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Alexander B.M.,Dana Farber Brigham and Womens Cancer Center | Ligon K.L.,Dana Farber Brigham and Womens Cancer Center | Wen P.Y.,Center for Neuro Oncology
Expert Review of Anticancer Therapy | Year: 2013

Radiation therapy has been the foundation of therapy following maximal surgical resection in patients with newly diagnosed glioblastoma for decades and the primary therapy for unresected tumors. Using the standard approach with radiation and temozolomide, however, outcomes are poor, and glioblastoma remains an incurable disease with the majority of recurrences and progression within the radiation treatment field. As such, there is much interest in elucidating the mechanisms of resistance to radiation therapy and in developing novel approaches to overcoming this treatment resistance. © 2013 2013 Expert Reviews Ltd. Source

Reardon D.A.,Center for Neuro Oncology | Reardon D.A.,Harvard University
Clinical Advances in Hematology and Oncology | Year: 2014

The outcome following conventional therapy for patients with primary and metastatic brain tumors remains poor. Most primary brain cancers are angiogenic, and much research has targeted angiogenesis therapeutically. Vascular endothelial growth factor drives angiogenesis in brain tumors, although other factors contribute. Aggregate data confirm that the safety profile of antiangiogenic agents is acceptable among patients with brain cancer; the risks for serious adverse events, such as stroke, hemorrhage, and thrombosis, are low and similar to those observed in other cancers. Evidence of antitumor activity includes encouraging rates of radiographic response and progression-free survival. In addition, the potent antipermeability effects of these agents can substantially reduce cerebral edema and corticosteroid requirement. Importantly, most data demonstrate that antiangiogenic agents preserve neurologic function and improve quality of life. Unfortunately, the impact of angiogenesis inhibition on overall survival appears to be modest at best in patients with brain cancer. In addition, mechanisms of resistance, including selection favoring invasion, remain poorly understood. Source

Chinnaiyan P.,H. Lee Moffitt Cancer Center and Research Institute | Won M.,Radiation Therapy Oncology Group | Wen P.Y.,Center for Neuro Oncology | Rojiani A.M.,Georgia Regents University | And 4 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2013

Purpose: To determine the safety of the mammalian target of rapamycin inhibitor everolimus (RAD001) administered daily with concurrent radiation and temozolomide in newly diagnosed glioblastoma patients. Methods and Materials: Everolimus was administered daily with concurrent radiation (60 Gy in 30 fractions) and temozolomide (75 mg/m2 per day). Everolimus was escalated from 2.5 mg/d (dose level 1) to 5 mg/d (dose level 2) to 10 mg/d (dose level 3). Adjuvant temozolomide was delivered at 150 to 200 mg/m2 on days 1 to 5, every 28 days, for up to 12 cycles, with concurrent everolimus at the previously established daily dose of 10 mg/d. Dose escalation continued if a dose level produced dose-limiting toxicities (DLTs) in fewer than 3 of the first 6 evaluable patients. Results: Between October 28, 2010, and July 2, 2012, the Radiation Therapy Oncology Group 0913 protocol initially registered a total of 35 patients, with 25 patients successfully meeting enrollment criteria receiving the drug and evaluable for toxicity. Everolimus was successfully escalated to the predetermined maximum tolerated dose of 10 mg/d. Two of the first 6 eligible patients had a DLT at each dose level. DLTs included gait disturbance, febrile neutropenia, rash, fatigue, thrombocytopenia, hypoxia, ear pain, headache, and mucositis. Other common toxicities were grade 1 or 2 hypercholesterolemia and hypertriglyceridemia. At the time of analysis, there was 1 death reported, which was attributed to tumor progression. Conclusions: Daily oral everolimus (10 mg) combined with both concurrent radiation and temozolomide followed by adjuvant temozolomide is well tolerated, with an acceptable toxicity profile. A randomized phase 2 clinical trial with mandatory correlative biomarker analysis is currently under way, designed to both determine the efficacy of this regimen and identify molecular determinants of response. © 2013 Elsevier Inc. Source

Arvold N.D.,Dana Farber Brigham and Womens Cancer Center | Reardon D.A.,Center for Neuro Oncology
Clinical Interventions in Aging | Year: 2014

Age remains the most powerful prognostic factor among glioblastoma (GBM) patients. Half of all patients with GBM are aged 65 years or older at the time of diagnosis, and the incidence rate of GBM in patients aged over 65 years is increasing rapidly. Median survival for elderly GBM patients is less than 6 months and reflects less favorable tumor biologic factors, receipt of less aggressive care, and comorbid disease. The standard of care for elderly GBM patients remains controversial. Based on limited data, extensive resection appears to be more beneficial than biopsy. For patients with favorable Karnofsky performance status (KPS), adjuvant radiotherapy (RT) has a demonstrated survival benefit with no observed decrement in quality of life. Concurrent and adjuvant temozolomide (TMZ) along with RT to 60 Gy have not been prospectively studied among patients aged over 70 years but should be considered for patients aged 65-70 years with excellent KPS. Based on the recent NOA-08 and Nordic randomized trials, testing for O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation should be performed routinely immediately after surgery to aid in adjuvant treatment decisions. Patients aged over 70 years with favorable KPS, or patients aged 60-70 years with borderline KPS, should be considered for monotherapy utilizing standard TMZ dosing for patients with MGMT-methylated tumors, and hypofractionated RT (34 Gy in ten fractions or 40 Gy in 15 fractions) for patients with MGMT-unmethylated tumors. The ongoing European Organisation for Research and Treatment of Cancer/National Cancer Institute of Canada trial will help clarify the role for concurrent TMZ with hypofractionated RT. For elderly patients with poor KPS, reasonable options include best supportive care, TMZ alone, hypofractionated RT alone, or whole brain RT for symptomatic patients needing to start treatment urgently. Given the balance between short survival and quality of life in this patient population, optimal management of elderly GBM patients must be made individually according to patient age, MGMT methylation status, performance score, and patient preferences. © 2014 Arvold and Reardon. Source

Cankovic M.,Ford Motor Company | Nikiforova M.N.,University of Pittsburgh | Snuderl M.,NYU Langone Medical Center | Adesina A.M.,Baylor College of Medicine | And 5 more authors.
Journal of Molecular Diagnostics | Year: 2013

Recent advances in modern molecular technologies allow for the examination and measurement of cancer-related genomic changes. The number of molecular tests for evaluation of diagnostic, prognostic, or predictive markers is expected to increase. In recent years, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation has been firmly established as a biomarker in patients diagnosed with gliomas, for both clinical trials and routine clinical management. Similarly, molecular markers, such as loss of heterozygosity (LOH) for 1p/19q have already demonstrated clinical utility in treatment of oligodendroglial tumors, and others might soon show clinical utility. Furthermore, nonrandom associations are being discovered among MGMT, 1p/19q LOH, isocitrate dehydrogenase (IDH) mutations, and other tumor-specific modifications that could possibly enhance our ability to predict outcome and response to therapy. While pathologists are facing new and more complicated requests for clinical genomic testing, clinicians are challenged with increasing numbers of molecular data coming from molecular pathology and genomic medicine. Both pathologists and oncologists need to understand the clinical utility of molecular tests and test results, including issues of turnaround time, and their impact on the application of targeted treatment regimens. This review summarizes the existing data that support the rationale for MGMT promoter methylation testing and possibly other molecular testing in clinically defined glioma subtypes. Various molecular testing platforms for evaluation of MGMT methylation status are also discussed. © 2013 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved. Source

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