Proton therapy with spot scanning: the Rinecker Proton Therapy Center in Munich

NOWOTWORY Journal of Oncology 2007 volume 57 Number 5 202e 209e Proton therapy with spot scanning: the Rinecker Proton Therapy Center in Munich Part 1: Clinical aspects Ralf A. Schneider, Lothar Wisser, Martin R. Arnold, Christian Berchtenbreiter, Hans-Jörg Borchert, Dirk E. Geismar, Monika C. Loscar, Manfred Mayr, Markus Wilms, Manfred Herbst Modern proton therapy promises despite demanding structural, technical and financial investments to be superior to techniques of photon therapy in radiation oncology. Therefore worldwide the number of proton therapy facilities is increasing rapidly. In comparison to conventional proton scattering techniques, treatment planning with spot scanning promises to be superior for reasons of higher conformality. The dose outside the target volume especially in front of the tumour can be lowered and the dose in the tumour be raised. Furthermore depending on tumour cell distribution a dose painting is possible: in comparison to planned overdosages in the tumour, the dose in uninvolved tissues inside the tumour can be reduced. In Europe the Rinecker Proton Therapy Center in Munich is the first facility being dedicated only for routine patient treatment. Sophisticated MRI, CT and PET systems will offer precise diagnostics for 3D proton radiation therapy planning. It is expected that 3500-4000 patients will be treated per year. The facility is totally computerised. The patient files concerning anamnestic data, diagnostics, planning and treatment data are digitised and archived. Results can be evaluated and easily published. Key words: proton therapy, spot scanning, IMPT, dose painting, extracranial stereotactic irradiation Introduction Historically the knowledge about proton beams began with Ernest O. Lawrence, who developed the first cyclotron at the University of California, Lawrence Berkeley Laboratory (LBL) in 1930. Proton radiation is a charged particle radiotherapy modality that provides radiation oncologists highly conformal treatments with reduced doses to the normal tissues outside the target volume relative to photon therapy. The reasons for this superiority are the intrinsic characteristics of accelerated protons, which have less deposition than photons of radiation proximal to the target volume. The maximum ionising energy is deposited in the target volume, followed by a sharp fall-off without any dose deposition behind the target, Figure 1. This physical beam quality with a 10% higher relative biological effectivness (RBE) of photons should allow the radiation oncologist to escalate dose in the target volume with the chance of increased tumour control (Tumour Control Probability TCP) and decreased radiation-induced side effects (Normal Tissue Complication Probability NTCP) due to reduced dose in the normal tissue. Rinecker Proton Therapy Center München, Germany Figure 1. Depth dose distribution of photons and protons The most important advantage of protons in comparison to heavy ions is the fact that the repair capacity of normal tissues exposed to protons is in general the same as after photon exposition. Based on these facts protons, especially scanned protons, allow a higher conformality of the irradiated volume in comparison to any other radiation treatment technique. The side effects will be minimised with comparable or even better tumour control rates. History of proton therapy In 1946 Robert A. Wilson proposed that protons might be a new cancer treatment option due to their physical

203e characteristics, which result in an optimal dose distribution in human tissues [1]. Patient treatments started in the mid-1950s at LBL. The first decades of proton treatment were characterised by collecting knowledge on how to use the new techniques and by analysing physical and biological effects of proton irradiation. Homogeneity of dose delivery was one of the main issues. Efficient proton treatment planning programmes had to be developed [2]. The integration of proton therapy into clinical practice of tumour treatment had to be managed [3, 4]. The study of technical solutions for the implementation of patient treatments using protons was a privilege of only a few physics research facilities around the world. Hence patient numbers were low and progress was principally limited by technical developments instead of by valid outcome statistics. Since 1961 the experiences at the Harvard Cyclotron Laboratory (HCL) has brought about fundamental changes in using protons as an established therapy modality for several diseases including uveal melanoma, chordoma and chondrosarcoma [5, 6]. The scientific investigastions were the basis for the first hospital-based proton therapy facility installed in 1990 in Loma Linda. In the beginning, proton irradiation was used mainly in combination with photons. Later, proton therapy replaced photon therapy for various tumours. Isocentric gantries were installed for the possibility to deliver protons from any direction, as with modern linear accelerators. The spectrum of indications grew quickly, technical and clinical procedures were optimised, standardised and implemented into daily routine for more efficient and practical work flow [7]. Currently, innovations in photon therapy such as 3D CT treatment planning, image fusion of MRI and CT, faster electronic data transfer and planning algorithms for highly conformal and complex target volumes, have been integrated