NIRS HIMAC Development and Cooperation Research Programs at

NIRS HIMAC Development and Cooperation Research Programs at HIMAC Contents: 1. Outline of HIMAC project 2. Previous achievements 3. Present developments 4. Framework of cooperation research A. Kitagawa Leader, Promotion of Heavy Ion Radiotherapy Team (Senior Researcher, Dept. of Accelerator and Medical Physics) Research Center for Charged Particle Therapy National Institute of Radiological Sciences

1. Outline of HIMAC project

1. Outline of HIMAC project NIRS HIMAC Comprehensive 10 -Year Strategy for Cancer Control 1984 1 st 1994 2 nd Japanese government • Ministry of Health • Ministry of Education • Science & Technology Agency Ministry of Education, …, Science & Technology (MEXT) 2004 3 rd 2014 Strategy HIMAC project

1. Outline of HIMAC project NIRS Construction of research facility HIMAC Ion species: He – Ar (He – Si for clinical) Treatment room: 3 (4 port) Experiment room: 2 (3 port) Size: 60 x 120 m Construction cost: 32. 6 GJPY (Building 14. 6 GJPY) (machine 18. 0 GJPY) *GJPY ~10 MUS$ ‘ 84 Feasibility study Design of machine Design of Buildings Construction of Buildings Installation of Utilities Manufacturing & installation of machine Research ‘ 85 Survey ‘ 86 ‘ 87 ‘ 88 ‘ 89 ‘ 90 ‘ 91 ‘ 92 ‘ 93 ‘ 94 Research & developments for devices technology (incl. biology) Machine Buildings Electricity, cooling system, … Injector Synchrotron Irradiation system, … commissioning Physics & Biology Clinical trials “Summary at the 10 th anniversary of the heavy ion radiotherapy”, edited by MEXT, Monbu-Kagaku Jihou No. 1541, August 2004, pp. 10 -49. (in Japanese)

2. Previous achievements

2. Previous achievements NIRS Registered patient number HIMAC 804 642 333 396 437 684 692 549 1463 patients have been treated from June 1994 to March 2003 Ministry of Health approved carbon-ion radiotherapy as ‘Advanced Medicine’ 691 648

2. Previous achievements NIRS Organization of clinical trials in NIRS HIMAC Carbon Ion Radiotherapy Network Committee Planning Committee Subcommittee by body parts Organizing of clinical study protocols Preparation of protocols by body parts Evaluation Committee Head&neck, Central nervous system, Lung, Liver, Urinary organs, Gynecological region, Bone&soft tissue, Eye, Pancreas, Lower gastrointestinal tract, Upper gastrointestinal tract Evaluation of therapeutic results Head&neck, Central nervous system, Lung, Liver, Urinary organs, Gynecological region, Bone&soft tissue, Eye, Pancreas, Lower gastrointestinal tract, Upper gastrointestinal tract Research Center for Charged Particle Therapy <Hospital> Review of eligibility Clinical study group Other medical institutions - Medical examination - Informed consent Planning, Follow-up <HIMAC> Irradiation Clinical Study Ethical Committee Review of the entire treatment flow Ethical Radiotherapy Committee Advanced Medical Technology Review Committee Review of individual patients Carbon Ion Radiotherapy Indication Committee “Progress to date in carbon ion radiotherapy - Present status and outlook”, edited by NIRS, Radiological Sciences Vol. 50 No. 7, July 2007, pp. 4 -65.

2. Previous achievements NIRS Summary of clinical results HIMAC Carbon ion radiotherapy has 3 large advantages, Better local control / survival ratios Hypo-fractionation: shorter treatment period 1 day treatment 1 fraction ~50. 0 Gy. E in 1 day before 5 years after 5 years overall survival ratio in inresectable cases 46% (<500 cc), 19% (>500 cc) Lower toxicities Delayed adverse reaction (>=G 2) 0. 3% (Rectum) 2. 4% (Genitourinary system) X-ray CT 3 year Local control 83% 5 years survival 55% (mean age=73. 9) cause specific survival 73% PET before 1 year after Publications D. Schulz-Ertner and H. Tsujii, Journal of Clinical Oncology, 2, 953 (2007). H. Tsujii et al. , New Journal of Physics 10, 075009 (2008). H. Tsujii and T. Kamada, Jpn. J. Clin. Oncol. 42, 670 (2012). Recent clinical results like NIRS-Med. Austron Joint Symposium http: //www. nirs. go. jp/ENG/publication/

