Protonterapia e applicazione clinica

Protonterapia e applicazione clinica

Hadrons since 1993. Hadrontherapy elettrons e Alternatives: hadrons are made by quarks Atom heavy particles radiotherapy particle therapy... Carbon neutrontherapy, ions = 6 protons + 6 neutrons protontherapy CIRT (Carbon... Protons Ionor RT),. Neutrons quark u or d

Electrons (X-rays): Carbon ion is 12 2000 times heavier than electron Nucleo più semplice: il protone p n Nucleus of Carbon made of 6 protons (p) and 6 neutrons (n) Simplest nucleus: the proton (p) Proton is 2000 times heavier than electron

Hadron Therapy electron negative ions proton neutron Helium Carbon Neon Boron Argon Oxigen X-rays General Radiation From Lighter to Heavier Particles

Protons First hospital-based protontherapy centre Proposed by R.Wilson in 1946 (Radiology, 1946) Years 50: first patients treated in First patient: 1992 Uppsala and Berkeley (Sweet W RS, NEJM, 1951) Years 70: first patients treated in Russia and Japan 7m synchrotron In 1990 the first clinical centre at Loma Linda University (CA)

Carbon Ions First patients treated in 1975 at Bevalac, Berkeley, CA, even ion properties were well know since the beginning of years 50 2000 patients treated with helium ions and 500 with neon ions in 20 years (Sweet W RS, NEJM, 1951) Since 1994 in Japan the first patient treated with carbon ions

Durante M, Orecchia R, Loeffler JS, 2017 60 Proton Centres 10 Carbon ion Centres Hadrontherapy Therapy Centres

1954-2015 Protons: 131240 C-ions: 19376 Others. Grand Total 154203

Europe 17 Particle Therapy facilities Six centers under construction: Belgium: 1 Denmark: 1 France:1 Netherland: 2 Slovak: 1 UK: 3 Seven centers in a planning stage: Belgium: 1 Italy: 1 Netherland: 2 Slovak: 1 Spain: 1 Switzerland: 2 Union of Light Ion Centres in Europe Sweden: 1 Uppsala Germany: 6 Heidelberg UK: 1 Berlin Russia Clatterbridge Munich Poland: 1 Essen Krakow Dresden Marburg Czech Rep. Czech: 1 France: 2 Slovakia Switzerland: 1 Prague Nice Villingen Orsay Austria: 1 Wiener Neustadt Italy: 3 Pavia Trento Catania The ULICE project is co-funded by the European Commission under FP7 Grant Agreement Number 228436.

Hadrontherapy at HIT (Heidelberg) > 250 million Euro

Single room facilities for protontherapy www.cnao.it MEVION S250 Superconducting SC Varian Probeam Superconducting SC 20-25 million Euro ProTom Radiance 330 Synchrotron IBA Proteus One Superconducting SC

Numbers of Cancers and Radiotherapy 7.0 million treated by radiotherapy - Alone or Combined - with surgery - with drugs - with both Atun R et al, Lancet Oncol 2016

Who?

Main Goal: OARs Sparing Carotid artery Rectum, Bowel, Nerve roots Optic nerve Mandibular bone Brain Stem

Comparison of dose distribution between IMRT and IMPT in T4N0 OPSCC Gregoire V et al, JC0 2015

Constrictor muscles sparing Swallowing muscles dosevolume parameters are strongly related with chronic RAD (Radiation Associated Dysphagia) Alterio D, R.Orecchia. Contouring of the Pharyngeal Superior Constrictor Muscle (PSMC). A cooperative study of the Italian Association of Radiation Oncology (AIRO) Head and Neck Group. Radiother Oncol 2014

Cervical spine osteosarcoma Before A 64 GyE/16 fx/4 weeks Patch technique CIRT at NIRS 7 years after (Imai, Lancet Oncology 2006)

UVEAL MELANOMA More than 12,000 patients treated 5-y LC rate > 95% (MGH/HCL Boston, PSI Villingen, Nice & Orsay, Clatterbridge, ) Eye preservation 90% Visual acuity >45%

Helium ions vs iodine125 plaque Brachytherapy Metanalysis (Wang Z et al, IJROBP 2013) Improved LC He 100% and 98%, BRT 84% and 79% at 5- and 12-y Improved DFS No difference in OS Protontherapy vs Brachytherapy Lower recurrence rate (OR=0.22)

