T.J. Postma

Effect of radiotherapy and other treatment-related factors on mid-term to long-term cognitive sequelae in low-grade gliomas : a comparative study

BACKGROUNDnBecause survival benefits of treatment with radiotherapy are questionable and such treatment can cause substantial damage to the brain over time, the optimum management strategy for low-grade gliomas remains controversial. We aimed to identify the specific effects of radiotherapy on objective and self-reported cognitive function, and on cognitive deterioration over time, in patients with low-grade gliomas treated with early radiotherapy.nnnMETHODSn195 patients with low-grade glioma (of whom 104 had received radiotherapy 1-22 years previously) were compared with 100 low-grade haematological patients and 195 healthy controls. Our analyses aimed to differentiate between the effects of the tumour (eg, disease duration, lateralisation) and treatment effects (neurosurgery, radiotherapy, antiepileptic drugs) on cognitive function and on relative risk of cognitive disability.nnnFINDINGSnLow-grade glioma patients had lower ability in all cognitive domains than did low-grade haematological patients, and did even less well by comparison with healthy controls. Use of radiotherapy was associated with poorer cognitive function; however, cognitive disability in the memory domain was found only in radiotherapy patients who received fraction doses exceeding 2 Gy. Antiepileptic drug use was strongly associated with disability in attentional and executive function.nnnINTERPRETATIONnOur findings suggest that the tumour itself has the most deleterious effect on cognitive function and that radiotherapy mainly results in additional long-term cognitive disability when high fraction doses are used. Additionally, the effects of other medical factors, especially antiepileptic drug use, on cognitive function in glioma patients deserve attention.

Neurotoxic complications of chemotherapy in patients with cancer: clinical signs and optimal management.

Neurotoxic side effects of chemotherapy occur frequently and are often a reason to limit the dose of chemotherapy. Since bone marrow toxicity, as the major limiting factor in most chemotherapeutic regimens, can be overcome with growth factors or bone marrow transplantation, the use of higher doses of chemotherapy is possible, which increases the risk of neurotoxicity.Chemotherapy may cause both peripheral neurotoxicity, consisting mainly of a peripheral neuropathy, and central neurotoxicity, ranging from minor cognitive deficits to encephalopathy with dementia or even coma.In this article we describe the neurological adverse effects of the most commonly used chemotherapeutic agents.The vinca-alkaloids, cisplatin and the taxanes are amongst the most important drugs inducing peripheral neurotoxicity. These drugs are widely used for various malignancies such as ovarian and breast cancer, and haematological cancers. Chemotherapy-induced neuropathy is clearly related to cumulative dose or dose-intensities. Patients who already have neuropathic symptoms due to diabetes mellitus, hereditary neuropathies or earlier treatment with neurotoxic chemotherapy are thought to be more vulnerable for the development of chemotherapy-induced peripheral neuropathy.Methotrexate, cytarabine (cytosine arabinoside) and ifosfamide are primarily known for their central neurotoxic side effects. Central neurotoxicity ranges from acute toxicity such as aseptic meningitis, to delayed toxicities comprising cognitive deficits, hemiparesis, aphasia and progressive dementia. Risk factors are high doses, frequent administration and radiotherapy preceding methotrexate chemotherapy, which appears to be more neurotoxic than methotrexate as single modality.Data on management and neuroprotective agents are discussed. Management mainly consists of cumulative dose-reduction or lower dose-intensities, especially in patients who are at higher risk to develop neurotoxic side effects. None of the neuroprotective agents described in this article can be recommended for standard use in daily practise at this moment, and further studies are needed to confirm some of the beneficial effects described.

How do brain tumors alter functional connectivity? A magnetoencephalography study

This study was undertaken to test the hypothesis that brain tumors interfere with normal brain function by disrupting functional connectivity of brain networks.

Long-term effects of vincristine on the peripheral nervous system.

SummaryForty patients with Non-Hodgkins Lymphoma treated with vincristine between 1984 and 1990 (cumulative dose 12 mg in 18–24 weeks) were investigated in order to evaluate the long term effects of vincristine on the peripheral nervous system. The patients were interviewed with emphasis on neuropathic symptoms. Physical and quantitative sensory examination with determination of vibratory perception and thermal discrimination thresholds were performed, four to 77 months (median 34 months) after vincristine treatment. Twenty-seven patients reported neuropathic symptoms. In 13 of these 27 patients symptoms were still present at the time of examination. In these patients sensory signs and symptoms predominated. In the other 14 patients symptoms had been present in the past. Symptoms persisted maximally 40 months since cessation of therapy. There was no age difference between patients with and without complaints at the time of examination. Normal reflexes were found in two third of patients. Neuropathic complaints were not very troublesome on the long term. It is concluded that with the above mentioned vincristine dose schedule signs and symptoms of vincristine neuropathy are reversible for a great deal and prognosis is fairly good.

Radiotherapy-induced cerebral abnormalities in patients with low-grade glioma

Abstract—Abnormalities on CT or MRI and neuropsychological performance in patients with low-grade glioma, with (n = 23) or without (n = 16) prior cerebral radiotherapy, were evaluated. Cerebral atrophy was observed in 14 of 23 patients (61%) treated with prior radiotherapy, and in 1 of 16 patients (6%) without prior radiotherapy. White matter abnormalities were observed in six patients, all of whom were treated with prior radiotherapy. These radiologic cerebral abnormalities correlated with cognitive performance.

The prognostic value of cognitive functioning in the survival of patients with high-grade glioma.

The authors studied cognitive functioning as a potential predictor of survival in 68 newly diagnosed patients with high-grade glioma. In a combined Cox proportional hazards model, the influence of tumor, treatment, and patient characteristics, including cognitive functioning, was studied. Older age and higher tumor grade were associated with poorer survival. Although cognitive impairment was not found to be an independent prognostic factor for the entire sample, it was associated with significantly poorer survival among older patients with World Health Organization grade IV gliomas. Assessment of cognitive functioning in these patients may improve clinical decision making and thus quality of treatment.

