Neurology -- Correspondence for Norden et al., 70 (10) 779-787

Correspondence published:

Bevacizumab for recurrent malignant gliomas: Efficacy, toxicity, and patterns of recurrence: Marc C. Chamberlain (4 June 2008)

Bevacizumab for recurrent malignant gliomas: Efficacy, toxicity, and patterns of recurrence: Maciej M. Mrugala (4 June 2008)

Reply from the Authors: Andrew D Norden, Geoffrey S. Young, Patrick Y. Wen (4 June 2008)

Bevacizumab for recurrent malignant gliomas: Efficacy, toxicity, and patterns of recurrence 4 June 2008

Marc C. Chamberlain,
University of Washington, Seattle Cancer Care Alliance
825 Eastlake Ave E, POB 19023, MS G4940, Seattle, WA 98109-1023
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Re: Bevacizumab for recurrent malignant gliomas: Efficacy, toxicity, and patterns of recurrence

chambemc{at}u.washington.edu Marc C. Chamberlain

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.

Bevacizumab for recurrent malignant gliomas: Efficacy, toxicity, and patterns of recurrence 4 June 2008

Maciej M. Mrugala,
University of Washington/Fred Hutchinson Cancer Research Center
1959 NE Pacific Street, Seattle, WA 98195
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Re: Bevacizumab for recurrent malignant gliomas: Efficacy, toxicity, and patterns of recurrence

mmrugala{at}u.washington.edu Maciej M. Mrugala

We congratulate Norden et al. for their interesting and important paper discussing efficacy, toxicity and patterns of recurrence in patients with malignant gliomas receiving bevacizumab. [1]
Bevacizumab-based regimens to treat recurrent high-grade glioma were embraced by the neuro-oncological community soon after the initial data were published. [6] This is expected considering that active treatment options were limited and radiographic responses seen with this therapy can be remarkable.
Most neuro-oncologists rely on enhancing (MRI) abnormalities to establish response to treatment, and non-enhancing tumor growth may not be readily appreciated. This study highlights that the assessment of both enhancing and non-enhancing disease should always be considered, and even more in patients receiving bevacizumab-based therapies.
We have observed similar patterns of progression at our institution. Several patients worsened clinically and were found to have changes in the non-enhancing tumor volume without changes in enhancement (in some cases continued improvement of the enhancing mass was seen). This effect was observed in patients receiving bevacizumab with irinotecan but also in few patients who were receiving carboplatin instead of irinotecan. It appears that the choice of the chemotherapeutic agent may not be as important and bevacizumab might be solely responsible for promotion of diffuse tumor recurrence.
This study again demonstrates that blockade of the VEGF pathway may not be sufficient to suppress tumor growth and alteration of additional molecular signals may be necessary to achieve therapeutic success. One of the novel targets responsible for regulation of tumor angiogenesis could be Delta-like 4 Notch ligand (DLL4). Preliminary results indicate that combined approaches for interrupting both DLL4 and VEGF pathways may improve anti-angiogenic therapy [7].
Norden et al. share their experiences regarding side effects of bevacizumab in patients with gliomas. Despite concerns about intracranial hemorrhages, the incidence appears to be low and in most instances asymptomatic. [1, 2] Moreover, anti-coagulation does not appear to increase the risk of hemorrhage. It is an important �clinical pearl� that may allow clinicians to use this therapy more comfortably.
Finally, authors describe steroid-sparing effects of bevacizumab. It is a desirable yet possibly confusing effect of anti-VEGF agents. [5] Interpretation of FLAIR changes and true differentiation and quantification of the edema and tumor might be difficult using current technology. Rebound effect after discontinuation of VEGF blockade is associated with clinical worsening and has to be recognized in patients treated for prolonged periods of time.
References
6. Stark-Vance V. Bevacizumab (Avastin) and CPT-11 (Camptosar) in the Treatment of Relapsed Malignant Glioma. Neuro-Oncology, 2005;7:369.
7. Li JL, et al. Delta-like 4 Notch ligand regulates tumor angiogenesis, improves tumor vascular function, and promotes tumor growth in vivo. Cancer Res, 2007;67:11244-11253.

Disclosure: The author reports no disclosures.

Reply from the Authors 4 June 2008

Andrew D Norden,
Brigham and Women's Hospital
44 Binney St, Boston, MA 02115,
Geoffrey S. Young, Patrick Y. Wen
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Re: Reply from the Authors

anorden{at}partners.org Andrew D Norden, et al.

We thank Drs. Chamberlain and Mrugala for their thoughtful comments. A major challenge in treating patients with recurrent malignant gliomas in the era of anti-angiogenic therapy involves the assessment of tumor response and progression on MRI scans.
Macdonald criteria for determining response and progression, described in 1990 before anti-angiogenic treatments were available, rely exclusively on the maximal cross-sectional area of enhancing tumor. [8] This approach is problematic if widely used treatments such as bevacizumab effectively control contrast enhancement but permit non-enhancing, infiltrative recurrence.
In response to Dr. Chamberlain�s query regarding overall survival in the cytotoxic chemotherapy group, there was no significant overall survival difference between the two cohorts.
In addition to the Notch ligand Delta-like 4 (DLL4), pro-angiogenic signaling molecules that may play a role in resistance to anti-vascular endothelial growth factor (VEGF) or anti-VEGF receptor therapies include basic fibroblast growth factor (bFGF) and stromal-derived factor 1-alpha (SDF1-alpha) [5], among many others. [9]
Inhibition of these targets may potentiate the effects of currently available anti-angiogenic therapies and translate into improved outcomes for patients with these devastating tumors.
References
8. Macdonald DR, Cascino TL, Schold SC, Jr., Cairncross JG. Response criteria for phase II studies of supratentorial malignant glioma. J Clin Oncol 1990;8:1277�1280.
9. Chi A, Norden AD, Wen PY. Inhibition of angiogenesis and invasion in malignant gliomas. Expert Rev Anticancer Ther 2007;7:1537-1560.
Disclosures: P.Y. Wen receives research support from Genentech, Inc. The other authors report no disclosures.