10.24 mm technical reportS series no. 46i This report covers all the aspects of the relative biological effectiveness (RBE) of ion beams, including laboratory measurements of RBE and the important variables that influence it, dose related quantities and units, and approaches to the clinical use of the concept of RBE based on experimental findings, theoretical models, and previous clinical experience with fast neutrons and ions. RBE is a simple concept but its clinical Technical Reports SeriEs No. 46i application is complex. Future developments in ion therapy will require a coherent approach to the reporting of therapies and their outcomes, not only for comparison with other ion facilities but also with conventional and newly developing photon irradiation techniques. The report is the result of a joint initiative between the IAEA and the International Commission on Radiation Relative Biological Units and Measurements, and is the only current extensive review of ion RBE. Relative Biological Effectiveness in Therapy Ion Beam Effectiveness in Ion Beam Therapy Jointly sponsored by the IAEA and ICRU INTERNATIONAL ATOMIC ENERGY AGENCY VIENNA ISBN 978–92–0–107807–0 ISSN 0074–1914 07-32641_D461_CovI-IV.indd 1 2008-04-01 10:47:19 RELATIVE BIOLOGICAL EFFECTIVENESS IN ION BEAM THERAPY TECHNICAL REPORTS SERIES No. 461 RELATIVE BIOLOGICAL EFFECTIVENESS IN ION BEAM THERAPY JOINTLY SPONSORED BY THE INTERNATIONAL ATOMIC ENERGY AGENCY AND THE INTERNATIONAL COMMISSION ON RADIATION UNITS AND MEASUREMENTS INTERNATIONAL ATOMIC ENERGY AGENCY VIENNA, 2008 COPYRIGHT NOTICE All IAEA scientific and technical publications are protected by the terms of the Universal Copyright Convention as adopted in 1952 (Berne) and as revised in 1972 (Paris). The copyright has since been extended by the World Intellectual Property Organization (Geneva) to include electronic and virtual intellectual property. 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B o x 1 0 0 1400 Vienna, Austria fax: +43 1 2600 29302 tel.: +43 1 2600 22417 email: [email protected] http://www.iaea.org/books © IAEA, 2008 Printed by the IAEA in Austria February 2008 STI/DOC/010/461 IAEA Library Cataloguing in Publication Data Relative biological effectiveness in ion beam therapy / jointly sponsored by the International Atomic Energy Agency and the International Commission on Radiation Units and Measurements. — Vienna : International Atomic Energy Agency, 2008. p. ; 24 cm. — (Technical reports series, ISSN 0074–1914 ; no. 461) STI/DOC/010/461 ISBN 978–92–0107807–0 Includes bibliographical references. 1. Ion bombardment — Therapeutic use. I. International Atomic Energy Agency. II. Series : Technical reports series (International Atomic Energy Agency) ; 461. IAEAL 08–00503 FOREWORD The use of ion beams for radiation therapy was first explored at the University of California’s Lawrence Berkeley National Laboratory, in the United States of America, and is currently undergoing investigation at institutions in both Japan and Germany with other facilities which are under development or planned. With respect to a role in radiation therapy, ion beams have two important features arising both from the physical aspects of their dose distribution in the patient and from potentially advantageous biological phenomena resulting from their high rate of energy deposition (high linear energy transfer (LET)) over a portion of the particle track which can often be located in the tumour volume. Probably the most important of these biological phenomena is a markedly increased efficiency of cell killing. The concept of relative biological effectiveness (RBE) has been introduced to account for this increased efficiency. RBE is defined as the ratio of a dose of photons to a dose of any other particle to produce the same biological effect. RBE is a simple concept but its clinical application is complex because it is a function of particle type, energy, dose, dose per fraction, fraction number, cell or tissue type, and varies between early and late reactions following therapy. Future developments in ion therapy will require a coherent approach to the reporting of therapies and their outcomes for comparison not only with other ion facilities but also with conventional and newly developing photon irradiation techniques. The International Commission on Radiation Units and Measurements (ICRU) has been involved in the production of a series of reports aimed at rationalizing the reporting of various forms of radiation therapy. Collaboration between the IAEA and the ICRU was initiated for proton therapy. The present publication reflects a continuation of the collaboration between the IAEA and the ICRU, and represents a beginning step in an attempt to standardize