and optimised for photon therapy. The same developments became important for the high conformality and precision of proton therapy. At least until today, worldwide more than 54,000 patients have received charged particle therapy for different malignancies and benign diseases. More than 47,000 have had proton therapy and the remainder received heavy particles, mostly carbon ions [8, 9]. Increasing treatment numbers have given valid answers about the outcome of proton therapy protocols for new indications [10, 11]. Consequently, radiation oncologists are highly interested in proton therapy as an option within the routine treatment methodologies in the daily practice of radiation oncology. This is especially, because in comparison with highly conformal photon therapy, the conformality of protons to the target volume is generally better. Proton therapy also has the possibility to increase the doses in the tumour and reduce the doses to uninvolved normal tissues and organs surrounding the target volume. Furthermore, technical innovations such as spot scanning and intensity modulation optimise the conformality of protons to the treatment volume with a better efficiency [12, 13]. With the dawn of the 21 st century the proton world changed completely. Several projects for proton centres, especially dedicated to patient treatment, have started, or have begun construction or are still in the planning stage. As a result of technical innovations such as spot scanning and stricter radiation protection regulations, protons are probably on their way to eventually replace photons in the future [14, 15]. Important questions still to be answered are not only the comparison with the results of the established photon therapy, but how to provide the financial resources for heavy ion therapy. In addition, there are also the possibilities in the future of compact and probably cheaper laser proton accelerators and the use of proton computed tomography [16-18]. Proton therapy in Europe The Paul Scherrer Institut (PSI) in Villigen, Switzerland is the only physics research facility worldwide using proton spot scanning in patients, with experience in extracranial proton therapy and especially in the treatment of paediatric patients. The PSI facility is expanding in order to increase its capacity and to be able to treat patients during the entire 12 months each year. Only about 300 patients have been treated since the beginning of the project in 1996. The world s most extensive experience in proton treatment of uveal melanoma is located at PSI. Since 1984 more than 4,500 patients have been treated with excellent results in terms of survival, eye preservation and eye vision [19]. The Centre de Protonthérapie d Orsay (CPO) in Paris, which started in 1991 will also expand in the next few years. At CPO only tumours of the eye, skull base and brain are treatable due to technical limits of the equipment. Nevertheless, until now more than 3,500 patients have been treated. Other centres exist in Nice, France (from 1991), in Clatterbridge, England (from 1989), in Uppsala, Sweden (from 1989), and in Catania, Italy (from 2002). Most of these centres using a fixed beam perform only eye treatments and research. In Russia three centres are established: Moscow (from 1969), St. Petersburg (from 1975) and Dubna (from 1999). In the next few years several of these older centres will be replaced or modernised by new facilities for hospital-based treatments. In addition, numerous new centres in Europe are already in a planning or planned. Radiation oncology and particle therapy in Germany Germany has a total population of 82.5 million and more than 85% are under social insurance schemes. The remainder of the population have private health insurance. 20% of the total population and currently 60%

204e Germany to build a particle project or at least to discuss building such a facility, e.g., in Essen, Kiel, Cologne, Leipzig, Marburg and Berlin. Some of these proposed proton centres hope to have the possibility of cooperation between university hospitals and private partnerships, whereas others will be completely private projects. The Rinecker Proton Therapy Center Figure 2. The Rinecker Proton Therapy Center. The treatment building (left) and guest house (right) of cancer patients in Germany will at least once in their lifetime receive radiation therapy. In total, approximately 240,000 treatments each year are performed in some 250 radiation oncology centres with more than 450 accelerators or 60 Co units. In conclusion there already exist three centres and five accelerators per million inhabitants. Until now only two facilities in Germany have been able to offer particle therapy, but only for a few patients. Dedicated to basic research and only partially to patient treatments are the heavy ion facility Gesellschaft für Schwerionen-Forschung (GSI) in Darmstadt (from 1997) and the Hahn-Meitner-Institut (HMI) in Berlin-Buch (from 1998) proton facility with 70 MeV fixed beam. Over 700 eye patients have been treated at HMI. The objective of the scientific project of the University of Heidelberg (currently under construction) will be the comparison of proton and heavy ion therapy (carbon ions). It will succeed the project at the GSI. There are also interests at more than 12 cities in The potential for high conformality with proton therapy fundamentally impressed the surgeon Hans Rinecker [20]. From the beginning he had the vision that proton therapy would become