Randomized phase II trial of irinotecan and bevacizumab as neo-adjuvant and adjuvant to temozolomide-based chemoradiation compared with temozolomide-chemoradiation for unresectable glioblastoma: final results of the TEMAVIR study from ANOCEF†.

BACKGROUND: Prognosis of unresectable glioblastoma (GB) remains poor, despite temozolomide (TMZ)-based chemoradiation. Activity of bevacizumab (BEV) and irinotecan (IRI) has been reported in recurrent disease. We evaluated BEV and IRI as neo-adjuvant and adjuvant treatment combined with TMZ-based chemoradiation for unresectable GB. PATIENTS AND METHODS: Patients with unresectable GB, age 18-70, IK ≥50 were eligible. The experimental arm (BEV/IRI) consisted of neo-adjuvant intravenous BEV, 10 mg/kg, and IRI, 125 mg/m(2), every 2 weeks for four cycles before radiotherapy (RT) (60 Gy), concomitant oral TMZ, 75 mg/m(2)/day, and BEV, 10 mg/kg every 2 weeks. Adjuvant BEV and IRI were given every 2 weeks for 6 months. The control arm consisted of concomitant oral TMZ, 75 mg/m(2)/day during RT, and 150-200 mg/m(2) for 5 days every 28 days for 6 months. The use of BEV was allowed at progression in the control arm. RESULTS: Patients (120) were included from April 2009 to January 2011. The working hypothesis was that treatment would increase the progression-free survival at 6 month (PFS-6) from 50% to 66%. The primary objective was not achieved, and only 30 out of 60 patients were alive without progression at 6 months (50.0% [IC95% (36.8; 63.1)] in the BEV/IRI arm when 37 out of 60 patients were required according to the Fleming decision rules. PFS-6 was 7.1 months in BEV/IRI versus 5.2 months in the control arm. The median overall survival was not different between the two arms (11.1 months). Main toxicities were three fatal intracranial bleedings, three bile duct or digestive perforations/infections (1 fatal), and six thrombotic episodes in the BEV/IRI arm, whereas there was one intracranial bleeding, two bile duct or digestive perforations/infections (1 fatal), and one thrombotic episode in the control arm. CONCLUSIONS: Neo-adjuvant and adjuvant BEV/IRI, combined with TMZ-radiation, is not recommended for further evaluation in the first-line treatment of unresectable GB. CLINICAL TRIAL REGISTRATION: Clinical trial registered under EUDRACT number 2008-002775-28 (NCT01022918).

Primitive cerebral melanoma: a diagnostic and management challenge. About 2 cases.

In this report of two cases of solitary cerebral meningeal melanoma, a rare tumor that presents both diagnostic and management challenges, the diagnosis of these lesions was based on a solitary leptomeningeal mass on MRI, a high mitotic rate on histology and the absence of extracerebral localizations. Although the radiological patterns can mimic those of other melanocytic tumors, MRI is a useful diagnostic tool for narrowing the differential diagnosis. Surgical removal remains the only effective treatment of these lesions, and can lead to prolonged survival in a few cases.

[Bevacizumab for the treatment of cerebral radionecrosis]. / Bévacizumab dans le traitement des radionécroses cérébrales.

Bevacizumab is a monoclonal antibody, which neutralizes the effect of vascular endothelium growth factor (VEGF) allowing regression of tumour vessels and a decrease in the permeability of the blood-brain barrier. Already used in oncology as adjuvant treatment for certain metastatic cancers and in second line for high-grade gliomas, it has been recently used as a treatment of cerebral radionecrosis resisting conventional drug treatment and hyperbaric oxygen. This article presents three patients with cerebral radionecrosis and treated by monthly infusions of bevacizumab (10 mg/kg per month). The patients had developed cerebral radionecrosis after radiation therapy for a malignant brain tumour. The radionecrosis was proved by magnetic resonance imaging and spectroscopy. The first patient received only one perfusion of bevacizumab, as the development of a lymphopenia prevented the patient from continuing with the treatment. The second patient received four infusions, but the absence of improvement of the clinical symptoms and progression of the radiolesion led to discontinuation of the treatment. The third patient developed several severe side effects, a transient ischemic accident and a perforated corneal ulcer, resulting again in premature discontinuation of treatment. The development of severe side effects, combined with the absence of notable clinical and radiologic improvements resulting from the use of bevacizumab as a treatment resulted in the premature interruption of such treatment, in all three patients.

Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group.

BACKGROUND: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models. PATIENTS AND METHODS: Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points. RESULTS: Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination. CONCLUSIONS: No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.

[Chemotherapy and targeted treatments in glioblastomas]. / Chimiothérapie et traitements ciblés des glioblastomes.

BACKGROUND AND PURPOSE: We review the indications and limitations of chemotherapy in glioblastoma multiform (GBM), including the role played by alkylating and other cytotoxic agents and the increased input of clinical research on targeted agents in GBM management. METHODS: In 2005, a phase III study clearly concluded in the benefit of adding temozolomide during and after radiotherapy treatment in GBM and thus defined the new standard of treatment in this devastating disease. This schedule increased the median survival from 12.1 to 14 months and the two- and five-year survival rates from 8 to 26%, and 3 to 10%, respectively, with a good tolerance profile. Moreover, methylation of the promoter of the O6 methylguanine DNA transferase (MGMT) gene exhibits a prognostic impact independently of therapeutic schedule but may also predict the benefit of adding temozolomide to radiotherapy. However, pitfalls in MGMT determination and lack of prospective validation have to be solved before considering MGMT as a decisional marker. More recently, antiangiogenic agents including enzastaurin, cediranib, bevacizumab, and others that target mainly the VEGF pathway, have been evaluated in this highly angiogenic disease. Among them, only bevacizumab has been associated with clear anti-tumor activity, although the lack of control studies limits the impact of the results to date. CONCLUSIONS: Recent studies conducted in GBM, both in the adjuvant and recurrent setting, have changed the natural course of the disease and opened a new area of clinical research, including imaging and response evaluation, predictive markers, and other targeted therapies.

[Genetic diseases and glioblastomas]. / Maladies génétiques et glioblastomes.

Some cancers are involved in inherited genetic syndromes. These genetic diseases are suspected of being involved in approximately 1% of gliomas. Few data are available on glioblastomas and their characteristics among these diseases. Familial syndromes known to predispose individuals to glioblastoma are neurofibromatosis type 1, Li-Fraumeni's syndrome, tuberous sclerosis, and Turcot's syndrome. This review discusses glioblastomas related to these diseases and the current knowledge on the statistical, clinical, and molecular biology data. Non-syndromic glioma families are discussed: a better understanding of molecular abnormalities in these groups should help understand the mechanisms of gliomagenesis. A case of malignant glioma requires the physician to actively search for the possibility of inherited factors and eventually suggest genetic counseling.

Guidelines on management of low-grade gliomas: report of an EFNS-EANO Task Force.

BACKGROUND: Diffuse infiltrative low-grade gliomas of the cerebral hemispheres in the adult are a group of tumors with distinct clinical, histological and molecular characteristics, and there are still controversies in management. METHODS: The scientific evidence of papers collected from the literature was evaluated and graded according to EFNS guidelines, and recommendations were given accordingly. RESULTS AND CONCLUSIONS: WHO classification recognizes grade II astrocytomas, oligodendrogliomas and oligoastrocytomas. Conventional MRI is used for differential diagnosis, guiding surgery, planning radiotherapy and monitoring treatment response. Advanced imaging techniques can increase the diagnostic accuracy. Younger age, normal neurological examination, oligodendroglial histology and 1p loss are favorable prognostic factors. Prophylactic antiepileptic drugs are not useful, whilst there is no evidence that one drug is better than the others. Total/near total resection can improve seizure control, progression-free and overall survival, whilst reducing the risk of malignant transformation. Early post-operative radiotherapy improves progression-free but not overall survival. Low doses of radiation are as effective as high doses and better tolerated. Modern radiotherapy techniques reduce the risk of late cognitive deficits. Chemotherapy can be useful both at recurrence after radiotherapy and as initial treatment after surgery to delay the risk of late neurotoxicity from large-field radiotherapy. Neurocognitive deficits are frequent and can be caused by the tumor itself, tumor-related epilepsy, treatments and psychological distress.

