Lower cognitive performance and white matter changes in testicular cancer survivors 10 years after chemotherapy.

OBJECTIVE: Chemotherapy (CT) is associated with adverse effects on cognition. Only few studies have investigated cognition in testicular cancer (TC) patients and studies on very late effects of CT on cognition are absent. Further, brain changes in relation to treatment have not been investigated in TC. The objective of the present study is to compare psychosocial functioning, cognitive performance and brain (micro)structure following surgery and CT for TC, against surgery (S)-only. METHODS: Twenty-eight CT (43.1±7.5 y) and 23 S-only (48.2±9.5y) TC survivors on average 14 yr post-treatment were examined using questionnaires, neurocognitive tests, and 3T-MRI [Diffusion Kurtosis Imaging (DKI), T1-weighted and Fluid Attenuated Inversion Recovery]. A multivariate cognitive performance score (Mahalanobis distance) was calculated to indicate the grade of cognitive performance. Kurtosis parameters, gray matter, and white matter (WM) volume were calculated from MRI data. RESULTS: Overall, the CT group showed lower cognitive performance (5.35±1.7) compared with the S-only group (4.4±0.9; P=0.03; d=0.70). Further, TC patients reported more memory problems after CT. DKI revealed a significantly higher radial kurtosis after CT in several anterior and posterior brain areas (P<0.05, corrected), but this was unrelated to cognitive performance. CONCLUSIONS: This cross-sectional study suggests that men receiving CT for TC are at risk for long-term lower cognitive performance. Although CT affected WM microstructure, this was unrelated to cognitive performance. More extensive, preferably prospective studies are warranted to confirm these results and to provide more insight into the possible mechanisms behind the observed cognitive sequelae after treatment for TC.

Late effects of adjuvant chemotherapy for breast cancer on fine motor function.

BACKGROUND: Adjuvant chemotherapy for breast cancer has been associated with deterioration of fine motor skill. Which aspects of motor performance are underlying this problem is unclear but important because manual motor deterioration could affect quality of life. The current study aims to investigate late effects of adjuvant chemotherapy for breast cancer on fine motor function, using both speed and accuracy measures. METHOD: We compared fine motor function of 174 women who had received adjuvant Cyclophosphamide Methotrexate 5-Fluorouracil chemotherapy for breast cancer on average 20 years ago with that of a population sample of 195 women without a history of cancer. Fine motor function was measured with the Purdue Pegboard Test and the Archimedes spiral test. RESULTS: The group of chemotherapy-exposed breast cancer survivors was slower in drawing an Archimedes spiral than the reference group. Furthermore, in the chemotherapy-exposed subjects, we found that older age is related to more crossings of the spiral template, more return movements, and more deviations from the template. Such relationships were not observed within the reference group. No significant between-group differences were found for any of the Purdue Pegboard measures. CONCLUSIONS: Compared with a population-based reference group, Cyclophosphamide Methotrexate 5-Fluorouracil chemotherapy-exposed breast cancer survivors demonstrated motor slowing while drawing an Archimedes spiral, on average 20 years after completion of primary treatment. Furthermore, the Archimedes spiral test is a more sensitive measure than the Purdue Pegboard Test to assess fine manual motor performance in long-term breast cancer survivors following chemotherapy.

Very Late Treatment-Related Alterations in Brain Function of Breast Cancer Survivors.

