Central nervous system gliomas.

Evidence-based practical guidelines on diagnosis, prognosis, and treatment on the most frequent adult brain tumours are delineated. In Europe, 27,000 new cases of malignant glial tumours and 1000 new cases of malignant ependymal tumours are diagnosed every year. The most common glial tumours are glioblastoma multiforme and anaplastic glioma, comprising more than 50% and 10%, respectively, of the total gliomas. Prognosis of gliomas is generally poor. Environmental and genetic factors have been correlated with an increased risk of developing brain tumours. Surgical resection represents the first treatment option for all histotypes. Role and timing of radiotherapy and chemotherapy as well as treatment for recurrent/progressive disease should be based on age, performance status, histopathological diagnosis, molecular markers, and previous therapy. Impaired neurocognitive and neuropsychological function is common in long-term survivors, regardless of the histology and grade of the tumour and should be taken into account in treatment planning.

Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials.

Patients with low-grade glioma frequently have brain tumor-related epilepsy, which is more common than in patients with high-grade glioma. Treatment for tumor-associated epilepsy usually comprises a combination of surgery, anti-epileptic drugs (AEDs), chemotherapy, and radiotherapy. Response to tumor-directed treatment is measured primarily by overall survival and progression-free survival. However, seizure frequency has been observed to respond to tumor-directed treatment with chemotherapy or radiotherapy. A review of the current literature regarding seizure assessment for low-grade glioma patients reveals a heterogeneous manner in which seizure response has been reported. There is a need for a systematic approach to seizure assessment and its influence on health-related quality-of-life outcomes in patients enrolled in low-grade glioma therapeutic trials. In view of the need to have an adjunctive metric of tumor response in these patients, a method of seizure assessment as a metric in brain tumor treatment trials is proposed.

Seizures and gliomas--towards a single therapeutic approach.

Epilepsy often develops in patients with glioma, and the two conditions share common pathogenic mechanisms. Altered expression of glutamate transporters, including the cystine-glutamate transporter (xCT) system, increases concentrations of extracellular glutamate, which contribute to epileptic discharge, tumour proliferation and peripheral excitotoxicity. Furthermore, mutation of the isocitrate dehydrogenase 1 gene in low-grade gliomas causes production of D-2-hydroxyglutarate, a steric analogue of glutamate. Dysregulation of intracellular chloride promotes glioma cell mitosis and migration, and γ-aminobutyric acid (GABA) signalling suppresses proliferation. In neurons, however, chloride accumulation leads to aberrant depolarization on GABA receptor activation, thereby promoting epileptic activity. The molecular target of rapamycin (mTOR) pathway and epigenetic abnormalities are also involved in the development of tumours and seizures. Antitumour therapy can contribute to seizure control, and antiepileptic drugs might have beneficial effects on tumours. Symptomatic treatment with antiepileptic drugs carries risks of adverse effects and drug interactions. In this Review, we discuss the potential for single therapeutic agents, such as the xCT blocker sulfasalazine, the chloride regulator bumetanide, and the histone deacetylase inhibitor valproic acid, to manage both gliomas and associated epilepsy. We also provide guidance on the evidence-based use of antiepileptic drugs in brain tumours. The development of solo therapies to treat both aspects of gliomas promises to yield more-effective treatment with fewer risks of toxicity and drug interactions.

Epilepsy and brain tumors.

Seizures are common in patients with brain tumors, and epilepsy can significantly impact patient quality of life. Therefore, a thorough understanding of rates and predictors of seizures, and the likelihood of seizure freedom after resection, is critical in the treatment of brain tumors. Among all tumor types, seizures are most common with glioneuronal tumors (70-80%), particularly in patients with frontotemporal or insular lesions. Seizures are also common in individuals with glioma, with the highest rates of epilepsy (60-75%) observed in patients with low-grade gliomas located in superficial cortical or insular regions. Approximately 20-50% of patients with meningioma and 20-35% of those with brain metastases also suffer from seizures. After tumor resection, approximately 60-90% are rendered seizure-free, with most favorable seizure outcomes seen in individuals with glioneuronal tumors. Gross total resection, earlier surgical therapy, and a lack of generalized seizures are common predictors of a favorable seizure outcome. With regard to anticonvulsant medication selection, evidence-based guidelines for the treatment of focal epilepsy should be followed, and individual patient factors should also be considered, including patient age, sex, organ dysfunction, comorbidity, or cotherapy. As concomitant chemotherapy commonly forms an essential part of glioma treatment, enzyme-inducing anticonvulsants should be avoided when possible. Seizure freedom is the ultimate goal in the treatment of brain tumor patients with epilepsy, given the adverse effects of seizures on quality of life.

