doi:10.1016/j.ijrobp.2003.09.027 ICTR 2003 Translational Research in Clinics WHERE NEXT WITH PREOPERATIVE RADIATION THERAPY FOR RECTAL CANCER? H. RODNEY WITHERS, M.D., D.SC.,* AND KARIN HAUSTERMANS, M.D., PH.D. † *Department of Radiation Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA; † Department of Radiation Oncology, University Hospital Gasthuisberg, Leuven, Belgium Purpose: The basic question for radiation oncologists is what we hope to achieve from treatments that are adjuvant to surgery: better local (pelvic) control and, hopefully, because of that, fewer metastases. Chemotherapy could add to the local effect of irradiation and may also decrease distant metastases directly. Selection criteria for individual treatment could enhance the therapeutic index. Local Control: Total mesorectal excision reduces the incidence of local recurrence, but preoperative (chemo) radiation is still indicated for more advanced tumors (T3–T4) and for lymph node involvement. Pelvic recur- rences arise from tumor clonogens residual beyond the surgical margins. Thus, the practice of shrinking fields to boost the dose to the primary tumor makes no sense, except for tumors that invade residual structures, such as the sacrum.Subclinical disease beyond the future surgical margins grows more quickly than the primary tumor, and hence treatment should be as intense as tolerable. A short treatment course (e.g. 5  5 Gy) is desirable, but this regimen, which is currently the gold standard, should be compared (as in the recently closed randomized Polish trial) with higher-dose, longer-duration chemoradiotherapy regimens. The recently closed EORTC trial 22921 examines the benefit of pre- and postoperative chemotherapy combined with a long schedule of radiation. Likewise, continuous infusion of a cycle-active agent rather than bolus administration is a logical addition to radiation therapy in the treatment of fast-growing subclinical tumor extensions. Systemic Disease: The reduction in distant metastasis rates attributable to adjuvant chemotherapy varies greatly among reports. If the reduction is of the order of 10 –25%, the efficacy of chemotherapy equates to as little as about 5 to 12.5 Gy and not more than 20 Gy of total body irradiation. Interval Between Radiation Therapy and Postradiation Surgery: Early excision after preoperative irradiation would be desirable if the primary tumor were still disseminating viable metastatic clonogens. Most tumors do not metastasize until they contain enough viable clonogens to render them clinically detectable. A dose of 10 Gy in 2 Gy fractions reduces at least 30-fold the absolute number of viable clonogens in the primary tumor, to levels that do not yield metastases from the untreated tumor. After a dose of 44 –50 Gy in 2 Gy fractions, there is little chance that the surviving tumor clonogens could regrow to a metastasis-yielding volume in any reasonable radiation–surgery interval. Thus there is no tumor-related necessity for early postradiation surgery. The importance of the interval between radiation and surgery is currently being addressed in a Swedish randomized trial. Prognostic and Predictive Characterization: Tumor volume should be included in the staging system. There are many tumor- and host-related characteristics that can be used to fingerprint the tumor to help select appropriate individual treatment. © 2004 Elsevier Inc. Rectal cancer, Surgery, (Chemo)radiation, Local control, Distant metastasis. INTRODUCTION Radiation therapy as an adjuvant treatment to surgery in the treatment of rectal cancer was commonly used in the post- operative setting. This approach allowed the use of patho- logic staging to help select patients for treatment and to analyze results. Now that the utility of adjuvant radiation therapy has been established and better methods for clinical staging have been introduced, the emphasis has shifted to preoperative irradiation with or without chemotherapy. The purpose of preoperative irradiation of rectal cancer is twofold: 1. To increase the probability of tumor control within the pelvis and to increase the frequency of sphincter pres- ervation. Reprint requests to: H. Rodney Withers, M.D., D.Sc., Depart- ment of Radiation Oncology, 200 UCLA Medical Plaza, Los Angeles, CA 90095-6951. Tel: (310) 794-1252; Fax: (310) 794- 9795; E-mail: withers@radonc.ucla.edu Presented at ICTR 2003, Lugano, Switzerland, March 16 –19, 2003. Acknowledgments—J. Haas helped prepare the manuscript. Received Sep 8, 2003. Accepted for publication Sep 15, 2003. Int. J. Radiation Oncology Biol. Phys., Vol. 58, No. 2, pp. 597– 602, 2004 Copyright © 2004 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/04/$–see front matter 597