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Journal ArticleDOI

Is There a Role for Bevacizumab in the Treatment of Glioblastoma

01 Oct 2013-Oncologist (AlphaMed Press)-Vol. 18, Iss: 10, pp 1080-1082

TL;DR: Whether the available evidence supports the use of bevacizumab in glioblastomas is discussed, and Drs.

AbstractBevacizumab gained accelerated approval from the U.S. Food and Drug Administration for use as monotherapy in progressive glioblastoma, based on improved radiologic response rates observed with bevacizumab monotherapy in two single-arm or noncomparative phase II trials. Drs. Chi and Chamberlain discuss whether the available evidence supports the use of bevacizumab in glioblastomas.

Topics: Bevacizumab (59%)

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Journal ArticleDOI
TL;DR: In glioblastoma patients, the risk of developing certain side effects, such as gastrointestinal perforation, venous thromboembolism, and intracranial hemorrhages, is slightly higher than in patients treated with bevacizumab for other tumor types.
Abstract: Bevacizumab, currently an option for treatment of different types of tumors including glioblastoma, has a peculiar toxicity profile related to its antiangiogenic effect. Because some bevacizumab-related adverse events can be life threatening, it is important to identify risk factors and to establish treatment protocols to minimize treatment-related morbidity and mortality. In glioblastoma patients, the risk of developing certain side effects, such as gastrointestinal perforation, venous thromboembolism, and intracranial hemorrhages, is slightly higher than in patients treated with bevacizumab for other tumor types. We performed a systematic review of the side effects of bevacizumab and their incidence, causal mechanisms, and available treatments. Finally, we identified risk factors and proposed preventive and therapeutic measures for these adverse events.

43 citations


Journal ArticleDOI
26 Nov 2013-Drugs
TL;DR: Ramucirumab, a fully humanized monoclonal antibody specifically directed against the extracellular domain of the receptor, administered intravenously every 2 or 3 weeks, is emerging as a novel antiangiogenic opportunity.
Abstract: Although antiangiogenic treatments have produced milestone advances in the treatment of several diseases, and have significantly extended the median survival of cancer patients, these agents share some weaknesses, including a limited impact on the overall cure rate, a fleeting effect because of redundant pathways or early appearance of resistance mechanisms, and the lack of predictive factors for treatment selection. Recent data suggest that antibodies targeting the vascular endothelial growth factor axis exert their activity through the inhibition of vascular endothelial growth factor receptor-2 phosphorylation, which has a pivotal role in the neoangiogenic process. Ramucirumab, a fully humanized monoclonal antibody specifically directed against the extracellular domain of the receptor, administered intravenously every 2 or 3 weeks, is emerging as a novel antiangiogenic opportunity. Starting with preclinical data and early clinical results, this concise review focuses on the development of the novel compound across multiple cancers (including gastrointestinal malignancies, breast cancer, lung carcinoma, and genitourinary tumors), and presents available data from randomized phase II and phase III trials. REGARD was the first phase III study to report on the efficacy of single-agent ramucirumab in patients with advanced cancer. Many other ongoing phase III trials are testing the efficacy of this interesting antiangiogenic compound as a single agent or in combination with chemotherapy in different cancer types.

