RESUMEN

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

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Encéfalo/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Imagen por Resonancia Magnética/métodos , Fibras Nerviosas Mielínicas/efectos de los fármacos , Fibras Nerviosas Amielínicas/efectos de los fármacos , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Encéfalo/patología , Neoplasias de la Mama/patología , Carboplatino/efectos adversos , Carboplatino/farmacología , Carboplatino/uso terapéutico , Quimioterapia Adyuvante/efectos adversos , Cognición/efectos de los fármacos , Ciclofosfamida/efectos adversos , Ciclofosfamida/farmacología , Ciclofosfamida/uso terapéutico , Femenino , Estado de Salud , Humanos , Persona de Mediana Edad , Fibras Nerviosas Mielínicas/patología , Fibras Nerviosas Amielínicas/patología , Pruebas Neuropsicológicas , Calidad de Vida , Sobrevivientes , Tiotepa/efectos adversos , Tiotepa/farmacología , Tiotepa/uso terapéutico , Factores de Tiempo

RESUMEN

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

Asunto(s)

Antineoplásicos/efectos adversos , Encéfalo/efectos de los fármacos , Neoplasias de la Mama/tratamiento farmacológico , Trastornos del Conocimiento/inducido químicamente , Cognición/efectos de los fármacos , Adulto , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Mapeo Encefálico , Bases de Datos Factuales , Función Ejecutiva/efectos de los fármacos , Femenino , Estudios de Seguimiento , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Recuerdo Mental/efectos de los fármacos , Persona de Mediana Edad , Pruebas Neuropsicológicas

RESUMEN

The Dutch parliament has recently accepted a tax law in which certain groups of alternative therapists can be exempt from VAT. To be eligible for this VAT exemption, the disciplines to which the therapists belong have to meet certain training requirements. In this article it is contended, in agreement with the Royal College of Physicians in the UK, that statutory regulation is inappropriate for disciplines whose therapies are neither of proved benefit nor appropriately tested. It legitimizes harmful therapies. This is illustrated by two serious accidents, previously described in this journal, caused by a chiropractor and a craniosacral therapist.

Asunto(s)

Terapias Complementarias/economía , Terapias Complementarias/legislación & jurisprudencia , Charlatanería/economía , Charlatanería/legislación & jurisprudencia , Impuestos , Medicina Basada en la Evidencia , Humanos , Países Bajos , Impuestos/legislación & jurisprudencia

RESUMEN

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

Asunto(s)

Androstadienos/efectos adversos , Antineoplásicos Hormonales/efectos adversos , Inhibidores de la Aromatasa/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Trastornos del Conocimiento/inducido químicamente , Moduladores Selectivos de los Receptores de Estrógeno/efectos adversos , Tamoxifeno/efectos adversos , Anciano , Anciano de 80 o más Años , Androstadienos/administración & dosificación , Antineoplásicos Hormonales/administración & dosificación , Inhibidores de la Aromatasa/administración & dosificación , Estudios de Casos y Controles , Femenino , Humanos , Persona de Mediana Edad , Países Bajos , Posmenopausia , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Moduladores Selectivos de los Receptores de Estrógeno/administración & dosificación , Tamoxifeno/administración & dosificación

RESUMEN

Methotrexate is a widely used cytostatic in chemotherapy cocktails for the treatment of cancer but is associated with cognitive impairment. Previous animal studies indicated that methorexate decreases hippocampal cell proliferation, which might contribute to the observed cognitive impairment. However, clinical studies have shown that cognitive impairment can also be noticed in some cancer patients before any systemic treatment is initiated. We aim in the present study to discern whether hippocampal cell proliferation is negatively affected by tumor growth and if the presence of a tumor amplifies the effects of methotrexate. Buffalo rats were subcutaneously injected with PBS or Morris Hepatoma 7777 cells to induce a tumor. Two weeks after this injection the animals received an intraperitoneal injection of methotrexate or saline. Three weeks later hippocampal cell proliferation was quantified using immunohistochemical staining. Treatment with Morris Hepatoma 7777 cells decreased the number of proliferating cells as compared to control animals. An overall tumor effect was absent mainly because methotrexate treatment significantly decreased cell proliferation with no differences between animals with or without a tumor. Neither methotrexate nor the tumor induced pica behavior. These findings indicate that although the presence of a tumor reduces hippocampal cell proliferation it does not affect the negative effect of methotrexate on this plasticity marker. Since sickness behavior is not induced by methotrexate or tumor presence it does not play a role in the development of cognitive deficits. This study further indicates that the effects of methotrexate on brain and behavior can be studied in healthy animals.

