There are promising new therapies that may prove to be effective in selected patients with brain tumors. Recently, accelerated approval was granted for bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), in recurrent or progressive glioblastoma (GBM). This approval was based on demonstration of durable responses with bevacizumab monotherapy in a phase 2 multicenter trial and our NCI intramural phase 2 trial NCI 06-C-0064. Responses were observed in 25.9% and 19.6% of patients and median duration of response was approximately 4 months. This has led to the testing of bevacizumab in newly diagnosed GBM. The Radiation Oncology Therapy Group (RTOG), an extramural NCI/CTEP-sponsored consortium, is conducting a phase 3 double-blind randomized trial of standard chemoradiotherapy with temozolomide bevacizumab for newly diagnosed GBM (RTOG 0825). Both tumor tissue and peripheral blood samples are acquired after written informed consent and are being stored at the RTOG tissue bank for genotyping. This resource provides an unprecedented opportunity to perform genomic correlations of response and treatment-related toxicity. Despite the significant advance with the introduction of bevacizumab in the treatment of GBM, most tumors eventually become nonresponsive and benefits in progression-free and overall survival are measured only in months. Tumor angiogenesis is a complex, genetically heterogeneous process that involves the interaction of multiple types of host and cancer cells and chemical factors, including endothelial cells, pericytes and bone-marrow circulating cells, as well as cancer and stromal cells. Clinically, both response and toxicity vary significantly between patients and these effects are currently unpredictable. We hypothesize that germline single-nucleotide polymorphisms (SNPs) are logical candidates to study as predictors of response because angiogenesis is largely a host-mediated event, as opposed to a process mediated by somatic mutations in the tumors cells. We started a collaboration with RTOG and its leadership with the objectives of: 1) Identify germline DNA variants that predict response to a treatment regimen with bevacizumab versus standard chemoradiation with temzolomide in patients with GBM. 2) Identify clinical predictors of toxicities to brain tumor treatment regimens, including: a) Identify predictors of myelosuppression and lymphopenia in GBM patients treated with temozolomide b) Identify predictors of thromboembolic events and severe hypertension after standard chemoradiation with temozolomide bevacizumab 3) Identify germline DNA variants associated with: a) severe myelosuppression and lymphopenia following treatment with temozolomide b) thromboembolic events and severe hypertension after standard chemoradiation with and without bevacizumab Brain irradiation continues to be the most important treatment for both metastatic and primary tumors. However, cranial radiotherapy can lead to delayed neurotoxicity characterized by variable degrees of leukoencephalopathy, brain atrophy and cognitive decline. Delayed radiation neurotoxicity can occur months to years after radiotherapy and tend to be progressive and irreversible. Its incidence depends on radiotherapy factors (dose per fraction, total dose, volume of tissue irradiated, energy of radiation and type of radiation planning), age (more common in older patients), use of chemotherapy or radiosensitizers and underlying CNS diseases. Moreover, the development of neurotoxicity is time-dependent and because many patients die from the brain tumor before developing neurotoxicity, death needs to be accounted as competing risk when estimating the incidence of neurotoxicity. For example, with whole-brain radiotherapy, 33% of patients developed late neurocognitive toxicity with a median followup of 10 months and actuarial rate of neurocognitive toxicity at 2 years was 49%. The underlying pathophysiology of radiation-induced neurotoxicity is unclear but could involve injury to oligodendrocyte precursor cells and subsequent demyelination and/or to the normal endothelial cells causing brain vascular damage. It is possible that genetic variation contributes to individual susceptibility to radiation induced neurotoxicity. The identification of germ line genetic markers that increase risk of radiation neurotoxicity is another objective of this project and may contribute to individualization of treatment in the future.
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