Title: Proton and particle radiotherapy — a report on the Franco–British seminar on the future of cancer treatment and imaging using new physics-based technologies
Abstract: Free AccessCommentaryProton and particle radiotherapy — a report on the Franco–British seminar on the future of cancer treatment and imaging using new physics-based technologiesN G BURNET, A KACPEREK, S E GOODMAN and S GREENN G BURNET1University of Cambridge Department of Oncology, Oncology Centre (Box 193 R4), Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, 2Douglas Cyclotron, Clatterbridge Centre for Oncology, Wirral, UK, 3British Embassy, 35 Rue Faubourg St. Honoré, 75383 Paris, Cedex 08, France, 4Department of Medical Physics, University Hospital Birmingham, Edgbaston, Birmingham B15 2TH, UKSearch for more papers by this author, A KACPEREK1University of Cambridge Department of Oncology, Oncology Centre (Box 193 R4), Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, 2Douglas Cyclotron, Clatterbridge Centre for Oncology, Wirral, UK, 3British Embassy, 35 Rue Faubourg St. Honoré, 75383 Paris, Cedex 08, France, 4Department of Medical Physics, University Hospital Birmingham, Edgbaston, Birmingham B15 2TH, UKSearch for more papers by this author, S E GOODMAN1University of Cambridge Department of Oncology, Oncology Centre (Box 193 R4), Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, 2Douglas Cyclotron, Clatterbridge Centre for Oncology, Wirral, UK, 3British Embassy, 35 Rue Faubourg St. Honoré, 75383 Paris, Cedex 08, France, 4Department of Medical Physics, University Hospital Birmingham, Edgbaston, Birmingham B15 2TH, UKSearch for more papers by this author and S GREEN1University of Cambridge Department of Oncology, Oncology Centre (Box 193 R4), Addenbrooke's Hospital, Hills Road, Cambridge CB2 0QQ, 2Douglas Cyclotron, Clatterbridge Centre for Oncology, Wirral, UK, 3British Embassy, 35 Rue Faubourg St. Honoré, 75383 Paris, Cedex 08, France, 4Department of Medical Physics, University Hospital Birmingham, Edgbaston, Birmingham B15 2TH, UKSearch for more papers by this authorPublished Online:13 Feb 2014https://doi.org/10.1259/bjr/26414068SectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail AboutThis commentary outlines the key points from the recent 1-day Franco–British seminar concerning proton and particle radiotherapy and the contribution to cancer treatment and imaging from new physics-based technologies.The state visit of the French President to London in March 2008 included discussions of economic and technical collaboration and the intention of the two governments to support Anglo–French collaboration on topics including cancer treatment and imaging. Against this background, on 14 March 2008, over 60 French and British scientists, clinicians and industry representatives met to discuss new developments in cancer treatment and imaging being undertaken in France and the UK. This 1-day seminar was organized by the Science and Innovation Network of the British Foreign Office and hosted by the British Ambassador to France at his residence in Paris.The aim of the seminar was to share the “state of the art” in the field of physics-based technologies related to proton and particle radiotherapy between French and British colleagues, to foster new collaborations, and to discuss particle therapy facilities available in France. The majority of the day's presentations can be viewed through the British Embassy's website [1]. Review references [2–6] are provided to help readers access the subject of charged particle therapy.Charged particle radiotherapyArguably, charged particle radiotherapy (CPT), particularly using protons, is the most important cutting-edge technology in clinical radiotherapy at present. This is underpinned by physics-based technological developments that may make machines smaller, easier and cheaper. However, the exact place of CPT remains to be fully established and will certainly require clinical trials.There is increasing evidence on the clinical value of CPT for a number of conditions. These can be divided into two main categories:Tumours that are relatively radiation resistant and lie adjacent to critical dose-limiting normal structures. These include chordoma and chondrosarcoma of the skull base [7–11].Tumours in children, particularly where the target volume is large. Considerations of the risk of second malignancy and the detrimental effects of radiotherapy dose on growth and endocrine function are important. There is clear evidence that the use of proton beams can reduce unnecessary dose in many non-target structures [10, 11]. The most dramatic example of this is in medulloblastoma [12].It is possible to make an argument for proton therapy for many other cancers but, although the physics evidence base is highly suggestive of benefit, the published medical evidence is limited [2–6].CPT is available in various forms: (i) low-energy proton therapy for treatment of some ocular tumours; (ii) high-energy proton therapy for treatment of a range of