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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.


Quant E.C.,Center for Neuro Oncology | Wen P.Y.,Center for Neuro Oncology
Current Oncology Reports | Year: 2011

Accuracy and reproducibility in determining response to therapy and tumor progression can be difficult to achieve for nervous system tumors. Current response criteria vary depending on the pathology and have several limitations. Until recently, the most widely used criteria for gliomas were "Macdonald criteria," based on two-dimensional tumor measurements on neuroimaging studies. However, the Response Assessment in Neuro-Oncology (RANO) Working Group has published new recommendations in high-grade gliomas and is working on recommendations for other nervous system tumors. This article reviews current response criteria for high-grade glioma, low-grade glioma, brain metastasis, meningioma, and schwannoma. © 2010 Springer Science+Business Media, LLC.


Wen P.Y.,Brigham and Women's Hospital | Wen P.Y.,Center for Neuro Oncology
Expert Review of Anticancer Therapy | Year: 2010

A number of important studies were presented at the CNS tumors section of the 2010 American Society of Oncology (ASCO) Annual Meeting. There was particular interest in a Phase II study showing that the mTOR inhibitor everolimus had significant activity in tuberous patients with subependymal giant cell astrocytomas. Two Phase III studies reported on the relative benefits of radiotherapy and chemotherapy in elderly patients with glioblastomas. Other studies focused on promising new agents such as XL184 and ANG1005. © 2010 Expert Reviews Ltd.


Lee E.Q.,Center for Neuro Oncology | Nayak L.,Center for Neuro Oncology | Wen P.Y.,Center for Neuro Oncology | Reardon D.A.,Center for Neuro Oncology
Current Treatment Options in Neurology | Year: 2013

Opinion statement: Regardless of MGMT status, standard of care for a patient with newly diagnosed glioblastoma (GBM), age ≤70 years, and adequate functional status is radiation and concurrent temozolomide followed by adjuvant temozolomide. For elderly patients, recent studies have suggested that standard radiation, hypofractionated radiation, or single agent temozolomide are acceptable treatment options. Randomized phase III studies of bevacizumab in combination with radiation and temozolomide for newly diagnosed GBM have completed accrual. Preliminary results reveal a clear progression-free survival benefit. Overall survival appears unchanged although follow-up has not fully matured and cross-over to bevacizumab upon progression among control patients may limit definitive conclusions. Although bevacizumab in the upfront setting may be considered for a subset of patients, it should not be used routinely in newly diagnosed patients until final results are available. Clinical trials evaluating promising therapeutics given in combination with standard temozolomide chemoradiation are critically needed. © 2013 Springer Science+Business Media New York.


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.


Quant E.C.,Center for Neuro Oncology | Drappatz J.,Center for Neuro Oncology | Wen P.Y.,Center for Neuro Oncology | Norden A.D.,Center for Neuro Oncology
Current Treatment Options in Neurology | Year: 2010

Opinions vary on the best treatment options for recurrent high-grade glioma. Some argue that bevacizumab should become standard of care for patients with recurrent glioblastoma, especially in light of recent FDA approval for this indication. However, this opinion is not uniformly accepted. Age, performance status, histology, tumor size and location, O6-methylguanine-DNA methyltransferase (MGMT) methylation status for glioblastoma, 1p/19q status for oligodendroglial tumors, and the number and types of prior therapies are important considerations. In addition, recurrent disease must be distinguished from -pseudoprogression- due to treatment effects. Enrollment in a clinical trial is the optimal choice for most patients with recurrent high-grade glioma after failure of radiation therapy and temozolomide. For patients who are ineligible or do not have access to clinical trials, then either bevacizumab monotherapy or bevacizumab in combination with a second agent such as irinotecan is recommended. Involved-field external beam radiation should be considered for patients with anaplastic gliomas who have not received radiation. For patients with anaplastic astrocytoma who progress after radiotherapy, temozolomide may be used. For patients with anaplastic oligodendroglioma who progress after radiotherapy, PCV chemotherapy and temozolomide are options. Oligodendroglial tumors with 1p/19q deletions are more likely to respond to treatment. In the past, carmustine was commonly used to treat recurrent high-grade glioma, but the utility of carmustine in the modern era is unknown because most studies were performed prior to the widespread use of temozolomide. High-precision re-irradiation such as stereotactic radiosurgery is another option in high-grade glioma, especially for patients with poor bone marrow reserve or inability to tolerate chemotherapy, but there is a paucity of studies with adequate controls. Surgery may be useful as adjuvant treatment for patients with symptoms due to mass effect or for patients requiring definitive histopathology, but it generally should be combined with another treatment modality. Emerging therapies, including dose-intense temozolomide regimens, targeted molecular inhibitors, other antiangiogenic therapies, viral gene therapies, immunotherapies, and convection-enhanced delivery of targeted immunotoxins, are still under investigation. © Springer Science+Business Media, LLC 2010.


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.


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.


Eisele S.C.,Center for Neuro Oncology | Reardon D.A.,Center for Neuro Oncology
Cancer | Year: 2016

Brainstem gliomas in adults are a rare and heterogeneous group of brain tumors that vary with regard to underlying pathology, radiographic appearance, clinical course and prognosis. Diffuse intrinsic pontine gliomas represent the most common subtype. Although still considered aggressive and most often lethal, these brain tumors are associated with a more insidious clinical course and more favorable prognosis compared to the highly aggressive form in children. Treatment options for patients with brainstem gliomas still are limited and insufficiently studied. A better understanding of the pathobiology of these tumors will be crucial for the development of more specific and effective therapies. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2799–2809. © 2016 American Cancer Society. © 2016 American Cancer Society


Reardon D.A.,Center for Neuro Oncology | Wen P.Y.,Center for Neuro Oncology
Nature Reviews Gastroenterology and Hepatology | Year: 2015

Heterogeneity within and across tumours is increasingly recognized as a critical factor that limits therapeutic progress for many cancers. Key studies reported in 2014 describe previously unappreciated patterns of geographical and temporal heterogeneity for glioblastoma (the mostcommon primary CNS tumour in adults), with important implications for ongoing therapeutic studies evaluating molecular targeted therapies. © 2015 Macmillan Publishers Limited.

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