Asunto(s)

Antimetabolitos Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Proliferación Celular/efectos de los fármacos , Hipocampo/efectos de los fármacos , Metotrexato/farmacología , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Neoplasias Encefálicas/fisiopatología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/fisiopatología , Línea Celular Tumoral , Conducta Alimentaria/efectos de los fármacos , Conducta Alimentaria/fisiología , Hipocampo/fisiopatología , Inmunohistoquímica , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/fisiopatología , Masculino , Trasplante de Neoplasias , Pica/inducido químicamente , Pica/fisiopatología , Ratas , Ratas Endogámicas BUF

RESUMEN

OBJECTIVE: Several prospective studies into the effects of adjuvant systemic therapy on cognitive functioning suggest that a proportion of breast cancer patients show cognitive deficits already before the start of systemic therapy. Owing to, among others, methodological inconsistency, studies report different rates of this pre-treatment cognitive impairment. We examined the impact of four different criteria of cognitive impairment and two types of reference groups (a study-specific healthy reference group versus published normative data) on the prevalence of cognitive impairment. METHODS: Two hundred and five postmenopausal breast cancer patients underwent a battery of neuropsychological tests before the start of endocrine therapy, 124 healthy subjects underwent the same tests. Proportions of cognitive impaired patients were calculated for each of four criteria for cognitive impairment, using (1) study-specific healthy controls and (2) published norms of healthy controls as reference groups. RESULTS: The prevalence of cognitive impairment varied greatly with the strictness of the criterion, as expected, but also was dependent on the reference group used. Cognitive impairment, relative to published norms, ranged from 1% for the strictest to 36.6% for the less strict criterion, cognitive impairment relative to study-specific healthy controls, ranged from 13.7 to 45.4% for the same criteria. CONCLUSION: This study highlights contrasting proportions of cognitive impairment by using different criteria for cognitive impairment and different reference groups. (Dis)advantages of the methods using a criterion for cognitive impairment, and of the use of published norms versus a study-specific reference group are discussed.

Asunto(s)

Neoplasias de la Mama/psicología , Trastornos del Conocimiento/diagnóstico , Adyuvantes Farmacéuticos/efectos adversos , Adyuvantes Farmacéuticos/uso terapéutico , Factores de Edad , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Menopausia/psicología , Persona de Mediana Edad , Pruebas Neuropsicológicas/normas , Prevalencia , Valores de Referencia

RESUMEN

Methotrexate is a cytostatic drug applied in adjuvant chemotherapy and associated with cognitive impairment in part of the cancer patients. In this paper we studied in rats whether a reduction in blood supply to the brain or neuroinflammation are possible mediators of this cognitive dysfunctionality. Methotrexate reduced hippocampal blood vessel density 1 week and 3 weeks after treatment as measured immunohistochemically with an endothelial barrier antigen. Since reduced brain vascularization may relate to lowered central glucose metabolism [(18)F]FDG PET was performed. Methotrexate reduced tracer uptake in the hippocampal region 1 week after treatment, which was not seen 3 weeks after treatment. Neuroinflammatory processes were explored via a number of methods: a microglia immunohistochemical marker was applied to hippocampal sections, [(11)C]PK11195 PET was performed, and cytokine levels in plasma and homogenized hippocampal tissue were measured. Methotrexate activated microglia in the hippocampus 1 week and 3 weeks after treatment. PET analysis, however, did not show an increase in hippocampal tracer uptake and the multiplex analysis of various cytokines showed that hippocampal cytokine levels were not increased after methotrexate administration. Methotrexate did reduce plasma cytokine levels indicating a suppression of peripheral immune functioning. Methotrexate reduces hippocampal blood vessel density, indicative of a reduced brain glucose metabolism, which may contribute to the cognitive impairment following methotrexate administration. Although methotrexate activates microglia activation in the hippocampus, no effects were seen in [(11)C]PK11195 tracer uptake or hippocampal cytokine levels. This suggests that the microglial activation in this study is not a marker for neuroinflammation.

