The national center for oncological hadron therapy: status of the project and future clinical use of the facility

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1 Tumori, 95: , 2009 The national center for oncological hadron therapy: status of the project and future clinical use of the facility Roberto Orecchia 1, Piero Fossati 2, and Sandro Rossi 3 1 Università di Milano, European Institute of Oncology, National Center for Oncological Hadron therapy; 2 Università di Milano, National Center for Oncological Hadron therapy; 3 National Centre for Oncological Hadron therapy, Milan, Italy ABSTRACT Aims and background. Hadron therapy is an advanced radiotherapy technique that employs charged particle beams. Several particles (pions, oxygen, neon and helium ions) have been investigated in the past, but at present only protons and carbon ions are used in clinical practice. Hadron therapy has been used for more than 50 years, more than 50,000 patients have been treated worldwide, and many new facilities are being built. Indications are still a matter of debate. The Italian National Center for Oncological Hadron Therapy (CNAO) is under construction in Pavia and will begin to treat patients in the near future. Methods. The CNAO will be a center capable of using both protons and carbon ions. In the first phase, three rooms with vertical and horizontal fixed beams will be available, subsequently the center will be upgraded with two more rooms equipped with a rotating gantry. The facility will use active scanning delivery systems and state-of-the-art immobilization and setup verification devices. One additional room will be devoted to physical and radiobiological research. The CNAO will be a high-patient-throughput facility capable of treating more than 3,000 patients per year. Seven areas of interest have been identified: lung cancer, liver cancer, head and neck malignancies, pediatric solid cancers, eye tumors, sarcoma and central nervous system cancers. A disease-specific working group has been created for each area and has defined selection criteria and protocols to be used at the CNAO. Two more working groups are being set up on gynecological and digestive (pancreas, biliary tract and rectum) tumors. All the patients will participate in clinical trials to establish with sound evidence the real indications for hadron therapy. National and international cooperation networks are being set up to facilitate patient referral and follow-up. A medical service is already operative to assist patients and in selected case to refer them abroad. Conclusions. The CNAO will be the only carbon ion facility in Italy and will have an international basin. Close cooperation with existing oncological centers is of paramount importance to fully exploit its potential. Introduction Hadron therapy is a kind of high-precision radiotherapy that employs subatomic particles called hadrons. Although, strictly speaking, the term hadrons can also refer to neutrons, it has become common to restrict the name hadrontherapy to treatments that employ positively charged particles, such as protons, helium ions, carbon ions, neon ions and oxygen ions. Hadrontherapy was proposed for the first time by the nuclear physicist Robert Wilson in and the first patient was treated at the Lawrence Berkeley Laboratories, California, in The pioneering age of hadron therapy was up to the 90 s: treatments were carried out in nuclear physics research centers and could rarely rely on adequate imaging, treatment planning, or patient Key words: carbon ion radiotherapy, hadron therapy, proton therapy. Correspondence to: Piero Fossati, Fondazione CNAO, Servizio Medico, Via Caminadella 16, Milan, Italy. Tel ; fax ; piero.fossati@cnao.it Roberto Orecchia, Istituto Europeo di Oncologia, Divisione di Radioterapia, Via Ripamonti 141, Milan, Italy. Tel ; fax ; roberto.orecchia@ieo.it Received May 7, 2008; accepted July 29, 2008.