PT in Skull Base Chordomas and Chondrosarcomas Hug et al, 1999 N. pts LLUMC 58 C (33) CS (25) Type RT GTV Dose, mean (Geq) X+p (9%): 0 to 15 ml (12%): >15 to 25 ml (79%): >25 Ml 71.9 (66.6-79.2) % LC 3 yrs: 67 (C) 5 yrs: 59 5 yrs: 79 (CS) F-up (Month s) 33 (7-75) 29 Munzenrider MGH 0 et al, 1999 5-y Local Control CS Igaki et al, 2004 Noel et al, 2005 Noel et al, 2004 22 9 Tsukuba 13 C X+p (5) only (8) C X+p NA 72 (70 75.6) Chordoma 59-81% Chondrosarcoma 79-98% Ares C et al, 2009 CPO 10 0 C X+p 23 cm3 (1-125 cm3) 33.7 ml (3.3 88.4) Median 72.0 (63.0-95.0) Median 67.0 (60.0-71.0) CPO 26 Cs X+p NA Median 67.0 (22-70) PSI 42 C (42) CS (22) p 25 ml n=24 (C), n= 15 (CS) 73.5 for C (67-74) 5 yrs: 73 (C) 5 yrs: 98 (CS) 3 yrs: 67.1 (C) 5 yrs: 46.0 2 yrs: 86 (C) 4 yrs: 53 41 (1-254 ) 69.3 (14.6-123.4) 31 (0-87) 3 yrs: 91 (CS) 34 (3-74) 3yrs: 87 5yrs: 81 (C) 38 (14-92) > 25 ml n=18 (C), n= 7 (CS) 68.4 for CS (63-74) 3 yrs: 94 (CS) 5 yrs: 94

Protons in pediatric tumors Reduction of radiationinduced risk for second cancer X-ray IMRT Proton CTV Protons 90% 90% 90% Heart 18.2 17.4 0.1 Right lung 3.5 21.9 0.1 Esophagus 11.9 32.1 10.2 Stomach 3.7 20.6 0.1 Photons Right kidney 3.3 29.8 0.1 Transvers colon 2.6 18.0 0.1

Radiation-induced large vessel cerebral vasculopathy Kralik SF et al, IJROBP 2017

Hadrontherapy: the clinical evidence Rare Diseases established indications 70 s 80 s 90 s

Italian Model - LEA in NHS 1. Chordoma & chondrosarcoma base/spine 2. Meningiomas 3. Brain tumors (trunk) 4. ACC Salivary Glands 5. Orbit tumors including eye melanoma 6. Sinonasal carcinoma 7. Soft Tissue & bone Sarcoma (every sites) 8. Recurrent tumors (retreatment) 9. Patients with immulogical desorders 34 10. Pediatric solid tumors 2017

Hadrontherapy- LEA in NHS Conditions for prescription Patients with a tumor as listed, without metastases, PS ECOG: 0-2, absence of concomitant disease or comorbobity at risk to significant decrease of life expentancy Reimbursement 1. Full cycle (24,000 E) 2. Boost (up to 6 fractions) (12,000 E) 3. Stereotactic treatment (1 to 3 fractions) (18,000 E)

Profile of European centers (EORTC) N. of centers % of centers Chordoma/chondrosarcoma 11 100 Sarcoma 11 100 Meningioma 11 100 Brain tumors (non M) 11 100 Head&Neck 8 73 Prostate 7 64 Uveal melanoma 6 40 Breast 2 18 Others 4 36 Weber DC, Orecchia R,. et al, Radiother Oncol 2017

Prostate. 1982-1995, T3-T4, 67.2 Gy vs 75.6 Gy MGH Boston Shipley, IJROBP, 1995 I I I I I I I First (and only) Phase III randomized trial

Prostate. Protontherapy More than 2500 patients early, intermediate and high risk Range of dose: from 67.2 to 82 GyE BFFS at 5 years: from 76 to 99% BFFS at 10 years: from 68 to 83% Shipley, 1979; Slater, 2004; Zietman, 2005; Mayahara, 2007; Nihei, 2010; Coen, 2010; Mendenhall, 2014

Prostate. Protontherapy Acute Toxicity GU Grade 3 : < 2% GI Grade 3 : < 1% Late Toxicity GU Grade 3 : < 5% GI Grade 3 : < 2% Shipley, 1979; Slater, 2004; Zietman, 2005; Mayahara, 2007; Nihei, 2010; Coen, 2010; Mendenhall, 2014

2012 3D-CRT 40.4% 2D-,BRT 36.0% IMRT 21.9% SBRT 1.1% PBRT 0.6% in a population of more than 100 million patients.. (Waddle MR et al, IJROBP 2017)