the future gold standard in radiation oncology. He started the 100% privately financed and independent Rinecker Proton Therapy Center (RPTC) project in Munich, the first facility initiated exclusively for routine patient treatment with protons, Figure 2. The expected start of patient treatment will be in a few months. RPTC is one of the largest proton therapy centres with four gantries and one fixed beam treatment room and has the capacity of treating more than 4,000 patients per year. The proton accelerator used for patient treatment at the RPTC is the superconducting cyclotron (ACCEL /Varian ), Figure 3. The constant output energy is 250 MeV corresponding to a penetration depth of 37 cm. According to each individual plan the protons are degraded to the energy needed to cover the treatment volume in depth. In the x and y directions the individual coverage of the target volume is performed by scanning the narrow proton beam (σ = 4 mm). The maximum target extension is 30 x 40 cm². Details of the treatment techniques will be published as the second part of this article in a subsequent issue of Nowotwory Journal of Oncology. Several German social and private insurance companies have already signed contracts about therapy reimbursement. The objective of the RPTC is to inte- 4Gantry Gantry 3 Fixed Beam Gantry 2 Room Gantry 1 Cyclotron Entrance Figure 3. RPTC ground plan: 250 MeV proton cyclotron (ACCEL /Varian ), beam line, four gantries and one fixed beam room

205e grate proton therapy into daily routine for all cancer treatments offering proton therapy as an alternative to even innovative photon therapy and in the distant future eventually as a replacement for it. Even surgery for early lung cancer may be replaced in selected cases. The background to these aims is the better dose distribution obtained with protons and the lower integral dose delivered to healthy tissue. This means for the patient fewer side effects and for the years following proton therapy, a reduced risk of secondary malignancies [21]. Also, the better radiation protection meets the demand of the more stringent radiation protection regulations in Germany and in Europe. Munich is the third largest city in Germany with a total population of 1.3 million inhabitants. The infrastructure is optimal for a project of this size with an international airport, good train connections, different categories of hotels, several health care institutions, two universities of the highest scientific standards and with university hospitals and several public as well as private research centres. The RPTC cooperates with the surgical hospital Chirurgische Klinik Dr Rinecker (CKR) and an internal hospital in the immediate vincinity of RPTC. The location is close to downtown Munich, Figure 4, next to one of the big city parks and at the riverside of the Isar. The RPTC expects to treat 3500-4000 patients a year, not only with established proton treatments of the eye and brain, of chordomas, chondrosarcomas and prostate cancer. New treatment options are also expected, including those for tumours of the lung, liver, stomach, pancreas, oesophagus, breast, rectum and head & neck. These will be based on the latest experience in proton and heavy ion therapy as well as on IMRT and stereotactic photon therapy. Hypofractionation schedules will also become integral part of the standard treatment at the RPTC, incorporating the latest knowledge of biologically effective doses (BED) in different tumour entities and normal tissues and also the excellent dose distributions in treatment planning which can be achieved with protons. All proposed treatment schedules will be stan dardised following clinical studies at RPTC or will follow the Figure 4. Downtown Munich, the Frauenkirche results of studies performed in cooperation with German and international institutions. Patient and treatment data will be collected and analysed by regular follow-ups and will consider not only survival and tumour control rates but also side effects and aspects of quality of life. Proton therapy for children & young adults Dose distribution and integral volume dose with proton therapy is advice especially important for children and young adults because of their long life expectancy and the necessity to reduce, as much as possible, the possibility of radiation induced secondary malignancies. Proton therapy dose distributions should be mandatory for these patients. It is therefore essential to ensure that treatment atmosphere, treatment procedure and time taken for the procedure is suitable for children. Oncological treatments of children should also be established by national and international studies in order to provide guidance to proton therapy centres. Publishing results of proton treatment data for these patients will inevitably be a process of long-term followup research and suitable databases should be organised immediately. The most important parameters will be treatment outcome, including an analysis of secondary malignancies and quality of life. Close cooperation with German and international paediatric societies are also necessary for such work. Diagnostics & imaging For initial examinations the following are available at RPTC: MRI (Philips Achieva 1.5T), PET-CT (Philips Gemini) and CT with 16-slice configurations; endoscopy, sonography and a laboratory for complete blood analysis. Data can be integrated into the planning IT system. RPTC s installations are exclusively dedicated to proton