Asunto(s)

Antimetabolitos Antineoplásicos/farmacología , Vasos Sanguíneos/efectos de los fármacos , Citocinas/metabolismo , Hipocampo/efectos de los fármacos , Metotrexato/farmacología , Microglía/efectos de los fármacos , Animales , Citocinas/sangre , Glucosa/metabolismo , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Inmunohistoquímica , Masculino , Microglía/fisiología , Tomografía de Emisión de Positrones , Ratas , Ratas Wistar , Factores de Tiempo

RESUMEN

Methotrexate (MTX) is a cytostatic agent used in adjuvant chemotherapy for treatment of breast cancer and is associated with cognitive impairment in a subgroup of patients. The aim of this paper is to test whether MTX can rapidly affect various brain structures resulting in decreased hippocampal cell proliferation and white matter damage. We also studied whether cell death occurs in the hippocampus following MTX. All these processes may contribute to the memory deficits reported in patients. The first study explored the effect of an intravenously injected high-dose MTX (250 mg/kg) on hippocampal cell proliferation, white matter, and cell death. Proliferation was not significantly decreased 1 day after administration of MTX, although a high individual variation was seen. However, 7 days after MTX treatment hippocampal cell proliferation was significantly lower compared to control animals. White matter density was decreased in the lateral corpus callosum of animals treated with MTX, 1 day, 1 week, and 3 weeks after treatment. MTX did not induce hippocampal cell death at any of the time intervals after treatment. The second study examined the effect of MTX on memory by subjecting animals to a learning task directly followed with MTX treatment. In both learning tasks, memory was impaired in treated animals. In the Morris water maze, animals treated with MTX spent significantly less time in the correct quadrant compared to control animals during the probe trial which was performed 1 week after training and treatment. In contextual fear conditioning, animals treated with MTX showed significantly less freezing behavior compared to control animals, 4 weeks after training and treatment. These studies suggest that the negative effect of MTX on hippocampal cell proliferation and white matter density may be part of the mechanisms underlying the cognitive impairment observed as side effect after cytotoxic treatment in humans.

Asunto(s)

Antimetabolitos Antineoplásicos/farmacología , Trastornos del Conocimiento/inducido químicamente , Condicionamiento Clásico/efectos de los fármacos , Hipocampo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Metotrexato/farmacología , Análisis de Varianza , Animales , Aprendizaje por Asociación/fisiología , Muerte Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Miedo , Estudios de Seguimiento , Hipocampo/citología , Ratas , Ratas Wistar , Factores de Tiempo

RESUMEN

OBJECTIVES: Constructive Technology Assessment (CTA) is a means to guide early implementation of new developments in society, and can be used as an evaluation tool for Coverage with Evidence Development (CED). We used CTA for the introduction of a new diagnostic test in the Netherlands, the 70-gene prognosis signature (MammaPrint) for node-negative breast cancer patients. METHODS: Studied aspects were (organizational) efficiency, patient-centeredness and diffusion scenarios. Pre-post structured surveys were conducted in fifteen community hospitals concerning changes in logistics and teamwork as a consequence of the introduction of the 70-gene signature. Patient-centeredness was measured by questionnaires and interviews regarding knowledge and psychological impact of the test. Diffusion scenarios, which are commonly applied in industry to anticipate on future development and diffusion of their products, have been applied in this study. RESULTS: Median implementation-time of the 70-gene signature was 1.2 months. Most changes were seen in pathology processes and adjuvant treatment decisions. Physicians valued the addition of the 70-gene signature information as beneficial for patient management. Patient-centeredness (n = 77, response 78 percent): patients receiving a concordant high-risk and discordant clinical low/high risk-signature showed significantly more negative emotions with respect to receiving both test-results compared with concordant low-risk and discordant clinical high/low risk-signature patients. The first scenario was written in 2004 before the introduction of the 70-gene signature and identified hypothetical developments that could influence diffusion; especially the "what-if" deviation describing a discussion on validity among physicians proved to be realistic. CONCLUSIONS: Differences in speed of implementation and influenced treatment decisions were seen. Impact on patients seems especially related to discordance and its successive communication. In the future, scenario drafting will lead to input for model-based cost-effectiveness analysis. Finally, CTA can be useful as a tool to guide CED by adding monitoring and anticipation on possible developments during early implementation, to the assessment of promising new technologies.

