Discontinuing bevacizumab in patients with glioblastoma: an ethical analysis.

Glioblastoma (GBM) is a highly lethal malignant brain tumor that expresses proangiogenic factors, including vascular endothelial growth factor (VEGF). Bevacizumab (Avastin®; Genentech, Inc., South San Francisco, CA), a monoclonal antibody against VEGF, is routinely used in the U.

Phase II study of Gleevec® plus hydroxyurea (HU) in adults with progressive or recurrent meningioma.

We prospectively evaluated the efficacy and safety of imatinib plus hydroxyurea in patients with progressive/recurrent meningioma. A total of 21 patients with progressive/recurrent meningioma were enrolled in this dual center, single-arm, phase II trial. All patients received 500 mg of hydroxyurea twice a day.

Is surgery at progression a prognostic marker for improved 6-month progression-free survival or overall survival for patients with recurrent glioblastoma?

Historically, the North American Brain Tumor Consortium used 6-month progression-free survival (PFS6) as the primary outcome for recurrent glioma phase II clinical trials. In some trials, a subset of patients received the trial treatment before surgery to assess tumor uptake and biological activity. We compared PFS6 and overall survival (OS) for patients with glioblastoma undergoing surgery at progression to results for those without surgery to evaluate the impact of surgical intervention on these outcomes.

Cilengitide in patients with recurrent glioblastoma: the results of NABTC 03-02, a phase II trial with measures of treatment delivery.

Cilengitide is a cyclic pentapeptide that is a specific inhibitor of the αvβ3 and αvβ5 integrins. Preclinical studies demonstrate antiangiogenic activity and anti-invasive activity in a number of glioma models. This study was designed to evaluate the efficacy and tumor delivery of cilengitide in patients with recurrent glioblastoma.

Safety of concurrent bevacizumab therapy and anticoagulation in glioma patients.

Venous thromboembolic events (VTE) are common in glioma patients and are typically treated with anticoagulant medications. The anti-angiogenic agent bevacizumab (BVZ) increases the risks of both VTE and hemorrhagic complications. Little is known about the hemorrhagic risk of anticoagulation in glioma patients receiving BVZ.

International retrospective study of over 1000 adults with anaplastic oligodendroglial tumors.

Treatment for newly diagnosed anaplastic oligodendroglial tumors is controversial. Radiotherapy (RT) alone and in combination with chemotherapy (CT) are the most well studied strategies. However, CT alone is often advocated, especially in cases with 1p19q codeletion.

Myeloid biomarkers associated with glioblastoma response to anti-VEGF therapy with aflibercept.

Purpose: VEGF and infiltrating myeloid cells are known regulators of tumor angiogenesis and vascular permeability in glioblastoma. We investigated potential blood-based markers associated with radiographic changes to aflibercept, which binds VEGF and placental growth factor (PlGF) in patients with recurrent glioblastoma.

Experimental Design: In this single-arm phase II trial, aflibercept was given intravenously every two weeks until disease progression.

Phase II study of aflibercept in recurrent malignant glioma: a North American Brain Tumor Consortium study.

Purpose: Antivascular endothelial growth factor (anti-VEGF) therapy is a promising treatment approach for patients with recurrent glioblastoma. This single-arm phase II study evaluated the efficacy of aflibercept (VEGF Trap), a recombinantly produced fusion protein that scavenges both VEGF and placental growth factor in patients with recurrent malignant glioma.

Patients And Methods: Forty-two patients with glioblastoma and 16 patients with anaplastic glioma who had received concurrent radiation and temozolomide and adjuvant temozolomide were enrolled at first relapse.

Application of novel response/progression measures for surgically delivered therapies for gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group.

Background: The Response Assessment in Neuro-Oncology (RANO) Working Group is an international, multidisciplinary effort to develop new standardized response criteria for clinical trials in brain tumors. The RANO group identified knowledge gaps relating to the definitions of tumor response and progression after the use of surgical or surgically based treatments.

Objective: To outline a proposal for new response and progression criteria for the assessment of the effects of surgery and surgically delivered therapies for patients with gliomas.

Neurocognitive function in patients with recurrent glioblastoma treated with bevacizumab.

Neurocognitive decline is a frequent adverse effect of glioblastoma. Antitumor therapies that are efficacious, as measured by traditional endpoints such as objective response (OR) and progression-free survival (PFS), and have beneficial effects on neurocognitive function (NCF) are of clinical benefit to these patients. We evaluated neurocognitive changes across time in 167 patients with recurrent glioblastoma treated with bevacizumab-based therapy in BRAIN, a phase II, randomized, multicenter trial.

Crude drugs as anticancer agents.

Although tremendous progress has been made in basic cancer biology and in the development of novel cancer treatments, cancer remains a leading cause of death in the world. The etiopathogenesis of cancer is complex. Besides genetic predisposition, known environmental factors associated with cancer are: diet, lifestyle, and environmental toxins.

A phase I/II trial of the histone deacetylase inhibitor romidepsin for adults with recurrent malignant glioma: North American Brain Tumor Consortium Study 03-03.