therapy patients not only for tumour staging and therapy planning. Diagnostics and imaging are therefore available for detailed follow-up examinations. Patient immobilisation during treatment Using high precision radiotherapy such as spot scanning it is necessary to immobilise the patient every day in a reproducible and safe position by using optimised positioning tools. For treatments of brain, eye and head & neck tumours, patients will be fitted with a bite block and if necessary additionally with a mask, fixed in an individualised vacuum body mould. Thoracic and abdominal immobilisation is necessary for some treatments and, this is achieved using a whole body mould including the possibility of fixing the patient in the mould with a cover sheet for an optimised positioning using a vacuum mould device (BodyFIX; Medical Intelligence/Elekta), Figure 5. To identify shifts of the target volume fiducial markers will be used routinely for several tumour locations. For example, gold markers will be implanted

206e Vacuum body mould Transfer plate (Schär Engineering AG) Patient transporter (Schär Engineering AG) Vacuum pump Figure 5. Immobilisation of a patient using a vacuum mould into the prostate gland in defined positions and a rectal balloon will be placed every day before the irradiation. Also for liver and lung tumours and other respiratory moving targets, internal markers will also be used to detect organ/tumour movements. This is especially necessary for tumours which can change due to breathing related motion. Controlled and reproducible apnea under anaesthesia will be effected during planning, positioning and irradiation procedures. For treatments of eye tumours, tantalum clips will mark the tumour region or other structures of the eye in order to define the geometry, translation and rotation of the organ, especially when using CT and MRI planning data. Patients with tumours in the upper abdomen or thorax, or infants and small children who are unable to cooperate will require an anaesthetic procedure. This is in order to obtain optimal immobilisation so as to control the motion of the target during planning and treatment, Figure 6. A completely equipped mobile anaesthesia workplace environment and a post-anaesthetic care unit (PACU) with eight beds spaces is integrated into our proton therapy centre. Figure 6. Patient undergoing anaesthesia prior to irradiation Treatment planning Although some cases will be able to be treated using standardised procedures with defined target volumes, there will certainly be some very complex individual treatment plans necessary. Interdisciplinary tumour conferences (Tumour Boards) at the RPTC will be established for evaluating these complex cases indivi dually. The basic findings will be discussed with the possible range of therapeutic options before making any final interdisciplinary decision. International colla boration under the umbrella of the PTCOG (Particle Co-Operative Group) will be conducted as a matter of course. Treatment planning will be conducted using CT with a 16-slice configuration. If necessary, contrast medium or additional MRI and/or PET examinations can be performed. 3D treatment planning (based on axial CT scans) is made with a spot scanning algorithm (XIO) from CMS. By optimising the beam direction and individually weighting every proton beam spot, whose Bragg peak contributes to the dose inside the target, it is possible to achieve the optimal dose inside the target and to spare the organ at risk outside the target. Because of the physical properties of protons there is no dose deposition beyond the target. By using the spot scanning technique, where the beam is moving on an arbitrary grid in order to cover the tumour, it is not only possible to modulate the fluence inside the beam (as with modern intensity-modulated photon radiation therapy: IMRT) but also to customise in depth the dose distribution in the third dimension. By combining beams from different angles it is possible to achieve dose distributions which are currently unimaginable in external beam photon radiation therapy, Figures 7-10. A special CMS eye planning system, also based on 3D CT data, is in progress of development and will have the ability to integrate MRI data. Control imaging of the treatment region will be performed frequently in order to determine any possible volume changes of the target which would then require modification of the treatment plan. Figures 7 and 8 compare dose distributions for photons and protons for the treatment of peripheral

207e Figure 7. Photons Figure 8. Protons Figure 9. Photons using IMRT Figure 10. Protons using IMPT lung cancer, using identical radiation beam directions The second example, Figures 9 and 10, is for an ENT tumour illustrating complete sparing of the parotid gland on the left and partial sparing on the right. Patient setup & irradiation For reproducible setup the vacuum body mould with the patient lying supine on it, is fixed on a transfer plate (Schär Engineering AG). This board is compatible for CT and MRI tables as well as for treatment tables. Moving of the fixed patient will be achieved by using patient transporters (Schär Engineering AG), Figure 5. Immobilisation and mobilisation will be performed outside the treatment rooms. Every gantry and fixed beam area is associated with two dedicated rooms for these procedures. This innovative concept allows a throughput of up to four patients per hour at each gantry. It is expected that RPTC will treat 3500-4000 patients per year in a daily double shift and a six day working week. Service and maintenance will be on Sundays and during nights. The treatment position of every patient will be controlled every day by a special position control system which is attached to the gantry. Two digital orthogonal radiographs (flat panels) allow the verification of the patient s position. Any necessary corrections will be automatically made after evaluation of bony landmarks and/or fiducial markers. The irradiation time will be appproximately one minute for a target volume of 1000 cc and a dose of 2 Gy, Figure 11. Figure 11. Gantry room

