Approval denied by the European Medicines Agency (EMA) for bevacizumab in the treatment of high-grade glioma recurrence: a good idea or a grave error?

Balañá, Carmen; Etxániz, Olatz; Bugés, Cristina; Martinez, A.

doi:10.1007/s12094-011-0642-9

Cited by 16 publications

(8 citation statements)

References 11 publications

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“…8,9 Bevacizumab use in the recurrent glioblastoma setting is not universal: the European Medicines Agency did not approve it, in part due to the absence of chemotherapy-alone comparative data at that time. 10,11 The role of continuing bevacizumab beyond initial progression remains controversial. Some clinicians favor continuing bevacizumab on the basis of metastatic colorectal cancer studies indicating benefit beyond progression, 12,13 and small retrospective glioblastoma studies have suggested that cessation may result in accelerated disease progression, rapid revascularization, and rebound edema.…”

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confidence: 99%

Continuing or ceasing bevacizumab beyond progression in recurrent glioblastoma: an exploratory randomized phase II trial

Hovey

Field

Rosenthal

et al. 2017

Neuro-Oncology Practice

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Background In patients with recurrent glioblastoma, the benefit of bevacizumab beyond progression remains uncertain. We prospectively evaluated continuing or ceasing bevacizumab in patients who progressed while on bevacizumab. Methods CABARET, a phase II study, initially randomized patients to bevacizumab with or without carboplatin (Part 1). At progression, eligible patients underwent a second randomization to continue or cease bevacizumab (Part 2). They could also receive additional chemotherapy regimens (carboplatin, temozolomide, or etoposide) or supportive care. Results Of 120 patients treated in Part 1, 48 (80% of the anticipated 60-patient sample size) continued to Part 2. Despite randomization, there were some imbalances in patient characteristics. The best response was stable disease in 7 (30%) patients who continued bevacizumab and 2 (8%) patients who stopped receiving bevacizumab. There were no radiological responses. Median progression-free survival was 1.8 vs 2.0 months (bevacizumab vs no bevacizumab; hazard ratio [HR], 1.08; 95% CI, .59–1.96; P = .81). Median overall survival was 3.4 vs 3.0 months (HR, .84; 95% CI, .47–1.50; P = .56 and HR .70; 95% CI .38–1.29; P = .25 after adjustment for baseline factors). Quality-of-life scores did not significantly differ between arms. While the maximum daily steroid dose was lower in the continuation arm, the difference was not statistically significant. Conclusions Patients who continued bevacizumab beyond disease progression did not have clear survival improvements, although the study was not powered to detect other than very large differences. While these data provide the only randomized evidence related to continuing bevacizumab beyond progression in recurrent glioblastoma, the small sample size precludes definitive conclusions and suggests this remains an open question.

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confidence: 99%

Continuing or ceasing bevacizumab beyond progression in recurrent glioblastoma: an exploratory randomized phase II trial

Hovey

Field

Rosenthal

et al. 2017

Neuro-Oncology Practice

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“…The FDA approved BVZ as a single agent for treatment of recurrent GBM with poor or refractory response to other therapies [ 17 ] . The European Medicines Agency rejected this indication, although some studies have questioned the decision [ 18 ] . No new agents have been approved for second-line therapy of GBM in Europe since the approval of TMZ in 1999.…”

Section: Discussionmentioning

confidence: 99%

“…BVZ remains one of the few Food and Drug Administration (FDA) approved and most commonly prescribed therapies for recurrent GBM. However, the reduction in tumor size following therapy is transient and it is unclear which patients are most likely to benefit from treatment [17,18] . GBM patient prognosis mainly depends on treatment administered, age, and Methyl Guanine Methyl Transferase (MGMT) methylation.…”

Section: Introductionmentioning

confidence: 99%

Pretreatment inflammatory indices predict Bevacizumab response in recurrent Glioma

