Gli Aspetti Tecnologici dell Adroterapia

Gli Aspetti Tecnologici dell Adroterapia Parte 1 Sandro Rossi Fondazione CNAO Corso teorico-pratico sull adroterapia: l alta tecnologia applicata alla clinica CNAO, Pavia, 17-18 Maggio 2013

Introduzione: il razionale dell adroterapia Stato dell arte: il Centro Nazionale di Adroterapia Oncologica Panoramica: la tecnologia e attività di R&S

Adroterapia consente di trattare casi difficili PRECISIONE Tumori vicini ad organi critici EFFICACIA Tumori radioresistenti, che non rispondono alla radioterapia convenzionale

Precisione dell adroterapia Posizione del tumore Direzione del fascio di radiazioni nella materia

Adroni: irraggiamento conforme Larghezza del tumore 5

Adroni: irraggiamento conforme Raggi-X (IMRT) 9 campi Protoni 1 campo

Ioni Carbonio: efficacia biologica 4 3 RBE 2 1 1 10 100 LET 10 20 kev/µm = 100 200 MeV/cm = 20 40 ev/(2 nm) (M. Belli et al.) Ridotta dipendenza da presenza di ossigeno 7

Patologie trattate con ioni carbonio al NIRS di Chiba

Numero di potenziali pazienti (Commissione Ministero della Salute Anno 2009) Terapia con Raggi-X (fotoni di 5 20 MeV) In Italia: 120'000 pz/anno Protonterapia Categoria A: pazienti elettivi = 1'000 pz/anno Categoria B: probabili vantaggi = 12'000 pz/anno Terapia con ioni carbonio % tumori radioresistenti 1'500 pz/anno Si giustifica il CNAO (ca. 2000 paz/anno) e in prospettiva altri centri per protoni

Prevista dal Ministero della Salute Art. 92 della Legge 23 dicembre 2000, n. 388 Insediata il 21 Novembre 2001

Oggi al CNAO lavorano 90 persone 48% L età media 45% femmine 55% maschi Ingressi di personale nel triennio 2010-2012

IL CNAO ESEMPIO DI SISTEMA LA RETE DI COLLABORAZIONI NAZIONALI Fondazione TERA: progetto definitivo, specifiche alta tecnologia, ricerca INFN: co-direzione AT, > 15 task tecnici, ricerca e formazione Università di Milano: coordinamento medico e formazione Università di Pavia: task tecnici, radiobiologia e formazione Università di Catania: fisica medica Università del Piemonte Orientale: attività mediche Politecnico di Milano: posizionamento paziente, radioprotezione Istituto Europeo di Oncologia: attività mediche, autorizzazioni Fondazione Ospedale San Matteo di Pavia: attività mediche, logistica Comune di Pavia: terreno e autorizzazioni Provincia di Pavia: viabilità e autorizzazioni

IL CNAO ESEMPIO DI SISTEMA LA RETE DI COLLABORAZIONI INTERNAZIONALI CERN (Geneva): task tecnici, progetto PIMMS GSI (Darmstadt): linac e componenti speciali LPSC (Grenoble): ottica, betatrone, low-level RF, sistema di controllo Med-Austron (Vienna): collaborazione tecnica per il centro MA Roffo Institute (Buenos Aires): attività mediche NIRS (Chiba): attività mediche, radiobiologia, formazione HIT (Heidelberg): attività di ricerca

Le fasi del CNAO Fase 0: organizzazione Anni: 2002-2004 Fase 1: costruzione Anni : 2005-2009

Giugno 2005

7 Novembre 2005 La costruzione del CNAO è terminata a fine 2009 19 Novembre 2009 16

Le aree del CNAO Espansione per gantry: spazio sufficiente per contenere due gantry simil-hit meeting rooms conference room Centrale elettrica (132 kv --> 15 kv) (2 x 20 MVA) library Circa 3500 mq Futuro Bld. della ricerca: circa 2000 mq direction offices

Il sincrotrone per protoni e ioni carbonio

Hospital based: safety, efficiency, reliability, maintainability Linac Ion Sources Synchrotron High Energy Transfer Lines Treatment Rooms

