International Journal of Radiation Oncology*Biology*Physics
Clinical investigationRectumBevacizumab, Oxaliplatin, and Capecitabine With Radiation Therapy in Rectal Cancer: Phase I Trial Results
Introduction
Angiogenesis is a critical element in tumor growth and dissemination. Vascular endothelial growth factor (VEGF) plays an important role in this process, effecting vascular permeability as well as endothelial-cell activation, migration, invasion, and proliferation. The overexpression of VEGF was associated with poor outcomes in colorectal cancer patients (1, 2). VEGF overexpression was also linked to radiation resistance in preclinical and clinical models (3). Bevacizumab (Avastin; Genentech Pharmaceuticals, South San Francisco, CA) is a humanized monoclonal antibody directed against VEGF. When combined with 5-fluorouracil (5-FU)-based chemotherapy, bevacizumab improves survival in patients with metastatic colorectal cancer, in both the first- and second-line settings (4, 5). Bevacizumab enhances tumor blood flow, reduces tumor interstitial pressure, and decreases mean vessel density when infused neoadjuvantly in rectal-cancer patients. These physiologic changes may enhance the activity of radiation and chemotherapy (6, 7). Oxaliplatin (Eloxatin; Sanofi-Aventis Pharmaceuticals, Paris, France) causes intrastrand and interstrand DNA crosslink formation, inhibiting tumor replication. When combined with 5-FU-based chemotherapy, oxaliplatin improves outcomes in Stage II–IV colon cancer (8, 9). In addition, oxaliplatin is a potent radiosensitizer. Neoadjuvant delivery of oxaliplatin with 5-FU-based chemotherapy and radiation therapy in rectal cancer patients is feasible, with encouraging response rates in pilot studies (10, 11, 12).
In rectal cancer, the combination of radiation therapy with fluoropyrimidines improves local control and survival compared with radiation therapy alone (13). Many patients are not cured with this therapy, and novel approaches to improve efficacy, toxicity, and convenience are needed. Capecitabine (Xeloda; Roche Pharmaceuticals, Basel, Switzerland), an oral fluorouracil analog, has theoretical and established advantages as a radiosensitizer in rectal cancer (14, 15, 16). Phase III studies demonstrated that capecitabine has equivalent efficacy to IV 5-FU in the therapy of both metastatic and resected colorectal cancer (17, 18, 19). To test the hypothesis that the combination of bevacizumab, capecitabine, and oxaliplatin with radiation therapy would be well-tolerated and clinically active, a Phase I–II study was initiated, evaluating this combination in patients with Stage II–IV rectal cancer.
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Methods and Materials
This protocol was reviewed and approved by the Duke University Institutional Review Board and the study performed in accordance with the Declaration of Helsinki, as amended in Somerset West in 1996. All patients were required to provide written, informed consent before entry into the trial.
Results
Eleven patients were enrolled in this Phase I study between September 2004–September 2005. Patient characteristics are summarized in Table 2. All patients had de novo disease; 4 had distant metastases at presentation.
Discussion
Radiation therapy with 5-FU-based chemotherapy improves local control, disease-free and overall survival in patients with rectal cancer (13, 20). In addition to its clinical activity as monotherapy and in combination regimens in advanced colorectal cancer, capecitabine is also active and well-tolerated as a radiosensitizer for localized rectal cancers (15, 16, 21). This study builds upon its platform, combining an oral fluoropyrimidine with a platinum agent and VEGF inhibitor. Oxaliplatin is a
Acknowledgments
The authors thank the patients who participated in these studies, their families and caregivers, study coordinator Amy Franklin, and Wanda Lawrence for assistance in manuscript preparation.
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Research support for this study was provided by Genentech Pharmaceuticals (South San Francisco, CA), Sanofi-Aventis Pharmaceuticals (Paris, France), and Roche Pharmaceuticals (Basel, Switzerland).
Conflict of interest: none.