Although adjuvant chemotherapy (CT) for breast cancer (BC) is associated with very late side-effects on cognition and brain function, studies on adverse effects of specific treatment regimens are scarce. Here, neurotoxicity profiles after different treatment strategies were compared in BC survivors randomized to high-dose (HI) or conventional-dose (CON-) CT, in women treated with radiotherapy (RT) -only and a healthy control (HC) group. We administered a neurocognitive test battery, a planning fMRI task (Tower of London) and episodic memory fMRI task (Paired Associates paradigm) in BC survivors who received CON-CT (n=24) and HC (n=27). Data were compared to BC survivors who received HI-CT (n=17) and RT-only (n=15) and who were previously assessed. Testing took place ±11.5 years post-CT. Furthermore, neurocognitive data were compared to neurocognitive data acquired ≤2 years post-treatment. Cognitive assessment revealed sustained cognitive decline in 10.5% of HI-CT, 8.3% of CON-CT, 6.7% of RT-only patients and 0% in the HC. Hypoactivation was found in task-related prefrontal and parietal areas for both CT-groups versus RT-only, with HI-CT showing more pronounced hypoactivation than CON-CT, combined with worse task performance. RT-only survivors performed at a similar level to HC while showing hyperactivation in task-related brain areas. Long after treatment, CT is associated with cognitive problems and task-related hypoactivation that depend on the specific cytotoxic regimen. This worse performance in patients who received CT could be explained by impaired brain functioning that is more severe with more intense CT.

Magnetic resonance imaging of the carotid artery in long-term head and neck cancer survivors treated with radiotherapy.

BACKGROUND: In head and neck cancer (HNC) patients, long-term treatment-related complications include radiotherapy (RT)-induced carotid vasculopathy and stroke. The current study investigated the magnetic resonance imaging (MRI) characteristics of the carotid wall in long-term HNC survivors treated with RT. METHODS: MRI of the carotid arteries was performed within a prospective cohort of 42 HNC patients on average 7 years after RT. Two independent radiologists assessed maximal vessel wall thickness of common and internal carotid arteries. In case of wall thickening (≥ 2 mm) the MRI signals as well as length of the thickened segment were assessed. RESULTS: Mean (SD) age of the 42 patients at baseline was 53 (13) years and mean (SD) follow-up time after RT was 6.8 (1.3) years. In total 62% were men and 60% had one or more cerebrovascular risk factors. Mean (SD) dose of RT on the common carotid arteries and internal carotid arteries was 57 Gy (11) and 61 Gy (10), respectively. Wall thickening was observed in 58% of irradiated versus 27% of non-irradiated common carotid arteries and 24% of irradiated versus 6% of non-irradiated internal carotid arteries (p < 0.05). Mean (SD) thickness of the irradiated and non-irradiated common carotid arteries was 2.5 (0.9) and 2 (0.7) mm (p = 0.02). Mean thickness of the irradiated and non-irradiated internal carotid arteries was 1.8 (0.8) and 1.5 mm (0.3) (n.s.). Mean length of the thickened vessel wall was 48 mm versus 36 mm in the irradiated versus non-irradiated common carotid arteries (p = 0.03) and 20 mm versus 15 mm in the irradiated versus non-irradiated internal carotid arteries (n.s.). No significant differences were observed for signal intensities of the vessel walls. CONCLUSIONS: Our study showed significantly more vessel wall thickening in irradiated versus non-irradiated carotid arteries years after RT for HNC, while no differences in signal intensities were observed.

Global and focal white matter integrity in breast cancer survivors 20 years after adjuvant chemotherapy.

OBJECTIVES: To date, only four small studies have investigated the effects of adjuvant chemotherapy for breast cancer on the microstructure of cerebral white matter with magnetic resonance imaging (MRI). These studies, which were conducted shortly up to 10 years post-treatment, showed that chemotherapy is associated with focal loss of microstructural white matter integrity. We investigated the long-term effect of chemotherapy on white matter microstructural integrity by comparing the brains of chemotherapy-exposed breast cancer survivors to those of a population-based sample of women without a history of cancer. EXPERIMENTAL DESIGN: Diffusion tensor imaging (DTI) MRI (1.5 T) was performed in 187 CMF (cyclophosphamide, methotrexate, and 5-flourouracil) chemotherapy-exposed breast cancer survivors, mean age 64.2 (sd = 6.5) years, who had been diagnosed with cancer on average 21.2 (sd = 4.4) years before, and 374 age-matched cancer-free reference subjects from a population-based cohort study. Outcome measures were whole-brain microstructural integrity as measured by fractional anisotropy and mean/axial/radial diffusivity and focal white matter integrity, which was analyzed with tract-based spatial statistics. All analyses were adjusted for age, cardiovascular risk factors, education, and symptoms of depression. PRINCIPAL OBSERVATIONS: No significant group differences were observed in white matter integrity. However, within the breast cancer survivors, time since treatment was inversely associated with lower global and focal white matter integrity. CONCLUSIONS: This cross-sectional study suggests that among chemotherapy-exposed breast cancer survivors white matter microstructural integrity deteriorates with accumulating time since treatment. This warrants further investigation.