Seizures and cancer: drug interactions of anticonvulsants with chemotherapeutic agents, tyrosine kinase inhibitors and glucocorticoids.

Patients with cancer commonly experience seizures. Combined therapy with anticonvulsant drugs (AEDs) and chemotherapeutic drugs or tyrosine kinase inhibitors carries inherent risks on drug-drug interactions (DDIs). In this review, pharmacokinetic studies of AEDs with chemotherapeutic drugs, tyrosine kinase inhibitors, and glucocorticoids are discussed, including data on maximum tolerated dose, drug clearance, elimination half-life, and organ exposure. Enzyme-inducing AEDs (EIAEDs) cause about a 2-fold to 3-fold faster clearance of concurrent chemotherapeutic drugs metabolized along the same pathway, including cyclophosphamide, irinotecan, paclitaxel, and teniposide, and up to 4-fold faster clearance with the tyrosine kinase inhibitors crizotinib, dasatinib, imatinib, and lapatinib. The use of tyrosine kinase inhibitors, particularly imatinib and crizotinib, may lead to enzyme inhibition of concurrent therapy. Many of the newer generation AEDs do not induce or inhibit drug metabolism, but they can alter enzyme activity by other drugs including AEDs, chemotherapeutics and tyrosine kinase inhibitors. Glucocorticoids can both induce and undergo metabolic change. Quantitative data on changes in drug metabolism help to apply the appropriate dose regimens. Because the large individual variability in metabolic activity increases the risks for undertreatment and/or toxicity, we advocate routine plasma drug monitoring. There are insufficient data available on the effects of tyrosine kinase inhibitors on AED metabolism.

Seizures in oligodendroglial tumors.

Epilepsy develops in more than 70-90% of oligodendroglial tumors and represents a favorable indicator for long-term survival if present as the first clinical sign. Presence of IDH1 mutation is frequently associated with seizures in oligodendrogliomas, next to alterations of glutamate and GABA metabolism in the origin of glioma-associated epilepsy. Treatment by surgery or radiotherapy results in seizure freedom in about two-thirds of patients, and chemotherapy to a seizure reduction in about 50%. Symptomatic anticonvulsive therapy with levetiracetam and valproic acid as monotherapy are both evidence-based drugs for the partial epilepsies, and their effective use in brain tumors is supported by a large amount of additional data. Pharmacoresistance against anticonvulsants is more prevalent among oligodendrogliomas, occurring in about 40% despite polytherapy with two anticonvulsants or more. Toxic signs of anticonvulsants in brain tumors involve cognition, bone marrow and skin. Previous neurosurgery, radiation therapy or chemotherapy add to the risks of cognitive dysfunction.

Seizure prognosis in brain tumors: new insights and evidence-based management.

Brain tumor-related epilepsy (BTE) is common in low- and high-grade gliomas. The risk of seizures varies between 60% and 100% among low-grade gliomas and between 40% and 60% in glioblastomas. The presence of seizures in patients with brain tumors implies favorable and unfavorable factors. New-onset seizures represent an early warning sign for the presence of a brain tumor and count as a good prognostic factor for survival. Recurrence or worsening of seizures during the course of disease may signal tumor progression. Each of the modalities for tumor control (i.e., surgery, radiotherapy, chemotherapy) contributes to seizure control. Nevertheless, one third of BTE shows pharmacoresistance to antiepileptic drugs (AEDs) and may severely impair the burden of living with a brain tumor. For symptomatic therapy of BTE, seizure type and individual patient factors determine the appropriate AED. Randomized controlled trials in partial epilepsy in adults to which type BTE belongs and additional studies in gliomas indicate that levetiracetam is the agent of choice, followed by valproic acid (VPA). In the case of recurring seizures, combining these two drugs (polytherapy) seems effective and possibly synergistic. If either one is not effective or not well tolerated, lacosamide, lamotrigine, or zonisamide are additional options. A new and exciting insight is the potential contribution of VPA to prolonged survival, particularly in glioblastomas. A practice guideline on symptomatic medical management including dose schedules of AEDs is supplied.

