic irradiation by comparing results from cross-disciplinary studies of early- and late-delayed radiotherapy effects. Focus is attained by concentrating on clinical treatment issues (volume of brain, dose, timing of effects, age, modality types, and stereotactic treatment techniques), rather than on methodological means or problems, which is necessary to understand the mechanisms and characteristics of radiotherapy-induced behavioral dysfunction including cognition. We make observations and hypotheses about the actual risks from radiotherapy that could be informative in the treatment decision process, and which may lessen the concerns of some patients and their families about the risks they take when receiving radiation. Conditions that predispose to radiation injury are reviewed: (1) higher doses even to part of the brain versus lower doses to the whole brain, (2) combined treatment modalities, (3) malignancy itself, (4) radiation early during postnatal brain development, and (5) late-delayed effects (more than 3 years posttreatment). Current neurocognitive frameworks for understanding cognitive change over time in children and adults are summarized, along with the literature on effects of brain tumors and treatment on depression. No studies have as yet identified candidate brain regions that are more sensitive to radiotherapy. Two studies have provided early, preliminary evidence for a specific vulnerability of visual attention/memory to the early stage of late radiation damage. Furthermore, radiation effects appear severe only in a minority of patients. Risk is related to direct and indirect effects of cancer type, concurrent clinical factors, and premorbid risk factors.

[Attention Process Training application within an intervention project on attentional processes in children with cancer]

Bernabeu Verdu J, Lopez Luengo B, Fournier Del Castillo C, Canete Nieto A, Suarez Rodriguez J, Castel Sanchez V.

Rev Neurol. 2004 Mar 1-15;38(5):482-7. [Article in Spanish]

Universidad de Valencia. Facultad de Psicologia, Valencia, España.

INTRODUCTION. Childhood cancer treatments have made a spectacular advance in recent years, obtaining survival rates of about 70%. These survival rates have permitted many children to reach adulthood, but also involve the appearance of previously unknown neurocognitive sequelae because of high mortality. DEVELOPMENT. Neuropsychological evaluation allows the detection of these deficits and the design of intervention. In children, rather than a loss of function there is a loss of the capacities that should develop in comparison with his/her peers. To obtain a base line to determine the affected and altered areas, it is equally vital to assess the acute and long term effects so as to evaluate the success of the intervention program. Attention Process Training (APT) is an individualized application program of attentional exercises of varying complexity in sustained, selective, alternating and divided attention. This program combines methods and techniques of cerebral damage rehabilitation, as well as educational and clinical psychology. It is completed with a self instruction training which is applied in situations of daily life. CONCLUSIONS. Child cancer treatment continues to carry long term neurocognitive sequelae. Neuropsychological evaluation is basic for its detection, allowing relevant information to be offered to parents and teachers, so as to facilitate design of individualized rehabilitation procedures. Attention training is basic for this type of population with generalized damage related to white matter, and forms part of a wider rehabilitation process that enhance the ecological validity of the program.

Cognitive status and quality of life after treatment for primary CNS lymphoma.

Harder H, Holtel H, Bromberg JE, Poortmans P, Haaxma-Reiche H, Kluin-Nelemans HC, Menten J, van den Bent MJ. h.harder@erasmusmc.nl

Neurology. 2004 Feb 24;62(4):544-7.