Long term cerebral and vascular complications after irradiation of the neck in head and neck cancer patients: a prospective cohort study: study rationale and protocol.

BACKGROUND: Successful treatment options for cancer result in more young long-term survivors prone for long-term complications. Carotid artery vasculopathy is a potential long-term complication after radiotherapy of the neck, resulting in cerebrovascular events and probably deficits in cognitive and motor functioning. Better insight into the underlying pathofysiology of radiotherapy induced carotid artery vasculopathy is needed for prognostic purposes and to develop preventive strategies. METHODS/DESIGN: The current study is a prospective cohort study on the long-term cerebral and vascular complications after radiotherapy of the neck, in 103 patients treated for head and neck cancer, included in our study database between 2002 and 2008. Baseline protocol (before radiotherapy) included screening for cerebrovascular risk factors and intima media thickness measurement of carotid arteries by ultrasonography. Follow-up assessment more than 5 years after radiotherapy included screening of cerebrovascular risk factors, cerebrovascular events, neurological examination with gait and balance tests, extensive neuropsychological examination, self-report questionnaires, ultrasonography of the carotid arteries with measurement of intima media thickness and elastography, magnetic resonance imaging of the brain and magnetic resonance angiography of the carotid arteries. DISCUSSION: The current study adds to the understanding of the causes and consequences of long-term cerebral and vascular changes after radiotherapy of the neck. These data will be helpful to develop a protocol for diagnostic and preventive strategies for long-term neurological complications in future head and neck cancer patients with anticipated radiotherapy treatment.

Correspondence between neurophysiological and clinical measurements of chemotherapy-induced peripheral neuropathy: secondary analysis of data from the CI-PeriNomS study.

Chemotherapy-induced peripheral neuropathy (CIPN) lacks standardized clinical measurement. The objective of the current secondary analysis was to examine data from the CIPN Outcomes Standardization (CI-PeriNomS) study for associations between clinical examinations and neurophysiological abnormalities. Logistic regression estimated the strength of associations of vibration, pin, and monofilament examinations with lower limb sensory and motor amplitudes. Examinations were classified as normal (0), moderately abnormal (1), or severely abnormal (2). Among 218 participants, those with class 1 upper extremity (UE) and classes 1 or 2 lower extremity (LE) monofilament abnormality were 2.79 (95% confidence interval [CI]: 1.28-6.07), 3.49 (95%CI: 1.61-7.55), and 4.42 (95%CI: 1.35-14.46) times more likely to have abnormal sural nerve amplitudes, respectively, compared to individuals with normal examinations. Likewise, those with class 2 UE and classes 1 or 2 LE vibration abnormality were 8.65 (95%CI: 1.81-41.42), 2.54 (95%CI: 1.19-5.41), and 7.47 (95%CI: 2.49-22.40) times more likely to have abnormal sural nerve amplitudes, respectively, compared to participants with normal examinations. Abnormalities in vibration and monofilament examinations are associated with abnormal sural nerve amplitudes and are useful in identifying CIPN.

Prospective cohort study of carotid intima-media thickness after irradiation.