2 170 R ORECCHIA, P FOSSATI, S ROSSI Related dose MV photons 135 MeV protons 254 MeV/u carbon ions Depth in water (cm) Figure 1 - Photons are characterized by an initial build-up region and then by an exponential fall-off. Protons and carbon ions deliver a uniform dose in the entrance channel and a higher dose in the Bragg peak. After, the peak proton dose falls to zero whereas carbon ions show a tail due to particle fragmentation. setup technologies. One of the most relevant experiences began in 1973 at the Massachusetts General Hospital in cooperation with the Harvard Cyclotron Laboratories and employed proton beams 3. Results obtained in this first phase prompted the construction in 1992 of the first hospital-based proton therapy facility in Loma Linda, California 4. More than 50,000 patients have been treated with protons worldwide. Treatments with different species of ions (helium, neon and others) were initially performed at the Bevalac Laboratories of the University of California at Berkeley in California 5 but were not subsequently pursued in the USA. The Heavy Ion Medical Accelerator in Chiba (HIMAC) was the first hospital-based facility to employ ions, and it began operation in 1994 in Japan 6. HIMAC selected carbon ions as the most promising particles. Carbon ions have been employed in another hospital-based Japanese center (Hyogo Ion Beam Medical Center, Hyogo) and in a physics research center in Germany (Gesellschaft für Schwerionenforschnung, Darmstaadt). More than 3,000 patients have been treated with carbon ions up to now. Protons and carbon ions are the only two particles that are used in modern hadrontherapy; they have a finite range of penetration in tissues which can be adjusted by varying their energy. They have an inverse depth dose profile and deposit most of their energy at the end of their path in the so-called Bragg peak. Distal to the Bragg peak, the dose falls sharply to zero for protons, whereas carbon ions show a distal tail in their dose profile due to particle fragmentation. Figure 1 shows the depth-dose profile of hadrons and photons. These physical characteristic are especially suited for the treatment of deep-seated tumors and allow the delivery of high doses to the target while sparing surrounding healthy tissues better than with the most sophisticated photon techniques. In addition to this increased conformality, carbon ions are characterized by an increased relative biological efficacy (RBE). This high RBE is due to their high density of ionization and the resultant clustered damage to the DNA with multiple double-strand breaks. Such damage is beyond the capability of repair mechanisms. An increased RBE could also result in worse side effects (as is the case for neutron therapy), but hadrons actually produce more spaced ionization in the first part of their path and denser at the end. Therefore, they deliver a low RBE dose to tissues in front of the target and a high RBE dose to the tumor. Carbon ions have the higest ratio between RBE in the Bragg peak and RBE in the entrance channel and therefore have replaced other ion species in clinical practice. Carbon ions are effective also against tumors traditionally considered radioresistant and are not affected by the level of oxygenation. Proton therapy has been traditionally considered the elective treatment for skull-base chordoma and chondrosarcoma 7,8 and for uveal melanoma 9,10. Even though there are few clinical data to support it, proton therapy has been considered beneficial also for paraspinal tumors 11. Good results have been recently achieved in these disease with sophisticated photon techniques, and some authors are questioning the role of proton therapy 12. Proton therapy has been used with promising results in a wide range of other diseases including bone and soft tissues sarcomas, hepatocellular carcinoma, non-small cell lung cancer, CNS malignancies, head and neck tumors, pediatric tumors, prostatic adenocarcinomas and rectal cancer recurrences 13,14. Experiences with carbon ions are still more preliminary but results have been extremely encouraging in chordoma and chondrosarcoma, salivary gland tumors, sarcomas, hepatocellular carcinoma, non-small cell lung cancer, advanced head and neck cancers, mucosal melanoma, recurrent rectal carcinoma, advanced uterine cervix carcinoma, bladder cancer, and prostate cancer 6, After many years in which hadrontherapy was available only in a few centers throughout the world, there is now much interest in this treatment modality in the oncology community. Ten new facilities have started treating patients in the last 10 years (Table 1), and 14 new ones are in an advanced phase of planning or construction and are expected to become operational in the next 5 years (Table 2). The National Center for Oncological Hadrontherapy (CNAO) is being built in Pavia. We herein report on the status of advancement of the CNAO and on the clinical activity that will be carried out there. The CNAO facility The Italian Ministry of Health created the CNAO Foundation in 2001 to build and run the facility and has mainly financed it. The founders of the CNAO are five

