Originally published as JCO Early Release 10.1200/JCO.2008.21.1771 on May 26 2009

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Efficacy, Safety, and Biomarkers of Neoadjuvant Bevacizumab, Radiation Therapy, and Fluorouracil in Rectal Cancer: A Multidisciplinary Phase II Study

Christopher G. Willett, Dan G. Duda, Emmanuelle di Tomaso, Yves Boucher, Marek Ancukiewicz, Dushyant V. Sahani, Johanna Lahdenranta, Daniel C. Chung, Alan J. Fischman, Gregory Y. Lauwers, Paul Shellito, Brian G. Czito, Terence Z. Wong, Erik Paulson, Martin Poleski, Zeljko Vujaskovic, Rex Bentley, Helen X. Chen, Jeffrey W. Clark, Rakesh K. Jain

From the Departments of Radiation Oncology, Radiology, Surgery, Medicine, and Pathology, Duke University Medical Center, Durham, NC; Departments of Radiation Oncology, Radiology, Nuclear Medicine, Pathology, Hematology/Oncology, Surgery, and the Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, MA; and the Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD.

Corresponding author: Christopher G. Willett, MD, Box 3085, Duke University Medical Center, Durham, NC 27710; e-mail: christopher.willett{at}duke.edu.

Purpose To assess the safety and efficacy of neoadjuvant bevacizumab with standard chemoradiotherapy in locally advanced rectal cancer and explore biomarkers for response.

Patients and Methods In a phase I/II study, 32 patients received four cycles of therapy consisting of: bevacizumab infusion (5 or 10 mg/kg) on day 1 of each cycle; fluorouracil infusion (225 mg/m²/24 hours) during cycles 2 to 4; external-beam irradiation (50.4 Gy in 28 fractions over 5.5 weeks); and surgery 7 to 10 weeks after completion of all therapies. We measured molecular, cellular, and physiologic biomarkers before treatment, during bevacizumab monotherapy, and during and after combination therapy.

Results Tumors regressed from a mass with mean size of 5 cm (range, 3 to 12 cm) to an ulcer/scar with mean size of 2.4 cm (range, 0.7 to 6.0 cm) in all 32 patients. Histologic examination revealed either no cancer or varying numbers of scattered cancer cells in a bed of fibrosis at the primary site. This treatment resulted in an actuarial 5-year local control and overall survival of 100%. Actuarial 5-year disease-free survival was 75% and five patients developed metastases postsurgery. Bevacizumab with chemoradiotherapy showed acceptable toxicity. Bevacizumab decreased tumor interstitial fluid pressure and blood flow. Baseline plasma soluble vascular endothelial growth factor receptor 1 (sVEGFR1), plasma vascular endothelial growth factor (VEGF), placental-derived growth factor (PlGF), and interleukin 6 (IL-6) during treatment, and circulating endothelial cells (CECs) after treatment showed significant correlations with outcome.

Conclusion Bevacizumab with chemoradiotherapy appears safe and active and yields promising survival results in locally advanced rectal cancer. Plasma VEGF, PlGF, sVEGFR1, and IL-6 and CECs should be further evaluated as candidate biomarkers of response for this regimen.

C.G.W., D.G.D., and E.d.T. contributed equally to this article. C.G.W., and R.K.J. are co-senior authors.

Supported by the Grants No. R21CA099237 (C.G.W.), P01CA80124, and R01CA115767 from the National Institutes of Health, and a grant from the National Foundation for Cancer Research (R.K.J.).

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

Clinical Trials repository link available on JCO.org.

Clinical trial information can be found for the following: NCT00052559 [ClinicalTrials.gov] .

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