Asunto(s)

Tecnología Biomédica/economía , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Evaluación de la Tecnología Biomédica/economía , Neoplasias de la Mama/fisiopatología , Difusión de Innovaciones , Eficiencia Organizacional , Femenino , Humanos , Países Bajos , Atención Dirigida al Paciente , Pronóstico

RESUMEN

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

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/psicología , Trastornos del Conocimiento/inducido químicamente , Anciano , Androstadienos/administración & dosificación , Androstadienos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ansiedad/inducido químicamente , Ansiedad/etiología , Quimioterapia Adyuvante , Cognición/efectos de los fármacos , Estudios Transversales , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Depresión/inducido químicamente , Depresión/etiología , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Fatiga/inducido químicamente , Fatiga/etiología , Femenino , Humanos , Persona de Mediana Edad , Posmenopausia , Estudios Prospectivos , Calidad de Vida , Tamoxifeno/administración & dosificación , Tamoxifeno/efectos adversos

RESUMEN

OBJECTIVE: Many cancer patients report cognitive changes following chemotherapy. In social psychology, there is ample evidence that psychological and physical complaints can increase with increased accessibility of relevant schemata. The accessibility of related concepts in memory may be facilitated through priming or by pre-existing knowledge, resulting in an increase of reported complaints. We examined whether pre-existing knowledge of chemotherapy-associated cognitive problems and priming the 'chemo-brain' schema increase the reporting of cognitive complaints. METHODS: Two hundred and sixty-one breast cancer patients were interviewed about cognitive problems and other cancer-related symptoms. Preceding the interview, half of the patients were primed with an introduction letter to the study in which the occurrence of cognitive complaints and its relation with chemotherapy was explicated. The remaining patients received a neutral letter that did not mention this relationship. RESULTS: Patients with pre-existing knowledge about chemotherapy-associated cognitive problems reported more cognitive complaints (M=3.04) than patients without this knowledge (M=2.21; p<0.001). The priming letter increased the reporting of cognitive complaints only for patients without a history of chemotherapy (p<0.05). All effects were independent of negative affect, age and education level. CONCLUSION: Our study shows that facilitating the accessibility of concepts related to chemotherapy-associated cognitive complaints directly increases the reporting of such complaints, in particular in patients without firsthand chemotherapy experience. This increase in prevalence of cognitive complaints following a chronically or temporarily accessible 'chemo-brain' schema has relevant implications for clinical practice and for scientific research in this area.

Asunto(s)

Antineoplásicos/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/psicología , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/psicología , Cultura , Educación del Paciente como Asunto , Rol del Enfermo , Adaptación Psicológica , Adulto , Afecto/efectos de los fármacos , Anciano , Antineoplásicos/uso terapéutico , Atención/efectos de los fármacos , Trastornos del Conocimiento/diagnóstico , Fatiga/inducido químicamente , Fatiga/psicología , Femenino , Humanos , Entrevista Psicológica , Recuerdo Mental/efectos de los fármacos , Persona de Mediana Edad , Disposición en Psicología , Trastornos del Inicio y del Mantenimiento del Sueño/inducido químicamente , Trastornos del Inicio y del Mantenimiento del Sueño/psicología

RESUMEN

OBJECTIVE: Neurocognitive problems that were observed in a number of breast cancer survivors treated with adjuvant chemotherapy initiated a series of EEG studies to examine the neurophysiological basis of these deficits. The aim of the present study was to examine the effects of various regimens of adjuvant chemotherapy on the N1 and P3 component of the event-related potential (ERP) in breast cancer patients 3-6 years after treatment. METHODS: Fifty-three breast cancer patients treated with various chemotherapy regimens were compared to 23 stage I breast cancer patients not treated with chemotherapy. An auditory oddball task was used to study the amplitude, latency and structure of the potential field of the N1 and P3. RESULTS: Patients treated with chemotherapy showed lower P3 amplitudes than patients not treated with chemotherapy. Differences were also observed in P3 latency between patients treated with different chemotherapy regimens. CONCLUSIONS: Our results indicate a general effect of all chemotherapy regimens under study on P3 amplitude and a more specific chemotherapeutic effect on P3 latency. SIGNIFICANCE: The present study provides evidence for the notion that different chemotherapy regimens have different effects on brain functioning.