Martínez-González¹,

Cabrera²,

Lloret³

et al. 2020

CDR

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Aim: It remains unclear what the best therapeutic option for recurrent glioma patients after Stupp treatment is. Bevacizumab (BVZ) is commonly administered in progression, but it appears that only some patients benefit. It would be useful to find biomarkers that determine beforehand who these patients are. Methods: The protocol included 31 high-risk progressing glioma patients after Stupp treatment who received BVZ 5-10 mg/kg every 14 days and temozolomide (3-19 cycles, 150-200 mg five days each 28-day cycle) during a mean of eight cycles of BVZ or until tumor progression or unacceptable toxicity. We analyzed the clinical outcome values of inflammatory indices measured before BVZ administration. Results: Lymphocyte level before BVZ administration was the best independent predictor of overall survival (HR = 0.34; 95%CI: 0.145-0.81; P = 0.015). The area under the receiver operating characteristic (ROC) curve was 0.823, with 1.645 being the optimal cutoff value, and 0.80 and 0.85 the sensitivity and specificity values, respectively. Responder and non-responder survival curves were also significantly different, considering the first and second tertiles as cutoff points. The number of BVZ cycles was not related to lymphopenia. Pretreatment neutrophil, platelet levels, platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR) did not have independent predictive value. Inflammatory variables were not correlated with each other. However, patients with high NLR and PLR simultaneously (double positive PLR-NLR) showed a worse clinical outcome than the rest (P = 0.043). Conclusion: Pretreatment lymphocyte levels and double positive PLR-NLR could be used as non-invasive hematological prognostic markers for recurrent gliomas treated with bevacizumab. A close relationship emerged between inflammation and angiogenesis.

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“…Furthermore, the EMA did not consider the differences in objective RR to be noteworthy and concluded that the validity of this parameter as a surrogate endpoint for clinical benefit had not been established. In addition, the results were presented in terms of OS and PFS, which were difficult to interpret due to the lack of a randomized concurrent control (35). Furthermore, the use of contrast-enhanced magnetic resonance imaging may overestimate the RR (17); therefore, RR and PFS may not be optimal surrogate endpoints for anti-angiogenic treatment.…”

Section: Efficacy Of Bevacizumab Treatment For Patients With Recurrenmentioning

confidence: 99%

Efficacy and safety of bevacizumab for the treatment of glioblastoma

Zhao

Zhang

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. Glioblastoma (GBM) is the most common and devastating primary malignant intracranial tumor in adults. The current first-line treatment for patients with newly diagnosed GBM is surgical resection followed by radiotherapy plus concomitant and adjuvant temozolomide. This treatment protocol may prolong the survival period of the patient, however it is not curative and more effective therapeutic strategies are required. GBM is a type of highly vascularized tumor with increased expression levels of vascular endothelial growth factor (VEGF), which is a significant mediator of angiogenesis. Since angiogenesis is essential for tumor growth, anti-angiogenic therapies hold potential for the treatment of GBM, and targeting VEGF has demonstrated promising results in previous studies. Bevacizumab (BEV) is a recombinant humanized monoclonal antibody that inhibits VEGF and is approved by the US Food and Drug Administration as a monotherapy treatment for patients with recurrent GBM and is associated with manageable toxicity. Previous studies have demonstrated that BEV may be an effective treatment for recurrent GBM, with prolonged progression-free survival and overall survival, and maintained patient quality of life and functional status. The present review article briefly outlines the mechanism of action of BEV and summarizes the current literature and clinical trial research on the role of BEV for the treatment of patients with recurrent and newly diagnosed

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Approval denied by the European Medicines Agency (EMA) for bevacizumab in the treatment of high-grade glioma recurrence: a good idea or a grave error?

Cited by 16 publications

References 11 publications

Continuing or ceasing bevacizumab beyond progression in recurrent glioblastoma: an exploratory randomized phase II trial

Continuing or ceasing bevacizumab beyond progression in recurrent glioblastoma: an exploratory randomized phase II trial

Pretreatment inflammatory indices predict Bevacizumab response in recurrent Glioma

Efficacy and safety of bevacizumab for the treatment of glioblastoma

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