tumours; and (iii) high-energy carbon ion (C-ion) therapy, which is of research interest and has particular potential to treat poorly oxygenated radio-resistant tumours. Only low-energy proton therapy is available in the UK, at the Clatterbridge Centre for Oncology on the Wirral. Ironically, this was the first hospital-based proton facility in the world and has been very successful in treating cancers of the eye. Efforts to obtain agreement for a high-energy clinical facility have been unsuccessful in the UK, despite several major initiatives over a number of years. In France, in contrast to the UK, there is a nationally coordinated evolving programme of high-energy proton and ion beam therapy, with three proton therapy centres in operation, rising to five CPT centres by 2013. Consequently, France presently has, and for the foreseeable future will have, the better CPT facilities of our two countries.At the time of writing, there is no decision on whether to build a high-energy proton (or C-ion) facility in the UK. However, the Department of Health Cancer Reform Strategy has identified patient referral abroad for treatment of certain cancers as an immediate priority. Formal arrangements have now been established by the NHS National Commissioning Group to facilitate the referral of English patients with skull base chordoma and chondrosarcoma to CPT centres abroad. Patient referrals to other countries (principally Switzerland, France, the USA and possibly Germany) are likely to increase over the next few years as the referral mechanism matures [13].During this time, it is essential that the UK clinical and scientific communities learn as much as possible about particle therapy in order to benefit patients referred abroad and to help to plan for British facilities in due course [14].Proceedings of the seminarThe seminar opened with a welcome from the British Ambassador, Sir Peter Westmacott. The scientific meeting then commenced with a welcome in French, English and Welsh by the chairman and UK-based organiser, Professor Bleddyn Jones (University Hospital, Birmingham). He began the scientific discussion by illustrating the march of technology using comparisons with aircraft development, including the (Anglo–French) Concorde project. He illustrated the obvious reduction in dose to non-target tissues afforded by the use of proton beams and their Bragg peaks [2]. He suggested that better radiotherapy technologies may incline patients away from surgery in favour of radiotherapy, particularly as cancer screening, imaging and early detection rates improve. Therefore, reducing the dose to normal tissues, with a consequent reduction in both toxicity and late second tumour formation, would be very attractive.Professor Jones outlined some of the lessons learned from the experience with neutron therapy in the UK, including the need for properly designed clinical trials, for which the UK has a strong heritage. Radiobiological modelling is also a notable UK strength [15], and significant modelling of CPT is under way within the UK despite there being no high-energy facility. Indeed, equations derived in Britain can be used to provide dose-compensation solutions for CPT treatment interruptions around the world. High-quality imaging is also essential to determine the target location. Although this applies to radiotherapy in general, CPT allows dose distributions to be more conformal to the target volumes so that the requirements for imaging are even greater.Particle therapyARCHADE project — CaenProfessor Jean Bouhris (Institut Gustave Roussy) described the ARCHADE (Advanced Resource Centre for Hadrontherapy in Europe) project at a Research Centre in Caen [16]. The project will explore the role of carbon-12 (12C) ions for radiotherapy, in combination with molecular targeted and chemotherapy drugs. Although the use of higher precision is a physical development, the use of carbon ions for radiotherapy and their combination with chemotherapy fall into the category of biological developments. This project involves strong collaboration with IBA, a Belgian company working on solutions for cancer diagnosis and therapy. It is the first 12C ion project for IBA, and the accelerator details were presented by Thomas Canon (IBA) [17]. The Caen facility will have two beam lines. The clinical facility will consist of a single fixed beam line with a scanned beam, and a robotic patient positioning system. The second beam line will supply an experimental area for radiobiology. Ion production will be from a fixed-energy super-conducting cyclotron (cf a synchrotron that can produce variable energy), operating at a temperature of 4° Kelvin (built from a design by JINR, Dubna, Russia). It will accelerate protons and C-ions in the same machine. The design of the machine is complete; it is anticipated that construction will start in mid 2009 and the facility is scheduled for clinical use in 2011.ETOILE project — LyonProfessor Marcel Bajard (Institut de Physique Nucléaire de Lyon) presented the