Asunto(s)

Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante/métodos , Potenciales Evocados/efectos de los fármacos , Tiempo de Reacción/efectos de los fármacos , Sobrevivientes , Estimulación Acústica/métodos , Adulto , Análisis de Varianza , Mapeo Encefálico , Estudios Cruzados , Electroencefalografía , Femenino , Humanos , Estudios Longitudinales , Persona de Mediana Edad , Pruebas Neuropsicológicas

RESUMEN

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

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Trastornos del Conocimiento/inducido químicamente , Cognición/efectos de los fármacos , Neoplasias Testiculares/tratamiento farmacológico , Adulto , Bleomicina/administración & dosificación , Bleomicina/efectos adversos , Cisplatino/administración & dosificación , Cisplatino/efectos adversos , Etopósido/administración & dosificación , Etopósido/efectos adversos , Fatiga/etiología , Humanos , Masculino , Pruebas Neuropsicológicas , Medición de Riesgo , Factores de Riesgo , Estrés Psicológico/etiología , Encuestas y Cuestionarios , Neoplasias Testiculares/radioterapia , Neoplasias Testiculares/cirugía , Factores de Tiempo

RESUMEN

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

Asunto(s)

Proliferación Celular/efectos de los fármacos , Trastornos del Conocimiento/inducido químicamente , Inhibidores Enzimáticos/toxicidad , Hipocampo/citología , Metotrexato/toxicidad , Análisis de Varianza , Animales , Conducta Animal/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Discriminación en Psicología/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Antígeno Ki-67/metabolismo , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Reconocimiento Visual de Modelos/efectos de los fármacos , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos

RESUMEN

Some breast cancer survivors experience cognitive decline following chemotherapy. We prospectively examined changes in cognitive performance among high-risk breast cancer patients who had received high-dose chemotherapy with cyclophosphamide, thiotepa, and carboplatin (CTC group; n = 28) or standard-dose chemotherapy with 5-fluorouracil, epirubicin, and cyclophosphamide (FEC group; n = 39); stage-I breast cancer patients who had received no systemic chemotherapy (no-CT group; n = 57); and healthy control subjects (n = 60). All patients underwent neuropsychologic testing before and 6 months after treatment (12-month interval); control subjects underwent repeated testing over a 6-month interval. No differences in cognitive functioning between the four groups were observed at the first assessment. More of the CTC group than the control subjects experienced a deterioration in cognitive performance over time (25% versus 6.7%; odds ratio [OR] = 5.3, 95% confidence interval [CI] = 1.3 to 21.2, P = .02). No such difference was observed for the FEC or the no-CT groups (FEC versus control: OR = 2.2, 95% CI = 0.5 to 9.1, P = .27; no-CT versus Control: OR = 2.2, 95% CI = 0.6 to 8.0; P = .21). Some cytotoxic treatment for breast cancer affects cognition in a subset of women.

Asunto(s)

Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Trastornos del Conocimiento/inducido químicamente , Cognición , Neoplasias de la Mama/patología , Femenino , Humanos , Estudios Longitudinales , Estadificación de Neoplasias , Estudios Prospectivos , Sobrevivientes

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Trastornos del Conocimiento/inducido químicamente , Fatiga/inducido químicamente , Adolescente , Adulto , Neoplasias de la Mama/psicología , Quimioterapia Adyuvante , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Pruebas Neuropsicológicas , Proyectos de Investigación , Factores de Riesgo , Tamaño de la Muestra

RESUMEN

BACKGROUND: The mechanisms underlying cognitive deficits found in a number of patients with breast cancer treated with adjuvant chemotherapy are still unclear. In the current study, we used a combination of measures of brain electric activity and cognitive performance during information processing to elucidate the origin of these cognitive deficits. PATIENTS AND METHODS: Twenty-nine patients at high risk with breast cancer treated with adjuvant conventional-dose cyclophosphamide/epirubicin/5-fluorouracil or adjuvant high-dose cyclophosphamide/thiotepa/carboplatin were compared with 23 patients with stage I breast cancer not treated with chemotherapy approximately 4 years after completion of treatment. We studied reaction times and the amplitudes and latencies of the P3, an electrophysiologic index of information processing, in a task with different conditions related to input, central, and output processing of information. RESULTS: The amplitude of the P3 component was significantly reduced in patients with breast cancer treated with high-dose cyclophosphamide/thiotepa/carboplatin compared with patients with breast cancer not treated with chemotherapy. We observed no significant differences in reaction times and P3 latency between the treatment groups. CONCLUSION: Our data show electrophysiologic alterations in patients with breast cancer treated with high-dose chemotherapy 4 years after completion of treatment. The observed P3 reduction might be a result of suboptimal phasic cortical arousal and problems with the allocation of processing resources in these patients.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/mortalidad , Trastornos del Conocimiento/inducido químicamente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Sistema Nervioso Central/efectos de los fármacos , Quimioterapia Adyuvante/efectos adversos , Trastornos del Conocimiento/diagnóstico , Estudios Transversales , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Electrofisiología , Femenino , Estudios de Seguimiento , Humanos , Mastectomía Segmentaria/métodos , Persona de Mediana Edad , Estadificación de Neoplasias , Probabilidad , Valores de Referencia , Estudios Retrospectivos , Medición de Riesgo , Tasa de Supervivencia