Delayed Radiation Toxicity after Focal or Whole Brain Radiotherapy for Low-Grade Glioma

To evaluate the influence of radiation volume and other risk factors for the development of delayed radiation toxicity in patients treated for low-grade glioma, a retrospective analysis of 41 adult patients treated with focal or whole brain radiotherapy (WBRT) was performed. For all patients CT and MRI scans were revised to quantify brain atrophy and white matter lesions. Medical data were reviewed concerning baseline and tumor characteristics, treatment, survival, signs and symptoms of clinical encephalopathy and cardiovascular risk factors. In patients treated with WBRT an increased risk was found for brain atrophy (RR 3.1), white matter lesions (RR 3.8) and clinical encephalopathy (RR 4.2). An increased risk of atrophy (RR 2.2) and white matter lesions (RR 2.9) was also found in patients aged over 40 years. Furthermore, brain atrophy and white matter lesions were more severe in patients treated with WBRT and in older patients. In conclusion, both the incidence and the severity of abnormalities is greater in patients treated with WBRT and in older patients.

SMART syndrome: a late reversible complication after radiation therapy for brain tumours

With intensified treatment leading to longer survival, complications of therapy for brain tumours are more frequently observed. Regarding radiation therapy, progressive and irreversible white matter disease with cognitive decline is most feared. We report on four patients with reversible clinical and radiological features occurring years after radiation for brain tumours, suggestive for the so called SMART syndrome (stroke-like migraine attacks after radiation therapy). All four patients (males, age 36–60 years) had been treated with focal brain radiation for a primary brain tumour or with whole-brain radiation therapy for brain metastases. Ranging from 2 to 10xa0years following radiation therapy patients presented with headache and focal neurological deficits, suggestive for tumour recurrence. Two patients also presented with focal seizures. MRI demonstrated typical cortical swelling and contrast enhancement, primarily in the parieto-occipital region. On follow-up both clinical and MRI features improved spontaneously. Three patients eventually proved to have tumour recurrence. The clinical and radiological picture of these patients is compatible with the SMART syndrome, a rare complication of radiation therapy which is probably under recognized in brain tumour patients. The pathophysiology of the SMART syndrome is poorly understood but bears similarities with the posterior reversible encephalopathy syndrome (PRES). These four cases underline that the SMART syndrome should be considered in patients formerly treated with radiation therapy for brain tumours, who present with new neurologic deficits. Before the diagnosis of SMART syndrome can be established other causes, such as local tumour recurrence, leptomeningeal disease or ischemic disease should be ruled out.

Seizure reduction in a low-grade glioma: more than a beneficial side effect of temozolomide

Background Seizures are a common symptom in patients with low-grade glioma (LGG), negatively influencing quality of life, if uncontrolled. Besides antiepileptic drugs, antitumour treatment might contribute to a reduction in seizure frequency. The aim of this study was to determine the effect of temozolomide (TMZ) chemotherapy on seizure frequency, to identify factors associated with post-treatment seizure reduction and to analyse the prognostic value of seizure reduction for survival. Methods We retrospectively reviewed adult patients with supratentorial LGG and epilepsy who received chemotherapy with TMZ as initial treatment or for progressive disease in two hospitals (VUmc Amsterdam; MCH The Hague) between 2002 and 2012. Results We identified 104 patients with LGG with epilepsy who had received TMZ. Uncontrolled epilepsy in the 3u2005months preceding chemotherapy was present in 66 of 104 (63.5%) patients. A ≥50% reduction in seizure frequency after 6u2005months occurred in 29 of 66 (43.9%) patients. Focal symptoms at presentation (OR 6.55; 95% CI 1.45 to 32.77; p=0.015) appeared to be positively associated with seizure reduction. Seizure reduction was an independent prognostic factor for progression-free survival (HR 0.32; 95% CI 0.15 to 0.66; p=0.002) and overall survival (HR 0.33; 95% CI 0.14 to 0.79; p=0.013), along with a histological diagnosis of oligodendroglioma (HR 0.38; 95% CI 0.17 to 0.86; p=0.021). Objective responses on MRI were similar for patients with and without seizure reduction. Conclusions TMZ may contribute to an important reduction in seizure frequency in patients with LGG. Seizure reduction following TMZ treatment has prognostic significance and may serve as an important clinical outcome measure in patients with LGG.

Peripheral neuropathy due to therapy with paclitaxel, gemcitabine, and cisplatin in patients with advanced ovarian cancer.

AbstractBackground: To evaluate the peripheral neuropathic changes induced by combination chemotherapy including paclitaxel (taxol), gemcitabine and cisplatin (TGC regimen).nPatients and methods: Eighteen patients with primary or recurrent ovarian cancer were treated with paclitaxel 150 or 110u2009mg/m2, respectively, together with gemcitabine 800u2009mg/m2 and cisplatin 75u2009mg/m2, 3 weekly for 6 cycles.Neurologic evaluation and quantitative assessment by vibration perception threshold (VPT) and grip strength took place before therapy, after 3 and 6 cycles of chemotherapy, and thereafter when possible.nResults: Both neuropathic symptoms and signs developed in all patients (100%), becoming most prominent 3 months after the last course of chemotherapy. Grade 3 peripheral neuropathy developed in one patient during chemotherapy, and in 3 additional patients after cessation of therapy.No significant differences were observed between chemo-naïve patients and pretreated patients.nConclusion: This TGC combination is well tolerated in terms of peripheral neuropathy during therapy, although the off-therapy worsening caused by cisplatin remains a problem.