Vyshak Alva Venur

Current Medical Treatment of Glioblastoma

Glioblastoma is the most common adult malignant primary brain tumor. Despite the advances in therapeutic options, survival of patients with glioblastoma remains dismal at 15-18 months. Current standard of care for newly diagnosed glioblastoma is maximal possible safe resection consistent with the preservation of neurologic function followed by concurrent temozolomide with radiation and adjuvant. Treatment options at recurrence include surgical resection with or without the placement of carmustine wafers, re-irradiation and chemotherapeutics such as nitrosoureas (lomustine, carmustine) or bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor (VEGF).

Immune Checkpoint Inhibitors in Brain Metastases: From Biology to Treatment.

Cancer immunotherapy has been a subject of intense research over the last several years, leading to new approaches for modulation of the immune system to treat malignancies. Immune checkpoint inhibitors (anti-CLTA-4 antibodies and anti-PD-1/PD-L1 antibodies) potentiate the hosts own antitumor immune response. These immune checkpoint inhibitors have shown impressive clinical efficacy in advanced melanoma, metastatic kidney cancer, and metastatic non-small cell lung cancer (NSCLC)-all malignancies that frequently cause brain metastases. The immune response in the brain is highly regulated, challenging the treatment of brain metastases with immune-modulatory therapies. The immune microenvironment in brain metastases is active with a high density of tumor-infiltrating lymphocytes in certain patients and, therefore, may serve as a potential treatment target. However, clinical data of the efficacy of immune checkpoint inhibitors in brain metastases compared with extracranial metastases are limited, as most clinical trials with these new agents excluded patients with active brain metastases. In this article, we review the current scientific evidence of brain metastases biology with specific emphasis on inflammatory tumor microenvironment and the evolving state of clinical application of immune checkpoint inhibitors for patients with brain metastases.

Prognostic scores for brain metastasis patients: use in clinical practice and trial design

Brain metastases (BM) are the most serious neurological complication of cancer that results in significant morbidity and mortality in these patients. The most common primary malignancies that lead to BM include lung, breast and melanoma. Until recently the outcomes of patients with BM has been dismal. The current therapeutic options include surgery, whole brain radiation therapy (WBRT), stereotactic radiation (SRS), systemic therapy and symptom management only. Prognostic scores, a useful tool for BM patients, as an estimation of a patients prognosis can guide tailored treatment for these patients. It is appropriate to recommend more aggressive approaches in patients with good performance status and limited disease and focus on symptom control and palliative measures when the disease is more advanced, or comorbidity preclude aggressive therapy. Due to vastly different outcomes, prognostic scores are important to stratify patients in clinical trials. A number of prognostic scoring systems for BM patients have been proposed that include Recursive Partitioning Analysis (RPA), the Score Index For Radiosurgery (SIR), the Basic Score for Brain Metastases (BSBM), the Rotterdam system (ROTTERDAM), the Golden Grading System (GGS), 2 Rades classification (RADES), the Graded Prognostic Assessment (GPA) and the disease specific Graded Prognostic Assessment (ds-GPA). In this article, we will review the important prognostic scoring systems and their utility in clinical decision making and trial design.

Bevacizumab in high-grade gliomas: past, present, and future

The survival of patients with high-grade gliomas (anaplastic gliomas and glioblastoma) remains poor despite current treatment modalities. However, an enhanced understanding of gliomagenesis is supporting the development of targeted molecular therapies with the potential for improving clinical outcomes. Glioblastoma (GBM) is characterized by extensive microvascular proliferation and the production of large amounts of VEGF. Bevacizumab is a humanized IgG1 monoclonal antibody that selectively binds with high affinity to human VEGF and neutralizes VEGF’s biologic activity. Preclinical data indicate that angiogenesis is essential for the proliferation and survival of GBM cells. A number of studies have evaluated the outcomes of both newly diagnosed and recurrent GBM patients with bevacizumab in a prospective manner. Here, we discuss the role of bevacizumab in the treatment of anaplastic gliomas and GBM in the recurrent and upfront setting.

Targeted Therapy in Brain Metastases: Ready for Primetime?

Brain metastasis is a serious complication of cancer that causes significant morbidity for patients. Over the last decade, numerous new driver somatic mutations have been recognized and targeted therapies are changing the landscape of treatment in lung cancer, breast cancer, and melanoma, which are also the three most common cancers that result in brain metastases. The common actionable mutations include the EGFR mutation and anaplastic lymphoma kinase (ALK) translocations in non-small cell lung cancer, the HER2 mutation in breast cancer, and the BRAF mutation in melanoma. However, most of the early trials with targeted agents excluded patients with brain metastases. With a better understanding of the biology, several recent trials of targeted therapy that focus on brain metastases have been reported and others are ongoing. Novel agents with better penetration across the blood-brain barrier are currently being investigated for patients with brain metastases. In this review, we discuss the current state of use and future directions of targeted therapies in brain metastases.

