PHYSICS CONTRIBUTION RADIOTHERAPYADAPTED TO SPATIAL AND TEMPORAL VARIABILITY IN TUMOR HYPOXIA A ˚ STE SØVIK, M.SC.,* y EIRIK MALINEN,PH.D.,* y HEGE K. SKOGMO, D.V.M., PH.D., x SØREN M. BENTZEN,PH.D., D.SC., k ØYVIND S. BRULAND, M.D., PH.D., {# AND DAG RUNE OLSEN,PH.D. yz * Department of Medical Physics, The Norwegian Radium Hospital, Oslo, Norway; y Department of Physics, University of Oslo, Oslo, Norway; z Department of Radiation Biology, The Norwegian Radium Hospital, Oslo, Norway; x Department of Companion Animal Clinical Sciences, The Norwegian School of Veterinary Science, Oslo, Norway; k Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin; { Department of Oncology, The Norwegian Radium Hospital, Oslo, Norway; and # Department of Clincal Medicine, University of Oslo, Oslo, Norway Purpose: To explore the feasibility and clinical potential of adapting radiotherapy to temporal and spatial varia- tions in tumor oxygenation. Methods and Materials: Repeated dynamic contrast enhanced magnetic resonance (DCEMR) images were taken of a canine sarcoma during the course of fractionated radiation therapy. The tumor contrast enhancement was assumed to represent the oxygen distribution. The IMRT plans were retrospectively adapted to the DCEMR im- ages by employing tumor dose redistribution. Optimized nonuniform tumor dose distributions were calculated and compared with a uniform dose distribution delivering the same integral dose to the tumor. Clinical outcome was estimated from tumor control probability (TCP) and normal tissue complication probability (NTCP) modeling. Results: The biologically adapted treatment was found to give a substantial increase in TCP compared with con- ventional radiotherapy, even when only pretreatment images were used as basis for the treatment planning. The TCP was further increased by repeated replanning during the course of treatment, and replanning twice a week was found to give near optimal TCP. Random errors in patient positioning were found to give a small decrease in TCP, whereas systematic errors were found to reduce TCP substantially. NTCP for the adapted treatment was similar to or lower than for the conventional treatment, both for parallel and serial normal tissue structures. Conclusion: Biologically adapted radiotherapy is estimated to improve treatment outcome of tumors having spatial and temporal variations in radiosensitivity. Ó 2007 Elsevier Inc. Adaptive radiotherapy, IMRT, Hypoxia, TCP. INTRODUCTION For tumors with a spatial variation in radiation sensitivity, a uniform dose distribution is generally not optimal (1, 2). Three-dimensional (3D) imaging of radiobiologically rele- vant parameters could form the basis for adaptive radio- therapy of heterogeneous tumors (3, 4), where selective dose boosting of radioresistant regions is used to improve the treatment outcome. The feasibility of creating targeted, nonuniform tumor dose distributions has been demonstrated (5–8). In these studies, treatment plans were scored in terms of the estimated tumor control probability (TCP) or quality functions, implicitly assuming a static distribution of radio- sensitivity throughout a fractionated treatment course. How- ever, the tumor microenvironment is not static (9, 10), implying that repeated imaging may be required to optimize the adapted treatment. Dose boosting in general may increase the tumor control probability (TCP), in part because of an increase in integral tu- mor dose. Hence, it is difficult to estimate the clinical gain at- tributable to improved biologic selectivity of the treatment. By tumor dose redistribution (5, 6, 11), the confounding effect of an increase in mean tumor dose is avoided by comparing non- uniform and uniform dose distributions of equal mean dose. Hypoxia is a known cause of resistance to radiation ther- apy (12) and is associated with reduced disease-free and overall survival for many solid tumors (13–17). Noninvasive imaging techniques are being developed for mapping the three-dimensional distribution of tumor oxygenation (18–23). It has been hypothesized that radiotherapeutic targeting of hypoxic regions may improve the treatment outcome for patients where hypoxia is the limiting factor (24, 25). Dynamic contrast enhanced magnetic resonance imaging (DCEMRI) may provide high resolution 3D maps of tumor Reprint requests to: Eirik Malinen, Ph.D., Department of Medical Physics, The Norwegian Radium Hospital, 0310 Oslo, Norway. Tel: (+47) 22781204; Fax: (+47) 22781108; E-mail: emalinen@fys.uio.no Supported by Norwegian Research Council Grant No. 27616. Conflict of interest: none. Received Jan 5, 2007, and in revised form April 16, 2007. Accepted for publication April 17, 2007. 1496 Int. J. Radiation Oncology Biol. Phys., Vol. 68, No. 5, pp. 1496–1504, 2007 Copyright Ó 2007 Elsevier Inc. Printed in the USA. All rights reserved 0360-3016/07/$–see front matter doi:10.1016/j.ijrobp.2007.04.027