Ardi Pambuku

Effectiveness of antiangiogenic drugs in glioblastoma patients: A systematic review and meta-analysis of randomized clinical trials

BACKGROUND glioblastomas are highly vascularized tumors and various antiangiogenic drugs have been investigated in clinical trials showing unclear results. We performed a systematic review and a meta-analysis to clarify and evaluate their effectiveness in glioblastoma patients. PATIENTS AND METHODS we searched relevant published and unpublished randomized clinical trials analyzing antiangiogenic drugs versus chemotherapy in glioblastoma patients from January 2006 to January 2016 in MEDLINE, WEB of SCIENCE, ASCO, ESMO and SNO databases. RESULTS fourteen randomized clinical trials were identified (7 with bevacizumab, 2 cilengitide, 1 enzastaurin, 1 dasatinib, 1 vandetanib, 1 temsirolimus, 1 cediranib) including 4330 patients. Antiangiogenic drugs showed no improvement in overall survival with a pooled HR of 1.00, a trend for an inferior outcome, in terms of overall survival, was observed in the group of patients receiving antiangiogenic drug alone compared to cytotoxic drug alone (HR=1.24, p=0.056). Bevacizumab did not improve overall survival. Twelve trials (4113 patients) were analyzed for progression-free survival. Among antiangiogenic drugs, only bevacizumab demonstrated an improvement of progression-free survival (HR=0.63, p<0.001), both alone (HR=0.60, p=0.003) or in combination to chemotherapy (HR=0.63; p<0.001), both as first-line treatment (HR=0.70, p<0.001) or in recurrent disease (HR=0.52, p<0.001). CONCLUSIONS antiangiogenic drugs did not improve overall survival in glioblastoma patients, either as first or second-line treatment, and either as single agent or in combination with chemotherapy. Among antiangiogenic drugs, only bevacizumab improved progression-free survival regardless of treatment line, both as single agent or in combination with chemotherapy.

Diagnostic Value of Plasma and Urinary 2-Hydroxyglutarate to Identify Patients With Isocitrate Dehydrogenase-Mutated Glioma

BACKGROUND Mutant isocitrate dehydrogenase (IDH) 1/2 enzymes can convert α-ketoglutarate into 2-hydroxyglutarate (2HG). The aim of the present study was to explore whether 2HG in plasma and urine could predict the presence of IDH1/2 mutations in patients with glioma. MATERIALS AND METHODS All patients had histological confirmation of glioma and a recent brain magnetic resonance imaging scan showing the neoplastic lesion. Plasma and urine samples were taken from all patients, and the 2HG concentrations were determined using liquid chromatography tandem mass spectrometry. RESULTS A total of 84 patients were enrolled: 38 with R132H-IDH1 mutated and 46 with wild type. Among the 38 patients with mutant IDH1, 21 had high-grade glioma and 17 had low-grade glioma. Among the 46 patients with IDH1 wild-type glioma, 35 and 11 had high- and low-grade glioma, respectively. In all patients, we analyzed the mean 2HG concentration in the plasma, urine, and plasma/urine ratio (Ratio_2HG). We found a significant difference in the Ratio_2HG between patients with and without an IDH1 mutation (22.2 ± 8.7 vs. 15.6 ± 6.8; p < .0001). The optimal cutoff value for Ratio_2HG to identify IDH1 mutation was 19 (sensitivity, 63%; specificity, 76%; accuracy, 70%). In the patients with high-grade glioma only, the optimal cutoff value was 20 (sensitivity, 76%; specificity, 89%; accuracy, 84%; positive predictive value, 80%; negative predictive value, 86%). In 7 of 7 patients with high-grade glioma, we found a correlation between the Ratio_2HG value and the response to treatment. CONCLUSION Ratio_2HG might be a predictor of the presence of IDH1 mutation. The measurement of 2HG could be useful for disease monitoring and also to assess the treatment effects in these patients.

Cisplatin and temozolomide combination in the treatment of supratentorial anaplastic ependymoma.

Anaplastic ependymomas are rare tumors in adult patients. Maximal safe resection and use of radiation therapy are standard treatment approaches in patients with anaplastic ependymoma. Recurrent anaplastic ependymomas are treated by reoperation when the tumors are surgically accessible, by radiotherapy if not previously administered and by salvage chemotherapy. However, the role of chemotherapy is still unclear. A few retrospective studies showed interesting results with platinum-based regimens, while the administration of temozolomide alone demonstrated conflicting results. We present, for the first time, the case of a patient with anaplastic ependymoma refractory to platinum-based chemotherapy and temozolomide only, but showing a prolonged reduction of the lesion after receiving combination chemotherapy with cisplatin and temozolomide. A brief review of the literature on the treatment of anaplastic ependymoma follows.

Neurocognitive functions and health-related quality of life in glioblastoma patients: a concise review of the literature.

The maintenance of quality of life in patients with high-grade glioma is an important endpoint during treatment, particularly in those with glioblastoma multiforme, given its dismal prognosis; thus, the primary aims of treatments are to reduce morbidity, restore or preserve neurological functions, and the capacity to perform daily activities. This review aims to summarise what is currently known about neurocognitive outcome and quality of life in patients with high-grade glioma, particularly in glioblastoma patients. We considered all the variables that can influence neurocognitive functions, the perception of quality of life and their role as predictors for treatment outcomes.