208e As the beam is available only in one gantry room at time it is important to be able to switch very quickly from one gantry to the next. During the beam-off time in the other treatment rooms the patients are positioned and aligned. Typically, the treatment procedure for a patient will be approximately 30 minutes. This includes immobilisation, positional verification and irradiation. Follow-up Every patient who has been treated at the RPTC, even those who are from countries other than Germany, will be given the opportunity to receive follow-ups at the RPTC. It is not only important for the patient to stay in contact with their radiation oncologist, but it is also important for the radiation oncologist to follow-up the patients and their side effects regularly as a control of treatment regimen which is a part of the general quality management It is planned to have a first follow-up at three months post-treatment, if necessary at six months, and thereafter annually. Individualised follow-up schedules will be made if necessary. For patients, who are not able to stay in personal contact, a close and intensive cooperation with their own oncologist from a centre other than RPTC will be both important and mandatory. Results of investigations such as CT and MRI should be made available and sent to the RPTC and then be evaluated and stored in the patient s record file. Research Clinical research in radiation oncology with protons is fundamental in order to be able to evaluate the treatment outcome of different tumours and of treatment schedules. At the RPTC, tumour control rates, acute and long-term side effects, questions relating to quality of life and to second malignancies will all be evaluated. It is emphasised that changing established dosages and fractionation schemes or target volume concepts requires intensive evaluation of follow-up data. The IT platform at the RPTC will allow extensive collection of data for every patient, whether they were treated with conventional or with study/research regimens. Some treatment data will be stored and entered into the public server (patient identification details will be removed). Updates of treatment modalities will be made and published in international journals. Additional support services to their home town every day, the RPTC offers the possibility to stay in a guesthouse, see Figure 2. This ensures maximum convenience for patients. care as inpatients, will be attended in the cooperating internal or surgical hospitals in the neighbourhood. For special requirements a complete care service is available. A professional service company will offer support to solve transportation and accommodation problems as well as answer questions relating to foreign language, religous or cultural problems. This service will also organise sightseeing tour programmes and other cultural activities for patients and for their families and friends. The goal of the RPTC is the patients maximum satisfaction and well-being which is seen as part of the fundamental basic structure that can improve treatment compliance and even perhaps outcome. Conclusions In comparison with photon IMRT, proton spot scanning, especially when using IMPT, is a more conformal treatment option with minimal doses to the integral volume of healthy tissues, leading to an optimisation of the tumour dose. Children and young adults with a long life expectancy prior to their illness will benefit greatly from proton therapy, with fewer side effects than with photons. With an expected 3500-4000 patients a year, this first private proton facility in Europe will influence the conventional treatment schemes used in proton therapy, by analysing and publishing therapy results from large numbers of patients. The results in terms of acute and chronic side effects as well as of quality of life will help to establish the position of proton therapy within the field of modern radiation oncology. Furthermore the project has to prove, that novel techniques in healthcare, which establish effective and innovative treatment options, even if they are expensive and complex, can be used in daily routine and in a profitable way. Dedication This publication is dedicated to the 65 th birthday of PD Dr. med. Dr. med. habil. Hans Rinecker. Ralf A. Schneider, MD Rinecker Proton Therapy Center Schäftlarnstr. 133 81371 München Germany e-mail: ralf.schneider@rptc-1.de The RPTC plans to have personal case managers who will be responsible for every patient during the complete duration of all their treatment procedures: starting with admission to the RPTC with an administrative workup. These managers will serve as a contact person for the patients and may also act as a co-worker for the radiation oncologist. For outpatients who are not able to travel

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