BACKGROUND: Carotid artery vasculopathy is a potential long-term complication after radiotherapy (RT) of the neck, resulting in cerebrovascular events. The underlying pathophysiology is not well understood and early markers are lacking. We aimed to study whether RT of the neck is associated with increase in carotid intima-media thickness (IMT) and stroke in the first 2 years after RT in patients with head and neck cancer (HNC). METHODS: In this prospective cohort study patients treated with RT of the neck were assessed for measurement of IMT before and 2 years after RT. Endpoints were changed in IMT and incidence of first-ever stroke. RESULTS: Between 2003 and 2008 we included 69 patients (median age, 57 years [25%-75% quartile, 51-64 years], median dose of RT 66 Gy [interquartile range, 60-70]) with baseline and follow-up measurement of IMT. Median IMT at baseline and follow-up was .60 and .62 mm (ratio of geometric means 1.01; 95% confidence interval, .96-1.08; P = .63). Four of 69 patients suffered from a stroke. Mean interval from RT to stroke was 6.8 months. CONCLUSIONS: Our study showed no increase of carotid IMT in the first 2 years after RT of the neck in patients treated for HNC. This indicates that the IMT is not a reliable early marker for postirradiation vasculopathy. However, a high rate of strokes was observed. A longer follow-up period is needed to find the starting point of RT-induced vascular changes.

Cluster-like headache and a cystic hypothalamic tumour as first presentation of sarcoidosis.

INTRODUCTION: Sarcoidosis is a granulomatous, multisystem inflammatory disease of unknown cause, which presents with a wide variety of symptoms. We describe a rare case of a newly diagnosed sarcoidosis, with cluster-like headache as a presenting symptom. CASE: A 31-year-old man presented with cluster headache with a cystic lesion in the hypothalamus. A non-caseating granuloma consistent with the diagnosis sarcoidosis was found at biopsy. Pulmonary involvement was confirmed on positron electron tomography-computed tomography (PET-CT). Treatment with prednisone led to regression of the hypothalamic lesion. Headache attacks did not recur. DISCUSSION: Cluster-like headache with a cystic hypothalamic lesion as first presentation of sarcoidosis has never been reported. Their possible relationship seems to underline the role of the hypothalamus in the central pain-regulatory areas in the brain, but is not undisputed. This case clearly demonstrates once again the relevance of neuroimaging in new-onset cluster-like headache.

Neurological immune-related adverse events of ipilimumab.

Ipilimumab enhances the T lymphocyte mediated immune response to both tumour cells and healthy tissue, improving survival in patients with metastatic melanoma but also leads to more immune-related adverse events (irAEs) than previously used treatments, such as dacarbazine. We present three patients with neurological irAEs from ipilimumab treatment: hypophysitis, meningitis and Guillain-Barré syndrome. Once an irAE occurs, ipilimumab should be stopped and corticosteroids started. Usually, ipilimumab-induced irAE symptoms improve within days to weeks, but can be life-threatening if unrecognised.

Effects of tamoxifen and exemestane on cognitive function in postmenopausal patients with breast cancer.

BACKGROUND: Cognitive effects of tamoxifen have been described. We augment data from a previous short-term (ST) follow-up study with long-term (LT) data to evaluate ST and LT cognitive effects of tamoxifen followed by exemestane and exemestane in breast cancer patients. METHODS: Patients from the Tamoxifen and Exemestane Adjuvant Multinational trial received 5 years exemestane (exemestane group, n = 114) or 2.5 years tamoxifen followed by 2.5 years exemestane (sequential group, n = 92). Neuropsychological performance was assessed pre-endocrine therapy, after 1 year (ST follow-up) and at 5 years (LT follow-up). A control group of healthy participants (n = 120) were assessed with parallel intervals. With random effects modeling we evaluated cognitive changes from baseline to ST and LT follow-up. Statistical tests were 2-sided. RESULTS: After controlling for age, intelligence quotient, attrition, menopausal symptoms, anxiety and/or depression, and/or fatigue, the sequential group showed ST and LT decline compared with control participants on verbal memory (effect size [ES] = 0.26, P = .01; ES = 0.34, P = .003) and executive function (ES = 0.27, P = .007; ES = 0.38, P = .002). Compared with the exemestane group, the sequential group demonstrated ST decline on information processing speed (ES = 0.33, P = .01) and executive function (ES = 0.32, P = .01) and LT decline on verbal memory (ES = 0.33, P = .02). The exemestane group showed no cognitive decline compared with control participants. CONCLUSION: Cognitive adverse effects of tamoxifen alone and after switching to exemestane were observed, suggestive of a carryover effect of tamoxifen. Our results underline the need for well-controlled, prospective trials studying cognitive effects of endocrine therapy.