3 CNAO: THE NATIONAL CENTER FOR ONCOLOGICAL HADRON THERAPY 171 Table 1 - Particle therapy facilities that have started operation in the past 10 years (updated 21 March 2007) Facility Country Particle Start of treatment Total no. of Date of total patients irradiated PSI, Villigen Switzerland Protons Dec 08 LLUMC, Loma Linda CA, USA Protons Dec 08 CPO, Orsay France Protons Dec 07 ithemba Labs South Africa Protons Dec 08 MPRI, Bloomington IN, USA Protons Dec 08 HIMAC, Chiba Japan Carbon ions Jan 08 NCC, Kashiwa Japan Protons Dec 07 HIBMC,Hyogo Japan Protons Dec 08 HIBMC,Hyogo Japan Carbon ions Dec 08 PMRC, Tsukuba Japan Protons Dec 08 FH Burr Proton Therapy MA, USA Protons Oct 08 Center, MGH Boston INFN-LNS, Catania Italy Protons Dec 07 SCC, Shizuoka Japan Protons Dec 08 WERC,Tsuruga Japan Protons Dec 08 WPTC, Zibo China Protons Dec 08 MD Anderson Cancer TX, USA Protons Dec 08 Center, Houston, TX FPTI, Jacksonville FL, USA Protons Dec 08 NCC, IIsan South Korea Protons Dec 08 PSI, Paul Scherrer Institut; LLUMC, Loma Linda University Medical Center; CPO, Centre de Protontherapie d Orsay; MPRI, Midwest Proton Radiotherapy Institute; HIMAC, Heavy Ion Medical Accelerator in Chiba; NCC, National Cancer Center; HIBMC, Hyogo Ion Beam Medical Center; PMRC, Photo-Medical Research Center; MGH, Massachusetts General Hospital; INFN-LNS: Istituto Nazionale di Fisica Nucleare, Laboratori Nazionali del Sud National Institute of Nuclear Physics, Southern National Laboratories); SCC, Shizuoka Cancer Center; WERC, Wakasa Wan Energy Research Center; WPTC, Wanjie Proton Therapy Center; FPTI, Florida Proton Therapy Institute; NCC, National Cancer Center. Table 2 - Particle facilities in a planning stage or under construction (updated 21 March 2008) Facility Country Particle Start of treatment planned RPTC, Munich Germany Protons 2009 Roberts Proton PA, USA Protons 2009 Therapy Center, Philadelphia Med-AUSTRON Austria Protons and? carbon ions ATREP, Trento Italy Protons? HIT, Heidelberg Germany Protons 2009 RPTC-2, Koeln Germany Protons and? carbon ions WPE, Essen Germany Protons 2009 PTC, Marburg Germany Protons and 2010 carbon ions NIPTRC, DeKalb Il, USA Protons 2011 NRoCK, Kiel Germany Protons and 2012 carbon ions RPTC, Rinecker Proton Therapy Center; ATREP, Agenzia Trentina per la Protonterapia (Trento Proton Therapy Agency); HIT, Heidelberg Ion Therapy; RPTC-2, Rinecker Proton Therapy Center 2; WPE, Westdeutsches Protonthrapiezentrum Essen (West Germany Proton Therapy Center in Essen); PTC, Proton Therapy Center; NIPTRC, Northern Illinois Proton Treatment and Research Center; NroCK, North European. Radiooncological Center at Kiel. major hospitals, located in Milan and Pavia, and the Therapy with Hadronic Radiation Foundation. The Foundation, lead by U. Amaldi, has promoted the CNAO since The Italian National Institute of Nuclear Physics has been the institutional participant of CNAO since 2003, together with the Universities of Milan and Pavia, the Polytechnic University of Milan, and the Town of Pavia. The basic design of the CNAO accelerator (synchrotron and beam transport lines) was developed by the European Counsel for Nuclear Research within the framework of the Proton-Ion Medical Machine Study from 1996 to The design has been fully engineered, first by Therapy with Hadron Radiation Foundation and then by the CNAO/National Institute of Nuclear Physics (with cooperation of the Gesellschaft für Schwerionenforschung, European Counsel for Nuclear Research, University of Pavia and Subatomic and Cosmologic Physics Laboratories/National Institute of Nuclear and Particle Physics Laboratory at Grenoble). The final design now appears as shown in Figure 2. The synchrotron will be the heart of the facility and will be able to accelerate proton and carbon ions to a maximum energy of 400 MeV/u (corresponding to 27 cm penetration depth in water). Three rooms equipped with fixed beam lines (two rooms with a horizontal beam and

4 172 R ORECCHIA, P FOSSATI, S ROSSI Three treatment rooms (3H-IV) Extraction line Synchrotron ring Ion sources Injection line Figure 3 - Layout of the CNAO. Figure 2 - Layout of the CNAO accelerators and beam transport lines. scanning 20 ). The narrow beam extracted from the accelerator is scanned over the target volume, which is therefore irradiated one subvolume at a time. Figure 4 illustrates this concept. CNAO will employ an active spot-scanning system. Two orthogonal magnetic fields will be used to scan the beam in planes parallel to its direction. Magnets are designed to allow scanning of square slices of 20 x 20 cm. Depth will be varied directly by adjusting the beam energy. The smallest step of penetration range achievable will be 0.2 mm. The synchrotron allows variation of the energy at each spill, so that every second it will be possible to