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Inflammatory Breast Cancer as a Model Disease to Study Tumor Angiogenesis: Results of a Phase IB Trial of Combination SU5416 and Doxorubicin

Authors' Affiliations: ¹ Connecticut Oncology & Hematology Associates/US Oncology, Torrington, Connecticut; ² Developmental Therapeutics Program and ³ Translational Research Core Facility, Case Comprehensive Cancer Center, Departments of ⁴ Biostatistics and Epidemiology, ⁵ Medicine, ⁶ Pharmacology, ⁷ Surgery, ⁸ Pathology, and ⁹ Radiology, Case Imaging Research Center, University Hospitals Case Medical Center, Cleveland, Ohio; ¹⁰ Department of Radiation Oncology, University of Arizona, Tucson, Arizona; ¹¹ The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins School of Medicine and The Johns Hopkins Hospital, Baltimore, Maryland; and ¹² Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Beth Overmoyer, Connecticut Oncology & Hematology Associates, 200 Kennedy Drive, Torrington, CT 06790. E-mail: beth.overmoyer{at}usoncology.com.

Purpose: We used inflammatory breast cancer (IBC) as a model disease to investigate biological changes associated with an antiangiogenesis agent, SU5416, combined with doxorubicin.

Experimental Design: Patients with stage IIIB or IV IBC were treated neoadjuvantly with the combination of SU5416 and doxorubicin for induction therapy. The dose of SU5416 (administered on days 1 and 4, every 3 weeks) and doxorubicin (administered on day 1 every 3 weeks) were escalated in cohorts of three patients starting at 110 and 60 mg/m², respectively, for a total of five cycles leading up to mastectomy. Patients underwent serial assessment (pharmacokinetic sampling, biopsy of breast, tumor blood flow dynamic contrast-enhanced magnetic resonance imaging, plasma angiogenesis, and endothelial cell damage markers) prior to treatment, at the end of cycles no. 2 and no. 5, and after mastectomy.

Results: Eighteen patients were enrolled; neutropenia was dose-limiting, and overall median survival was not reached (50 months of study follow-up). Four patients (22%) experienced congestive heart failure, which resolved and were likely attributable to a smaller volume of distribution and higher C_max of doxorubicin in combination with SU5416. We did observe a significant decline in tumor blood flow using Kep calculated by Brix (pretreatment versus post-cycle no. 5; P = 0.033), trend for a decline in tumor microvessel density after treatment, and low baseline levels of soluble intracellular adhesion molecule were associated with improved event-free survival.

Conclusions: This study showed evidence of an unfavorable cardiac interaction between SU5416 and doxorubicin, which prohibits further investigation of this combination. However, this study supports the importance of using IBC as a model for investigating angiogenesis inhibitors.

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