Tumour and surgery effects on cognitive functioning in high-grade glioma patients.

BACKGROUND: Many high-grade glioma (HGG) patients have cognitive impairments, which impact daily functioning. Cognitive impairments can be caused by tumour-, treatment-, and patient-related factors. The effect of the tumour and of surgical resection on cognition is, however, not well known. We investigated tumour and surgical effects on cognitive functioning in patients with HGG. METHODS: At baseline, preceding surgery, 62 patients with HGG underwent neuropsychological testing concerning seven cognitive domains: verbal and working memory, attention, executive functioning, psychomotor function, information processing speed, and visuoconstructive abilities. Thirty-nine patients were included in follow-up testing after surgery, but before subsequent treatment. Tumour size and site, use of anti-epileptic drugs and corticosteroids, and extent of resection were recorded. RESULTS: Compared to healthy controls, cognitive functioning of patients was significantly impaired in all domains. Prior to surgery 79 % (49 of 62) of patients had cognitive impairment in at least one domain. At median follow-up of 5 weeks after surgery, 59 % (23 of 39) of patients were cognitively impaired in at least one domain. At follow-up, 49 % showed improvement, while 23 % declined. Left hemisphere tumour localization was associated with worse verbal memory (P=0.004), and larger tumours in this hemisphere with poorer executive functioning (P < 0.001). Changes in cognitive performance at follow-up relative to baseline were not related to tumour characteristics or extent of resection. CONCLUSIONS: Tumour-related cognitive deficits are present in a majority of HGG patients preceding surgery. Surgery does not result in cognitive deterioration in the short term in most patients.

Seizure characteristics and prognostic factors of gliomas.

Epilepsy in neuroepithelial tumors is highly prevalent. Neurogliomas (dysembryoplastic neuroepitheliomas [DNETs] and gangliogliomas) have a seizure incidence of 80-100%, low-grade gliomas of 60-85%, and glioblastoma of 30-60%. With each type, the appearance of seizures is usually the presenting clinical symptom, and with neuroglial tumors often the only clinical sign. Tumor locations in the temporal and insular cortex are associated with a higher risk of developing epilepsy in both neuroglial tumors and low-grade gliomas. Focal seizures with or without alteration of consciousness and/or secondary generalization are common. Focal seizures with altered consciousness are present in 50-70% of neuroglial tumors, and secondarily generalized seizures in 70% of low-grade gliomas. Surgical treatment, particularly gross tumor resection, contributes strongly to seizure freedom, especially in neuroglial tumors. Refractory epilepsy is more common in low-grade gliomas, occurring in 30-35%. Recurrence or worsening of seizures is often associated with tumor recurrence in glioblastomas. Translational studies have revealed a strong prevalence of IDH1 enzyme mutation together with the presence of seizures and long-term survival in low-grade gliomas. Disturbances of glutamate metabolism occur both in low-grade tumors and glioblastomas, and provide insight into mutual cellular pathway abnormalities contributing to both seizure development and tumor growth. Likewise, the recent clinical observations on antitumor activity of the anticonvulsant valproic acid in glioblastoma now provide promising outlooks on single therapies that target both seizures and gliomas.

Pregnancy in women with gliomas: a case-series and review of the literature.

The occurrence of pregnancy in women with brain tumors confronts both patients and physicians with difficult decision making at each stage of pregnancy. We studied the course of events of nine pregnancies in seven women with low-grade glioma in our hospital over a 10 year period. Five patients had a surgical resection, one a biopsy and one woman was followed by wait-and-see policy before pregnancy. In two women, a therapeutic abortion was carried out in the first trimester because of signs of progression, necessitating surgical removal of the tumor. In the other five women pregnancy had an uncomplicated course. Based on a literature review, we found 28 women diagnosed with a known glioma before becoming pregnant. All pregnancies but one, were uneventful and all women had a normal delivery, including the seven cases with exposure to chemotherapy and in whom healthy babies were born. A total of 75 pregnant women were identified in whom new onset glioma developed, which was high-grade in 56 %, and becoming symptomatic in 51 % during the third trimester, usually by focal neurological deficits. We conclude that in relation to pregnancy, low-grade gliomas are more often seen in women already known with a brain tumor, while high-grade gliomas represent more frequently a new onset phenomenon. Based on these observations, guidelines are given on initiation of antitumor therapy during pregnancy, seizure management, counseling on therapeutic abortion, and on the timing and choice of obstetrical interventions.

Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme.

BACKGROUND: To examine the efficacy of valproic acid (VPA) given either with or without levetiracetam (LEV) on seizure control and on survival in patients with glioblastoma multiforme (GBM) treated with chemoradiation. METHODS: A retrospective analysis was performed on 291 patients with GBM. The efficacies of VPA and LEV alone and as polytherapy were analyzed in 181 (62%) patients with seizures with a minimum follow-up of 6 months. Cox-regression survival analysis was performed on 165 patients receiving chemoradiation with temozolomide of whom 108 receiving this in combination with VPA for at least 3 months. RESULTS: Monotherapy with either VPA or LEV was instituted in 137/143 (95.8%) and in 59/86 (68.6%) on VPA/LEV polytherapy as the next regimen. Initial freedom from seizure was achieved in 41/100 (41%) on VPA, in 16/37 (43.3%) on LEV, and in 89/116 (76.7%) on subsequent VPA/LEV polytherapy. At the end of follow-up, seizure freedom was achieved in 77.8% (28/36) on VPA alone, in 25/36 (69.5%) on LEV alone, and in 38/63 (60.3%) on VPA/LEV polytherapy with ongoing seizures on monotherapy. Patients using VPA in combination with temozolomide showed a longer median survival of 69 weeks (95% confidence interval [CI]: 61.7-67.3) compared with 61 weeks (95% CI: 52.5-69.5) in the group without VPA (hazard ratio, 0.63; 95% CI: 0.43-0.92; P = .016), adjusting for age, extent of resection, and O(6)-DNA methylguanine-methyltransferase promoter methylation status. CONCLUSIONS: Polytherapy with VPA and LEV more strongly contributes to seizure control than does either as monotherapy. Use of VPA together with chemoradiation with temozolomide results in a 2-months' longer survival of patients with GBM.

Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951.

PURPOSE: Anaplastic oligodendroglioma are chemotherapy-sensitive tumors. We now present the long-term follow-up findings of a randomized phase III study on the addition of six cycles of procarbazine, lomustine, and vincristine (PCV) chemotherapy to radiotherapy (RT). PATIENTS AND METHODS: Adult patients with newly diagnosed anaplastic oligodendroglial tumors were randomly assigned to either 59.4 Gy of RT or the same RT followed by six cycles of adjuvant PCV. An exploratory analysis of the correlation between 1p/19q status and survival was part of the study. Retrospectively, the methylation status of the methyl-guanine methyl transferase gene promoter and the mutational status of the isocitrate dehydrogenase (IDH) gene were determined. The primary end points were overall survival (OS) and progression-free survival based on intent-to-treat analysis. RESULTS: A total of 368 patients were enrolled. With a median follow-up of 140 months, OS in the RT/PCV arm was significantly longer (42.3 v 30.6 months in the RT arm, hazard ratio [HR], 0.75; 95% CI, 0.60 to 0.95). In the 80 patients with a 1p/19q codeletion, OS was increased, with a trend toward more benefit from adjuvant PCV (OS not reached in the RT/PCV group v 112 months in the RT group; HR, 0.56; 95% CI, 0.31 to 1.03). IDH mutational status was also of prognostic significance. CONCLUSION: The addition of six cycles of PCV after 59.4 Gy of RT increases both OS and PFS in anaplastic oligodendroglial tumors. 1p/19q-codeleted tumors derive more benefit from adjuvant PCV compared with non-1p/19q-deleted tumors.

Enzyme induction with antiepileptic drugs: cause for concern?

Several commonly prescribed antiepileptic drugs (AEDs)-including phenobarbital, phenytoin, and carbamazepine-stimulate the synthesis of a broad range of monooxygenase and conjugating enzymes. These agents are well known to reduce the duration and action of many lipid- and non-lipid-soluble drugs, including anticoagulants, cytotoxics, analgesics, antiretrovirals, glucocorticoids, statins, antihypertensives, oral contraceptives, psychoactive drugs, immunosuppressants, and of course, other AEDs. This process, therefore, may be associated with a number of clinical problems including higher cancer mortality, progressive AIDS, transplant rejection, and unwanted pregnancy. Withdrawal of enzyme-inducing AEDs will increase the concentration of induced drugs, bringing with it substantial risk of toxicity if doses are not concomitantly reduced. Yet the potential widespread adverse health consequences of these interactions, both with AED initiation and withdrawal, remain largely underappreciated. Furthermore, induction also affects enzymes involved in endogenous metabolic pathways, and can alter bone biochemistry, gonadal steroids, and lipid markers. Therefore, enzyme-inducing AEDs may contribute to the development of a number of comorbidities, including osteoporosis, sexual dysfunction, and vascular disease. This process continues as long as the patient takes the inducer. Modern AEDs that do not possess this property have similar efficacy for the common epilepsies. Accordingly, perhaps consideration should be given to starting treatment with, or even switching patients to, non-enzyme-inducing AEDs.

