Cancer Res

Cancer Res. of patients had grade 3 or greater treatment-related gastrointestinal toxicity (22.0% during chemoradiotherapy, 13.4% during maintenance chemotherapy). Unacceptable radiotherapy protocol deviations (ie, inappropriately generous volume contoured) correlated with grade 3 or greater gastrointestinal toxicity during chemoradiotherapy (45% 18%; adjusted odds ratio, 3.7; 95% CI, 0.98 to 14.1; = .05). Conclusion The addition of bevacizumab to chemoradiotherapy followed by bevacizumab and gemcitabine resulted in a similar median survival to previous Radiation Therapy Oncology Group studies in patients with locally advanced pancreatic cancer. Prospective QA may help limit toxicity in future trials. INTRODUCTION Locally advanced pancreatic cancer is a challenging malignancy to treat. Approaches that use chemotherapy, chemoradiotherapy, or both have significant limitations. AntiCvascular endothelial growth factor (VEGF) Cbased regimens have been successful in combination with chemotherapy in the metastatic setting in colorectal,1 lung,2 renal,3,4 and breast carcinomas.5 When this trial was developed, bevacizumab in combination with gemcitabine was considered a promising regimen for patients with metastatic pancreatic cancer on the basis of a phase II trial that showed a median survival of 9.2 months.6 Ionizing radiation induces VEGF expression,7 which may protect endothelial cells exposed to radiation. Inhibition of VEGF with bevacizumab, therefore, may enhance the cytotoxicity of radiation because of the potentiation of endothelial cell death. In vivo studies have shown that a radioresistant phenotype can be overcome by using agents that neutralize VEGF activity or prevent its signaling.7C9 Alternatively, enhancement of radiotherapy by bevacizumab could occur through the prevention of VEGF binding to VEGF receptors present on pancreatic tumor cells.10,11 In a phase I trial Maribavir at the M. D. Anderson Cancer Center, 47 patients were treated with escalating doses of bevacizumab in combination with capecitabine and radiation. During that trial, three of Maribavir the first 30 patients were found to have duodenal bleeding at the tumor site. All three were suspected of having tumor that invaded the duodenum at presentation. Subsequent protocol modification to exclude such patients led to the successful accrual of 17 more patients without subsequent bleeding events. At the dose level of bevacizumab 5 mg/kg, six of 12 patients had partial response, and there were Rabbit Polyclonal to Cytochrome P450 2B6 no grade 3 gastrointestinal toxicities. This study, Radiation Therapy Oncology Group (RTOG) 0411, was designed to assess the 1-year overall survival rate and safety of bevacizumab with radiation in a cooperative group setting. PATIENTS AND METHODS Patient Eligibility Criteria Cytologic or Maribavir histologic proof of localized unresectable adenocarcinoma of the pancreas and a Zubrod performance score of 0 or 1 were required. Unresectability was based on institutional criteria that used either computed tomography (CT) or magnetic resonance imaging (MRI) and chest x-ray within 4 weeks of protocol entry. Patients who had received chemotherapy more than 2 years before enrollment for diseases other than pancreatic cancer were eligible provided they had no evidence of disease. There was no upper age restriction. Patients were required to have an absolute granulocyte count of 1,500 cells/L, a platelet count 100,000 cells/L, a calculated creatinine clearance greater than 50/mL/min, an AST level less than three times the upper limit of normal, an ALT level less than three times upper Maribavir limit of normal, a serum bilirubin level of less than 2.0 mg/dL, and an international normalized ratio 1.5 before registration. All patients had to sign a study-specific consent form, and the study was approved by the Human.