RESUMEN

Cognitive deficits are found in a number of breast-cancer patients who have undergone adjuvant (Cyclophosphamide, Methotrexate, and 5-Fluorouracil (CMF)) chemotherapy, but the underlying mechanisms are still unclear. The objective of this study is to investigate information processing in these patients with concurrent registration of brain activity. Twenty-six breast-cancer patients treated with adjuvant CMF chemotherapy and a control group of 23 stage I breast-cancer patients not treated with chemotherapy were examined. Mean time since treatment for the CMF patients was 5.1 years after the last CMF course, and for the control patients 3.6 years after termination of radiotherapy. An information processing task was administered with concurrent EEG registration. Reaction times and the amplitudes and latencies of an Event Related Potential component (P3) in different task conditions related to input, central, and output processing of information were studied. Significant differences in latency and amplitude of the P3 component were found between the treatment groups with an earlier and reduced P3 in the chemotherapy group. Patients treated with chemotherapy had longer reaction times (although not significantly different) than the control group on all task conditions. Our data provide further evidence for long-term neurocognitive problems in breast-cancer patients treated with adjuvant (CMF) chemotherapy and offer new information regarding abnormalities in brain functioning in these patients.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/fisiopatología , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/fisiopatología , Adulto , Análisis de Varianza , Neoplasias de la Mama/complicaciones , Estudios de Casos y Controles , Quimioterapia Adyuvante/efectos adversos , Ciclofosfamida/administración & dosificación , Electroencefalografía , Potenciales Evocados , Femenino , Fluorouracilo/administración & dosificación , Humanos , Metotrexato/administración & dosificación , Persona de Mediana Edad , Pruebas Neuropsicológicas , Tiempo de Reacción

RESUMEN

PURPOSE: To determine whether hypnotherapy reduces anxiety and improves the quality of life in cancer patients undergoing curative radiotherapy (RT). METHODS AND MATERIALS: After providing written informed consent, 69 patients were randomized between standard curative RT alone (36 controls) and RT plus hypnotherapy (33 patients). Patients in the hypnotherapy group received hypnotherapy at the intake, before RT simulation, before the first RT session, and halfway between the RT course. Anxiety was evaluated by the State-Trait Anxiety Inventory DY-1 form at six points. Quality of life was measured by the Rand Medical Outcomes Study 36-item Health Survey (SF-36) at five points. Additionally, patients answered a questionnaire to evaluate their experience and the possible benefits of this research project. RESULTS: No statistically significant difference was found in anxiety or quality of life between the hypnotherapy and control groups. However, significantly more patients in the hypnotherapy group indicated an improvement in mental (p <0.05) and overall (p <0.05) well-being. CONCLUSION: Hypnotherapy did not reduce anxiety or improve the quality of life in cancer patients undergoing curative RT. The absence of statistically significant differences between the two groups contrasts with the hypnotherapy patients' own sense of mental and overall well-being, which was significantly greater after hypnotherapy. It cannot be excluded that the extra attention by the hypnotherapist was responsible for this beneficial effect in the hypnotherapy group. An attention-only control group would be necessary to control for this effect.

Asunto(s)

Ansiedad/terapia , Hipnosis , Neoplasias/radioterapia , Calidad de Vida , Adulto , Anciano , Anciano de 80 o más Años , Ansiedad/psicología , Distribución de Chi-Cuadrado , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/psicología , Estudios Prospectivos

RESUMEN

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.

Asunto(s)

Antineoplásicos/efectos adversos , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/prevención & control , Neoplasias/tratamiento farmacológico , Trastornos del Conocimiento/diagnóstico , Humanos