40 citations


Journal ArticleDOI
TL;DR: The results of a phase II, single arm trial of a heat shock protein peptide complex -96 (HSPPC 96) vaccine in patients who underwent complete resection of recurrent GBM showed that increased extent of resection at recurrence could improve overall survival, supporting the rationale for repeat resection.
Abstract: We would like to thank Dr. Chamberlain for his thoughtful critique of our study and for highlighting the merits and limitations of an autologous heat-shock protein based vaccine for recurrent glioblastoma (GBM). We reported the results of a phase II, single arm trial of a heat shock protein peptide complex -96 (HSPPC 96) vaccine in patients who underwent complete resection of recurrent GBM. Chamberlain comments on the applicability of this therapy to all patients with recurrent GBM, estimating that only 15% of patients would meet the eligibility criteria of having a complete surgical resection. Although the requirement of repeat surgical resection with the goal of near-total tumor removal is a limitation of nearly all vaccine-based therapies for recurrent GBM, the true rate at which this can be accomplished is much greater than 15%. At most U.S. tertiary care centers, including all four centers contributing to our study, repeat surgical resection at first recurrence of GBM has become standard of care. We previously reported our institutional case series of patients undergoing repeat surgical resection for GBM, in which we demonstrated complete resection was attained in over 50% of patients regardless of the extent of resection at initial operation.1 Additionally, we demonstrated that increased extent of resection at recurrence could improve overall survival, supporting the rationale for repeat resection.1 Similar rates of complete resection at recurrence have been demonstrated in other large institutional case series.2,3 With the addition of new surgical technologies, including intra-operative MRI, vital dyes, and the advancement of functional mapping, the ability to obtain safer and more complete resections is constantly increasing. For those patients in whom a complete resection is not achievable, there may still be a role for vaccine therapy. Although most current vaccine trials require a minimal burden of residual disease for enrollment, the rationale for this requirement is theoretical and has not been proven clinically. There may be a role for vaccine-based therapy, possibly in combination with immune modulating drugs, for patients with subtotal resection, and this is an area of current exploration. Chamberlain also raises concerns regarding the ability to generate vaccine from resected tissue and the delay to administration of the vaccine after surgery. In the study, 13 patients (20%) had insufficient tumor resected to produce vaccine for participation. There has undoubtedly been a learning curve for the procurement of tissue and production of the vaccine over time. Since the early days of the study, we have modified surgical techniques to reduce tissue loss and improved manufacturing practices to increase the vaccine yield. Among the later patients enrolled in the study and the subsequent randomized phase II trial of the HSPPC-96 vaccine with or without bevacizumab, we have rarely encountered the problem of insufficient tumor to generate vaccine. Additionally, the manufacturing time for the vaccine is only 16 days, including required time for quality assurance. In the reported study, there was a required post-resection delay of 4 weeks prior to vaccine administration. The purpose of this delay was to allow recovery from surgery and weaning of immunosuppressive post-operative steroids. The delay was pre-determined at the time of study design but could be shortened in the future with appropriate rationale. Finally, Chamberlain comments that the progression-free survival outcomes reported in the trial are not significantly better than those observed with conventional salvage therapy, such as bevacizumab. The primary endpoint of the trial was designed to evaluate overall survival because of the mechanism of action of vaccine-based therapy and the difficulty of assessing true progression. As most patients will not have tissue confirmation at second progression, the determination of progression is largely based on imaging. Differentiating between true progression and pseudoprogression can be difficult, particularly in patients receiving a vaccine that is expected to result in an intra-tumoral inflammatory response and increased contrast enhancement on imaging. By comparison, bevacizumab is known to decrease contrast enhancement and may mask early progression. Therefore, a radiographic comparison of progression between bevacizumab and vaccine-based therapies may overestimate progression-free survival in patients receiving bevacizumab and underestimate progression-free survival in patients receiving vaccine. To ensure that an unequivocal measure of response was assessed, overall survival was selected as the primary endpoint. Additionally, unlike conventional therapies that are only effective during administration, vaccines generate immunologic memory and may continue to have beneficial effects on survival even after progression. Therefore, the only true measure of efficacy is overall survival. When assessing this endpoint, median overall survival from intervention in our study was 42 weeks. Although the trial was single armed, making a direct comparison of efficacy against conventional therapies impossible, the results suggest that further investigation in a randomized controlled trial is warranted. Immunotherapy remains the most likely adjuvant treatment to effectively target gliomas with minimal toxicity. The introduction of immunomodulatory agents such as anti-CTLA-4, anti-PD1, and anti-PD-L1 antibodies now provides a new pathway to potentiate the immune response elicited by tumor vaccines, and overcome local and systemic immunosuppression in glioma patients. We are grateful to Dr. Chamberlain for asking important questions regarding our study, as well as other studies over the years.4–14 The answers to most of these questions can only come from thoughtfully designed, randomized clinical trials that test the experimental agents against standard therapies. Currently, the largest randomized trial for a brain tumor vaccine ever initiated by the National Cancer Institute is accruing patients through the Alliance for Clinical Trials in Oncology cooperative group with the endorsement of RTOG. This 3-arm trial will assess survival in recurrent GBM patients receiving the HSPPC-96 vaccine with bevacizumab vs. patients receiving bevacizumab alone vs. patients receiving the vaccine alone followed by bevacizumab at progression. We anticipate the results of this trial to definitively answer the role of vaccine-based therapy in the treatment of patients with recurrent GBM.

16 citations


Journal ArticleDOI
TL;DR: With the increasing use of moAbs in treatment regimens, it is strongly recommended that clinicians are knowledgeable about the side effects associated with these agents, their management and monitoring, to optimize the clinical treatment of cancer patients.
Abstract: Introduction: The introduction of monoclonal antibodies (moAbs) into clinical practice revolutionized the treatment strategies in several solid tumors. These agents differ from cytotoxic chemotherapy for their mechanism of action and toxicity. By targeting specific antigens present on healthy cells and modulating immune system activity, these biological drugs are able to generate a wide spectrum of peculiar adverse events that can negatively impact on patients' quality of life. Areas covered: In this review, the main side effects associated with the use of moAbs have been described to show their incidence and current management strategies, which may drive clinicians in their daily practice. Expert opinion: The majority of these drugs represents an example of successful innovation, since they are able to induce a significant improvement of patients' survival and quality of life without any increase in related side effects as compared to standard cancer treatments. For this reason, they have become new milestones in personalized therapy for different non-hematological malignancies. With the increasing use of moAbs in treatment regimens, it is strongly recommended that clinicians are knowledgeable about the side effects associated with these agents, their management and monitoring, to optimize the clinical treatment of cancer patients.

6 citations


Cites background from "Is There a Role for Bevacizumab in ..."

  • ...Therefore, a careful selection of patients should be made to evaluate the potential hemorrhagic risk and reduce the incidence of this serious complication [87]....