OBJECTIVE: To evaluate the cognitive status and quality of life (QOL) in a cohort of 19 consecutive patients treated in a prospective European Organization for Research and Treatment of Cancer study (20962) for primary CNS lymphoma (PCNSL). All patients were in complete remission after combined modality treatment with IV and intrathecal high-dose methotrexate (MTX)-based chemotherapy followed by whole brain radiotherapy (WBRT). METHODS: An extensive neuropsychological assessment, including QOL measures, was conducted in 19 patients with PCNSL. The results were compared with matched control subjects with systemic hematologic malignancies treated with systemic chemotherapy or non-CNS radiotherapy. In addition, a neuroradiologic evaluation was carried out in 18 patients with PCNSL. RESULTS: Cognitive impairment was found in 12 patients with PCNSL (63%) despite a complete tumor response. Four patients (21%) showed severe cognitive deficits, and the percentage of impaired test indices correlated with age. In comparison, only two control subjects (11%) showed cognitive dysfunction (p = 0.002). Forty-two percent of the patients with PCNSL, in contrast to 81% of the control subjects, resumed work. White matter abnormalities were observed in 14 patients with PCNSL, and 14 had cortical atrophy. Cortical atrophy correlated with cognitive functioning, age, and Karnofsky performance score. Group differences in cognitive status and QOL could not be explained by anxiety, depression, or fatigue. CONCLUSIONS: Combined modality treatment for primary CNS lymphoma is associated with cognitive impairment even in patients aged <60 years.

Does hormone therapy for the treatment of breast cancer have a detrimental effect on memory and cognition? A pilot study.

Jenkins V, Shilling V, Fallowfield L, Howell A, Hutton S. v.jenkins@biols.susx.ac.uk

Psychooncology. 2004 Jan;13(1):61-6.

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.

Estrogen- and tamoxifen-associated effects on brain structure and function.

Eberling JL, Wu C, Tong-Turnbeaugh R, Jagust WJ. jleberling@lbl.gov

Neuroimage. 2004 Jan;21(1):364-71.

We evaluated the effects of estrogen and tamoxifen, a selective estrogen receptor modulator, on positron emission tomography (PET) measures of brain glucose metabolism and magnetic resonance imaging (MRI) measures of hippocampal atrophy. Three groups of postmenopausal women were studied, women taking estrogen (ERT+), women with breast cancer taking tamoxifen (TAM), and women not taking estrogen or tamoxifen (ERT-). All subjects received a PET scan, an MRI scan, and cognitive testing. The TAM group showed widespread areas of hypometabolism in the inferior and dorsal lateral frontal lobes relative to the other two groups. The ERT- group showed lower metabolism in the inferior frontal cortex and temporal cortex with respect to the ERT+ group. The TAM group also showed significantly lower semantic memory scores than the other two groups. Finally, the TAM group had smaller right hippocampal volumes than the ERT+ group, an effect that was of borderline significance. Both right and left hippocampal volumes were significantly smaller than the ERT+ group when a single outlier was removed. The ERT- group had hippocampal volumes that were intermediate to the other two groups. These findings provide physiological and anatomical evidence for neuroprotective effects of estrogen.

Cognitive dysfunction and subjective complaints of cancer patients. a cross-sectional study in a cancer rehabilitation centre.

Poppelreuter M, Weis J, Kulz AK, Tucha O, Lange KW, Bartsch HH. poppelreuter@tumorbio.uni-freiburg.de

Eur J Cancer. 2004 Jan;40(1):43-9.

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

Cognitive function, fatigue, and menopausal symptoms in women receiving adjuvant chemotherapy for breast cancer.

Tchen N, Juffs HG, Downie FP, Yi QL, Hu H, Chemerynsky I, Clemons M, Crump M, Goss PE, Warr D, Tweedale ME, Tannock IF.

J Clin Oncol. 2003 Nov 15;21(22):4175-83.

