Institut Curie CPO and France programs Annalisa Patriarca

Institut Curie – CPO and France programs Annalisa Patriarca on behalf of the Institut Curie – Centre de Protonthérapie d’Orsay team Status and future perspectives charged particle therapy, 17 – 18 December 1 - A. Patriarca, Institut Curie – CPOof and France programs, 17 - 18 December, Fondazione 2013, Fondazione CNAO

Plan 1) Presentation of the Institut Curie and of the Proton therapy center in Orsay (IC – CPO) 2) IC – CPO clinical program 3) IC – CPO involvement in physics and radiobiology research 4) IC – CPO experimental plan 1 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

Institut Curie: a dedicated cancer center working on treatment, and basic, translational, clinical research ü Hospital Group • Paris Hospital • Proton therapy center in Orsay (IC - CPO) • René-Huguenin Hospital in Saint-Cloud ü Research Center • 15 units (>1000 person) in Paris and Orsay which are associated with universities and the French national research centers (CNRS, Inserm). René-Huguenin Hospital Paris Area Orsay Proton therapy Center ü Translational Research Department • scientific innovations to improve patient care • preclinical studies for cancer understanding 2 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

The Radiation Oncology Department Radiation therapy facility of the Institut Curie Hospital (Paris, Orsay, St Cloud): • • 9 linear accelerators 4 high-dose-rate and pulsed-dose-rate brachytherapy systems Brachytherapy by 125 Iodine plaque and seeds 2 simulators-scanners 2 dedicated scanners for scanography 2 tomotherapy machines 1 cyclotron with 3 proton treatment rooms (IC - CPO Orsay) Around 4900 patients treated per year 10% with Proton therapy 3 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

IC – CPO team organization Operation Tests and QA Maintenance R&D

Important milestones in the IC – CPO history 1957 : 1 st French synchrocyclotron (160 Me. V) in Orsay 1975 - 1979 : Recasting of the synchrocyclotron (201 Me. V) 1987 - 1989 : Modifications of equipment and building for medical treatments 1991 : 1 st ophthalmological treatment 1993 : 1 st head & neck treatment 2004 : Integration to Institut Curie 2004 - 2010 : Expansion Project (new cyclotron + 1 gantry) July 2010 : 1 st treatment with new cyclotron 26 Oct 2010 : 3 rd treatment room (gantry) opened More than 6000 patients treated since 1991 5 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

IC – CPO : 1991 – April 2010 Second room opened : Couch or chair treatment l head&neck First room opened : Chair treatment l ophtalmology l head & neck 6 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

1 st treatment room ü Eye treatments • 300 patients/year • Choroidal Melanomas: 87% • Conjunctival Melanomas: 5% • Choroidal Hemangiomas: 4% • Iris Melanomas: 2% • Others: 1% ü Hypofractionation: • 4 fractions of 15 Gy/w • 8 fractions of 7. 5 Gy/2 w ü TPS: EYEPLAN ü Imaging system: Hamamatsu flat panel ü Alignment system: Dispot software ü Robotic positioner 7 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

2 nd treatment room ü Head & neck treatment since 1996 • Supine or seated treatment positions • Treatment capacity : 14 patients/day • Conventional fractionations of 1. 8 Gy 5 days/w ü TPS Isogray ü Imaging system • Dicom imaging system • Flat panel sensor + CPO acquisition software ü Patient alignment system (Rotaplus) • Fiducial markers (anatomical in development) • Pair of orthogonal images • Automatic correction matrix sent to positionner 8 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

IC – CPO since 2010 Y 1 Existing IC - CPO ESS Head&neck treatments (201 Me. V) Momentum slits Dégradeur PY 1 Connection point P 2 Continuous energy selection between 70 Me. V and 230. 67 Me. V PY 2 C 235 Y 2 eye treatments (76 Me. V) and Head&neck treatments (201 Me. V) 9 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO Gantry Universal Nozzle: • Double Scattering • Uniform Scanning IBA • Pencil Beam Scanning equipment

(IBA source) SIS => Y 2 DS => Y 1, GTR US => GTR 11 10 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO PBS => GTR

Gantry room: open October 2010 15 patients/day: üHead&neck (Pediatric with anestesia) üSpine üSacrum Field size: ü circular collimators: from 2 to 22 cm ü rectangular collimator: 30 cm x 40 cm Forte robot (industrial Kuka robot) : ü Isocentric motion (+/- 0. 5 mm (1σ)) inside treatment volume ü 6 DOF : pitch & roll (+/- 15°) Alignment system ü Verisuite software Credit : Eric Bouvet / Institut Curie Patient survey system: Medusa 11 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

Workflow (intracranial) 1 st Consultation 1 Week markers implantation IRM+TDM Tumor contouring TPS Protons Simulation Proton Fields 4 Weeks W-2 W-1 Milling D-4 7 Weeks 12 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO QA D-2

Workflow (ophtalmic) Markers Echography 1 st implantation Consultation W-3 W-2 D-10 TPS Protons Simulation Proton Fields D-1 Milling D-1 3 Weeks 13 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO QA D-1

