Angiogenesis Inhibition: The Next Frontier in Multimodal Therapy for Glioblastoma Multiforme
Posted on: 08/21/2007
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Angiogenesis Inhibition: The Next Frontier in Multimodal Therapy for Glioblastoma Multiforme
Rohit R Sharma; Ralph R Weichselbaum
Nat Clin Pract Oncol. 2007;4(8):454-455. ©2007 Nature Publishing Group
Background: The selection and timing of administration of antineoplastic agents might be improved by a more thorough understanding of characteristics of the stromal, vascular, and tumor cell compartments.
Objectives: To determine the time course and reversibility of structural and functional tumor vascular normalization (VN) by the antiangiogenic agent AZD2171 (cediranib) in patients with glioblastoma multiforme (GBM).
Design and intervention: This prospective, phase II study enrolled patients with recurrent GBM who had concluded radiotherapy and chemotherapy, and who were on a stable dose of corticosteroids. AZD2171 (45 mg orally daily) was administered continuously, with no maximum duration of therapy. Noninvasive MRI imaging was performed to assess tumor-associated edema and tumor contrast enhancement, vascular permeability, and relative vessel size. Plasma levels of the following angiogenic proteins were measured: VEGFA, soluble vascular endothelial growth factor receptor 1 (VGFR1) and VGFR2, placental growth factor, stromal cell-derived factor 1α (SDF-1-α), basic fibroblast growth factor (bFGF), and interleukin 8. Immunohistochemistry was used to detect the presence of VGFR1, VGFR2, VGFR3, platelet-derived growth factor alpha (PGFRA), and PGFRB, in archived primary GBM tumor specimens.
Outcome measures: Progression-free and overall survival were the primary end points. Radiographic response and toxicity, tumor volume and blood vessel permeability, and biomarkers for vascular response were also assessed.
Results: In 16 patients with recurrent disease, tumor specimens expressed three of the five AZD2171 targets (VGFR2, PGFRA, and PGFRB). Although variable responses were observed, 56% and nearly 19% of patients showed a >50% and a 25–50% reduction in gadolinium tumor enhancement, respectively. At 6 months, median progression-free survival was 111 days, and median overall survival was 211 days. A mean decrease in tumor vessel size occurred between days 1 and 28, but this effect was reversed by day 56. These changes in vessel size were accompanied by a reduction in tumor vascular permeability, which lasted until day 112. There was a concomitant diminution of GBM-associated edema, which permitted eight patients to decrease their corticosteroid usage and a further three patients to discontinue corticosteroid treatment. AZD2171 therapy was associated with several adverse effects that necessitated a break from drug treatment, including hypertension, elevated transaminases, thrombocytopenia, elevated thyroid-stimulating hormone, grade 4 headache, and hypertension. Suspension of AZD2171 therapy was associated with a reversible increase in both tumor enhancement volume and the extracellular–extravascular volume fraction. Increases in bFGF, soluble VGFR2, SDF-1-α, and viable levels of circulating endothelial cells, and a decrease in placental growth factor, were noted in patients experiencing tumor progression while on AZD2171 therapy. bFGF and SDF-1-α levels were also correlated with an increase in vessel size.
Conclusion: AZD2171 reversibly normalizes GBM tumor vasculature, and the concomitant decrease in vascular permeability reduces both edema and the need for corticosteroid treatment. SDF-1-α and bFGF are potential markers for cancer relapse.
The complex interaction between tumor cells, tumor vasculature, and the surrounding stroma creates a microenvironment supportive of cancer. The Jain group propose that antiangiogenic agents normalize the tumor vasculature, resulting in more efficient delivery of drugs and oxygen to the tumor, and enhanced efficacy of cytotoxic agents that are most lethal when cell oxygenation is normal.[1,2]
Batchelor and co-workers investigated the effects of antiangiogenic therapy using AZD2171 treatment (cediranib) in 16 patients with recurrent GBM, and defined the time course of VN. Standard therapies for GBM had failed in these patients and all had a very short predicted survival time.