Romidepsin, a potent histone deacetylase inhibitor, has shown activity in preclinical glioma models. The primary objectives of this trial were to determine the pharmacokinetics of romidepsin in patients with recurrent glioma on enzyme-inducing antiepileptic drugs (EIAEDs) and to evaluate the antitumor efficacy of romidepsin in patients with recurrent glioblastoma who were not receiving EIAEDs. Two dose cohorts were studied in the phase I component of the trial (13.

Signal transduction inhibitors and antiangiogenic therapies for malignant glioma.

Detailed characterization of the cancer genome in a large number of primary human glioblastomas has identified recurrent alterations that result in deregulation of signal transduction pathways and are "druggable" with a growing number of small molecule pharmaceuticals. While many of these compounds have shown clinical activity in other human cancers harboring similar genetic alterations, the clinical experience in glioblastoma has been disappointing thus far with only rare and transient radiographic responses. Our understanding of drug resistance is confounded by the uncertainty of drug delivery across the blood brain barrier and the limited knowledge to what extent the growth of these tumors depends on any particular signaling pathway.

Clinical trial end points for high-grade glioma: the evolving landscape.

To review the strengths and weaknesses of primary and auxiliary end points for clinical trials among patients with high-grade glioma (HGG). Recent advances in outcome for patients with newly diagnosed and recurrent HGG, coupled with the development of multiple promising therapeutics with myriad antitumor actions, have led to significant growth in the number of clinical trials for patients with HGG. Appropriate clinical trial design and the incorporation of optimal end points are imperative to efficiently and effectively evaluate such agents and continue to advance outcome.

A phase II study evaluating the efficacy and safety of AMG 102 (rilotumumab) in patients with recurrent glioblastoma.

This phase II study evaluated the efficacy and safety of AMG 102 (rilotumumab), a fully human monoclonal antibody against hepatocyte growth factor/scatter factor (HGF/SF), in patients with recurrent glioblastoma (GBM). Patients with histologically confirmed, measurable recurrent GBM or gliosarcoma (World Health Organization grade 4) and ≤3 relapses or prior systemic therapies received AMG 102 (10 or 20 mg/kg) by infusion every 2 weeks. The primary endpoint was best confirmed objective response rate (central assessment) per Macdonald criteria.

Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas.

Malignant gliomas are highly lethal tumors resistant to current therapies. The standard treatment modality for these tumors, surgical resection followed by radiation therapy and concurrent temozolomide, has demonstrated activity, but development of resistance and disease progression is common. Although oncogenic Ras mutations are uncommon in gliomas, Ras has been found to be constitutively activated through the action of upstream signaling pathways, suggesting that farnesyltransferase inhibitors may show activity against these tumors.

Glioblastoma recurrence after cediranib therapy in patients: lack of "rebound" revascularization as mode of escape.

Recurrent glioblastomas (rGBM) invariably relapse after initial response to anti-VEGF therapy. There are 2 prevailing hypotheses on how these tumors escape antiangiogenic therapy: switch to VEGF-independent angiogenic pathways and vessel co-option. However, direct evidence in rGBM patients is lacking.

Corticosteroid use in patients with glioblastoma at first or second relapse treated with bevacizumab in the BRAIN study.

Background: Vascular endothelial growth factor inhibitors have corticosteroid-sparing effects in patients with high-grade gliomas. We assessed corticosteroid use in patients with recurrent glioblastoma treated with bevacizumab (BEV) in the BRAIN study (J Clin Oncol 2009;27:4733-4740).

Methods: BRAIN was a phase II, multicenter, randomized, noncomparative trial of BEV alone (n = 85) or in combination with irinotecan (CPT-11) (n = 82) in adults with recurrent glioblastoma.

Longitudinal MRI evidence for decreased survival among periventricular glioblastoma.

While the prognosis of patients with glioblastoma (GBM) remains poor despite recent therapeutic advances, variable survival times suggest wide variation in tumor biology and an opportunity for stratified intervention. We used volumetric analysis and morphometrics to measure the spatial relationship between subventricular zone (SVZ) proximity and survival in a cohort of 39 newly diagnosed GBM patients. We collected T2-weighted and gadolinium-enhanced T1-weighted magnetic resonance images (MRI) at pre-operative, post-operative, pre-radiation therapy, and post-radiation therapy time points, measured tumor volumes and distances to the SVZ, and collected clinical data.

Response assessment in neuro-oncology.

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.

Response as a predictor of survival in patients with recurrent glioblastoma treated with bevacizumab.

Development of effective therapies for recurrent glioblastoma multiforme (GBM) and reliable, timely evaluation of their benefit are needed. Understanding the relationship between objective response (OR) and survival is important for determining whether OR can provide an early signal of treatment activity in clinical trials. We performed a landmark analysis to evaluate the association between OR and survival at 9, 18, and 26 weeks for 167 patients with recurrent GBM who participated in BRAIN, a phase II trial that evaluated efficacy of bevacizumab alone or in combination with irinotecan, using the Cox regression models adjusted for age, baseline Karnofsky performance score, first vs second relapse, and treatment arm.