ETOILE (Espace de Traitement Oncologique par Ions Légers dans le Cadre Européen (Area for Oncological Treatment by Light Ions in Europe)) project, which will also focus on the use of light ions [18]. There will be three treatment rooms: two with fixed horizontal beams, and one with an isocentric gantry. The facility will produce both protons and carbon ions, with both actively scanned and passively scattered beams. The centre intends to treat a broad range of clinical sites. Research questions will include relative biological effectiveness (RBE) modelling and patient imaging. It will also question whether a gantry offers a real advantage. The clinical implementation will include a permanent committee to oversee the creation of a network for patient referrals, decisions concerning the appropriateness of referrals and acceptance of patients for C-ion therapy, and the coordination of research.The centre is anticipating treating 1000 patients per year, with the rooms used 13 h per day for treatment and 3 h per day for quality assurance. The cost is very approximately estimated to be about €20 000 per patient. This is a public–private partnership, and authorization for the project was given in 2007.Orsay clinical facilityProfessor Jean-Louis Habrand (Institut Curie, Orsay) introduced the proton facility at Orsay, located 25 miles south of the centre of Paris and now part of the Institut Curie [19]. The facility currently uses passive double scattering and a fixed beam. Dr Samuel Meyroneinc described the development on the Orsay site that is currently under way. This will include expansion to three proton treatment rooms, including a gantry in one of these. The rebuild will start treating patients in 2010. A conventional photon radiotherapy facility is also being developed on site, which is not available at present.Professor Habrand gave an excellent summary of the clinical experience with proton therapy at Orsay. Many patients receive only the final part of their treatment using protons, but over time it is intended to increase the proportion of the therapy dose delivered by protons. He described their approach to skull base tumours, which is to deliver 70 Gy to chondrosarcomas and 74 Gy to skull base chordomas [8]. For poor prognosis meningioma, they expect to give 68 Gy [20]. These doses are substantially higher than is considered possible even with current optimal X-ray techniques. The beam is able to produce a dose gradient of 15% per millimetre. For cranial treatments, they use fiducial markers implanted into the scalp for image guidance. In paediatrics, which is one of their main interests, the proton beam is able to avoid dose to the surrounding brain, and this is seen as a major indication. The new expanded facility will also have the capability to treat prostate and lung cancers.DiscussionThe presentations on clinical facilities were exclusively from the French side. Motivation in France is high to develop these new technologies and to take them into clinical trials for the benefit of cancer patients. It was clear that the prevailing view in France is that the major clinical research question is whether C-ions are better than protons, at least within a limited and specific set of indications.Radiation source technology developmentsNon-scaling fixed-field alternating gradient acceleratorsProfessor Ken Peach (John Adams Institute, University of Oxford) gave an excellent overview of novel accelerator solutions for particle therapy. Current cyclotrons can produce proton beams but not heavier particles. Their application is to some extent limited by the fact that the protons have a fixed energy at the time of extraction from the cyclotron. Conversely, synchrotrons are more flexible, allowing variable energy and production of heavier particles. However, these machines are larger, much more complex, relatively difficult to operate and to keep operational, and of course more expensive.He described the main potential advantages, and the critical technical challenges, involved in the development of non-scaling fixed-field alternating gradient (FFAG) accelerators, which are the basis of the UK CONFORM (COnstruction of a Non-scaling FFAG for Oncology, Research and Medicine) project [21]. Currently, FFAG accelerators are being designed as a possible replacement for synchrotrons and have potential application for a clinical facility. These machines use a fixed magnetic field and accelerate particles very rapidly. The magnets are complex and large, and have to deliver a magnetic field of very high gradient. They are therefore difficult to design and build. However, the non-scaling aspect of the design allows the use of more simple magnets. Currently, an FFAG accelerator is being built in Daresbury (a project entitled EMMA (Electron Model of a Muon Accelerator)), and one of the objectives is its evaluation as a potential radiotherapy delivery system [22]. It is hoped that by 2010 it will be clear whether this machine is capable of delivering a clinical beam.In