As demonstrated by MRI, AZD2171 reduced tumor vessel size, large vessel blood volume, blood flow in small and large vessels, and vascular permeability. These parameters signify VN within the brain tumors. Vascular transformation began as early as day 1 of AZD2171 therapy and was sustained for 56 days, at which time a reversal in tumor vessel size indicated the impending conclusion of the 'window period' for drug efficacy. Cessation of AZD2171 treatment led to a reversal of these changes; however, resumption following drug suspension, once again, produced similar VN. The authors interpret these findings as indicating a reversible VN effect of AZD2171 on GBM vasculature. They also hypothesize, on the basis of their previous preclinical results, that administering conventional cytotoxic agents during VN induced by angiogenesis inhibitors could produce a greater antitumor effect than when cytotoxic agents are given outside this time period.[3,4]
AZD2171-induced VN led to a reduction in edema in this study. The 11 patients who were previously on corticosteroids for the treatment of edema had a reduction or elimination of their steroid requirement; therefore, AZD2171 might replace conventional steroid therapy, with a resultant improvement in the efficacy of concurrently administered chemotherapy. Also, radiotherapy exacerbates cerebral edema, and so AZD2171, by decreasing edema, might improve radiotherapy tolerability. Importantly, both the tumor and the surrounding edema are accounted for in the target volume when planning radiotherapy. A reduction in edema could reduce the target volume required, thereby decreasing the exposure of surrounding brain tissue to radiation. Target reduction should be considered with caution, however, because of the diffuse infiltrative nature of GBM and uncertainty about tumor burden at the margins of the fields. Lastly, the improvements in blood flow and tissue oxygenation produced by VN and reduced edema could also improve the efficacy of radiotherapy and chemotherapy.
bFGF and SDF-1-α levels in the blood of patients with GBM could serve as biomarkers for relapse during antiangiogenic therapy, and as future therapeutic targets.
Angiogenesis inhibition expands the options available for the treatment of otherwise fatal GBM. VN marks a time period during which tumors might be more sensitive to cytotoxic agents, and thereby establishes a temporal rationale for the administration of chemotherapy and radiotherapy. Also, AZD2171 might be a substitute for corticosteroids in the treatment of edema. Lastly, this study shows impressive imaging and biological data. As with other phase II studies, larger patient numbers are required to firmly establish efficacy, and caution must be exercised when comparisons are made with historical controls.
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- Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307: 58–62
- Yuan F et al. (1996) Time-dependent vascular regression and permeability changes in established human tumor xenografts induced by an anti-vascular endothelial growth factor/vascular permeability factor antibody. Proc Natl Acad Sci USA 93: 14765–14770
- Segers J et al. (2006) Potentiation of cyclophosphamide chemotherapy using the anti-angiogenic drug thalidomide: importance of optimal scheduling to exploit the 'normalization' window of the tumor vasculature. Cancer Lett 244: 129–135
- Tong RT et al. (2004) Vascular normalization by vascular endothelial growth factor receptor 2 blockade induces a pressure gradient across the vasculature and improves drug penetration in tumors. Cancer Res 64: 3731–3736
- Winkler F et al. (2004) Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell 6: 553–563
The synopsis was written by Rohit R Sharma and Ralph R Weichselbaum.
Department of Radiation and Cellular Oncology, University of Chicago Pritzker School of Medicine, 5758 South Maryland Avenue, Chicago, IL 60637, USA Email firstname.lastname@example.org
Rohit R. Sharma earned his medical degree from UMDNJ–Robert Wood Johnson Medical School. He completed his training in General Surgery at the Montefiore Medical Center–Albert Einstein College of Medicine in New York. Currently, he is a Fellow in Surgical Oncology at the University of Chicago.
Ralph R Weichselbaum is the Daniel K Ludwig Professor and Chairman of Radiation Oncology, and Head of the Ludwig Center for Metastasis Research, at the University of Chicago. He has authored over 400 peer-reviewed publications. His research interests are regulation of gene transcription by ionizing radiation and the applications of gene therapy to radiotherapy and chemotherapy. His major clinical interest is combined-modality treatment of head and neck cancer with radiochemotherapy.
Disclosure: RR Sharma declared he has no competing interests. RR Weichselbaum has declared stock, consulting fees and research agreement with GenVec.
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