This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sathornsumetee, S. Articles by Rich, J. N. Search for Related Content PubMed Articles by Sathornsumetee, S. Articles by Rich, J. N. Social Bookmarking                            What's this?

Tumor Angiogenic and Hypoxic Profiles Predict Radiographic Response and Survival in Malignant Astrocytoma Patients Treated With Bevacizumab and Irinotecan

Sith Sathornsumetee, Yiting Cao, Jennifer E. Marcello, James E. Herndon, II, Roger E. McLendon, Annick Desjardins, Henry S. Friedman, Mark W. Dewhirst, James J. Vredenburgh, Jeremy N. Rich

From the Department of Medicine, Division of Neurology, and Departments of Surgery, Bioinformatics, Pathology, Pediatrics, Radiation Oncology, Biomedical Engineering, and Pharmacology and Cancer Biology; the Preston Robert Tisch Brain Tumor Center; and the Cancer Center Biostatistics Unit, Duke Comprehensive Cancer Center; Duke University Medical Center, Durham, NC

Corresponding author: Jeremy N. Rich, MD, Departments of Medicine, Surgery, and Pharmacology and Cancer Biology, Duke University Medical Center, DUMC 2900, Durham, NC 27710; e-mail: rich0001{at}mc.duke.edu

Purpose The combination of a vascular endothelial growth factor (VEGF) –neutralizing antibody, bevacizumab, and irinotecan is associated with high radiographic response rates and improved survival outcomes in patients with recurrent malignant gliomas. The aim of these retrospective studies was to evaluate tumor vascularity and expression of components of the VEGF pathway and hypoxic responses as predictive markers for radiographic response and survival benefit from the bevacizumab and irinotecan therapy.

Patients and Methods In a phase II trial, 60 patients with recurrent malignant astrocytomas were treated with bevacizumab and irinotecan. Tumor specimens collected at the time of diagnosis were available for further pathologic studies in 45 patients (75%). VEGF, VEGF receptor-2, CD31, hypoxia-inducible carbonic anhydrase 9 (CA9), and hypoxia-inducible factor-2 were semiquantitatively assessed by immunohistochemistry. Radiographic response and survival outcomes were correlated with these angiogenic and hypoxic markers.

Results Of 45 patients, 27 patients had glioblastoma multiforme, and 18 patients had anaplastic astrocytoma. Twenty-six patients (58%) had at least partial radiographic response. High VEGF expression was associated with increased likelihood of radiographic response (P = .024) but not survival benefit. Survival analysis revealed that high CA9 expression was associated with poor survival outcome (P = .016).

Conclusion In this patient cohort, tumor expression levels of VEGF, the molecular target of bevacizumab, were associated with radiographic response, and the upstream promoter of angiogenesis, hypoxia, determined survival outcome, as measured from treatment initiation. Validation in a larger clinical trial is warranted.

Supported by the Childhood Brain Tumor Foundation, the Pediatric Brain Tumor Foundation of the United States, Accelerate Brain Cancer Cure, Duke Comprehensive Cancer Center Stem Cell Initiative Grant (J.N.R.), and National Institutes of Health Grants No. NS047409, NS054276, and CA116659 (J.N.R.). J.N.R. is a Damon Runyon-Lilly Clinical Investigator supported by the Damon Runyon Cancer Research Foundation and a Sidney Kimmel Foundation for Cancer Research Scholar.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				F. M. Iwamoto, L. E. Abrey, K. Beal, P. H. Gutin, M. K. Rosenblum, V. E. Reuter, L. M. DeAngelis, and A. B. Lassman Patterns of relapse and prognosis after bevacizumab failure in recurrent glioblastoma Neurology, October 13, 2009; 73(15): 1200 - 1206. [Abstract] [Full Text] [PDF]

				W. B. Pope, H. J. Kim, J. Huo, J. Alger, M. S. Brown, D. Gjertson, V. Sai, J. R. Young, L. Tekchandani, T. Cloughesy, et al. Recurrent Glioblastoma Multiforme: ADC Histogram Analysis Predicts Response to Bevacizumab Treatment Radiology, July 1, 2009; 252(1): 182 - 189. [Abstract] [Full Text] [PDF]

				L. Paleari, E. Negri, A. Catassi, M. Cilli, D. Servent, R. D'Angelillo, A. Cesario, P. Russo, and M. Fini Inhibition of Nonneuronal {alpha}7-Nicotinic Receptor for Lung Cancer Treatment Am. J. Respir. Crit. Care Med., June 15, 2009; 179(12): 1141 - 1150. [Abstract] [Full Text] [PDF]

				A. S. Chi, A. G. Sorensen, R. K. Jain, and T. T. Batchelor Angiogenesis as a Therapeutic Target in Malignant Gliomas Oncologist, June 1, 2009; 14(6): 621 - 636. [Abstract] [Full Text] [PDF]

				T. F. Liu, J. Cai, D. M. Gibo, and W. Debinski Reoxygenation of Hypoxic Glioblastoma Multiforme Cells Potentiates the Killing Effect of an Interleukin-13-Based Cytotoxin Clin. Cancer Res., January 1, 2009; 15(1): 160 - 168. [Abstract] [Full Text] [PDF]

				A. Veeravagu, Z. Liu, G. Niu, K. Chen, B. Jia, W. Cai, C. Jin, A. R. Hsu, A. J. Connolly, V. Tse, et al. Integrin {alpha}v{beta}3-Targeted Radioimmunotherapy of Glioblastoma Multiforme Clin. Cancer Res., November 15, 2008; 14(22): 7330 - 7339. [Abstract] [Full Text] [PDF]

				T. Martens, Y. Laabs, H. S. Gunther, D. Kemming, Z. Zhu, L. Witte, C. Hagel, M. Westphal, and K. Lamszus Inhibition of Glioblastoma Growth in a Highly Invasive Nude Mouse Model Can Be Achieved by Targeting Epidermal Growth Factor Receptor but not Vascular Endothelial Growth Factor Receptor-2 Clin. Cancer Res., September 1, 2008; 14(17): 5447 - 5458. [Abstract] [Full Text] [PDF]

				A. Idbaih, F. Ducray, M. Sierra Del Rio, K. Hoang-Xuan, and J.-Y. Delattre Therapeutic Application of Noncytotoxic Molecular Targeted Therapy in Gliomas: Growth Factor Receptors and Angiogenesis Inhibitors Oncologist, September 1, 2008; 13(9): 978 - 992. [Abstract] [Full Text] [PDF]