PURPOSE: There is evidence that cognitive dysfunction, fatigue, and menopausal symptoms may occur in women receiving adjuvant chemotherapy for breast cancer. Here, we determine their incidence and severity, and interrelationships between them and quality of life. PATIENTS AND METHODS: In this study, 110 women receiving adjuvant chemotherapy each nominated a female relative, friend, or neighbor (matched by age) as a control; 100 eligible matched pairs were evaluated. Patients and controls completed the following assessments: the High-Sensitivity Cognitive Screen, and the Functional Assessment of Cancer Therapy-General (FACT-G) quality of life scale with subscales for fatigue (FACT-F) and endocrine symptoms (FACT-ES). They also performed tests of attention and reaction time. RESULTS: Patients and controls were well matched for age and level of education. There was a higher incidence of moderate or severe cognitive impairment in the patient group (16% v 4%; P =.008). Patients experienced much more fatigue than controls (median FACT-F scores, 31 v 46; P <.0001) and more menopausal symptoms (median FACT-ES scores, 58 v 64; P <.0001). Self-reported quality of life of the patients was poorer than for controls, especially in physical and functional domains (median FACT-G scores, 77 v 93; P <.0001). There was strong correlation between fatigue, menopausal symptoms, and quality of life (P <.0001 for each pair), but none were significantly associated with the presence of cognitive dysfunction. CONCLUSION: Adjuvant chemotherapy causes cognitive dysfunction, fatigue, and menopausal symptoms in women with breast cancer. Priority should be given to the study of strategies that might reduce these toxic effects.

Neuropsychological functioning following systemic treatment in women treated for breast cancer: a review.

Morse R, Rodgers J, Verrill M, Kendell K.

Eur J Cancer. 2003 Nov;39(16):2288-97.

The aim of this review was to evaluate the effect of treatment and illness-related factors on neuropsychological functioning in women treated for breast cancer. Eight studies were identified examining neuropsychological test performance following systemic treatment. Six of the eight studies suggest that neuropsychological functioning may be impaired following treatment. However, there are a number of important methodological issues which limit interpretation of these results. Therefore, it is unclear whether neuropsychological outcome differs according to a range of treatment, biomedical and psychological factors. Larger samples with longitudinal follow-up are required in order to examine the treatment-related factors that best predict cognitive deficits.

Mechanisms of chemotherapy-induced cognitive disorders: neuropsychological, pathophysiological, and neuroimaging perspectives.

Saykin AJ, Ahles TA, McDonald BC.; saykin@dartmouth.edu

Seminars in Clinical Neuropsychiatry. 8 (4): 201-16.
Recent studies have indicated the frequent occurrence of neuropsychologic deficits and cognitive complaints after systemic cancer chemotherapy. Most early reports were retrospective, but prospective longitudinal studies are underway. Although the available evidence suggests a fairly diffuse pattern of changes, memory and executive functions could be preferentially affected. Preliminary data also suggest that some individuals might be more vulnerable than others, leading to investigation of genetic and other risk factors. The greatest gap in our knowledge regarding chemotherapy-related cognitive changes is a lack of understanding of the mechanism or mechanisms that account for the observed changes. Several pathophysiological candidates include direct neurotoxic effects leading to atrophy of cerebral gray matter (GM) and/or demyelination of white matter (WM) fibers, secondary immunologic responses causing inflammatory reactions, and microvascular injury. Altered neurotransmitter levels and metabolites could constitute an additional mechanism related to neurotoxic effects. Advanced brain imaging techniques can directly or indirectly assess many of these mechanisms, but to date there has been very limited application of these tools. Morphometric magnetic resonance imaging (MRI), functional MRI (fMRI), diffusion tensor imaging (DTI), and MR spectroscopy (MRS) are noninvasive techniques that could yield important complementary data regarding the nature of neural changes after chemotherapy. Electrophysiological studies and targeted molecular imaging with positron emission tomography (PET) could also provide unique information. We review the minimal imaging data available at present and also note studies of other brain disorders or treatment effects that might serve as a model for imaging chemotherapy-induced changes. Large-scale prospective studies are needed to help isolate the pathophysiological mechanisms underlying the cognitive deficits associated with chemotherapy.

The relationship of APOE genotype to neuropsychological performance in long-term cancer survivors treated with standard dose chemotherapy.