the discussion that followed, the issue was raised of whether the UK should wait for this new technology to be developed from the CONFORM project before proceeding with development of a clinical proton facility within the UK. Professor Peach's view is that this would not be a wise move, as the technology testing is still two or more years away, and the development for clinical purposes will take rather longer.Laser-based proton and ion sourcesThere is already a strong sense of collaboration between the French and UK groups working on laser-based proton sources. These groups have a substantial background of collaboration working on European laser facilities, and this has led to an informal coordination between the major efforts being undertaken separately in each country to develop laser sources for particle therapy. This informal coordination is an excellent model for the future.SAPHIR projectThe French SAPHIR (Sapphire) project to develop a laser-based proton treatment system was described by Dr Gilles Riboulet (Amplitude Technologies) [23]. He emphasised the core elements of the project involving laser development to meet the critical challenges of high power and high repetition rate, including the complex issue of dynamic power adjustment. Unlike conventional systems, the beam line will transport light photons into the treatment room, with proton production at an end station within the treatment room. It is hoped that this technology will deliver a useable treatment solution with substantially reduced costs compared with standard proton facilities, and be small enough for a hospital installation.There was speculation about whether the very short but intense pulses of photons, producing short pulses of proton irradiation, might have different biological effects as the result of the very high intermittent dose rate.LIBRA projectDr David Neely (Rutherford Appleton Laboratory) described the UK LIBRA (Laser Induced Beams of Radiation and their Applications) project to develop a Laser Plasma Accelerator as a potential method of accelerating protons for therapy [24]. The Laser Plasma Accelerator can achieve an accelerating potential of 180 GV cm−1 (cf 10 V cm−1 in a thunderstorm). Although older lasers were only able to produce 1 pulse per hour owing to thermal limitations, a new laser is currently being built that should be able to produce 1 pulse every 20 s. The laser beam hits the target and produces a secondary electron wave. This passes through the target, resulting in a very high electric field that pulls ions off the target. Changing the target material changes the ion produced. It is possible to produce C-ions for acceleration, or even heavier ions. The energy of the ions is dependent on the intensity of the laser beam and, in general, as designs improve, this intensity is increasing. There is potential for designing a gantry that could be of a relatively small size, e.g. 1 m3 and weighing less than 1 ton. This project is focusing on target technology, and its impact on beam spectra and angular distributions. Several radiobiological studies are also planned to examine any specific aspects of the laser-induced beam.It is still too early to tell if this concept might work as a method to produce a radiotherapy treatment beam, but this should become clear within the next 2–4 years. It might also be possible to use the extremely short laser pulse to produce secondary effects, allowing imaging of the position of the energy deposition. A smaller laser designed with a smaller gantry and multiple end stations may also be of interest for the production of radioisotopes.Developments in imaging and treatmentIon beam analysis and cellular irradiation – University of SurreyProfessor Karen Kirkby (University of Surrey) discussed irradiation of cells and analysis using ion beams. She described the Engineering and Physical Sciences Research Council (EPSRC)-funded network on the Biomedical Application of High Energy Ion Beams, a successful multidisciplinary collaboration, which she led from 2004–2007 [25]. The network brought together a community of UK scientists and clinicians to develop UK particle therapy capabilities. The network successfully delivered a number of grants, funding for PhD projects and several site visits, as well as annual meetings. The network was funded to the tune of £64 000 and contributed to grants in excess of £16 million (a ratio of 1:250).The Surrey Ion Beam Centre is developing new ion beam analysis capabilities with funding from EPSRC and the Wolfson Foundation [26]. Of particular note is the new vertical beam line for the irradiation of living cells, and its array of imaging and elemental mapping capabilities [27]. This beam line will be able to target ion beam irradiation of cells with a 10 nm accuracy, and irradiate up to 100 000 cells per hour. For analysis, elemental mapping down to a 100 nm resolution is possible for elements heavier than sodium. For example, the intracellular distribution of platinum moieties from platinum-based