Starting point THE PATIENT Hospital based: safety, efficiency, reliability, maintainability 1 Beam particle species p, He 2+, Li 3+, Be 4+, B 5+, C 6+, O 8+ 2 Beam particle switching time 10 min 3 Beam range 1.0 g/cm 2 to 27 g/cm 2 in one treatment room 3.1 g/cm 2 to 27 g/cm 2 in two treatment rooms Up to 20 g/cm 2 for O 8+ ions 4 Bragg peak modulation steps 0.1 g/cm 2 5 Range adjustment 0.1 g/cm 2 6 Adjustment/modulation accuracy ± 0.025 g/cm 2 7 Average dose rate 2 Gy/min (for treatment volumes of 1000 cm 3 ) 8 Delivery dose precision ± 2.5% 9 Beam axis height (above floor) 150 cm (head and neck beam line) 120 cm (elsewhere) 10 Beam size 1 4 to 10 mm FWHM for each direction independently 11 Beam size step 1 1 mm 12 Beam size accuracy 1 ± 0.25 mm 13 Beam position step 1 0.8 mm 14 Beam position accuracy 1 ± 0.2 mm 15 Field size 1 5 mm to 34 mm (diameter for ocular treatments) 2 2 cm 2 to 20 20 cm 2 (for H and V fixed beams) 16 Field position accuracy 1 ± 0.5 mm 17 Field dimensions step 1 1 mm 18 Field size accuracy 1 ± 0.5 mm (Basic specifications of CNAO facility)

(Cortesia di GSI) Tecnica di irraggiamento sistema attivo 4 (Cortesia Aprile 2008 di Siemens Medical)

Le fasi del CNAO Fase 0: organizzazione Anni: 2002-2004 Fase 1: costruzione Anni : 2005-2009 Fase 2: sperimentazione Anni: 2010-2013 Fase 3: funzionamento Anni : 2014

Certificazione di qualità: ISO 9001 e ISO 13485

Dosimetry and Radiobiology Preventive intercomparison CNAO vs INT-MI with X-rays (linac 6 MV, 2 Gy): difference < 0.1% (in collaborazione con gruppi radiobio INFN) (16 energie) Field10x10 cm 2, 33x33 spots, scanning step 3 mm

Results Survival curves of cells crypts in 3 SOBP positions Facility Cobalt-60 γ rays Beam D 10 (Gy) position --- 14.86±0.08(*) Variance D 10 RBE 10 Variance (%) NIRS Proximal 10.38 (+) 1.44 (*) Middle 9.46(+) 1.57(*) Distal 8.29(+) 1.80(*) GSI Proximal 10.21(+) 1.47(*) Middle 9.40(+) 1.63(*) Distal 8.37(+) 1.80(*) CNAO Proximal 9.85 5.1 % NIRS 3.5% GSI 1.51 4.7% NIRS 2.7 % GSI Middle 9.75 3.1% NIRS 1.52 3.18% NIRS 3.7% GSI Distal 8.5 2.5% NIRS 1.5% GSI 6.7% GSI 1.75 2.78% NIRS 2.78% GSI Carbon beam at CNAO is biologically identical to the ones in NIRS and GSI (difference in RBE < 7%)

PROTONI 22 Settembre 2011: il trattamento del primo paziente

13 Novembre 2012: 1 paziente con ioni Carbonio al CNAO Recidiva locale di carcinoma adenoideo cistico 12 frazioni da 4.1 GyE, 4 frazioni a settimana, 49.2 GyE totali. Boost di ulteriori 4 frazioni da valutare in base a tolleranza. 3 campi in IMPT

Provenienza geografica pazienti arruolati Ioni Carbonio Protoni Abruzzo 1 Basilicata 1 Calabria 1 1 Campania 2 Emilia Romagna 3 4 Lazio 6 Liguria 2 4 Lombardia 7 12 Marche 2 Piemonte 1 7 Puglia 1 6 Sardegna 1 Sicilia 1 2 Toscana 3 6 Veneto 3 3 Totale complessivo 22 58 12 11 10 9 8 7 6 5 4 3 2 1 0 Ioni Carbonio Protoni

La fase di funzionamento I trattamenti saranno effettuati nell ambito del Sistema Sanitario Nazionale e una rete consentirà il reclutamento efficiente dei pazienti A regime il CNAO arriverà a trattare circa 2000 pazienti per anno Una sala sperimentale sarà realizzata al CNAO e tempo fascio sarà dedicato ad attività di ricerca clinica, radiobiologica e traslazionale

European Network for LIGht ion Hadron Therapy

Expansion and Research spaces integrated in facility layout Extra space to host 2 C-gantries Laboratories and research spaces Experimental Room Project of research beamline ready fall 2013 Beam line devoted to clinical, radiobiology and physics research (collaboration with INFN) (Partial underground level of CNAO)

Panoramica Tecnologia e attività di R&S: Accelerators Technology Dose Delivery Systems Gantry for carbon ions Patient positioning and dose verification Imaging and software ACKNOWLEDGMENTS: U. AMALDI (Useful ref.: U. Linz Ed., Ion Beam Therapy, Springer 2011 and refs therein)

Loma Linda University Medical Center: first patient 1992 First hospital based protontherapy centre (1992) 2009:160 sessions/d 7m synchrotron Optivus Ltd. commercialises this centre