Ahles TA, Saykin AJ, Noll WW, Furstenberg CT, Guerin S, Cole B, Mott LA.; tim.a.ahles@dartmouth.edu

Psychooncology. 2003 Sep;12(6):612-9

PURPOSE: The primary purpose of this study was to compare the neuropsychological performance of long-term survivors of breast cancer and lymphoma treated with standard dose chemotherapy who carried the epsilon 4 allele of the Apolipoprotein E (APOE) gene to those who carry other APOE alleles. PATIENTS AND METHODS: Long-term survivors (mean=8.8+/-4.3 years post-treatment) of breast cancer (N=51, age=55.9+/-8.8) or lymphoma (N=29, age=55.8+/-11.6) who had been treated with standard-dose chemotherapy completed a standardized battery of neuropsychological and psychological tests. Survivors were also classified into two groups based on the presence (N=17) or absence (N=63) of at least one epsilon 4 allele of APOE. RESULTS: Analysis of covariance, controlling for age, gender, education, diagnosis, and WRAT-3 reading subtest (a proxy measure of baseline IQ), indicated that survivors with at least one epsilon 4 allele scored significantly lower in the visual memory (p<0.03) and the spatial ability (p<0.05) domains and tended to score lower in the psychomotor functioning (p<0.08) domain as compared to survivors who did not carry an epsilon 4 allele. No group differences were found on depression, anxiety, or fatigue. CONCLUSIONS: The results of this study provide preliminary support for the hypothesis that the epsilon 4 allele of APOE may be a potential genetic marker for increased vulnerability to chemotherapy-induced cognitive decline.

The impact of adjuvant therapy for breast cancer on cognitive function: current evidence and directions for research.

Rugo HS, Ahles T.

Semin Oncol. 2003 Dec;30(6):749-62

Available evidence supports the hypothesis that adjuvant chemotherapy for breast cancer can produce cognitive deficits, and that these deficits may have a significant impact on patients' quality of life. Studies have generally compared the results of a variety of cognitive measures performed following treatment to standardized population-based norms or to cancer patients who received local therapy, rather than to the individual's baseline level of functioning. Several longitudinal studies are in progress or in the planning stages to better quantify and understand the incidence and impact of cognitive effects of adjuvant chemotherapy, and to identify possible susceptibility factors in subgroups. Although the neurocognitive changes appear to be subtle, there may be enough data to consider discussing the possibility of cognitive dysfunction as an adverse effect when assessing the risks and benefits of adjuvant chemotherapy. Likewise, as the aromatase inhibitors are increasingly given to larger numbers of women in the adjuvant setting, it will be important to understand the cognitive impact of estrogen deprivation. Finally, there is interest in examining supportive pharmacologic or behavioral measures that might prevent or decrease cognitive effects in this setting. Herein, the data on cognitive changes associated with chemotherapy for breast cancer, current and future research directions, as well as possible treatments are reviewed.

Neuropsychological effects of treatments for adults with cancer: a meta-analysis and review of the literature.

Anderson-Hanley C, Sherman ML, Riggs R, Agocha VB, Compas BE. chanley@skidmore.edu

J Int Neuropsychol Soc. 2003 Nov;9(7):967-82.

A meta-analysis was conducted to evaluate possible neuropsychological effects of treatments for cancer in adults. A search revealed 30 studies, encompassing 29 eligible samples, and leading to inclusion of a total of 838 patients and control participants. A total of 173 effect sizes (Cohen's d) were extracted across 7 cognitive domains and as assessed in the literature via 3 methods of comparison (post-treatment compared with normative data, controls, or baseline performance). Statistically significant negative effect sizes were found consistently across both normative and control methods of comparison for executive function, verbal memory, and motor function. The largest effects were for executive function and verbal memory normative comparisons (-.93 and -.91, respectively). When limiting the sample of studies in the analyses to only those with relatively "less severe" diagnoses and treatments, the effects remained. While these results point toward some specific cognitive effects of systemic cancer therapies in general, no clear clinical implications can yet be drawn from these results. More research is needed to clarify which treatments may produce cognitive decrements, the size of those effects, and their duration, while ruling out a wide variety of possible mediating or moderating variables.

Neuropsychologic impact of standard-dose systemic chemotherapy in long-term survivors of breast cancer and lymphoma.

