Bevacizumab for recurrent malignant gliomas: Efficacy, toxicity, and patterns of recurrence
Marc C.Chamberlain, University of Washington, Seattle Cancer Care Alliance, 825 Eastlake Ave E, POB 19023, MS G4940, Seattle, WA 98109-1023chambemc@u.washington.edu
Submitted June 04, 2008
I congratulate Norden et al. for their report of 55 patients with recurrent high-grade gliomas treated with chemotherapy (85% with irinotecan or CPT-11) and bevacizumab. [1-3] Several aspects of this report merit commentary:
1. Unlike prior reports, 6-month progression free survival was best for glioblastoma (GBM) vs. anaplastic gliomas (42% vs. 32%). [3]
2. The contribution of chemotherapy in combination with bevacizumab remains unclear. A number of reports evaluating CPT-11 as a single agent for recurrent GBM concluded CPT-11 had little efficacy. [4]
3. At time of progression, continuation of bevacizumab resulted in a feeble response. Escape from anti-vascular endothelial growth factor (VEGF) therapy (bevacizumab) likely represents recruitment of compensatory proangiogenic stimuli. [5]
4. Radiographic assessment of response, determined primarily by change in the contrast enhancing tumor volume, is problematic with anti-angiogenic therapies. [3,5] Bevacizumab therapy normalizes GBM vascularity resulting in both loss of contrast enhancement, normalization of tumor blood volume and perfusion and improvement in peritumoral edema. As illustrated by Norden et al, failure of antiangiogenic therapy initially appears as an increase in FLAIR signal before re-emergence of contrast enhancement.
5. It is unclear whether the control group treated with chemotherapy had similar overall survival from time of re-treatment as compared to the bevacizumab group, as longer survival is associated with increased glioma invasiveness. Nonetheless, when comparing these patient groups, no statistically significant increase incidence of diffuse spread was seen.
6. Toxicity of bevacizumab was modest and although a high incidence of deep vein thrombosis and pulmonary embolism was observed, separation as an independent toxicity of antiangiogenic therapies is difficult because of the thrombosis commonly seen in GBM. Notably, concurrent use of anticoagulation appears safe without an apparent increased risk of hemorrhage.
7. Determining predictive markers to anti-angiogenic therapy might prevent administration of expensive, toxic and potentially ineffective therapy. Norden et al suggest that bevacizumab response might be predicted based on comparing the ratio of pre-treatment FLAIR volume to the contrast enhancing tumor volume. This finding needs confirmation and perhaps reflects a subgroup of angiogenic-signal dependent tumors characterized by a robust peritumoral FLAIR volume.
Norden et al. emphasize the complexity of treating patients with recurrent high-grade gliomas and remind neurologists that the approach to malignant gliomas continues to evolve and will increasingly utilize targeted therapies such as antiangiogenic agents.
References
1. Norden AD, Young GS, Setayesh K, et al. Bevacizumab for recurrent malignant glioma: efficacy, toxicity and patterns of recurrence. Neurology 2008;70:779-787.
2. Vredenburgh JJ, Desjardins A, Herndon JE, et al: Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 2007;13:1253-1259.
3. Pope WB, Lai A, Nghiemphu P, Mischel P, Cloughesy TF. MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology 2006;66: 1258-1260.
4. Prados MD, Lamborn K, Yung WKA, et al. A phase 2 trail of irinotecan (CPT-11) in patients with recurrent malignant glioma: a NABTC study. Neuro Oncol 2006;8:189-193.
5. Batchelor TT, Sorensen AG, diTomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11:83-95.
I congratulate Norden et al. for their report of 55 patients with recurrent high-grade gliomas treated with chemotherapy (85% with irinotecan or CPT-11) and bevacizumab. [1-3] Several aspects of this report merit commentary:
1. Unlike prior reports, 6-month progression free survival was best for glioblastoma (GBM) vs. anaplastic gliomas (42% vs. 32%). [3]
2. The contribution of chemotherapy in combination with bevacizumab remains unclear. A number of reports evaluating CPT-11 as a single agent for recurrent GBM concluded CPT-11 had little efficacy. [4]
3. At time of progression, continuation of bevacizumab resulted in a feeble response. Escape from anti-vascular endothelial growth factor (VEGF) therapy (bevacizumab) likely represents recruitment of compensatory proangiogenic stimuli. [5]
4. Radiographic assessment of response, determined primarily by change in the contrast enhancing tumor volume, is problematic with anti-angiogenic therapies. [3,5] Bevacizumab therapy normalizes GBM vascularity resulting in both loss of contrast enhancement, normalization of tumor blood volume and perfusion and improvement in peritumoral edema. As illustrated by Norden et al, failure of antiangiogenic therapy initially appears as an increase in FLAIR signal before re-emergence of contrast enhancement.
5. It is unclear whether the control group treated with chemotherapy had similar overall survival from time of re-treatment as compared to the bevacizumab group, as longer survival is associated with increased glioma invasiveness. Nonetheless, when comparing these patient groups, no statistically significant increase incidence of diffuse spread was seen.
6. Toxicity of bevacizumab was modest and although a high incidence of deep vein thrombosis and pulmonary embolism was observed, separation as an independent toxicity of antiangiogenic therapies is difficult because of the thrombosis commonly seen in GBM. Notably, concurrent use of anticoagulation appears safe without an apparent increased risk of hemorrhage.
7. Determining predictive markers to anti-angiogenic therapy might prevent administration of expensive, toxic and potentially ineffective therapy. Norden et al suggest that bevacizumab response might be predicted based on comparing the ratio of pre-treatment FLAIR volume to the contrast enhancing tumor volume. This finding needs confirmation and perhaps reflects a subgroup of angiogenic-signal dependent tumors characterized by a robust peritumoral FLAIR volume.
Norden et al. emphasize the complexity of treating patients with recurrent high-grade gliomas and remind neurologists that the approach to malignant gliomas continues to evolve and will increasingly utilize targeted therapies such as antiangiogenic agents.
References
1. Norden AD, Young GS, Setayesh K, et al. Bevacizumab for recurrent malignant glioma: efficacy, toxicity and patterns of recurrence. Neurology 2008;70:779-787.
2. Vredenburgh JJ, Desjardins A, Herndon JE, et al: Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin Cancer Res 2007;13:1253-1259.
3. Pope WB, Lai A, Nghiemphu P, Mischel P, Cloughesy TF. MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy. Neurology 2006;66: 1258-1260.
4. Prados MD, Lamborn K, Yung WKA, et al. A phase 2 trail of irinotecan (CPT-11) in patients with recurrent malignant glioma: a NABTC study. Neuro Oncol 2006;8:189-193.
5. Batchelor TT, Sorensen AG, diTomaso E, et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 2007;11:83-95.
Disclosure: The author reports no disclosures.