[Neurologic side effects of cytotoxic drugs]. / Complications neurologiques des chimiothérapies.

Damage to the nervous system is a common side effect of antineoplastic therapy. The improvements in treating systemic malignancies have been accompanied by the reports of neurological toxicity that has important impact on quality of life and may even limit the use of the treatment. Neurotoxicity can be induced by synergistic or additive effects of cytotoxic drugs and nervous system exposure is related to routes and doses of administered drugs. Neurological toxicity may be a dose-limiting factor that prevents the more aggressive use of cytotoxic drugs. With the increasing use of multiple modality therapy, dose-intensive therapy and experimental therapy, the incidence of neurological toxicity is still rising. Early diagnosis is essential. Indeed, when neurological complications are diagnosed with delay, they are rarely reversible. Neuroprotective agents are still evaluated. The neurologic complications of the more commonly used chemotherapeutic agents, hormones and targeted molecular agents are discussed.

[Spinals and paraspinals tumors treated by CyberKnife: feasibility and efficacy]. / Tumeurs spinales et paraspinales traitées par irradiation stéréotaxique par CyberKnife((R)) au centre Antoine-Lacassagne de Nice.

PURPOSE: Stereotactic radiotherapy using the CyberKnife has become a key treatment in the multidisciplinary management of secondary tumours, as well as primary benign or malignant tumours located within or adjacent to vertebral bodies and the spinal cord. The aim of this treatment is to improve local control and clinical response, including previously irradiated cases. PATIENTS AND METHODS: In this study, we present the first patients treated with CyberKnife between December 2006 and December 2007 for spinal or paraspinal tumours. The primary aim was to assess the feasibility and tolerance of stereotactic radiotherapy using the CyberKnife. Secondary aims were to establish the short-term local control, to calculate the local progression-free survival and overall survival. Clinical examination and imaging procedures were performed every three months. Response was assessed according to RECIST criteria. RESULTS: During that period, 16 patients were treated with CyberKnife. Thirteen patients had been pre-treated, three of whom had received spinal cord doses considered to be maximal. Three patients did not receive previous irradiation. The median age was 59 (36-74). The most frequent symptoms were pain (n = 8) and motor weakness (n = 4). The median dose was 30 Gy (16-50). The median number of fractions was 3 (1-5). No patient developed acute myelitis. Three patients developed acute reaction. Overall survival at 18 months was 72.4%, with a mean survival of 18.2 months (95% CI: 15.4-20.9). Local progression-free survival at 18 months was 58.4%, with a mean value of 16.9 months (95% CI: 13.6-20.2). CONCLUSION: The use of stereotactic radiotherapy with CyberKnife represents a major progress in the management of paraspinal tumours. The main advantages are better sparing of the spinal cord and the possibility of increasing the dose to the tumour target volume.

Molecular study of CEBPA in familial hematological malignancies.

Familial aggregation in patients with several haematological malignancies has been described, but the genetic basis for this familial clustering is not known. Few genes predisposing to familial haematological malignancies have been identified, among which RUNX1 and CEBPA have been described as predisposing genes to acute myeloid leukemia (AML). Recent studies on RUNX1 suggest that germline mutations in this gene predispose to a larger panel of familial haematological malignancies than AML. In order to strengthen this hypothesis, we have screened CEBPA for germline mutations in several families presenting aggregation of hematological malignancies (including chronic or acute, lymphoid or myeloid leukemias, Hodgkin's or non Hodgkin's lymphomas, and myeloproliferative or myelodysplastic syndromes) with or without solid tumours. Although no deleterious mutations were found, we report two novel and rare variants of uncertain significance. In addition, we confirm that the in frame insertion c.1175_1180dup (p.P194_H195dup) is a germline polymorphism.

[Diagnostic and prognostic values of 1p and 19q deletions in adult gliomas: critical review of the literature and implications in daily clinical practice]. / Valeurs diagnostique et pronostique des délétions 1p et 19q dans les gliomes de l'adulte. Revue critique de la littérature et implications en pratique clinique.