Ahles TA, Saykin AJ, Furstenberg CT, Cole B, Mott LA, Skalla K, Whedon MB, Bivens S, Mitchell T, Greenberg ER, Silberfarb PM.; Tim.A.Ahles@dartmouth.edu

J Clin Oncol. 2002 Jan 15;20(2):485-93.

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.

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

Schagen SB, Muller MJ, Boogerd W, Rosenbrand RM, van Rhijn D, Rodenhuis S, van Dam FS.

Ann Oncol. 2002 Sep;13(9):1387-97.

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.

Effects of epoetin alfa on cognitive function, mood, asthenia, and quality of life in women with breast cancer undergoing adjuvant chemotherapy.

O'Shaughnessy JA. Joyce.O'Shaughnessy@USOncology.com

Clin Breast Cancer. 2002 Dec;3 Suppl 3:S116-20

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.

Assessing cognitive dysfunction in breast cancer: what are the tools?

Freeman JR, Broshek DK; jf4z@virginia.edu

Clin Breast Cancer. 2002 Dec;3 Suppl 3:S91-9.

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.

Cognitive effects of standard-dose chemotherapy in patients with cancer.

Ahles TA, Saykin A.

Cancer Invest. 2001;19(8):812-20.

Adult cancer survivors have reported experiencing persistent changes in cognitive function following treatment with chemotherapy. Increasing evidence supports the hypothesis that standard-dose chemotherapy can produce cognitive deficits in a subgroup of adult cancer survivors. Although these cognitive changes tend to be subtle deficits in memory, concentration, and the ability to remain focused or organized, these alterations in cognitive ability can have a significant impact on patients' quality of life generally, and on meeting career and educational goals specifically. This manuscript reviews the literature relevant to the cognitive impact of standard-dose chemotherapy in adults, outlines methodological issues related to the study of cognitive functioning in people with cancer, and discusses future directions for research in this area.

Radiotherapeutic effects on brain function: double dissociation of memory systems.

Armstrong CL, Corn BW, Ruffer JE, Pruitt AA, Mollman JE, Phillips PC. armstrong@email.chop.edu

Neuropsychiatry Neuropsychol Behav Neurol. 2000 Apr;13(2):101-11

OBJECTIVE: The neurocognitive sequelae of therapeutic cranial irradiation are not well characterized in adults with primary brain tumors. To address this problem, we prospectively examined neuropsychological findings during two phases of radiation effects. BACKGROUND: Investigations of radiation effects have revealed variable outcomes that range from no radiation-associated morbidity to severe cognitive impairment, but have relied on case reports or retrospective studies of late-delayed changes in white matter or in cognition. No reliable radiographic or neurocognitive tools exist to describe the multiple phases of radiation effects. METHOD: Twenty adult patients (median age, 39 years) from a university hospital were treated with radiotherapy (RT) for low-grade primary brain tumors. Prospective longitudinal neuropsychological studies were compared at baseline (after surgery and before irradiation) and at 3, 6, and 12 months after RT to examine early-delayed effects, including verbal memory changes in 20 patients and visual memory changes in 11 patients. We also examined cognitive changes during the late-delayed phase for up to 3 years after RT and determined whether early-delayed memory deficit predicted late-delayed memory deficit in a small subset of patients. A comprehensive neuropsychological battery was used, including verbal and visual memory tests designed to compare learning, storage, and retrieval. RESULTS: Patients demonstrated normal verbal memory at baseline, decrement, and then rebound in verbal retrieval. Deficit at baseline and recovery up to 1 year after RT defined visual memory. Together, these observations constitute a double dissociation of memory functions. No changes over time were observed in other neurocognitive tests or in fatigue or mood measures. Time-dependent patterns of each long-term memory test were examined in relation to lesion site in individual patients. CONCLUSIONS: The double dissociation of memory functions after RT may provide markers for the damaging and facilitative early-delayed effects of RT. Late-delayed effects were not predicted based on early-delayed changes in a small sample.