2. Previous achievements NIRS HIMAC Extension for heavier ion species 18 GHz NIRS-HEC ECRIS Waveguide Gas inlet Mirror magnet 500 l/s. TMP Extraction electrode (movable) High voltage platform Plasma chamber Sextupole magnet 500 l/s. TMP Acceleration gap (Insulator) Einzel lens Analyzer magnet Faraday Cup & Slit

NIRS HIMAC 2. Previous achievements Extention of experiment rooms

2. Previous achievements NIRS Time sharing acceleration HIMAC Example of operation time (April 2009 - March 2010) Schematic diagram of HIMAC E INJ E USY LSY UBT EE EE Treatment Rooms LBT HIMAC can provide individual beams for three different users at the same time. Failure rate: INJ=0. 7%, USY=0. 1%, LSY=0. 1%

2. Previous achievements NIRS HIMAC Medical application of radioisotope beams Principle of the measurement b+ Production method of RIB emitting nuclei 15 O 12 C 13 N decay 11 C Method 1 11 C 12 C Method 2 positron 11 C, 10 C Observation of a pair of annihilation g-ray from outside of patient . . . Method 3 Human body Methods of production for b+ 1. In-vivo activation method: Stable beam produces b+-emitter as target fragment. 2. Autoactivation method: Stable beam changes to b+-emitter as projectile fragment. 3. Radioactive nuclear beam method: directly shows it’s position with high signal-to-noise ratio. 1 G. W. Bennett et al. . , Science 200, 1151 (1978). / 2 C. A. Tobias et al. . , Int. J. Radiat. Oncol. Biol. Phys. 3, 35 (1977). / 3 A. Chatterjee et al. . , Int. J. Radiat. Oncol. Biol. Phys. 7 (1981) 503.

2. Previous achievements NIRS Trials at HIMAC 1 -D range information in the PMMA phantom Beam condition 10 C & 11 C beam energy : 346 Me. V/u (range=156. 9 mm in PMMA) Momentum width : 0. 8% (FW) (Drange=3. 6 mm) Beam size : 7 mm (FWHM) Intensity : 300 -500 k pps (110 -180 m. Gy) 0. 95*diameter Range shifter 10 C spherical PMMA (150, 180 diam. ) Accuracy of the centroid of the stopping point in the phantom / 11 C = 0. 6 mm Plastic scintillator Y. Iseki et al. . , Phys. Med. Biol. 49 (2004) 1 Metabolism study by rabbits Beam condition 10 C & 11 C beam energy : Momentum width : Beam size : Intensity : Absorber (PMMA) 15 cm alive rabbits 346 Me. V/u 10 C 0. 4% (FW) 3 - 7 mm (FWHM) 24 k (10 C) pps 300 k (11 C) 3 -components Biological model of wash out 11 C Fast component 1 Brain Blood flow dead rabbits 10 C / 11 C 20 cm Plastic Scintillator Muscle 12 cm H. Mizuno et al. . , Phys. Med. Biol. 48 (2003) 2269. 10 C 11 C Intermidiate component 2 Component-3 τ~10191± 2200 s （35± 1 %） Component-1 τ~2. 0± 1. 8 s （35± 3 %） Component-2 τ~140± 18 s （30± 3 %） Component-3 τ~3175± 378 s （52± 2 %） Component-1 τ~10± 8 s （30± 4 %） Component-2 τ~195± 52 s （19± 3 %） Cell Slow component 3

2. Previous achievements NIRS 3 -D irradiation system HIMAC Position scanning in a slice by the scanning magnets Range scanning by the range shifter Beam energy from the accelerator is fixed multi-leaf collimator ridge filter pencil beam collimater PSD monitor positron camera position monitor Q Magnet scatterer scanning magnets (h. & v. ) dose monitor range shifter patient chair (main/sub) 5430 mm Maximum scanning volume 10 x 18 cm (WE) Scanning speed (x, y) 2 ms/cm But, it’s difficult to utilize moving target! E. Urakabe et al. . , Jpn. J. Appl. Phys. 40 (2001) 2540.

3. Present developments

3. Present developments NIRS HIMAC Developments of prototypes (2004 -2005) Linac Synchrotron Magnet Ion source Design concept: Optimization for carbon beam only!! Acc. cavity Irradiation system Magnet power supply Size and Cost 1/3 of HIMAC K. Noda et al. , J. Radiat. Res. 48: Suppl. A A 43 (2007).