irradiate a layer at a different depth. Scanning magnets, sensors to measure position and intensity of the beam, and control systems will be integrated in the nozzle. Different spot size will be available (with a radial size adjustable from 4 to 10 mm, in steps of 1 mm). The active scanning system and the dose rate have been designed to be able to deliver 2 Gy to a volume of 1 liter in min. With spot scanning it is possible to use inverse dose optimization algorithms similar to those created for intensity-modulated radiotherapy and therefore to perform the so-called intensity-modulated particle therapy, which can fully exploit the favorable physical features of hadrons. Figure 5 shows the difference in dose distribution achievable with protons using different dose-delivery techniques. Other key features necessary to take advantage of the high spatial precision of hadron therapy are an accurate identification of the target and a precise and reproducible patient setup. The facility will be equipped with one computerized axial tomography scanner, two positron emission tomography/computerized tomography scanners and one magnetic resonance imaging scanner, which will be dedicated to treatment simulation and in-treatment response evaluation. Treatments will be performed with patients immobilized on specially designed couches or chairs (with the possibility of a bite block) that will be docked to a stateone room with vertical and horizontal beams) will be operative for patient treatment from the first phase. The facility will be upgraded in a second phase with two more rooms equipped with rotating gantries. In every room it will be possible to perform proton therapy and carbon ion therapy, and all the devices are designed for both the beams. Switching between protons and carbon ions on a patient by patient basis will be possible without impacting on the time schedule of the facility. An experimental beam line with a dedicated room will be available from the first phase for radiobiology and physics research and development. Figure 3 shows the facility layout; buildings and extraction lines are already predisposed for the gantry rooms. Older facilities employ passive dose delivery techniques. The narrow beam produced by the accelerator is broadened through passive scattering to obtain a wide field. The width of the monochromatic Bragg peak (which is only a few millimeters) is increased to some centimeters to match the thickness of the target (with ridge filters 17 or with rotating modulator wheels 18 ), realizing the spread out Bragg peak. Wide fields so obtained are shaped with collimators. Finally, the distal edge of each field is conformed to the target with a personalized bolus. This technique results in an unnecessary dose proximal to the target. Moreover, passive devices interposed in the beam path produce secondary neutrons that deposit an integral dose whose long-term effects are in part not yet known. Most new facilities rely on an active dose-delivery system (raster scanning 19 or spot

5 CNAO: THE NATIONAL CENTER FOR ONCOLOGICAL HADRON THERAPY 173 Scanning system Scanning magnets Wire chambers Ionization chambers Example: Depth 5 cm: Proton 80 Mev Carbon 150 MeV/u Depth 25 cm: Proton 195 Mev Carbon 380 MeV/u Monitor system Relative dose Radiation control Cross-section through the irradiated tumor volume. Every section represents a different beam range. The treated elements are shown in green. Target volume and will be carried into the treatment room on a trolley predisposed for docking with the mobilization device, thus realizing a time optimization through a pipeline approach. Three-dimensional setup verification will be available. The realization of the CNAO began in September 2002 with the final design of the high technology part, which has been completed. The building is finished, and assembly of the components has started. The two ion sources (each capable of producing protons and carbon ions) are already in place, and the first beam was emitted on May 31, The year 2008 was devoted to completion of high-technology installation and beam commissioning. Patient treatments will start at the end of commissioning. 0 Depth Clinical activity at the CNAO Figure 4 - Dose delivery with a 3D active scanning technique (courtesy of Siemens Medical). POOR 1 field, passive scattering 3 fields, passive 1 field, active, uniform dose 1 field of 3, active, 3 of 3 fields, active, intensity modulated intensity modulated 3 fields, active, uniform dose GOOD Target outlined in yellow Critical structures in red Figure 5 - Comparison of active and passive dose delivery techniques. Intensity-modulated particle therapy (bottom right) allows exploitation of the physical characteristics of hadrons with optimal sparing of organs at risk even when surrounded by the target. Reprinted with permission from: Michael Goitein, Antony J. Lomax, and Eros S. Pedroni. Physics Today, volume 55, issue 9, pp (2002). Copyright 2002, American Institute