Requirements for Boron Neutron Capture Therapy (BNCT) at a Nuclear Research Reactor Editor(S): W
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Requirements for Boron Neutron Capture Therapy (BNCT) at a Nuclear Research Reactor Wolfgang A.G. Sauerwein and Ray L. Moss BNCT TEAM The European BNCT Project EUR 23830 EN - 2009 The mission of the JRC-IE is to provide support to Community policies related to both nuclear and non-nuclear energy in order to ensure sustainable, secure and efficient energy production, distribution and use. European Commission Joint Research Centre Institute for Energy Contact information Address: ESE Unit, Institute for Energy, JRC Petten, 1775 ZG, Petten, The Netherlands E-mail: [email protected] Tel.: 0031 224 565126 Fax: 0031 224 565615 http://ie.jrc.ec.europa.eu/ http://www.jrc.ec.europa.eu/ Legal Notice Neither the European Commission nor any person acting on behalf of the Commission is responsible for the use which might be made of this publication. Europe Direct is a service to help you find answers to your questions about the European Union Freephone number (*): 00 800 6 7 8 9 10 11 (*) Certain mobile telephone operators do not allow access to 00 800 numbers or these calls may be billed. A great deal of additional information on the European Union is available on the Internet. It can be accessed through the Europa server http://europa.eu/ JRC 48624 EUR 23830 EN ISBN 978-92-79-12431-0 ISSN 1018-5593 doi:10.2790/11743 Luxembourg: Office for Official Publications of the European Communities, 2009 © European Communities, 2009 Reproduction is authorised provided the source is acknowledged Printed in The Netherlands 1 Foreword On 11-12 November 2005, a workshop took place in Prague entitled “Requirements for BNCT at a Nuclear Research Reactor”, which was funded by the JRC’s Enlargement and Integration Action. (E&IA). The intention of the workshop was to exchange knowledge between the EU BNCT programme at the HFR Petten and other existing clinical and preclinical research programmes on BNCT throughout Europe, with the special aim to transfer information towards groups and places that are preparing their own national BNCT projects. The future of nuclear research institutes will depend on their ability to open research programmes into new areas and to link nuclear technologies with other applications. Medicine is one of the most interesting but also sensitive areas for such multidisciplinary work. Boron Neutron Capture Therapy (BNCT) is a dedicated and well-known topic that demonstrates such a link in an exemplary way. This book expands on some of the topics presented at the workshop. It is intended to support scientists, clinicians and politicians that are interested to develop a local or national BNCT activity. We would like to thank the Joint Research Centre of the European Commission, which has strongly supported the workshop and the publication of this book but especially some of the research activities and technological developments that can be reported here. We also thank Jiri Burian, Victor Nievaart and Andrea Wittig for the tremendous efforts they made to prepare the workshop. Raymond Moss1 and Wolfgang Sauerwein2 1 R.L.Moss, ESE Unit, Institute for Energy, European Commission, Petten, The Netherlands 2 W.A.G.Sauerwein, Strahlenklinik, University Hospital, Essen, Germany 3 5 Contents Page Foreword 1. Introduction 5 2. Organisational Aspects 2.1 Interdisciplinary collaboration at a BNCT facility 7 2.2 Regulatory affairs and Licensing for a BNCT facility 13 2.3 Quality assurance 17 2.4 Radiation protection 27 3. The BNCT Irradiation Facility 3.1 General requirements 29 3.2 Design 32 3.3 Beam characterization 35 3.4 Boron analysis 40 4. Medical Aspects 4.1 Medical physics and clinical dosimetry 43 4.2 Radiobiology 48 4.3 Drug 4.3.1 Good Manufacturing Practice (GMP) production for BSH and BPA 59 4.3.2 Pharmaceutical issues 64 4.4 Clinical trials 67 4.5 Patient care 72 4.6 Treatment planning 74 5. A preclinical research programme: The Italian Research Project in BNCT 82 6. BNCT: The current situation in Europe 90 6.1 Petten 90 6.2 Helsinki 93 6.3 Rez 96 6.4 Pavia 99 6.5 Budapest 101 6.6 Kiev 104 6.7 Sofia 107 6.8 Poland 109 6.9 Vilnius 112 6.10 Obninsk 116 6.11 Bratislava 118 6.12 Mainz 122 6.13 Casaccia (Rome) 124 6.14 Bucharest 128 6.15 Designing your own BNCT Programme 130 List of Contributors 134 7 1. Introduction W. Sauerwein, R.L. Moss Boron Neutron Capture Therapy is a binary form of radiation therapy using the high propensity of the non-radioactive nuclide boron-10 to capture thermal neutrons resulting in the prompt nuclear reaction 10)B(n,α 7Li. The products of this reaction have high linear energy transfer characteristics (α particle approximately 150 keVµm-1, 7Li-nucleus approximately 175 keVµm-1). The path lengths of these particles are in the range of 4.5 µm to 10 µm: hence resulting an energy deposition limited to the diameter of a single cell. Theoretically, therefore, it