3. Present developments NIRS HIMAC Gunma University Project (2006 -2010) Demonstration of the hospital-specified facility - Dedicated carbon beam only with max. 400 Me. V/u & 1 x 109 pps - Wobbler & layer-stacking irradiation systems - Technology transferred to manufacturing companies - Construction cost (machine&building) ~ 12 GJPY *GJPY~10 MUS$ ‘ 01 Feasibility study & fundamental design (at NIRS) Gunma University Heavy ion Medical Center Manufacturing Design of machine and Buildings Construction of Buildings Installation of Utilities Manufacturing & installation of machine Clinical trials ‘ 02 ‘ 03 ‘ 04 ‘ 05 ‘ 06 ‘ 07 Survey Developments of devices ‘ 08 ‘ 09 ‘ 10 Project funded by Japanese government Machine & Buildings Machine Buildings Electricity, cooling system, … Injector commissioning Synchrotron Irradiation system, … Clinical trials T. Ohno, Cancers 2011, 3, p. 4046.

NIRS HIMAC 3. Present developments Comprehensive Strategy [3 rd Comprehensive 10 -Year Strategy for Cancer Control, 2004 -2013] 2004 “Workshop for popularization of the charged-particle radiotherapy” was held by MEXT and the summary report has been distributed. 2005 “The guideline for charged particle radiotherapy in Japan” has been authorized by the Japanese Society of medical Physics (JSMP). 2004 -5 Design of a hospital-specified facility and development on prototypes of various components at NIRS was funded by MEXT. 2005 -7 “Research on radiation protection for proton and heavy ion radiotherapy” was funded by MHLW. 2006 -10 Construction of the 3 rd facility at Gunma University as a demonstration model was funded by MEXT. 2007 -12 “Program for the Human Resources Development Relating to Charged Particle Radiotherapy” has been funded by MEXT. 2007 - Approved the construction of “the next-generation irradiation systems” at NIRS. 2010 First treatment at Gunma University. 2011 Start of clinical trials with the respiratory gated 3 D scanning at NIRS.

3. Present developments NIRS Present facilities HIMAC GHMC Gunma (2010) SAGA-HIMAT Saga (2013) Heavy ion (under construction) Proton (including shutdown) Proton (under construction) Other plans HIBMC Hyogo (2001) HIMAC Chiba (1994) i. ROCK Kanagawa (2015)

3. Present developments NIRS HIMAC Research topic of irradiation methods Target volume I. a) Wobbler Unexpected dose II. a) Scanning III. Scanning with respiratory gate Head, Prostate, Lung, Liver… I. b) Layer-stacking wobbler II. b) Scanning without respiratory gate Head, Prostate, Lung, Liver…

3. Present developments NIRS HIMAC New research buildings For various research, the new treatment research building has been constructed. The clinical trial of a fast 3 D-scanning irradiation system as the nextgeneration irradiation technology started since 2011. New facility HIMAC Hospital 2011 Gold Award

3. Present developments NIRS Operation summary of new facility HIMAC Year 2011 2012 -2013 Ion Carbon Operation period May. 2011 ~ Nov. 2011 Sep. 2012 ~ Aug. 2013 Patient Number 11 248 Target Pelvis, Head and neck Pelvis, Uterus, Head and neck Treatment room Room E, F Targets in 2012

3. Present developments NIRS Treatment planning system HIMAC Step 1: Scan Path Optimization Application of simulated annealing algorithm Step 2: Extra-dose to Optimization Delivered beam Effective higher than 108 pps T. Inaniwa et al. , Med. Phys. 34, 3302 -3311 (2007)

3. Present developments NIRS New patient positioning system HIMAC Residual positional error in 2011 Treatment time for one patient 2011 Total Entering Positioning Irradiation (inc. prep. ) Exit 2012 20 min 13 min 2. 5 min 12 min 7 min 2. 5 min 3 min 1 min (old system ~ roughly 25 min. ) S. Mori et al, Journal of Radiation Research, 53, 760 (2012).

3. Present developments NIRS HIMAC Experimental Study on respiratory gating n Moving phantom 24 ch pinpoint chambers in water Comparison Plan - Measurement 8 rescans d. D/D < 1. 7% Physical Dose : 1 Gy, Respiratory cycle : 4. 3 s, Amplitudes : 7 mm (20 mm ungated). T. Furukawa et al. , Med. Phys. 37, 4874 (2010) Y. Shirai, Proc. NIRS-Med. Austron Joint Symposium (2013).