Neurocognitive Dysfunction in Cancer Patients

Matthew M. Clark, PhD, Teresa A. Rummans, MD, Andrew J. Saykin, PsyD, Tim AAhles, PhD,

Oncology Vol 14, No 1 (January 2000)

Many cancer patients experience impairments of neurocognitive function, including memory loss, distractibility, difficulty in performing multiple tasks (multitasking), and a myriad of other symptoms. Patients may also concurrently suffer from mood disturbance and symptoms that compromise their ability to function adequately, including fatigue and pain. The etiologies of these problems are diverse and include the direct effects of cancer within the central nervous system (CNS), indirect effects of certain cancers (eg, paraneoplastic brain disorders), and both diffuse and highly specific effects of cancer treatments on the brain. In addition to these cancer-related causes, patients may have coexisting neurologic or psychiatric disorders that affect their cognition and mood. Careful assessment of patients complaining of neurocognitive or behavioral problems is essential to providing appropriate interventions and maximizing their ability to carry out usual activities.

Impairment of cognitive function in women receiving adjuvant treatment for high risk breast cancer: High dose versus standard dose chemotherapy.

van Dam FSA M, Schagen SB Muller et al. (1998)

Journal of the National Cancer Institute, 1998, 90, 210-218.
“** One of the first controlled studies assessing cognitive function of breast cancer survivors treated with chemotherapy compared with breast cancer survivors treated with local therapy (surgery, local radiation). IQ, age, time since treatment, and affective variables (depression and anxiety) were controlled for. Individuals treated with chemotherapy were found to have lower neuropsychological performance.”

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

Schagen SB, Hamburger HL, Muller MJ, Boogerd W, van Dam FS.

J Neurooncol. 2001 Jan;51(2):159-65.

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.

(“** Another study assessing the neurocognitive effects of chemotherapy among cancer survivors as compared to matched controls (i.e., cancer survivors treated with local therapies such as and surgery and radiation. Chemotherapy recipients had lower performance on standardized neuropsychological tests.”

Neurocognitive dysfunction in cancer patients.

Meyers CA.

Oncology, 2000, 14, 75-79.
(1):75-9; discussion 79, 81-2, 85.

Meyers CA.

Many cancer patients experience impairments of neurocognitive function, including memory loss, distractibility, difficulty in performing multiple tasks (multitasking), and a myriad of other symptoms. Patients may also concurrently suffer from mood disturbance and symptoms that compromise their ability to function adequately, including fatigue and pain. The etiologies of these problems are diverse and include the direct effects of cancer within the central nervous system (CNS), indirect effects of certain cancers (e.g., paraneoplastic brain disorders), and both diffuse and highly specific effects of cancer treatments on the brain. In addition to these cancer-related causes, patients may have coexisting neurologic or psychiatric disorders that affect their cognition and mood. Careful assessment of patients complaining of neurocognitive or behavioral problems is essential to providing appropriate interventions and maximizing their ability to carry out usual activities.

Cognitive function after systemic therapy for breast cancer.

Olin JJ.

Oncology, 2001, 15, 613-624.
* Comprehensive review of cognitive function following systemic chemotherapy among breast cancer survivors.

Cisplatin-based therapy: A neurological and neuropsychological review.

Troy L McFarland K Littman-Power S Kelly BJ Walpole ET Wyld D Thomson D

Psychooncology 2000, 9, 29-39.
** Review of cytotoxic therapies and hypothesized mechanisms which may give rise to low neuropsychological performance among cancer patients.

Cognitive effects of standard-dose chemotherapy in patients with cancer.

Ahles TA, Saykin A.

Cancer Investigation, 2001, 19, 812-820.
* Comprehensive review of research on the neuropsychological effects of systemic chemotherapy among adult cancer survivors.

Delayed effects of therapeutic bgrain irradiation.

Stewart-amidei, C. (1995)

Neuro-Oncology, 7(1),125-133

Radiation-induced Dementia in patients cured of brain metastases.

DeAngelis, L. M., Delattre, J. Y., & Posneer, J. B. (1989).

Neurology, 39, 789-796