The utilization rate for PBRT was extremely low compared with that of conventional RT The number of pediatric patients accounted for only 9.7% of the overall treatments, as opposed to the number of adults with prostate cancer, which represented 55.4% of the overall treatments IMRT had a 10-fold increase for all patients, and a 18-fold increase for prostate cancer In the current enviroment the use of PBRT has likely had little impact on national expenditures on cancer care, but as the number of facilities continues to rise, utilization rates are to change in a population of more than 100 million patients.. (Waddle MR et al, IJROBP 2017)

Lung cancer Evidence from study in patients with NSCLC is only advantegeous over EBRT for certain patients Respiratory motion is a major problem when delivering CPT, and expecially IMPT Mohan R, Grosshans D, Adv Drug Deliv Rev 2017

Phase I/II study T1-T3N0 medically inoperable 5-y LR free: 85.0% 5-y RR free: 89.2% Pneumonitis G2: 11.4% G3: 2.9% Chang JY, Radiother Oncol 2017

PTCOG Subcommitte. Consensus PBT and concurrent guidelines CT for Phase II study implementing pencilbeam canning Proton Unresectable Stage III 5-y PFS: 22.0% 5-y therapy LRR free: 72.0% for thoracic malignancies Pneumonitis G2: 16.0% G3: 12.0% Esophagitis Chang JY G4 et 2% al, IJROBP 2017 Chang JY, JAMA Oncol 2017

Lung cancer Durante M, Orecchia R, Loeffler JS, 2017

P+ ongoing randomized trials Study Institution Condition R03CA188162 IMPT versus IMRT NCT01617161 P+ versus IMRT NCT01512589 IMPT versus IMRT RADCOMP (NCT02603341) P+ versus X-rays NRG 1542 P+ versus SBRT MDACC Houston MGH Boston MDACC Houston Penn University NRG Oncology Oropharynx Low Risk & Intermediate Risk prostate Oesophagus PMRT stage II-III breast Hepatocellular

Hepatocellular carcinoma A systematic review 13 cohorts One randomized trial (PBT vs TACE) 9 phase I/II trials 2 retrospective studies 3-y LC rates: 71.4-95% 5-y OS 25-42.3% Late G3/4 toxicities 18/787 patients (<2%) Igaki H et al, Int J Clin Oncol 2017 Yearly number of patients treated in Japan A) PBT; B) CIRT gray (liver); other sites (black)

SBRT/Proton based liver mets MGH/Boston Phase II study Importance of tumor genotype Hystology Size Hong TS et al, J Natl cancer Inst 2017)

Breast cancer. Protontherapy Lomax AJ et al (Villigen & Geneva, Switzerland). Potential role of intensity-modulated photons and protons in the treatment of the breast and regional nodes. IJROBP, 55: 785, 2003 X-e P+ X-e P+ Partial Breast Irradiation Locoregional IMRT 1 IMRT 2 IMRT 1 Irradiation IMRT 2 Left Breast Irradiation Orecchia R et al, Curr Opinion Oncol 2015 only the 2-field, energy-modulated proton plan had the potential to preserve target dose homogeneity while simultaneously minimizing the dose delivered to both lungs, heart, and the contralateral breast

Durante M, Orecchia R, Loeffler JS, 2017

http://folder.cnao.it Experimental Phase www.cnao.it CNAO in Pavia dual center active scanning Protons /Carbon Ions 133 patients up to serviziomedico@cnao.it December 2013 1 2 3 4 experimental room (2017) in room 3D imaging Clinical Phase (National Health System) Started since January 2014 Synchrotron P-C 400 mev/u

C-12 ongoing randomized trials Study Institution Condition NCTO1182753 p+ versus C-12 Heidelberg Skull base low- and intermediate-grade chondrosarcoma NCTO1182779 p+ versus C-12 ETOILE NCTO2838602 C-12 versus IMRT BAA-N01CM51007-51 C-12 versus IMRT CIPHER: C-12 versus IMRT (+ CT) Heidelberg Lyon/CNAO /HIT NCI/Shanghai Phase I/III Dallas/NIRS/ CNAO Skull base Chordoma H&N adenoid cystic carcinoma and sarcomas Locally advanced pancreatic cancer Locally advanced pancreatic cancer

Pancreas cancer CTV1 : Main tumor+n2 nodes and plexus 9 fractions, prone position, 2 fields www.cnao.it CTV2 ( Main tumor) 3 fractions, 1 field, rolled position 43.2 Gy RBE in 9 fx 14.4 Gy RBE in 3 fx

In the future, we could use targeted particles exactly as now we are using targeted drugs... Molecular Imaging & Biology driven studies

Grazie!!!!!!