chemotherapy can be mapped.Internal hadron therapy — NantesProfessor Jean-Francois Chatal (Institut National de la Sante et de la Recherche Medicale, Nantes) described the Arronax cyclotron, which will be ready in the summer of 2009 [28, 29]. It will produce protons (up to 70 MeV), α-particles and neutrons for the manufacture of radiopharmaceuticals for clinical trials of both imaging and therapy. Under the title of “nuclear oncology”, they will focus on the production of both new radionuclides and novel carrier ligands for internal hadron therapy.Currently available radionuclides are not ideal. For example, the half-life of fluorine (∼2 h) is too short for labelling an antibody for radio-immunotherapy, while yttrium-90 produces no γ-radiation and so no imaging is possible. They are aiming to produce pairs of radionuclides from the same atom, one of which produces a positron for dosimetry, and the other an electron for therapy. These include copper-64 and -67, scandium-44 and -47, and iodine-124 and -131.The centre in Nantes will also have a vertical ion beam, suitable for Petri dish and cell flask irradiation experiments.DiscussionIn discussion, Professor Jones observed that treatment which is not dependent on outlining the gross tumour volume or making assumptions about the necessary extent of the clinical target volume would be attractive [30], because it would overcome uncertainties in the extent of imageable tumour or non-imageable microscopic spread. This would be possible with internal hadron therapy, the localization of which is dependent not on imaging and its interpretation but rather on the biology of the disease.Molecular imagingProfessor Bertrand Tavitian (Commissariat à l'Énergie Atomique) gave an overview of research in cancer imaging using physics-based technologies, and the CANCEROPOLE projects spanning the years 2004–2007 and 2008–2010 in particular. These bring together a wide range of imaging modalities to solve clinical problems [31]. His group is part of the Emil project (European Molecular Imaging Laboratories), which includes 58 partners in 13 countries. There is a programme that focuses on the imaging of solid cancers, and a theme specifically researching molecular MRI approaches.This group has already had considerable success with an image processing project that uses temporal/dynamic data to inform decisions on the spatial organization of tissues. In particular, they have developed “local means analysis” to aid autosegmentation [32]. This technology is now being introduced into clinical use.Shear wave ultrasound for diagnostics and therapyIt was at the l'École Supérieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI) that some of the original work on sonar was performed and, appropriately, Professor Mathias Fink (ESPCI) explained recent developments in ultrasound, for both imaging and therapy [33, 34]. Ultrasound vibrations can be propagated as compression or shear waves. Conventional ultrasound uses compression; however, shear waves can also be produced, and the movement of these can be imaged. This technique appears to be able to distinguish malignant from benign lesions, such as those in the breast. This technology is now undergoing clinical trials in the USA and Europe via a commercial company (Supersonic Imaging).For therapy, high-frequency ultrasound is well known but its application for brain tumours has always been limited by the distorting effect of the skull. Professor Fink described novel work on a time-reversal technique. A time-reversal pattern can be reconstructed from a sonic signal, amplified and returned to destroy the relevant zone within a brain lesion. This is being developed in monkeys, and early results suggest that localized lesioning is possible. A human system is under development.Low energy monochromatic X-rays for diagnostics and therapyDr Alessandro Variola, (Laboratoire de l'Accélérateur Linéaire, Orsay) [35] described the ThomX monochromatic X-ray source for imaging and therapy. This produces coherent X-rays in the 30–90 keV energy range, permitting diffraction-enhanced imaging. The mono-energetic nature of the X-rays brings new opportunities for use of contrast agents for both imaging and potentially the enhancement of radiation dose in some therapy applications. This might include injection of iododeoxyuridine (IUdR), followed by the use of a monochromatic X-ray beam of 33.2 keV to produce an Auger electron cascade, causing DNA double-strand breaks. A treatment system is in the design phase.Cellular and molecular imaging for in vitro analysisDr Borivoj Vojnovic (Radiation Oncology & Biology group (ROB), Oxford) described work on optical imaging of single cells irradiated at the University of Surrey ion beam centre [36]. The new vertical beam line will have the most modern imaging end station available anywhere. Methods for recording and automated revisiting of the position of individual cells or nuclei have been developed. The imaging techniques aim to remove the need for staining (and