doi:10.1016/j.ijrobp.2006.11.017 CLINICAL INVESTIGATION Rectum PHASE I TRIAL OF PREOPERATIVE HYPOFRACTIONATED INTENSITY-MODULATED RADIOTHERAPY WITH INCORPORATED BOOST AND ORAL CAPECITABINE IN LOCALLY ADVANCED RECTAL CANCER GARY M. FREEDMAN, M.D.,* NEAL J. MEROPOL, M.D., † ELIN R. SIGURDSON, M.D., PH.D., ‡ JOHN HOFFMAN, M.D., ‡ ELAINE CALLAHAN, L.G.P.N.,* ROBERT PRICE,PH.D.,* JONATHAN CHENG, M.D., † STEVE COHEN, M.D., † NANCY LEWIS, M.D., † DEBORAH WATKINS-BRUNER, R.N., M.S.N., PH.D., § ANDRÉ ROGATKO,PH.D., ¶ AND ANDRE KONSKI, M.D.* Departments of *Radiation Oncology, † Medical Oncology, and ‡ Surgical Oncology, University of Pennsylvania School of Medicine; § University of Pennsylvania School of Nursing, Philadelphia, PA; ¶ Winship Cancer Institute, Atlanta, GA Purpose: To determine the safety and efficacy of preoperative hypofractionated radiotherapy using intensity- modulated radiotherapy (IMRT) and an incorporated boost with concurrent capecitabine in patients with locally advanced rectal cancer. Methods and Materials: The eligibility criteria included adenocarcinoma of the rectum, T3-T4 and/or N1-N2 disease, performance status 0 or 1, and age >18 years. Photon IMRT and an incorporated boost were used to treat the whole pelvis to 45 Gy and the gross tumor volume plus 2 cm to 55 Gy in 25 treatments within 5 weeks. The study was designed to escalate the dose to the gross tumor volume in 5-Gy increments in 3-patient cohorts. Capecitabine was given orally 825 mg/m 2 twice daily for 7 days each week during RT. The primary endpoint was the maximal tolerated radiation dose, and the secondary endpoints were the pathologic response and quality of life. Results: Eight patients completed RT at the initial dose level of 55 Gy. The study was discontinued because of toxicity—six Grade 3 toxicities occurred in 3 (38%) of 8 patients. All patients went on to definitive surgical resection, and no patient had a pathologically complete response. Conclusion: This regimen, using hypofractionated RT with an incorporated boost, had unacceptable toxicity despite using standard doses of capecitabine and IMRT. Additional research is needed to determine whether IMRT is able to reduce the side effects during and after pelvic RT with conventional dose fractionation. © 2007 Elsevier Inc. Rectal cancer, Radiotherapy, Intensity-modulated radiotherapy, Hypofractionation, Capecitabine. INTRODUCTION This phase I trial sought to develop a novel regimen for preoperative rectal cancer, building on previous studies using dose escalation, capecitabine, and intensity-modu- lated radiotherapy (IMRT). This regimen maintained an overall treatment time of 5 weeks using hypofractionation, or the use of greater than the standard 1.8-Gy fractions daily, and the daily incorporation of a tumor bed boost rather than a standard sequential boost. The goals of this study were to determine the maximal tolerated dose (MTD) of concomitant boost RT by escalating dose of the boost in successive cohorts of patients. The incorporation of IMRT as the means of dose escalation was meant to maintain the toxicity at acceptable levels. The pathologic tumor response and patient quality of life were two additional endpoints for the study. METHODS AND MATERIALS Patient selection The Fox Chase Cancer Center Institutional Review Board ap- proved the study, and all patients provided informed consent. The inclusion criteria were histologically confirmed invasive adenocar- Reprint requests to: Gary M. Freedman, M.D., Department of Radiation Oncology, Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111. Tel: (215) 728-3016; Fax: (215) 214-1629; E-mail: G_Freedman@FCCC.edu Supported in part by a grant from Roche Laboratories Inc. Conflict of interest: none. Acknowledgments—The authors thank Terry White for her assis- tance in the management of the clinical study, Katherine Farlow for her assistance in the preparation of the study protocol, corre- spondence, and manuscript, and Paul Engstrom, M.D. and Louis Weiner, M.D. for referral or treatment of patients in the clinical study. Received Aug 9, 2006, and in revised form Nov 10, 2006. Accepted for publication Nov 10, 2006. Int. J. Radiation Oncology Biol. Phys., Vol. 67, No. 5, pp. 1389 –1393, 2007 Copyright © 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter 1389