Losses of chromosomes 1p and 19q are deemed correlated with diagnosis of oligodendroglioma, higher chemosensitivity and better prognosis. We reviewed the literature to evaluate the usefulness of these correlations in daily clinical practice. The rates of deletions relative to histology (WHO classifications) were extracted from 33 studies, including 2666 patients. The 1p deletions and 1p19q codeletion mean rates were respectively 65.4 and 63.3% in oligodendrogliomas, 28.7 and 21.6% in oligoastrocytomas, 13.2 and 7.5% in astrocytomas, 11.6 and 2.9% in glioblastomas. The presence of 1p deletion and 1p19q codeletion were strongly correlated with the histological diagnosis corresponding to oligodendroglioma. Calculation of specificity, sensitivity, predictive positive values and false negative rates suggests that presence of deletion 1p or codeletion represents a strong argument in favor of the diagnosis of oligodendroglioma. However, considering the high false negative rate, absence of such deletions does not rule out the diagnosis. In grade 3 oligodendroglial tumors, the probability of responding to chemotherapy, and the duration of response, were higher when codeletions were present. This suggests that, in these tumors, the presence of codeletion is a strong argument in favor of adjuvant chemotherapy. However, chemotherapy should not be systematically excluded when codeletions are absent, as the chances of response are about 33% in this situation. Data concerning low-grade gliomas were more controversial. Oligodendroglial tumors with 1p deletion or 1p19q codeletion seemed to have a better prognosis, as five-year survival rates were 50% higher than in tumors without deletion. This might be explained by the correlation between 1p deletion and other identified prognosis factors: (1) higher chemosensitivity, (2) tumor location more frequently in the frontal lobe, leading to better resection and lower risk of neurological deficit, (3) slower growth rate, (4) higher risk of epilepsy, leading to an early detection.

Treatment of newly diagnosed symptomatic pure low-grade oligodendrogliomas with PCV chemotherapy.

Based on studies relating to anaplastic oligodendroglioma (OG) chemosensitivity and benefit of time to progression or overall survival, chemotherapy for pure OG has been proposed. Several studies have reported the efficacy of various chemotherapeutic agents in a small number of patients with low-grade gliomas, e.g. pure astrocytomas, OG or mixed histologies. The 5-year survival rate varies from 61% to 89% with a mean time to progression of 5 years. We report the outcome of 33 consecutive patients with pure low-grade OG diagnosed between 1990 and 2006 systematically treated for residual or non-removable tumor with PCV chemotherapy regimen as the front-line treatment after surgery. All the tumors were low grade (grade II) pure OG according to the WHO classification. All patients were symptomatic at presentation and underwent neurosurgical procedure for histological diagnosis. Response was evaluated by clinical assessment and brain magnetic resonance imaging. Twenty-one men and 12 women with a mean age at pathological diagnosis of 46.5 years were studied. The most common first symptom was partial epileptic seizure (73.7%). Six patients (18%) had initial gadolinium enhancement, associated with methoxyisobutyl (MIBI) hypermetabolism (P < 0.001). The resection was partial in seven cases (21%), and 26 patients (79%) had biopsy only. Eleven patients (36%) had a malignant transformation during the follow-up with a median time to progression of 19 months. Favorable prognostic factors were lack of contrast enhancement (P < 0.0001), and age <40 years (P < 0.0003); 90% of patients were progression-free at 1 year. Survival rates at 2, 5 and 10 years were 85%, 75% and 50%, respectively. Up-front chemotherapy with PCV regimen is a good treatment for symptomatic pure low-grade OG, as it increases the number of progression-free patients and time to progression. These results suggest that radiotherapy could be postponed until the malignant transformation occurs to delay cognitive side effects of irradiation.

Turcot syndrome confirmed with molecular analysis.