thereby remove a criticism of work to date) [37].The capability will exist to image particle tracks using markers that bind to proteins found at the site of double-strand breaks. Förster resonance transfer uses two separate fluorophores that can be used to investigate the interactions of proteins. This method has very good spatial resolution for assessing the presence of molecules together or their interaction. It can also produce excellent three-dimensional imaging. These techniques can therefore probe radiobiological effects near beam/tumour edges. These exciting facilities were officially opened in November 2008.Image-based particle therapy for brain tumoursDr Raj Jena (Addenbrooke's Hospital and University of Cambridge) gave the final scientific presentation of the day. His underlying concept was to use advanced imaging to turn a biological problem — that of tumour spread — into a physics problem for high-precision dose delivery using particle beams. He described work using advanced MRI techniques to understand the probable dissemination routes or infiltration paths for aggressive brain tumours. Standard approaches limit the dose that can be delivered to such tumours, as the volume to be treated is generally large because of the substantial clinical target volume margin needed to allow for (non-imageable) microscopic infiltration. In general, this margin is equal in all directions. Diffusion tensor imaging allows visualization of white matter tracts and, in particular, can help us to identify probable regions of tumour infiltration. This offers the prospect of modifying the target volume to concentrate on tumour and regions of infiltration, allowing these regions to be treated to a higher dose than is usually possible, and avoiding high dose to non-infiltrated areas [38]. He described how important it is to triage patients and select them appropriately for different treatment strategies. He also noted that edge relapse of glioblastoma has been described after C-ion therapy.His work uses software produced and kindly given to him by a French group. Such imaging may help to refine target volume definition and would therefore be highly appropriate for particle therapy with the objective of delivering complex dose painting. He is currently developing a model based on diffusion tensor imaging, which can simulate growth and migration of tumour, based on the imaging from individual patients.DiscussionThe discussion session began by posing three questions:What can the UK do for France?What can France do for the UK?What can we do better together?A clear common theme emerged, i.e. there is a need for funding for exchange visits and joint workshops, with the specific objective of developing joint proposals. As travel funds are hard to come by in both countries, this should be addressed as a priority.There was useful discussion about treatment gantries. For many brain treatments, a fixed gantry is satisfactory, particularly combined with a robotic couch. Some other tumour sites and brain cases probably need a gantry. Fixed beams could be used in a transitional phase of treatment facility development, and are certainly much cheaper. Speed of patient throughput may be better with a gantry. Could a 90° range of movement be satisfactory? This gantry question, and the consequences of altering beam directions, will need further evaluation.There were also questions over whether opportunities might exist for radiobiological research in a trans-channel framework. Strong opportunities for collaboration across the Channel exist, such as the use of the microbeam facility at the University of Surrey and irradiation of spheroids and animals in France. Such collaboration might be able to address several issues, including the production of in vitro data to confirm and refine old results, especially on RBE, and to inform newer models of biological responses to irradiation. A particular topic of interest, with considerable clinical relevance, might be the comparison between the induction of malignant transformation in cells following X-ray intensity-modulated radiotherapy techniques and particle radiotherapy.There was interest in developing methods to image the deposition of dose, especially in the Bragg peak, and its biological effects.The discussion on clinical applications highlighted a conceptual difference between France and the UK. In France, C-ion therapy is seen as the experimental modality, whereas proton radiotherapy is “just radiotherapy”, considered to be one aspect of conventional radiotherapy.The UK has very little experience or training in particle therapy, which will have to be addressed, even in the context of patients being referred abroad for treatment. There was discussion of exchange visits, and a clear recommendation that trainees should go on courses, e.g. the newly started ESTRO (European Socie
Publication Year: 2009
Publication Date: 2009-03-01
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 3
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