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References
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Journal ArticleDOI
TL;DR: Bvacizumab, alone or in combination with irinotecan, was well tolerated and active in recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial.
Abstract: Purpose We evaluated the efficacy of bevacizumab, alone and in combination with irinotecan, in patients with recurrent glioblastoma in a phase II, multicenter, open-label, noncomparative trial. Patients and Methods One hundred sixty-seven patients were randomly assigned to receive bevacizumab 10 mg/kg alone or in combination with irinotecan 340 mg/m2 or 125 mg/m2 (with or without concomitant enzyme-inducing antiepileptic drugs, respectively) once every 2 weeks. Primary end points were 6-month progression-free survival and objective response rate, as determined by independent radiology review. Secondary end points included safety and overall survival. Results In the bevacizumab-alone and the bevacizumab-plus-irinotecan groups, estimated 6-month progression-free survival rates were 42.6% and 50.3%, respectively; objective response rates were 28.2% and 37.8%, respectively; and median overall survival times were 9.2 months and 8.7 months, respectively. There was a trend for patients who were taking corticoste...

2,078 citations


Journal ArticleDOI
TL;DR: It is concluded that single-agent bevacizumab has significant biologic and antiglioma activity in patients with recurrent glioblastoma.
Abstract: Purpose To evaluate single-agent activity of bevacizumab in patients with recurrent glioblastoma. Patients and Methods Patients with recurrent glioblastoma were treated with bevacizumab 10 mg/kg every 2 weeks. After tumor progression, patients were immediately treated with bevacizumab in combination with irinotecan 340 mg/m2 or 125 mg/m2 every 2 weeks, depending on use of enzyme-inducing antiepileptic drugs. Complete patient evaluations were repeated every 4 weeks. Results Forty-eight heavily pretreated patients were accrued to this study. Thromboembolic events (12.5%), hypertension (12.5%), hypophosphatemia (6%), and thrombocytopenia (6%) were the most common drug-associated adverse events. Six patients (12.5%) were removed from study for drug-associated toxicity (five thromboembolic events, one bowel perforation). Thirty-four patients (71%) and 17 patients (35%) achieved radiographic response based on Levin and Macdonald criteria, respectively. Median progression-free survival (PFS) was 16 weeks (95% CI...

1,351 citations


Journal ArticleDOI
TL;DR: By controlling edema, cediranib significantly increased survival of mice in the face of persistent tumor growth, suggesting anti-VEGF agents may be able to improve survival of patients with glioblastoma, even without inhibiting tumor growth.
Abstract: Purpose Recent clinical trials of antivascular endothelial growth factor (VEGF) agents for glioblastoma showed promising progression-free and overall survival rates. However, available clinical imaging does not separate antitumor effects from antipermeability effects of these agents. Thus although anti-VEGF agents may decrease tumor contrast-enhancement, vascularity, and edema, the mechanisms leading to improved survival in patients remain incompletely understood. Our goal was to determine whether alleviation of edema by anti-VEGF agents alone could increase survival in mice. Methods We treated mice bearing three different orthotopic models of glioblastoma with a VEGF-targeted kinase inhibitor, cediranib. Using intravital microscopy, molecular techniques, and magnetic resonance imaging (MRI), we measured survival, tumor growth, edema, vascular morphology and function, cancer cell apoptosis and proliferation, and circulating angiogenic biomarkers. Results We show by intravital microscopy that cediranib sig...

289 citations


Journal ArticleDOI
TL;DR: This trial determined if the addition of Bev to standard CRT improves survival (OS) or progression-free survival (PFS) in newly diagnosed GBM.
Abstract: 1 Background: Chemoradiation (CRT) with temozolomide (TMZ/RT→TMZ) is the standard of care for newly diagnosed GBM. This trial determined if the addition of Bev to standard CRT improves survival (OS) or progression-free survival (PFS) in newly diagnosed GBM. Methods: This phase III trial was conducted by the RTOG, NCCTG, and ECOG. Neurologically stable pts > 18 yrs with KPS ≥ 60, and > 1cm3 tumor tissue block, were randomized to Arm 1: standard CRT + placebo or Arm 2: standard CRT plus Bev (10 mg/kg iv q 2wks). Experimental treatment began at wk 4 of radiation then thru 6-12 cycles of maintenance chemotherapy. Protocol specified co-primary endpoints were OS and PFS, with significance levels of .023 and .002, respectively. At progression, treatment was unblinded and pts allowed to crossover or continue Bev. Symptom, QOL and neurocognitive (NCF) testing was performed in the majority of pts. Secondary analyses evaluated impact of MGMT methylation (meth) and prognostic 9 gene signature status. Results: From 97...

99 citations


Journal ArticleDOI
TL;DR: Patients with histologically proven glioblastoma, with a first recurrence after chemo-irradiation with temozolomide, having concluded radiotherapy more than 3 months ago, with adequate bone marrow, renal and hepatic function, and WHO performance status (PS) 0-2 are enrolled.
Abstract: 2001 Background: Bevacizumab (BEV) is widely used in recurrent glioblastoma, alone or in combination with other agents. There is however no well-controlled trial to support the use for this indicat...

63 citations