Protontherapy is booming 45,000 40,000 40,000 patients > 84 000 patients 45 40 35,000 30,000 25,000 20,000 22 PT centers 35 33 centres (+16 planned) 30 25 20 15,000 15 10,000 Research centres 10 5,000 Hospitals 5 0 1950 1960 1970 1980 1990 2000 2010 0 Carbon Ions: > 9000 patients; 6 centres (+2 planned)

IBA Protontherapy: a market exists Hitachi Mitsubishi Varian EPAC - 30 June 2006 37

Coming up: Single room facility 250 MeV synchrocyclotron rotating around the patient MEVION S250 Superconducting SC Diameter 1.8 m

HIMAC Heavy Ion Medical Accelerator in Chiba (First patient in 1995) Expansion in 2010 Carbon Ion facilities 2 synchrotrons 800 MeV/u, therapy and nuclear physics Superconducting gantry Japan: Hyogo + Gunma (China Lanzhou 2013+Shangai 2014)

HIT - Heidelberg First patient: end 2009 So far about 1.000 patients Ion- Sources Synchrotron High Energy Beam Transport Line Quality Assurance LINAC Gantry Treatment halls by Siemens Medical

Med-Austron (based on CNAO/INFN design + DDS) 3 ion sources for phase 1 (one additional source possible) Pre-accelerator RFQ & IH Linac Main accelerator synchrotron (77 m circ.) CNAO/CERN/PIMMS design Extraction line Irradiation rooms: research: horizontal, medical: horizontal & vertical, horizontal, proton-gantry

New medical accelerators (?): IBA Superconducting cyclotron 700 tons

New medical accelerators (?): FFAG + Simplicity of fixed field (original idea dates back to 1950 s) + Potential for fast (ms) variable energy + Rapid cycling (200 Hz, repainting) - High intensities - Multistage accelerators - Complicated magnets - Complicated RF cavity - Dense lattice (ext. diff.) Only existing reasearch facility: KURRY 150 MeV proton scaling FFAG

New medical accelerators (?): BNL fast cycling synchrotron (first publication 1999 s, S. Peggs et al.) Injection linac at 8 MeV/u Racetrack, FODO in the arcs, D=0 ss Fast inj+extr, C = 60 m (from D. Trbojevic et al. IPAC2011) 30 Hz repetition rate (repainting?) Fast energy change

New medical accelerators (?): TERA cyclinac for C-ions 150 MeV/u Linac for Image Guided Hadron THerapy LIGHT 150-400 MeV/u CABOTO = CArbon BOoster for Therapy in Oncology 400 MeV/u Source Cyclotron Linac RF power system EBIS - SC K 600 - SC 200 tons CCL @ 5.7 GHz 16 modules 16 Klystrons (P peak = 12 MW) 300 Hz Energy is adjusted in 2 ms in the full range by changing the power pulses sent to the accelerating modules Charge in the spot is adjusted every 2 ms with the computer controlled source

Technology status and R&D: Panoramica Accelerators Technology Dose Delivery Systems Gantry for carbon ions Patient positioning and dose verification Imaging and software

Methods for imparting the dose with carbon ions: layer stacking (NIRS+Japan) Wobbling and multileaf collimator adapted to transverse shape of each slice (energy changed with synchrotron and range shifter) Conformation, components activation, secondary neutrons

Methods for imparting the dose with carbon ions: active scanning: raster scanning à la GSI (HIT+CNAO) The synchrotron beam is moved continuously Energy changed with the synchrotron NIRS decided recently to adopt the active scanning

Improvements: beam extraction optimization Extracted beam Ripples Beam Transverse beam size Resonance lines x, p/p, Q h High-density, slow -moving Low-density, fast moving Slow extraction Intensity dinamic range: 1000 FWHM = 4-10 mm Intensity ripple ( I/I) ± 20% at 2 khz (extraction with a betatron core - PIMMS) Bucket channeling 0 V 50 ms

Improvements: On-line imaging Minimal choice: breathing synchronisation (already applied in Chiba and HIT) External surrogates with correlation models X-rays Ultrasound, MRI Particle radiography Interesting also for IMRT: lots of efforts and devices (Review in Riboldi et al, Lancet Oncology 2012) (Courtesy of Medical Intelligence)

Improvements: tumour tracking with active scanning GSI approach p +1 or C +6 Tranverse variation Energy variation 4D

Monitoring system (CNAO) Double system of ICs: (integral, stripx,y) (integral, pixel) Two measures: Intensity, Position, Profile Redout frequency: 1 MHz (integral), 10 khz (strip, pixel) Resolution: 0.1 mm strip, 0.2 mm pixel Area: 20 x 20 cm2 Non uniformity < 1% Short term stability < 0.3% (NIMA 698 (2013) 202-207) Issue: monitoring spots of C-ions at low intensity

