Bevacizumab for recurrent malignant gliomas: Efficacy, toxicity, and patterns of recurrence
Maciej M.Mrugala, University of Washington/Fred Hutchinson Cancer Research Center, 1959 NE Pacific Street, Seattle, WA 98195mmrugala@u.washington.edu
Submitted June 04, 2008
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.
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.