is possible to selectively irradiate those tumour cells that have taken up a sufficient amount of 10B and simultaneously spare normal cells. The basic nuclear reaction in shown in more detail below: Shortly after the discovery of the neutron by Chadwick in 1932 [1] and the description of the 10)B(n,α 7Li reaction by Taylor and Goldhaber 1935 [2], the basic idea to use neutron capture reactions in cancer treatment was published by Locher in 1936 [3]. The first clinical applications in humans were performed in the USA from 1951 to 1961 [4], but were considered a failure. In 1968, Hatanaka started to treat patients suffering from malignant glioma [5]. He used the drug BSH and a thermal neutron source for intra-operative irradiation, which resulted in long survival in some of his patients. His pioneering work led to an increased interest around the world for investigating BNCT further. In 1987, BPA was introduced by Mishima in Japan to treat superficial melanoma with BNCT [6]. In the early 1990s, epithermal neutron sources were developed in the USA and Europe to treat deeper- seated tumours. These facilities created the conditions to start controlled perspective clinical trials in Brookhaven, Petten and Cambridge (MA) in 1996. These were soon followed by the creation of similar facilities in Finland, Sweden, the Czech Republic, Japan and Argentina where patients were treated. A far different approach was applied at Pavia where the thermal column at the TRIGA reactor was used to treat explanted livers with multiple metastases from colo-rectal cancer. Despite all these activities, BNCT has still to be considered as an experimental modality and further research activities are mandatory to develop this promising idea to a clinically available therapy. To perform the clinical trials that are mandatory for such development, additional radiation facilities are necessary. This book addresses in particular the needs of such facilities and the on-going activities in Europe at nuclear research institutions interested in BNCT. These developments are of increasing importance as some of the first epithermal neutron facilities mentioned above have been de-commissioned or under threat of closure. More often than not, these closures are due to political and economical reasons and not due to the clinical results. The use of a research reactor for patient treatment is not only dependent on the engineering and physics aspects, but also on the regulatory issues strongly depending on national laws. The clinical trials themselves are highly complex, applying to a human patient “new”, non-commercially available drugs and an irradiation beam not used in conventional radiotherapy. Some contributions in this book attract the attention on these aspects that have to be considered at the moment at the moment when first discussions start if a nuclear research facility may host BNCT. BNCT results in a highly complex dose distribution with different dose components having different biological effects. This challenging side of BNCT is addressed from the point of view of radiation biology and medical physics. The key factor for success and failure in BNCT is the collaboration between very different disciplines, ranging from nuclear physics to surgery; from chemistry to radiation oncology; and from mathematics to radiation biology. Such a diverse collection of intellect requires dedicated coordination structures to develop the synergies needed to move forward. As an example, the Italian national programme on pre- clinical BNCT activities is included in this monograph. References [1] Chadwick, J., “Possible existence of a neutron”, Nature, February 1932 [2] Taylor, H.J. and Goldhaber, M., Detection of nuclear disintegration in a photographic emulsion, Nature 135:341, 1935 [3] Locher, G.L., "Biological effects and therapeutic possibilities of neutrons," Am. J. Roentgenol. Radium Ther, 1936, 36: 1-13 [4] Slatkin, D.N., A History of Boron Neutron Capture Therapy of Brain Tumours, Brain, Vol. 114, No. 4, pp1609-1629, 1991 [5] Hatanaka,H. et al, "Clinical experience of boron-neutron capture therapy for gliomas - a comparison with conventional chemo-immuno-radiotherapy", in Boron-Neutron Capture Therapy for Tumours, Ed. H.Hatanaka, Niigata, Japan: Nishimura, 1986 [6] Y. Mishima, M. Ichihashi, S. Hatta, C. Honda, K. Yamamura and T. Nakagawa, New thermal neutron capture therapy for malignant melanoma: melanogenesis-seeking 10B molecule - melanoma cell interaction from in vitro to first clinical trial, Pigment Cell. Res. 2 (1989), pp. 226–234 9 2. Organisational Aspects BNCT requires the collaboration of specialists from different disciplines, who will have a very different education and, consequently, a different professional culture. At a first glance the combination of nuclear technology and medicine would appear to be the principle components, however other specialities have to contribute, which cannot be easily included in these two areas.