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.
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La neurotoxicité des traitements cytotoxiques et cytostatiques est fréquente mais peu connue. Elle dépend des produits utilisés et peut être le facteur limitant du traitement oncologique avec un ...impact immédiat sur la qualité de vie. La connaissance et la détection précoce des complications neurologiques des traitements chimiothérapiques ont un impact majeur sur la prise en charge des malades. Les symptômes neurologiques varient selon la nature des produits utilisés dans leur topographie, leur physiopathologie, leur intensité et leur évolution. Les progrès dans les stratégies thérapeutiques en oncologie se sont associés à de nouvelles toxicités. Les symptômes dépendent des voies d’administration utilisées, des doses, de la pharmacodynamique et de la cinétique du médicament. Les traitements neuroprotecteurs sont en cours d’évaluation. Les diagnostics différentiels les plus fréquents sont les syndromes paranéoplasiques, eux aussi sous-diagnostiqués, et les atteintes spécifiques du cancer. Une fois installées, les manifestations neurotoxiques ne sont pas toujours réversibles. La prise en charge pluridisciplinaire de ces malades par les neurologues, les oncologues et les spécialistes de la douleur permet d’obtenir une meilleure qualité des soins.
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.
Le bévacizumab est un anticorps monoclonal qui neutralise l’activité du
vascular endothelium growth factor (VEGF), permettant une diminution de la néoangiogénèse et une diminution de la perméabilité ...de la barrière hémato-encéphalique. Déjà utilisé en cancérologie en traitement adjuvant, dans certains cancers métastatiques et en deuxième ligne pour les tumeurs gliales, il est plus récemment proposé dans le traitement des radionécroses cérébrales réfractaires aux traitements médicamenteux et à l’oxygénothérapie hyperbare. Nous rapportons les cas de trois patients, traités pour une radionécrose cérébrale par du bévacizumab à la posologie de 10
mg/kg en perfusion mensuelle. Les patients avaient développé une radionécrose cérébrale suite à l’irradiation d’une tumeur maligne cérébrale. La radionécrose était diagnostiquée à l’imagerie par résonance magnétique en associant les séquences conventionnelles et non conventionnelles. Un cas ne reçut qu’une perfusion de bévacizumab, une lymphopénie importante ne permit pas la poursuite du traitement. Un deuxième cas bénéficia de quatre perfusions, mais l’absence d’amélioration des symptômes cliniques et d’évolution des lésions à l’imagerie firent interrompre le traitement. Quant au troisième cas, il développa des effets indésirables graves après trois perfusions, un accident vasculaire cérébral ischémique et un ulcère de cornée perforé, conduisant également à l’interruption prématurée du traitement. L’apparition d’effets indésirables graves ainsi que l’absence d’efficacité clinique et radiologique du bévacizumab entraînèrent l’arrêt prématuré du traitement chez nos trois patients.
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.
Abstract 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.
Abstract 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.
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 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/m2, every 2 weeks for four cycles before radiotherapy (RT) (60Gy), concomitant oral TMZ, 75 mg/m2/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/m2/day during RT, and 150–200 mg/m2 for 5 days every 28 days for 6 months. The use of BEV was allowed at progression in the control arm.
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.
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 registered under EUDRACT number 2008-002775-28 (NCT01022918).