of Physics. of-the art, 6 degrees of freedom, mobilization device. Setup verification will be performed with orthogonal kv images of diagnostic quality. Additionally, an optoelectronic system with marker detection and surface detection capability will be used. The CNAO aims to have a high patient throughput. The design of the facility has specifically addressed this issue, and dedicated (computer-aided) positioning rooms have been built. Patients will be positioned on the couch (or on the chair) outside the treatment room The CNAO will be able to use both proton and carbon ions. At steady state it will devote 80% of the time to ions and the remaining 20% to protons. Carbon ion radiotherapy (CIRT) is still in its early stage, and indications have not been clearly defined. The CNAO will be a center for research and therapy: one of its purposes is to conduct prospective clinical trials to define, with a methodologically correct approach, the real indications for hadron therapy. All patients treated at the CNAO will participate in clinical trials. At present, most Italian patients affected by skull base chordoma and chondrosarcoma or by uveal melanoma are referred abroad to receive proton therapy (with relevant costs for the national health system). Once it begins its clinical activity, the CNAO will be able to treat all such patients with proton therapy. In a subsequent phase, trials of CIRT (alone or randomized against proton therapy) could be carried out for selected patients with advanced disease or an unfavorable prognosis. According to a document of the Associazione Italiana di Radioterapia Oncologica working group 21, elective indications for proton therapy may comprise (besides those already cited) half of skull-base meningiomas and 10%-15% of pituitary adenomas and cranial nerve schwannomas (Table 3), for a total of 830 new cases per year. An update in this analysis has further increased the number of elective indications to more than 1000 patients per year. In the same documents, potential indications were also examined. Tables 4 and 5 report the potential indications for proton therapy and CIRT (at present, CIRT is not considered elective in any situation). In Italy, more than 15,000 patients each year could potentially benefit from proton therapy and more than 3,000 could benefit from CIRT 22. The activity the CNAO is designed to reach steady state in three years with two 8-h shifts from Monday to Friday. A workflow analysis has been performed (mainly considering a Loma Linda University Medical Center organiza-

6 174 R ORECCHIA, P FOSSATI, S ROSSI Table 3 - Elective indications for proton therapy Tumor type New patients No. eligible % eligible per year for protons for protons Uveal melanoma Chordoma Chondrosarcoma (head, trunk) Meningioma (base of skull) Paranasal sinus cancer CNS schwannoma Pituitary adenoma Total Table 4 - Tentative indications for proton therapy Tumor type New patients No. eligible % eligible per year for protons for protons Brain gliomas Brain metastases Head & neck tumors Undiff. thyroid cancer NSCLC 31, Thymoma Esophageal tumors Biliary tract tumors Liver cancer 13, Pancreatic carcinoma Cervical carcinoma Bladder carcinoma 16, Prostatic tumors 22, Pelvic recurrence >500 > Pediatric solid tumors AVM Macular retinal degeneration?? Total >114,490 >15, NSCLC, non-small cell lung cancer; AVM, arteriovenous malformation. Table 5 - Tentative indications for carbon ion radiotherapy Tumor type New patients No. eligible % eligible per year for protons for protons Salivary gland tumors Mucosal melanoma (head & neck) Bone sarcoma Soft tissue sarcoma NSCLC HCC Prostatic carcinoma Total NSCLC, non-small cell lung cancer; HCC, hepatocellular carcinoma. tional approach as a starting point) and has shown that the facility will be able to deliver more than 18,000 treatment sessions per year. Hadron therapy, and especially CIRT, has shown a consistent trend toward hypofractionation. Ions do not have the shoulder in the dose-survival curve, which is the radiobiological rationale for conventional (1.8-2 Gy) radiotherapy fractionation. At the HI- MAC, the mean number of fractions per patient is at present 13 and is still decreasing. At the CNAO, treatments will be carried out not only as exclusive therapy but also as a boost after photon radiotherapy. It is estimated that about 3,400 patients per year will be treated at the CNAO at steady state. This number of patients is clearly smaller than the number of potential indications. There is therefore the need to define selection criteria to deliver hadron therapy to patients who are more likely to benefit from it. To achieve this goal, the CNAO foundation has identified seven groups of diseases that are considered at high priority: lung tumors, liver tumors, sarcomas, head and neck tumors, eye tumors, central nervous system lesions and pediatric tumors. A disease-specific working group has been created for each of these diseases under the leadership of