Programmed death-1/programmed death-1 ligand axis as a therapeutic target in oncology: Current insights

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Journal of Receptor, Ligand and Channel Research 2015:8 1–7 Journal of Receptor, Ligand and Channel Research Dovepress

Melanoma brain metastasis: the impact of stereotactic radiosurgery, BRAF mutational status, and targeted and/or immune-based therapies on treatment outcome

OBJECTIVE The goal of this study was to investigate the impact of stereotactic radiosurgery (SRS), BRAF status, and targeted and immune-based therapies on the recurrence patterns and factors associated with overall survival (OS) among patients with melanoma brain metastasis (MBM). METHODS A total of 366 patients were treated for 1336 MBMs; a lesion-based analysis was performed on 793 SRS lesions. The BRAF status was available for 78 patients: 35 had BRAF mut and 43 had BRAF wild-type ( BRAF-WT) lesions. The Kaplan-Meier method evaluated unadjusted OS; cumulative incidence analysis determined the incidences of local failure (LF), distant failure, and radiation necrosis (RN), with death as a competing risk. RESULTS The 12-month OS was 24% (95% CI 20%-29%). On multivariate analysis, younger age, lack of extracranial metastases, better Karnofsky Performance Status score, and fewer MBMs, as well as treatment with BRAF inhibitors (BRAFi), anti-PD-1/CTLA-4 therapy, or cytokine therapy were significantly associated with OS. For patients who underwent SRS, the 12-month LF rate was lower among those with BRAF mut lesions (6%, 95% CI 2%-11%) compared with those with BRAF-WT lesions (22%, 95% CI 13%-32%; p < 0.01). The 12-month LF rates among lesions treated with BRAFi and PD-1/CTLA-4 agents were 1% (95% CI 1%-4%) and 7% (95% CI 1%-13%), respectively. On multivariate analysis, BRAF inhibition within 30 days of SRS was protective against LF (HR 0.08, 95% CI 0.01-0.55; p = 0.01). The 12-month rates of RN were low among lesions treated with BRAFi (0%, 95% CI 0%-0%), PD-1/CTLA-4 inhibitors (2%, 95% CI 1%-5%), and cytokine therapies (6%, 95% CI 1%-13%). CONCLUSIONS Prognostic schema should incorporate BRAFi or immunotherapy status and use of targeted therapies. Treatment with a BRAF inhibitor within 4 weeks of SRS improves local control without an increased risk of RN.

Coexistent pulmonary granular cell tumor and adenocarcinoma of the lung

We report a case of granular cell tumor (GCT) of the lung with coexistent invasive adenocarcinoma. GCTs are rare tumors and often benign and amenable to local bronchoscopic excision. However, occasionally they are more aggressive and locally infiltrative requiring definitive surgical resection. Our patient had a central and infiltrative GCT, in addition a very small (6 mm) peripheral nodule in the same lobe as the GCT, which after careful examination of the surgical specimen during grossing was found to be an invasive adenocarcinoma. There are a few reports in the literature of GCTs with coexistent bronchogenic cancer. Our case highlights the importance of careful evaluation and exploration of the surgical specimens during grossing of patients with GCTs. In GCT patients presenting with additional pulmonary nodules, a more definitive surgical approach should be considered.

Prophylactic use of Granulocyte-colony stimulating factors (G-CSF) in cancer patients: Adherence to NCCN guidelines.

209 Background: G-CSF are used for prophylactic and therapeutic treatment of febrile neutropenia (FN). NCCN guidelines (version 1.2015) recommend prophylactic use of G-CSF based on the chemotherapy regimen and patient related risk factors, especially for the high (> 20%) and intermediate (10-20%) risk groups for developing FN. This study investigates the practice patterns and adherence to NCCN guidelines for use of G-CSF at a community based academic outpatient facility. METHODS Cleveland Clinic IRB was obtained. Charts of all patients with underlying non-small cell lung cancer, small cell lung cancer, and breast cancer, treated in the year 2013, were reviewed for G-CSF use on their initial chemotherapy encounter. Risk assessment for developing FN was assessed based on individual risk factors and chemotherapy regimen. Analysis was obtained for appropriate guideline based use of G-CSF. RESULTS A total of 172 (n = 172) patients were included in the study. Overall, 63% (108/172) of patients had breast cancer; 81% (140/172) were female, most patients (64%, 108/170) were aged < 65 years; 29% (49/172) had metastatic disease; and almost all patients (91%, 106/117) had good ECOG performance status (0 or 1). The overall risk of FN was estimated to be low (< 10%) for 9% (16/172) of patients, intermediate (10-20%) for 45% (77/172) of patients, and high (> 20%) for 45%. Overall, 5% (8/172) of patients did not follow the NCCN guidelines. Only 86% of the patients in metastatic group were adherent to NCCN guidelines compared to 99% of patients in non-metastatic group (p< .01). Among patients with metastatic disease, 14% (7/49) did not follow NCCN guidelines; in a univariable analysis, among patients with metastatic disease - risk of neutropenia (p < .0001), age (p < .01), and prior chemotherapy and or radiation (p = .04), were associated with whether or not the NCCN guidelines were followed. CONCLUSIONS In our limited study population, more use of G-CSF was seen among patients with metastatic cancer with a higher number of metastatic patients being non-adherent to NCCN guidelines. Further research is required to elucidate the potential benefit and cost-effectiveness of G-CSF use in the palliative setting.

An alternative titration schedule of axitinib in metastatic renal cell carcinoma.

444 Background: Titration of axitinib for metastatic renal cell carcinoma (mRCC) is currently based on tolerance with escalation from 10 mg/day to 14 mg/day and then to 20 mg/day. However, not all patients who can be titrated upward require a higher dose for response, nor do all patients tolerate the increased dose levels. An alternative titrating strategy was employed based on radiographic response, tolerance, and using intermediate dosing levels. Methods: In this retrospective analysis of mRCC, axitinib was initiated at 10 mg/day (5 mg BID). Response was assessed with CT scans at 6 weeks after each dosing change. Patients with response by MASS criteria and acceptable toxicity ( grade 2 toxicity the dose was reduced by 1 mg/day. Results: Twenty-eight patients were started on axi...