Cerebral ganglioneuroblastoma of adult onset: two patients and a review of the literature.

Ganglioneuroblastoma is a rare tumor variant of neuroblastoma. Only five cases have been observed in the adult brain, and we report here on two more adult patients with cerebral ganglioneuroblastoma. Additionally, a review was carried out on all 50 published adult cases with ganglioneuroblastoma, located in the adrenal gland (9), mediastinum (8), retroperitoneal area (7), the brain parenchyma (7), or the spinal cord (3). Median age at onset was 39 years, and 52% of patients were female. For extracranial locations, treatment usually consisted of surgery followed by radiotherapy and adjuvant chemotherapy. Of the cases with cerebral involvement only one patient did not receive any treatment. The other six patients underwent surgical resection and radiation therapy, in four cases followed by chemotherapy with temozolomide. The median survival of cerebral ganglioneuroblastomas was 14 months and did not differ from the whole group of ganglioneuroblastomas (12 months). For cerebral ganglioneuroblastoma, the preferred regimen would seem to be neurosurgical removal, followed by chemoradiotherapy including temozolomide.

Seizures in low- and high-grade gliomas: current management and future outlook.

Major difficulties in patients with epilepsy and brain tumors include refractory seizures, potential interactions between anticonvulsants and chemotherapeutic agents and enhanced risks of toxicity, including cognitive deterioration. For seizure control, levetiracetam, valproic acid, topiramate and lamotrigine can each be considered as agents of first choice. We advocate starting with levetiracetam monotherapy, based on efficacy, good tolerability and the absence of interactions. If levetiracetam alone is not sufficiently effective, we propose adding a second antiepileptic drug, rather than switching to monotherapy with another anticonvulsant. Under these circumstances we advise the use of valproic acid as an add-on over topiramate or lamotrigine, based on its reported clinical activity in brain tumor patients. The combination of levetiracetam and valproic acid seems synergistic, and produces few or no cognitive side effects. Antitumor therapy by neurosurgery, cranial radiation or chemotherapy contribute substantially to reducing seizure activity. Future research on seizure management in brain tumor patients should focus on better insight into the influence of multidrug resistance proteins on anticonvulsant drug transport over the blood-brain barrier, efficacy of new anticonvulsants with no or few interactions with other drugs, synergistic combinations of anticonvulsants in order to limit toxicity and therapeutic drug monitoring of anticonvulsants in current clinical practice and in new drug studies, including the effects of concomitant administration of chemotherapeutic agents.

Efficacy of anti-epileptic drugs in patients with gliomas and seizures.

Although seizures in brain tumor patients are common, the knowledge on optimal anti-seizure therapy in this patient group is limited. An observational study was carried out using a database of all patients from the neuro-oncology service during the period 2000-2005, with data on seizure characteristics, therapy with AEDs, the underlying brain tumor and its treatment. A total of 140 brain tumor patients were studied of whom 23.6% had a low-grade glioma, 53.6% a high-grade glioma, and 22.8% belonged to a mixed group existing of ependymoma, meningioma, and brain metastasis. Epilepsy as the presenting sign was more frequent in low-grade vs. high-grade gliomas (69.7 vs. 52%, P = 0.087), and a total of 75.8% of patients developed seizures with low-grade and of 80.0% with high-grade gliomas. Of all 99 patients with seizures, 80.1% received valproic acid (VPA) as first choice, and either levetiracetam (LEV), carbamazepine (CBZ) or lamotrigine (LMT) as the most frequent next choice. Patients treated with a combination of VPA and LEV showed the highest percentage of responders (81.5%), with a decline in seizure frequency of more than two categories in 55.6% and seizure freedom in 59%. No correlation was found between the use of VPA and survival. A combination of VPA and LEV seems effective, if seizure control cannot be achieved by VPA alone. This indicates that adding levetiracetam may be preferable over sequential trials of AED monotherapy in treatment-resistant seizures in patients with brain tumors.

Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial.

BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. METHODS: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. FINDINGS: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. INTERPRETATION: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. FUNDING: EORTC, NCIC, Nélia and Amadeo Barletta Foundation, Schering-Plough.

Management of temozolomide toxicity by nurse practitioners in neuro-oncology.

PURPOSE/OBJECTIVES: To investigate the toxicity of temozolomide (TMZ) in patients with brain tumors and appropriate nursing interventions. DESIGN: Explorative analysis of prospective data. SETTING: A TMZ clinic led by a nurse practitioner (NP). SAMPLE: Group A (n = 71) received a standard dose of TMZ daily for five days 200 mg/m2 every four weeks; group B (n = 19) received a dose-intense schedule of TMZ daily for 21 days 75 mg/m2 every four weeks. METHODS: Toxicities were scored according to National Cancer Institute Common Terminology Criteria, and results in the two groups were compared. MAIN RESEARCH VARIABLES: Thrombopenia, neutropenia, and lymphopenia; nausea and vomiting; and NP interventions. FINDINGS: Of observed toxicities during six cycles, grade 3-4 thrombopenia was seen most frequently in group A. Neutropenia and subsequent interventions occurred more frequently in group A than in group B. Subsequent interventions consisted of dose delays and reductions. When patients were treated for a longer duration of time with TMZ, grade 3-4 lymphopenia occurred significantly more often in group B, necessitating Pneumocystis carinii pneumonia prophylaxis. CONCLUSIONS: Degree of toxicity using a 5-day 200 mg/m2 or 21-day 75 mg/m2 schedule every four weeks was similar to that found in other studies. IMPLICATIONS FOR NURSING: Through awareness of toxicity in relation to knowledge of brain tumors, NPs can become more effective in active management of TMZ toxicity.

Molecular analysis of anaplastic oligodendroglial tumors in a prospective randomized study: A report from EORTC study 26951.

Recent studies have shown that the clinical outcome of anaplastic oligodendroglial tumors is variable, but also that the histological diagnosis is subject to interobserver variation. We investigated whether the assessment of 1p/19q codeletion, polysomy of chromosome 7, epidermal growth factor receptor (EGFR) gene amplification (EGFR(amp)), and loss of chromosome 10 or 10q offers additional prognostic information to the histological diagnosis and would allow molecular subtyping. For this study, we used the clinical data and tumor samples of the patients included in multicenter prospective phase III European Organisation for Research and Treatment of Cancer (EORTC) study 26951 on the effects of adjuvant procarbazine, chloroethyl cyclohexylnitrosourea (lomustine), and vincristine chemotherapy in anaplastic oligodendroglial tumors. Fluorescence in situ hybridization was used to assess copy number aberrations of chromosome 1p, 19q, 7, 10, and 10q and EGFR. Three different analyses were performed: on all included patients based on local pathology diagnosis, on the patients with confirmed anaplastic oligodendroglial tumors on central pathology review, and on this latter group but after excluding anaplastic oligoastrocytoma (AOA) with necrosis. As a reference set for glioblastoma multiforme (GBM), patients from the prospective randomized phase III study on GBM (EORTC 26981) were used as a benchmark. In 257 of 368 patients, central pathology review confirmed the presence of an anaplastic oligodendroglial tumor. Tumors with combined 1p and 19q loss (1p(loss)19q(loss)) were histopathologically diagnosed as anaplastic oligodendroglioma, were more frequently located in the frontal lobe, and had a better outcome. Anaplastic oligodendroglial tumors with EGFR(amp) were more frequently AOA, were more often localized outside the frontal lobe, and had a survival similar to that for GBM. Survival of patients with AOA harboring necrosis was in a similar range as for GBM, while patients with AOA with only endothelial proliferation had better overall survival. In univariate analyses, all molecular factors except loss of 10q were of prognostic significance, but on multivariate analysis a histopathological diagnosis of AOA, necrosis, and 1p(loss)19q(loss) remained independent prognostic factors. AOA tumors with necrosis are to be considered WHO grade IV tumors (GBM). Of all molecular markers analyzed in this study, especially loss of 1p/19q carried prognostic significance, while the others contributed little prognostic value to classical histology.