Late effects of high-dose adjuvant chemotherapy on white and gray matter in breast cancer survivors: converging results from multimodal magnetic resonance imaging.

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.

Global and focal brain volume in long-term breast cancer survivors exposed to adjuvant chemotherapy.

A limited number of studies have associated adjuvant chemotherapy with structural brain changes. These studies had small sample sizes and were conducted shortly after cessation of chemotherapy. Results of these studies indicate local gray matter volume decrease and an increase in white matter lesions. Up till now, it is unclear if non-CNS chemotherapy is associated with long-term structural brain changes. We compared focal and total brain volume (TBV) of a large set of non-CNS directed chemotherapy-exposed breast cancer survivors, on average 21 years post-treatment, to that of a population-based sample of women without a history of cancer. Structural MRI (1.5T) was performed in 184 chemotherapy-exposed breast cancer patients, mean age 64.0 (SD = 6.5) years, who had been diagnosed with cancer on average 21.1 (SD = 4.4) years before, and 368 age-matched cancer-free reference subjects from a population-based cohort study. Outcome measures were: TBV and total gray and white matter volume, and hippocampal volume. In addition, voxel based morphometry was performed to analyze differences in focal gray matter. The chemotherapy-exposed breast cancer survivors had significantly smaller TBV (-3.5 ml, P = 0.019) and gray matter volume (-2.9 ml, P = 0.003) than the reference subjects. No significant differences were observed in white matter volume, hippocampal volume, or local gray matter volume. This study shows that adjuvant chemotherapy for breast cancer is associated with long-term reductions in TBV and overall gray matter volume in the absence of focal reductions. The observed smaller gray matter volume in chemotherapy-exposed survivors was comparable to the effect of almost 4 years of age on gray matter volume reduction. These volume differences might be associated with the slightly worse cognitive performance that we observed previously in this group of breast cancer survivors.

Cerebral hyporesponsiveness and cognitive impairment 10 years after chemotherapy for breast cancer.

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.

Phase 3 Randomized Trial of Prophylactic Cranial Irradiation With or Without Hippocampus Avoidance in SCLC (NCT01780675).

INTRODUCTION: To compare neurocognitive functioning in patients with SCLC who received prophylactic cranial irradiation (PCI) with or without hippocampus avoidance (HA). METHODS: In a multicenter, randomized phase 3 trial (NCT01780675), patients with SCLC were randomized to standard PCI or HA-PCI of 25 Gy in 10 fractions. Neuropsychological tests were performed at baseline and 4, 8, 12, 18, and 24 months after PCI. The primary end point was total recall on the Hopkins Verbal Learning Test-Revised at 4 months; a decline of at least five points from baseline was considered a failure. Secondary end points included other cognitive outcomes, evaluation of the incidence, location of brain metastases, and overall survival. RESULTS: From April 2013 to March 2018, a total of 168 patients were randomized. The median follow-up time was 26.6 months. In both treatment arms, 70% of the patients had limited disease and baseline characteristics were well balanced. Decline on the Hopkins Verbal Learning Test-Revised total recall score at 4 months was not significantly different between the arms: 29% of patients on PCI and 28% of patients on HA-PCI dropped greater than or equal to five points (p = 1.000). Performance on other cognitive tests measuring memory, executive function, attention, motor function, and processing speed did not change significantly different over time between the groups. The overall survival was not significantly different (p = 0.43). The cumulative incidence of brain metastases at 2 years was 20% (95% confidence interval: 12%-29%) for the PCI arm and 16% (95% confidence interval: 7%-24%) for the HA-PCI arm. CONCLUSIONS: This randomized phase 3 trial did not find a lower probability of cognitive decline in patients with SCLC receiving HA-PCI compared with conventional PCI. No increase in brain metastases at 2 years was observed in the HA-PCI arm.

The impact of different definitions and reference groups on the prevalence of cognitive impairment: a study in postmenopausal breast cancer patients before the start of adjuvant systemic therapy.

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.

Treatment modalities for leptomeningeal metastases.