Plan 1) Presentation of the Institut Curie and of the Proton therapy center in Orsay (IC – CPO) 2) IC – CPO clinical program 3) IC – CPO involvement in physics and radiobiology research 4) IC – CPO experimental plan 14 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

Actual clinical indications at IC – CPO Adult tumors • Eyes tumors (Melanoma, hemangioma) • Chordoma, Chondrosarcoma • Meningioma (malign. atypic. Intraorbit. ) • Sacrum sarcoma Pediatric tumors • Craniopharyngioma • Rhabdomyosarcoma • Ependymoma, Medulloblastoma, Low Grade Glioma • Other CNS Tumors (Germ Cell Tumors, PNET…) • Base of Skull tumor (chordoma) • Sacrum sarcoma 15 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

IC – CPO clinical program Tumors Actual 2015 Oeil 311 300 Others adults 67 160 Pédiatric 39 120 Total 417 550 to 600 YEAR 2011 2012 2013 2014 2015 NUMBER OF FRACTIONS 4 600 6 000 7 000 8 000 >8 000 16 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

IC – CPO clinical program Intra-Cranial Tumors - Ratio Pediatric/Adult 100% 89% 88% 90% 93% 96% 90% 91% 90% 82% 74% 72% 73% 66% 65% 63% 66% 63% ENFANTS 38% 33% 28% 26% 28% 37% ADULTES 34% 25% 18% 11% 13% 10% 7% 0% 93 94 95 96 97 98 10% 9% 10% 4% 99 00 01 02 03 04 05 06 11081209 07 17 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO 0 0

IC – CPO clinical program: Pencil Beam Scanning üMore clinical possibilities üTreatment quality enhancement IMRT Protons 18 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO IMPT

IC – CPO clinical program ü Development of new clinical protocols combining chemotherapy and radiation therapy ü Moving tumours (liver, lung) ü Hypo fractionation ü IGRT ü RT adaptative 19 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

IC – CPO clinical program and real life Sessions vs unexpected events at ICPO (and expectations) Damage on the guidance system of the ion source (left) and stripe on the shaft (right) Damage on deflector insulator 20 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

Plan 1) Presentation of the Institut Curie and of the Proton therapy center in Orsay (IC – CPO) 2) IC – CPO clinical program 3) IC – CPO involvement in physics and radiobiology research 4) IC – CPO experimental plan 21 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

IC – CPO developments programs ü TPS ü OIS ü Imaging and positioning 22 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

TPS developments: from double scattering to pencil beam scanning Ù 1995 -2008: Development of in-house TPS with DS and US algorithms for horizontal and gantry beam lines (ray tracing, pencil beam, DRR, compensators). Ù 2008 -2012: Use of Monte Carlo simulations (MCNPX): monitor units predictions, secondary neutron doses, TPS benchmarking. C 1 CI 1 C 2 C 3 CI 2 CI 3 C 4 C 5 Fantôme d’eau Water Modulator Modulateur Range shifter Scatterer diffuseur Concrete shield Blindage en béton Blindage shield Telescopic Nez Telescopique Nozzle Ù 2013 -2014: Installation of PBS (IBA universal nozzle), analytical models for pencil beam scanning, with superposition of elemental pencil beams and IMPT developments (gradient optimization). 23 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

OIS: from prescription to dose measurements ÙR&V for horizontal treatment rooms and gantry 24 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

Imaging and positioning developments ü Image registration without fiducial markers both in gantry and in the horizontal treatment rooms üImproving positioning accuracy (robot coupled with Polaris system) üMotion detection in the patient survey system 25 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

The IC-CPO involvement in national research programs: Physics PROUESSE Project: PRotontherapie développement et validation d’un OUtil de modélisation Et Simulation monte carlo précises et rapides du dépôt de do. SE MCNPX modélisation de la ligne MCNPX beamline modellization 26 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

The IC-CPO involvement in national research programs: Physics SAPHIR: Accelerated Proton Source by High Intensity laser for Radiotherapy Ù Partnership between 10 companies/laboratories to prove the technologic and economic viability of the Plasma Laser for the protontherapy Ù The ICPO part is: - the medicalization of the proton beam - the radioprotection of the building 2013: 34 Me. V LOA, mesurements/Monte Carlo on the laser plasma beamline 27 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

The IC-CPO involvement in national research programs: Physics (CNRS - CEA) 2012 - : CNRS (centre d’Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC) - Laboratoire de Physique Corpusculaire (LPC) Clermont Ferrand CEA (SHFJ) collaboration ü Dose on line monitoring PMMA phantoms irradiation with a 86. 8 Me. V proton beam (4 Gy at Bragg peak) + detection blocs: ü Monte Carlo (GATE) validation for range determination in antropomorphic phantoms ü Detectors for the on line monitoring ü PET- based dose monitoring for proton therapy: preliminary assessment of the influence of an accurate beam modeling on the simulated β+ activity spatial distributions. C. Robert et al. PTCOG 52 2013 28 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