NIRS HIMAC 3. Present developments Example of new developments Y. Iwata et al. . , Proc. IPAC 2011, 3601 (2011). Y. Iwata, Proc. NIRS-Med. Austron Joint Symposium (2013).

3. Present developments NIRS HIMAC Biological model for treatment LQ model scattering dose 10% LET reaction HSG depth But, • Human body has nonuniform density. • Real beam has spatial distribution, divergence, contamination of impurity, etc… survival dose If, • Uniform irradiation field • Parallel beam depth

3. Present developments NIRS HIMAC MKM model for microscopic understanding Cell nucleus is divided into many independent sub-volumes. Dose response in the sub-volume is independent on radiation type. Cell response is given by the sum of the lethal events in all subvolumes. rd Parameter search is necessary Adequate model size Incident dependent term Target dependent term Overkill correction Etc…. Rn Track structure model (Kiefer and Chatterjee) extrapolated for LET=0 constant rd N. Matsufuji, Proc. NIRS-Med. Austron Joint Symposium (2013).

4. Framework of cooperation research

4. Framework of cooperation research NIRS HIMAC PAC and evaluation of the proposals All proposals! Call for proposals NIRS researchers follow the same process Submit proposals Twice every year PAC evaluates all proposals PAC When accepted Collaborative researcher Scheduling of beam time Registered workers for radiation safety Announcement of beam time ½ year schedule Start of experiments

4. Framework of cooperation research NIRS Number of proposals in each year HIMAC Rough breakdown of beam time 160 140 120 100 Number of proposals Medicine 80 Biology 60 Physics 40 20 0 199 4 199 6 199 8 200 0 200 2 Year 4 Beam time ~ 5000 hours / year 200 6 200 8 201 0 201 2 Industrial use ~ less than 1 %

4. Framework of cooperation research NIRS Weekly schedule HIMAC Monday Maintenance or Treatment Weekdays(daytime) Treatment ~10 h Weekdays(night) Experiment ~10 h Weekends Experiment ~24 h Mon Tue Thu Fri Sat Sun Upper Ring Lower Ring Linac Typical schedule Therapy 1 month shutdown Biology • Twice per year (March & August) • Maintenance • Commissioning of new devices • Treatment=180 days/year Physics or others Maintenance (No Beams) Sunday Shutdown or Experiment Wed

5. Example of experiment

5. Example of experiment NIRS HIMAC • Visualization of the track in scintillator Visualizing the track of single ion in a scintillation material for… • Quality assurance in particle radiotherapy (transmitted particle detection) • Understanding of radiation quality of therapeutic ion beams • Understanding of fundamental physics • inter- and intra-nucleus transportation of ions • Track structure Range analysis Single ion track detection (C-290 Me. V/n)

NIRS HIMAC 5. Example of experiment Visualization of track structure Fe horizontal J 375 XLF 1 Gy 30 min after irradiation Xray Track in the cells, visualized by fluorescent marker Courtesy of Nakako Nakajima, NIRS.

NIRS HIMAC 5. Example of experiment Hyperfine study In-beam Mössbauer spectroscopy of 57 Fe/57 Mn 58 Fe Emission Mössbauer spectra of 57 Fe in Mg. O 57 Mn The reproducibility of the primary beam was checked by a pair of multi-wire proportional chambers installed at the production-target position. The reproducibility of the radioactive beam was confirmed by the measurement of TOF-E. A typical switching time from therapy to the RIB irradiation on the experimental sample is less than one hour except for the ion source preparation. Independent ion sources are usually assigned for therapy and the experiments.

5. Example of experiment NIRS HIMAC Installation of local injector Prototype injector for the hospital-specified facility • It has been developed and tested in March 2006. • It has been installed for the local injector into HIMAC in 2011. • Presently, it supplies carbon beam for experiments

NIRS HIMAC Summary 1. HIMAC project is carried out under the comprehensive strategy and is covered the budget of government. 2. About 8000 patient has been treated and the facility has been utilized for various developments and research. 3. Between 2004 and 2013, the promotion of carbon ion radiotherapy is 1 st priority. Other developments the new irradiation techniques are in progress. (Of cause, improvements of clinical protocols too) 4. Many developments and research are carried out under the framework of cooperation research. About 5, 000 hours are delivered