Turcot syndrome is clinically characterized by the occurrence of primary brain tumor and colorectal tumor and has, in previous reports, been shown associated with germline mutations in the genes APC, MLH1, MHS6, and PMS2. To date, only few families have been documented by molecular analysis. We report two new families with Turcot syndrome to illustrate and review its characteristics and facilitate diagnosis. Molecular analysis revealed two germline mutations, one in the MLH1 gene and one in MSH2. The latter has never been describe in the literature. Personal and familial relevant anamnestic data from patients with glioma might aid in the diagnosis of genetic disorders. The subsequent molecular characterization may contribute to the appropriate care of affected patients and asymptomatic gene carriers.

[Turcot's syndrome confirmed by molecular biological tests]. / Syndrome de Turcot confirmé par biologie moléculaire.

INTRODUCTION: Turcot's syndrome is characterized clinically by the concurrence of a primary brain tumor and a familial adenomatous polyposis or a hereditary nonpolyposis colorectal cancer. OBSERVATION: We report a case of a 45-year-old woman who underwent in 1995 neuro-oncological treatment for an anaplastic astrocytoma (grade III according to the World Health Organization classification). Treatment included complete surgery, radiotherapy, a first-line nitrosourea-based chemotherapy regimen and a second-line platinium salt-based regimen. It was then noted that the patient's brother had colorectal cancer. A genetic study detected a germ-line mutation on the hMSH2 gene specific of HNPCC syndrome (Human Non Polyposis Colorectal Cancer). Colonoscopy was normal. Eight years after the diagnosis, the patient developed a gliomatosis cerebri and died. CONCLUSION: Relevant personal and familial history can provide the clue to the diagnosis of Turcot's syndrome. Molecular diagnosis may contribute to appropriate care of affected patients.

First-line nitrosourea-based chemotherapy in symptomatic non-resectable supratentorial pure low-grade astrocytomas.

At the present time, there are no proven beneficial effects of chemotherapy (CT) for the treatment of pure low-grade astrocytomas. Brain radiotherapy (RT) still remains the standard treatment in order to reduce or delay tumor progression or symptoms, despite possible long-term neurologic complications. We report 10 patients, with histologically proven pure low-grade fibrillary astrocytomas, to which we administered a first-line nitrosourea-based CT. All patients were symptomatic with pharmaco-resistant epilepsy or neurologic symptoms, and had been rejected for neurosurgical resection. All patients with epilepsy had a clinical improvement with reduction in seizure frequency and 60% became seizure-free. CT was well tolerated; all patients developed myelosuppression with 40% of grade III/IV hematotoxicity. Seven were alive at the time of writing with a mean follow-up of 6.5 years (3.5-12) from first recorded symptoms. The three deceased patients died 7.5, 7.5, and 8.5 years from first symptoms. These results demonstrate that some patients with symptomatic non-resectable fibrillary low-grade astrocytomas can be treated with up-front CT to improve their neurologic status. This report suggests that benefits of CT on symptoms, survival, and quality of life should be prospectively compared with RT.

Salvage PCV chemotherapy for temozolomide-resistant oligodendrogliomas.

The authors investigated the results of PCV chemotherapy within a cohort of 24 patients treated within the EORTC study 26971 on temozolomide chemotherapy in recurrent oligodendroglioma. The genotype of the tumors was assessed with fluorescent in situ hybridization with locus specific probes for the region 1p36. Four of the 24 patients responded (17%). Fifty percent of patients were still free from progression at 6 months and 21% were free from progression at 12 months. Although a clear relation existed between loss of 1p and response to temozolomide chemotherapy, this relation was absent in salvage PCV chemotherapy.

[Neoadjuvant chemotherapy for symptomatic non operable grade II fibrillary astrocytoma in adults]. / Chimiothérapie néoadjuvante dans les astrocytomes fibrillaires de grade II symptomatiques non opérables de l'adulte.

We collected 6 case-reports of symptomatric non removable low grade fibrillary astrocytoma of adults treated with a procarbazine-CCNU-vincristine chemotherapy regimen. All patients had drug-resistant epilepsy but brain imaging was stable. Total gross resection was rejected because of Volume or tumor location. After 4 to 7 cycles of chemotherapy, 2 patients had partial response and one minor response on brain MRI. All of them were seizure-free. Progression free survival was not reached at 5 Years. Up-front chemotherapy for low-grade astrocytomas may be useful and has to be prospectively evaluated.