Secondary involvement of the leptomeninges represents an infrequent but devastating (and nearly always fatal) complication of solid tumors, hematologic malignancies (both leukemia and lymphoma), and primary brain tumors. Clinical suspicion of neoplastic meningitis (NM) may be raised by the appearance of multivariate neurological symptoms; however, a definitive diagnosis is often difficult to obtain. Improved treatments for primary malignancies and advances in diagnostic imaging technology have led to an apparent increase in the number of patients diagnosed with NM. Unfortunately, therapeutic options remain limited, particularly for patients with chemoresistant tumors. Optimized treatment remains controversial and may rely upon a combination of chemotherapy (intrathecal and/or intravenous) and concurrent focal radiotherapy. This review discusses the advantages and disadvantages of intra-cerebrospinal fluid (CSF) versus systemic strategies for treating NM. Clinical trial evidence is presented for the different treatment modalities. In addition, the therapeutic potential of intra-CSF therapy for cancer prophylaxis is discussed. Earlier diagnosis and more aggressive preventive treatment regimens may provide substantial increases in survival and favorably affect quality of life. Additional data from large-scale, well-controlled trials are required to more accurately assess the efficacy of intra-CSF versus systemic treatment in NM. Future treatment options using novel targets for intra-CSF therapy will be addressed as well.

Persistent neuropathy after treatment with cisplatin and oxaliplatin.

BACKGROUND: The aims of the current explorative study were to assess persistent neuropathy in 45 patients up to 6 years after treatment with cisplatin or oxaliplatin and to determine the most adequate method to evaluate neuropathy. Furthermore, the effect of possible determinants on persistent neuropathy was investigated. MATERIAL AND METHODS: The assessment of neuropathy was performed using a questionnaire, by neurological tests, and by vibration threshold (VT) measurements. Because VT determination gives the most objective information, VT measurements were used for further analyses. RESULTS AND DISCUSSION: The analyses revealed that neuropathy of the hands was related to follow-up time, with an observed recovery half-life of 6.8 (+/- 3.1) years. No significant reversibility of neuropathy of the feet within the observation period could be demonstrated. For cisplatin, the severity of neuropathy was related to the cumulative dose and sodium thiosulfate use. Oxaliplatin induced neuropathy did not appear to be related to the dose within the studied dose range. No relationship with platinum levels, renal function, glutathione transferase genotypes, diabetes mellitus, alcohol use, or co-medication could be demonstrated. This study was performed as an explorative study and the issues discussed need to be investigated further.

Neuropsychological functioning in postmenopausal breast cancer patients treated with tamoxifen or exemestane after AC-chemotherapy: cross-sectional findings from the neuropsychological TEAM-side study.

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.

Persistent neurocognitive problems after adjuvant chemotherapy for breast cancer.

BACKGROUND: Neurocognitive problems have been observed in a number of women previously treated with adjuvant chemotherapy for breast cancer. The present study aims to combine the results of neuropsychological and electrophysiological techniques collected in patients with breast cancer treated with cyclophosphamide/methotrexate/5-fluorouracil (CMF) at different time points. PATIENTS AND METHODS: Patients with breast cancer treated with adjuvant CMF chemotherapy (n = 63) were examined with neuropsychological tests 1 year after treatment and compared with healthy women (n = 60; T1 portion of the study). Based on neuropsychological test performance, patients were classified as cognitively impaired or unimpaired. Four years later, behavioral and neurophysiological measures (T2 portion of the study) were collected during an information-processing task in a subgroup of patients (n = 26). At T2, we compared the results of cognitively impaired patients (n = 8) with those of patients classified as cognitively unimpaired at T1 (n = 18). RESULTS: In the initial neuropsychological assessment, 33.3% of the patients were classified as cognitively impaired, compared with 10% of healthy women. At T2, impaired patients who received CMF showed longer P3 latencies, lower P3 amplitudes, longer reaction times, and made more errors in an information processing task compared with unimpaired patients who received CMF. CONCLUSION: The results indicate the persistence of neurocognitive problems < or = 5 years after completion of chemotherapy and consistency across different assessment techniques.