Comparison of dimensions GSI carbon ion gantry PSI proton gantry (Courtesy M. Pullia)

Heidelberg ion gantry: unique in the World! First patient October 19 th, 2012 (Courtesy T. Haberer) Main Parameters Diameter [m] 13 Length [m] 25 Overall weight [t] 600 Maximum power [kw] 600 Rotational weight [t] 420 Maximum allowed deformation [mm] 0,5

HIMAC superconducting gantry is in construction Combined function magnets: bending and focusing (BM1 ~ BM6) Scanning magnets at the middle point (Courtesy T. Murakami) Combined function magnets (BM9 ~ BM10) -> square irradiation field -> parallel beams Bmax = 2.88 T Gmax = 9.0 T/m B and G changing vs cycle

Novel gantry for carbon ions The ULICE WP6 collaboration realized a conceptual design of a mobile isocenter gantry, Rationale for the choice Innovative layout Cheaper and simplified mechanical structure Less magnets in the gantry line Total weight reduced as well as deformations Well known magnet technology Layout scalable to SC magnets

Project in progress by CEA (France) in collaboration with IBA 12.2 tons B = 5 tesla 90 magnet following a design by INFN-Genoa and TERA Two layer helical wires on a straight cylinder give a dipole field (S. Caspi et al.) Project in progress at LBL - Berkeley ISSUES: field quality for scanning beams; changing fields (energy) for active scanning

High precision devices for patient positioning (Treatment room #1 at CNAO)

3D Real-time IR Optical Tracking (OTS) Real time reconstruction of spherical markers and surfaces Sub-millimeter accuracy : peak 3D errors <0.5 mm 3D data flow @70 Hz X-ray Patient Verification System (PVS) 2 X-ray tubes (deployable), 2 flat panels (deployable) Supporting structure rotation: ±180 Rotation and deployment accuracy: ± 0.15mm, ± 0.1 Patient Positioning System (PPS) Automatic couch or chair docking Absolute accuracy: 0.3 mm Cone beam CT CT on rails Markers, low density fixation materials

Projectile Pre-collision Post-collision 12 C 11 C Dose visualisation: in beam PET Projectile fragment Atomic nucleus of tissue 16 O 15 O Neutron Target fragment D ose [kgy] 6 Dose 4 2 0 ] Counts [10 3 5 0 Activity β + 0 50 100 150 200 Depth [mm] Courtesy of GSI ISSUES: low statistics; blood flow dilution; off-line PET logistics

Proton Range Radiography (PRR) Secondaries emission and reconstruction Electronic telescope for the measure of position and residual range of protons; it gives the density map of the traversed volumes; it permits to check in real time the treatment planning assumptions on position and dimensions of the traversed tissues and organs. Nuclear Scattering Tomography (NST) Three-dimensional map of the tissues densities obtained by vertex reconstruction of high energy protons interactions (> 600 MeV). Interaction Vertex Imaging (IVI) Density of interaction vertex reconstruction gives information on the Bragg peak position. (U. Amaldi et al.) PROMPT radiation (Gamma) - Enlight

1(+1) CT Medical Imaging rooms Advanced Medical Imaging Modalities (fusion sw) 1 MR (3T) room 1(+1) CT-PET rooms CNAO Surface Level NIRS - 30th November 2007 Advanced 3D molecular imaging modalities tumour molecular profiling dose painting with different LET ions ( sources and accelerators choices) (O. Jäkel, in IBT, Springer2011)

Treatment Planning System TPS is directly related to scanning modality and RBE evaluation model Need to include management of moving organs and integration of in-room imaging (TPS used at CNAO)

Oncological Information System Siemens TPS Imaging Modalities (CT, MR, CT-PET)) DICOM DICOM RT Ion PT Archive (Short-term) DICOM RT Ion DICOM RT Ion DICOM PACS Long Term Storage PPS-PVS Elekta MOSAIQ V 2.0 DICOM RT Ion DOP OIS Management of patients data in multiple rooms: patient throughput Networking with hospitals and clinics: patient recruitment R&V DTMI CNAO Synchrotron Control System and Dose Delivery System

Conclusioni I centri di protonterapia sono centri commerciali (e single room solutions sono in arrivo). Non si può dire altrettanto dei centri con ioni carbonio. Gli sviluppi della tecnologia in adroterapia non si limitano al settore degli acceleratori, ma investono uno spettro molto ampio di sistemi: alcuni più urgenti di altri. Collaborazioni, confronti, rete sono parole chiave per il successo dell adroterapia e sono utili per stabilirne l evidenza clinica (l aumento del numero di pazienti trattati è un fattore importante).

GRAZIE PER L ATTENZIONE