Long-term outcome of oligodendrogliomas.

BACKGROUND: Favorable prognostic factors for oligodendroglial tumors include age younger than 40 years, low tumor grade, and extent of resection. OBJECTIVE: To assess survival time and prognostic factors of 100 patients with oligodendrogliomas diagnosed between 1995 and 2002. METHODS: The tumors were rated histologically by the WHO classification as low grade (grade II) or anaplastic (grade III). One hundred patients were categorized into three groups: group A: grade II, group B: secondary grade III (low grade with anaplastic transformation during the follow-up), group C: de novo grade III. All patients were symptomatic at presentation and underwent neurosurgical procedure for histologic diagnosis. Follow-up was performed with clinical assessment, brain MRI, and MIBI scintigraphy. RESULTS: There were 66 men and 34 women (mean age at diagnosis 46.7 years). The most common first symptom was partial epileptic seizure (75%). Fifty-six patients had initial gadolinium enhancement (A: 15.6%; B: 36.8% as grade II, 95% as grade III; C: 90%), generally associated with MIBI hypermetabolism (p < 0.0001). Survival rates at 2, 5, and 10 years were A: 88%, 88%, 85%; B: 79%, 64%, 42%; C: 43%, 16%, 15%. CONCLUSIONS: Secondary anaplastic oligodendroglioma patients were younger than patients with de novo anaplastic oligodendrogliomas. Histologic confirmation is mandatory because some low grade oligodendrogliomas had gadolinium enhancement on MRI and some anaplastic did not. Survival time was longer for secondary than for de novo anaplastic oligodendrogliomas without difference in the duration of the malignant phase of the disease.

European Organization for Research and Treatment of Cancer (EORTC) open label phase II study on glufosfamide administered as a 60-minute infusion every 3 weeks in recurrent glioblastoma multiforme.

BACKGROUND: Glufosfamide is a new alkylating agent in which the active metabolite of isophosphoramide mustard is covalently linked to beta-D-glucose to target the glucose transporter system and increase intracellular uptake in tumor cells. We investigated this drug in a multicenter prospective phase II trial in recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS: Eligible patients had recurrent GBM following surgery, radiotherapy and no more than one prior line of chemotherapy. Patients were treated with glufosfamide 5000 mg/m(2) administered as a 1-h intravenous infusion. Treatment success was defined as patients with either an objective response according to Macdonald's criteria or 6 months progression-free survival. Toxicity was assessed with the Common Toxicity Criteria (CTC) version 2.0. RESULTS: Thirty-one eligible patients were included. Toxicity was modest, the main clinically relevant toxicities being leukopenia (CTC grade >3 in five patients) and hepatotoxicity (in three patients). No responses were observed; one patient (3%; 95% confidence interval 0 to 17%) was free from progression at 6 months. Pharmacokinetic analysis showed a 15% decrease in area under the curve and glufosfamide clearance in patients treated with enzyme-inducing antiepileptic drugs, but no effect of these drugs on maximum concentration and plasma half-life. CONCLUSION: Glufosfamide did not show significant clinical antitumor activity in patients with recurrent GBM.

[Chemotherapeutic neurotoxicity]. / Neurotoxicité des chimiothérapies chez l'adulte.

Not uncommonly, damage to the nervous system occurs as a complication of antineoplastic therapy. Neurotoxicity can be induced by synergistic or additive effects of cytotoxic treatments and nervous system exposure is related to routes and doses. Improvements in treating systemic malignancy have been accompanied by reports of neurologic toxicity that has important impact on quality of life and may even limit use of the treatment. Neurological toxicity may be a dose-limiting factor that prevents more aggressive use of that form of treatment. With the increasing use of multi-modality therapy, dose-intensive therapy and experimental therapy, the incidence of neurological toxicity continues to rise. It points out the need for continuous clinical evaluation to detect their appearance. When neurological complications are diagnosed late, they are rarely reversible. Neuroprotective agents are still under evaluation.