The IC-CPO involvement in national research programs: Radioprotection (IRSN) 1) Monte Carlo modelisation of the treatment rooms (i. e secondary particle cartography) 2) Simulations and measurements of the dose due to secondary neutrons during a pediatric proton therapy treatment ü Estimation des doses dues aux neutrons secondaires reçues par les patients en protonthérapie : cas des traitements ophtalmologiques. F. Martinetti, Phd thesis, 2009 ü Monte Carlo simulation of a proton therapy beam line dedicated to intracranial treatments, R. Sayah, Phd thesis, 2012

The IC-CPO involvement in national research programs: Radiobiology (IC – Research department) ü RBE caracterisation for proton beams of 76 Me. V and 201 Me. V : cell type and SOPB position dependence ü Projects: • RBE dependence on high dose rates • RBE, repair mechanisms and signaling pathways activated following conventional dose-rate protons vs. X-rays ü Radiobiological characterization of two therapeutic proton beams wit h different initial energy spectra used at the Institut Curie proton therapy centre in Orsay, V. Calugaru, Phd thesis, 2011 30 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

IC-CPO collaborations: a special one From 1998 - : INFN and INFN spin off (De. Tec. Tor) • TERA chip technology MOPI pixel chamber MLIC multi leaf ionization chamber 31 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

Plan 1) Presentation of the Institut Curie and of the Proton therapy center in Orsay (IC – CPO) 2) IC – CPO clinical program 3) IC – CPO involvement in physics and radiobiology research 4) IC – CPO experimental plan 32 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

Institut Curie development of an experimental radiation biology facility ü A dedicated experimental room • proton beam (230 Me. V max energy) • pencil beam scanning available üTwo new animal X-ray generators • a basic X-rays generator (320 k. V) • a small animal image guided radiation research platform ü Dedicated animal care facility (level 2) üCell culture laboratory (level 2) ü A level 1 laboratory • preparation of tissue samples ü Storage room, offices 33 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

Development of the experimental radiation biology facility ü IC – CPO involvement • Availability of a dedicated beam line to not interfere with the clinical activity • Preparation room • Support in radiobiology experimental studies, physical research and clinical research • Development of specific devices for in vitro and in vivo radiation biology experiments • Ability to conduct full animal experiments 34 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

Experimental room (preliminary studies) Deviation Shielding Beam line 35 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

Paill 5 ass e H ot te c hi m iq u e S t o c k a g e Con géla teur 352 Pai llas se aration room for the users P o rt o ir c a g e s tabulation/DASRI 324 périmentati n animale ontention Double aillasse P paillasse 1 2 a Pièce de e culture t 324 cellulaire Paillass e e r Microscopie 4 Paillas se r e PS M tels tar

IC – CPO involvement in France Hadron consortium ü FRANCE HADRON - a national infrastructure distributed on 5 nodes : • ETOILE Center in Lyon, • ARCHADE Center in Caen, • Centre Antoine Lacassagne / IMPACT in Nice, • Curie Institute / ICPO in Orsay, • Claudius Regaud Institute / PERICLES in Toulouse. with the partnership of CNRS/IN 2 P 3 (IPNL & LPC) and of IRSN, and the support of INSERM, INCa, CEA, ENLIGHT, ULICE and 16 industrials et public institutions including CNES, Thales, Mérieux. . . ü FRANCE HADRON objectives • To optimize technical means and procedure for hadrontherapy • To federate and organize national research • To build new research beam lines for protons and carbon ions • To fund beam time and beam line access for research 37 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

France Hadron scientific project

IC – CPO involvement in France Hadron consortium ü IC – CPO as irradiation platform: • 300 hours/year for experiences with external users • Dedicated proton experimental room at the IC – CPO • Dedicated room for the users • Commissioning of 200 Me. V proton beam in the ophthalmic treatment room to make experiences even without the dedicated room 39 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

IC – CPO involvement in France Hadron consortium ü First experiences in the frame of France Hadron • 2013 (200 Me. V): collaboration with CNRS – centre d’Imagerie et Modélisation en Neurobiologie et Cancérologie (IMNC) – et l’Institut des sciences moléculaires d’Orsay (ISMO) • Project: investigations on the enhancement of therapeutic index in proton therapy by using nanoparticles • Irradiations in vitro et in vivo 40 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

IC – CPO programs conclusions ü Clinical: increase the activity, enhance its quality and diversify the localisations • Improving the patient workflow • Reliability of the system as high as possible • PBS treatments üResearch: • Involvement in France Hadron • Support for the radiobiology platform of the Institut Curie • Continuity of the collaboration with universities, national research institutes, and industrial companies 41 - A. Patriarca, Institut Curie – CPO and France programs, 17 - 18 December, Fondazione CNAO

Hadrontherapy France 2012 Orleans Neutrontherapy 1980 -1991: 2000 pats Orsay Protontherapy LE&HE 1991 - … 5949 pats Nice Neutrontherapy 1993 -1995: 60 pats Protontherapy LE 1991 - … ~ 4692 pats Lyon Protons + Carbon ? 201 X? Caen Protons + R&D C ? 201 X? Announced in meeting Toulouse Protontherapy 201 X?

THANK YOU FOR YOUR ATTENTION http: //protontherapie. curie. fr/ 43 – A. Patriarca, Institut– CPO and France programs, 17 - 18 December, Fondazione CNAO