La présence de délétion 1p et 19q est réputée corrélée au diagnostic d’oligodendrogliome, à une plus grande chimiosensibilité et à un meilleur pronostic. Nous avons revu la littérature afin d’évaluer ...l’utilité de ces corrélations en pratique clinique. Après analyse de 33 études incluant 2666 patients, les taux moyens de délétion 1p et de codélétion 1p19q étaient respectivement 65,4 et 63,3 % dans les oligodendrogliomes, 28,7 et 21,6 % dans les oligoastrocytomes, 13,2 et 7,5 % dans les astrocytomes, 11,6 et 2,9 % dans les glioblastomes. La présence de délétions 1p ou de codélétions constitue un argument fort en faveur d’un diagnostic histologique oligodendroglial, mais leur absence ne permet pas d’éliminer le diagnostic d’oligodendrogliome. La probabilité de réponse à la chimiothérapie d’un oligodendrogliome de grade 3 est plus grande en présence de codélétion. L’existence de codélétion constitue donc un argument supplémentaire en faveur d’une décision de chimiothérapie, mais l’absence de codélétion ne permet pas d’écarter cette décision. La présence de délétion 1p ou de codélétion est un facteur de bon pronostic pour les oligodendrogliomes et les gliomes mixtes. Ce meilleur pronostic peut s’expliquer par plusieurs facteurs associés à ces deletions : meilleure chimiosensibilité, localisation tumorale préférentiellement frontale, croissance tumorale plus lente et découverte plus précoce.
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.
Oligodendroglial tumors are chemotherapy-sensitive tumors, with two thirds of patients responding to combination chemotherapy with procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ), ...a new alkylating and methylating agent, has demonstrated high response rates in patients with recurrent anaplastic astrocytoma. We investigated TMZ as first-line chemotherapy in recurrent oligodendroglial tumors (OD) and mixed oligoastrocytomas (OA) after surgery and radiation therapy.
In a prospective, nonrandomized, multicenter, phase II trial, patients were treated with 200 mg/m2 of TMZ on days 1 through 5 in 28-day cycles for 12 cycles. Patients with a recurrence after prior surgery and radiotherapy, and with measurable and enhancing disease on magnetic resonance imaging (MRI) were eligible for this study. Patients with large lesions and mass effect or with new clinical deficits were not eligible. Pathology and the MRI scans of all responding patients were centrally reviewed.
Thirty-eight eligible patients were included. In three patients, pathology review did not confirm the presence of an OD or OA. TMZ was generally well tolerated. The most frequent side effects were hematologic; only one patient discontinued treatment for toxicity. In 20 (52.6%) of 38 patients (95% exact confidence interval, 35.8% to 69.0%), a complete (n = 10) or partial response to TMZ was observed. The median time to progression was 10.4 months for all patients and 13.2 months for responding patients. At 12 months from the start of treatment, 40% of patients were still free from progression.
TMZ provides an excellent response rate with good tolerability in chemotherapy-naive patients with recurrent OD. A randomized phase III study comparing PCV with TMZ is warranted.
To assess the efficacy and toxicity of chemotherapy alone in patients older than 60 years with primary CNS lymphoma.
Fifty patients with a median age of 72 years and a median Karnofsky performance ...score (KPS) of 50 were eligible for this multicenter phase II study. The protocol consisted of high-dose methotrexate (MTX), lomustine, procarbazine, methylprednisolone, and intrathecal chemotherapy with MTX and cytarabine. The patients received one induction cycle; if objective response was achieved, five additional maintenance cycles were administered every 6 weeks. The median follow-up of patients was 3 years.
Twenty four patients (48%) achieved an objective response (compete response CR, 42%; partial response, 6%), with a median duration of CR of 27 months (range, 3 to 47+ months). Overall median survival time was 14.3 months, and 1-year progression-free survival was 40% (95% confidence interval CI, 26% to 53%). Myelosuppression was the most frequent side effect, with grade 3 to 4 neutropenia in 19% of patients. One patient died during chemotherapy, as a result of pulmonary embolism. Most patients improved or preserved their cognitive functions (47% and 45% of the patients, respectively) and KPS (36% and 52% of the patients, respectively) until relapse, whereas cognitive and KPS decline attributed to delayed treatment neurotoxicity occurred in 8% and 12% patients, respectively.
In the elderly, this chemotherapy regimen compares favorably with radiotherapy (RT) alone and reduces considerably the risk of delayed neurotoxicity associated with combined chemoradiotherapy. Chemotherapy alone is an appropriate strategy in older patients to delay or avoid RT.
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