An Overview of Fotemustine in High-Grade Gliomas: From Single Agent to Association with Bevacizumab

Fotemustine is a third-generation nitrosourea showing efficacy in various types of tumors such as melanoma and glioma. We reviewed the most important studies on fotemustine treatment in glioma patients analyzing its pharmacological profile and its activity and safety. Fotemustine was used as single agent or in association with new targeted drugs such as bevacizumab; fotemustine was used both as first-line chemotherapy before temozolomide era and in refractory-temozolomide patients during temozolomide era. Finally, analyzing and comparing the activity and safety of fotemustine alone or in combination with bevacizumab versus other nitrosoureas such as lomustine, we may suggest that the combination treatment with bevacizumab and fotemustine may be active and tolerable in patients with high grade gliomas.

Cognitive Rehabilitation in Patients with Gliomas and Other Brain Tumors: State of the Art

Disease prognosis is very poor in patients with brain tumors. Cognitive deficits due to disease or due to its treatment have an important weight on the quality of life of patients and caregivers. Studies often take into account quality of life as a fundamental element in the management of disease and interventions have been developed for cognitive rehabilitation of neuropsychological deficits with the aim of improving the quality of life and daily-life autonomy of patients. In this literature review, we will consider the published studies of cognitive rehabilitation over the past 20 years.

Temozolomide treatment of a malignant pheochromocytoma and an unresectable MAX-related paraganglioma

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are neuroendocrine tumors with a strong genetic background. The mainstay of treatment for PCC/PGLs is surgery. However, for unresectable lesions, no curative treatment is currently available. Temozolomide (TMZ) has been shown to determine radiological and biochemical response in malignant PCC/PGLs. We report two cases of PCC/PGLs treated with TMZ. Case 1 is a 51-year-old man with local and distant recurrence (liver and bone metastases) of right adrenal PCC. Case 2 is a 54-year-old woman with a PCC/PGL syndrome caused by a mutation in MAX gene (c.171+1G>A), operated on for bilateral adrenal PCC and presenting with a large unresectable abdominal PGL. Both patients presented hypertension due to catecholamine hypersecretion. TMZ determined radiological response according to RECIST criteria, reduction of urinary catecholamine levels, and controlled hypertension in both patients. Furthermore, the current study demonstrates, for the first time, that MAX-related PGLs are responsive to TMZ.

Elderly patients with glioblastoma: where are we going?

The recent publication in the New England Journal of Medicine of the multicentric randomized trial in elderly glioblastoma patients led by Dr. Perry and his colleagues (1) addresses an important question: should older patients be treated with the combination of radiation therapy and temozolomide followed by maintenance temozolomide?

P17.53THE COMBINATION OF CARMUSTINE WAFERS AND FOTEMUSTINE IN RECURRENT GLIOBLASTOMA PATIENTS: OUR EXPERIENCE

BACKGROUND: In the last years, few advances have been made improving progression-free survival and overall survival in patients with glioblastoma multiforme. There is no standard treatment for recurrent disease. We analyzed the feasibility of a multimodal strategy with second surgery plus carmustine wafers in the surgical cavity followed by intravenous fotemustine administration. METHODS: Retrospectively, we analyzed patients with recurrent glioblastoma treated with this multimodal strategy: carmustine wafers positioned during second surgery and subsequently, fotemustine drug as second-line treatment performed between 14 and 21 days after the second surgery. Intravenous fotemustine was administrated at 100mg/m2 every week for 3 consecutive weeks followed by a 5-week rest period; subsequently, an infusion every 3 weeks until progression disease or unacceptable toxicity or until a maximum of 12 cycles. During fotemustine therapy tumor response was evaluated by clinician assessment and by brain magnetic resonance imaging according to Macdonald criteria every two months or when clinically indicated. RESULTS: Twenty-four patients were analyzed. The median age was 53.6 years; all patients had KPS between 90 and 100, 19 patients (79%) performed a gross total resection >98% and 5 (21%) a gross total resection >90%. Seventeen patients were available for MGMT gene analysis and 10 (59%) patients had methylated MGMT gene promoter. The median time from first and second surgery was 17 months. The median progression-free survival from second surgery was 6 months (95% CI 3.9-8.05) and the median OS was 14 months (95% CI 11.1 - 16.8 months). No significant association was found between the resection rate (GTR >98% vs GTR >90%) and PFS (p = 0.4) and OS (p = 0.9). All patients were evaluable for toxicity which was predominantly haematological: 5 patients (21%) experienced grade 3-4 thrombocytopenia and 3 patients (12%) grade 3-4 leukopenia . Among non-haematological toxicity: 5 patients (21%) had grade 1-2 asthenia, 2 patients (8%) had grade 1-2 nausea/vomiting and 2 patients (8%) reported hypertransaminasemia. CONCLUSION: This multimodal strategy may be feasible in patients with recurrent glioblastoma; in particular, for patients in good clinical conditions

The combination of carmustine wafers and fotemustine in recurrent glioblastoma patients: A monoinstitutional Experience

Background. To date, there is no standard treatment for recurrent glioblastoma. We analyzed the feasibility of second surgery plus carmustine wafers followed by intravenous fotemustine. Methods. Retrospectively, we analyzed patients with recurrent glioblastoma treated with this multimodal strategy. Results. Twenty-four patients were analyzed. The median age was 53.6; all patients had KPS between 90 and 100; 19 patients (79%) performed a gross total resection > 98% and 5 (21%) a gross total resection > 90%. The median progression-free survival from second surgery was 6 months (95% CI 3.9–8.05) and the median OS was 14 months (95% CI 11.1–16.8 months). Toxicity was predominantly haematological: 5 patients (21%) experienced grade 3-4 thrombocytopenia and 3 patients (12%) grade 3-4 leukopenia. Conclusion. This multimodal strategy may be feasible in patients with recurrent glioblastoma, in particular, for patients in good clinical conditions.