a physician with recognized expertise in the field. Each working group is composed of radiation oncologists, medical oncologists, surgeons, diagnostic radiologists and organ specialists. The working groups have analyzed the literature and have produced documents with recommendations on tentative indications for trials to be conducted at the CNAO. Special care has been taken to also consider alternative available treatments in an effort to propose hadron therapy to those patients for whom it is reasonable to expect a significant benefit. A central board has been established to review documents written by the working groups and will eventually produce protocols for the trials that will start next year. Two more working groups are being set up on gynecological malignancies and on digestive cancers (pancreatic, biliary tract and rectal tumors). Another key issue for the CNAO is to ensure a correct patient referral. The CNAO will be the only carbon ion facility in Italy, and therefore its basin will be the whole country (besides foreign patients). At present, a website has been created with general information ( and a medical service has been set up to provide consultation on specific cases. To allow a rational use of the facility, it is necessary to establish a close network with other oncological centers. In the near future, we plan to make CNAO treatment protocols widely available to health providers and to create specific tools for a quick patient referral (also employing telematic approaches). A close cooperation with oncological centers and primary care providers is also needed to coordinate staging and follow-up (to be done mostly at the referring center) and treatment to be done at the CNAO. An even closer cooperation will be necessary when hadron therapy is used within a multimodality treatment approach. An international cooperation has already started with the foreseen European carbon ion centers (Heidelberg Ionenstrahl-Therapie, MedAustron, ETOILE, ARCHADE, and Phillips University of Marburg) within the framework

7 CNAO: THE NATIONAL CENTER FOR ONCOLOGICAL HADRON THERAPY 175 of the project Union of Light Ion Centers in Europe). The aim of the project is to perform multicentric trials and to establish a shared database of all treated patients. Besides clinical activity, the experimental room will be used for basic research in radiobiology and physics and to test in cellular and animal models the safety and effectiveness of the beam and the adequacy of the models employed. Conclusions The CNAO will begin to treat patients in the near future. Hadron therapy has the potential to achieve a better local control with fewer unwanted side effects. Its real indications are still a matter of debate. The CNAO wants to provide state-of-the-art treatments and help to establih hadron therapy indications with a sound clinical and scientific methodology. Passionate and irrational opinions have been expressed in the past in favor of and against hadron therapy. The most common argument against hadron therapy has been the increase in cost with little (or no) proven clinical benefit. Cost-effectiveness is an important parameter but by no means the most important in cancer therapy. It is extremely difficult to account for all the expenses and savings involved. The cost of different therapies can be accurately estimated, but it is exceedingly difficult to calculate the costs of treatment of recurrences (and the consequent savings achievable with more effective therapies) or of supportive care for chronic side effects (and the consequent savings from less toxic therapies). The economic analysis varies significantly if the treatment is paid for by private insurance or by a public health system. In the latter case, the most relevant feature may be the final ability of the patient to resume his previous life, which can result in a savings if he is working and paying taxes or in an expense if he is retired. An economic analysis performed by Goitein and Jermann 23 showed that proton therapy is at present about 2.4 times more expensive than intensity-modulated radiotherapy. However, in the USA Medicare reimbursement for simple proton therapy treatment is less than for intensity-modulated radiotherapy. Quantitative cost-effectiveness analyses have been published, according to which proton therapy may be not only cost-effective but also cost-saving for pediatric medulloblastoma 24, and similar results were estimated when considering also breast cancer, prostate cancer and head and neck malignancies 25. CIRT has been found to be as cost effective as intensity-modulated radiotherapy for skull base chordoma 26. The CNAO has been financed by the Italian government and does not have to reimburse any capital investment, therefore it is not a good model for economic analysis. In addition to providing sound clinical evidence, it will also help to assess the cost-effectiveness of carbon ions. 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