the reporting of ion beam radiotherapy using concepts previously developed by the ICRU for reporting other therapies but with special emphasis on the use and reporting of weighting factors related to RBE. Such standardization will facilitate the comparison of therapeutic results obtained with ions not only between centres using this approach but also with centres using other modern forms of radiation therapy, such as proton and intensity modulated radiation therapy with photon beams. A Technical Meeting on Relative Biological Effectiveness in Ion Beam Therapy, jointly sponsored by the IAEA and the ICRU, was held in Vienna, in June 2004. The meeting dealt primarily with the review of experimental measurements of RBE and approaches to the clinical use of the concept of RBE based on experimental findings, theoretical models and previous clinical experience with fast neutrons and ions. Four of the papers presented at this meeting appear as Annexes I–IV in this publication. They were selected as examples related to methods used in different research centres. This publication was prepared by an editorial group comprising E. Blakely of the Lawrence Berkeley National Laboratory, J. Hendry of the IAEA, and P. DeLuca, R. Gahbauer, B. Michael, A. Wambersie and G. Whitmore of the ICRU. The group was chaired by G. Whitmore. The IAEA officer responsible for this publication was J. Hendry of the Division of Human Health. EDITORIAL NOTE Although great care has been taken to maintain the accuracy of information contained in this publication, neither the IAEA nor its Member States assume any responsibility for consequences which may arise from its use. The use of particular designations of countries or territories does not imply any judgement by the publisher, the IAEA, as to the legal status of such countries or territories, of their authorities and institutions or of the delimitation of their boundaries. The mention of names of specific companies or products (whether or not indicated as registered) does not imply any intention to infringe proprietary rights, nor should it be construed as an endorsement or recommendation on the part of the IAEA. CONTENTS 1. RELATIVE BIOLOGICAL EFFECTIVENESS IN ION BEAM THERAPY. 1 1.1. Introduction . 1 1.1.1. Role of radiation therapy in the treatment of cancer . 1 1.1.2. Present situation and future trends . 2 1.1.3. Rationale for ion therapy . 3 2. BIOLOGICAL WEIGHTING OF ABSORBED DOSE: THE SPECIFIC ISSUE OF RBE IN ION BEAM THERAPY . 8 2.1. Absorbed dose . 8 2.2. Need for weighting factors . 9 2.3. Reference irradiation conditions . 10 2.3.1. Radiation quality . 10 2.3.2. Reference fractionation scheme . 10 2.4. Fractionated external photon therapy . 11 2.4.1. Weighting factor for differences in dose per fraction . 11 2.4.2. Example . 12 2.5. Brachytherapy and differences in dose rate . 12 2.6. Influence of overall time . 13 2.7. Radiation quality and RBE . 14 2.7.1. The RBE concept . 14 2.7.2. Application of the RBE concept in radiation therapy . 14 2.7.2.1. RBE and dose prescription . 15 2.7.2.2. Selection of the most clinically relevant RBE or weighting factors for ions . 18 2.7.2.3. Selection of Wion based on the linear quadratic model . 19 2.7.2.4. Evaluation of WIsoE from clinical considerations or outcomes . 22 2.7.3. Ion RBE in therapy applications: Summary . 23 3. QUANTITIES AND UNITS . 26 3.1. Absorbed dose, D . 26 3.2. Biological weighting factor, WB . 27 3.2.1. Fractionated photon beam therapy . 27 3.2.2. Brachytherapy . 28 3.2.3. External beam therapy with non-conventional radiation quality . 28 3.3. Biologically weighted absorbed dose, DB . 29 3.4. Recommendations for reporting . 30 3.4.1. Reporting the isoeffective dose weighting factor, WIsoE. 30 3.4.2. General recommendations for reporting radiation therapy . 31 3.4.3. Review of some current practices for weighting and reporting weighted dose and isoeffective dose in centres using particle irradiations . 31 3.4.3.1. Proton beam therapy . 31 3.4.3.2. The Darmstadt–Heidelberg approach in carbon ion therapy . 32 3.4.3.3. The Chiba approach in carbon ion therapy . 32 3.4.3.4. Equivalent dose . 32 3.4.4. ICRU/IAEA recommendations for reporting the isoeffective dose, DIsoE . 33 4. RADIOBIOLOGY OF HIGH LET RADIATION: NEUTRONS AND IONS . 36 4.1. Radiobiological rationale for the use of high LET radiation . 36 4.1.1. Increased RBE . 36 4.1.2. Reduction in the oxygen enhancement ratio with increasing LET . 39 4.1.3. Reduction of the variation in radiosensitivity related to the position of the cell in the mitotic cycle . 40 4.1.4. Reduced repair with high LET radiation . 41 4.1.5. Effect of tumour differentiation and growth rate . 43 4.2. Patient selection for high LET radiotherapy . 45 4.3.