Protonterapia

e

applicazione

clinica

Hadrons

“hadrons are made by quarks”

... Carbon ions =

6 protons + 6 neutrons

Atom

... Protons or

Neutrons

quark “u” or “d”

elettrons “e”

since 1993 …….

Hadrontherapy

Alternatives:

heavy particles radiotherapy

particle therapy

neutrontherapy,

protontherapy

CIRT (Carbon Ion RT),

….

Nucleo più

semplice:

il protone

Electrons

(X-rays):

Simplest nucleus:

the proton (p)

Nucleus of Carbon

made of 6 protons (p)

and 6 neutrons (n)

p

Proton is 2000 times heavier than electron

Carbon ion

is 12×2000

times heavier

than electron

n

Hadron Therapy

X-rays

electron

negative

ionsproton

neutronHelium Carbon ArgonBoronNeon

General RadiationFrom Lighter to Heavier Particles

Oxigen

Protons

Proposed by R.Wilson in 1946 (Radiology, 1946)

Years ’50: first patients treated in Uppsala and Berkeley (Sweet W RS, NEJM, 1951)

Years ’70: first patients treated in Russia and Japan

In 1990 the first clinical centre at LomaLinda University (CA)

• First hospital-based proton-

therapy centre

• First patient: 1992

7m synchrotron

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 ionsand 500 with neon ions in 20 years (Sweet

W RS, NEJM, 1951)

Since 1994 in Japan the first patienttreated with carbon ions

Hadrontherapy Therapy Centres

Durante M, Orecchia R, Loeffler JS, 2017

60 Proton Centres

10 Carbon ion Centres

1954-2015

Protons: 131240

C-ions: 19376

Others …….

Grand Total 154203

Union of Light Ion Centres in Europe

The ULICE project is co-funded by the European Commission under FP7

Grant Agreement Number 228436.

Six centers

under construction:

Belgium: 1

Denmark: 1

France:1

Netherland: 2

Slovak: 1

UK: 3

Slovakia

Czech Rep.

Russia

Europe

17 Particle Therapy facilities

Italy: 3

Pavia

Trento

Catania

Germany: 6

Heidelberg

Berlin

Munich

Essen

Dresden

Marburg

UK: 1

Clatterbridge

Czech: 1

Prague

Poland: 1

Krakow

France: 2

Nice

Orsay

Sweden: 1

Uppsala

Switzerland: 1

Villingen Austria: 1

Wiener Neustadt

Seven centers in

a planning stage:

Belgium: 1

Italy: 1

Netherland: 2

Slovak: 1

Spain: 1

Switzerland: 2

Hadrontherapy at HIT (Heidelberg)

> 250 million Euro

www.cnao.it

Single room facilities for protontherapy

IBA – Proteus One

Superconducting SC

MEVION S250

Superconducting SC

Varian – Probeam

Superconducting SC

ProTom – Radiance 330

Synchrotron

20-25 million Euro

Numbers of Cancers and Radiotherapy

Atun R et al, Lancet Oncol 2016

7.0 million treated

by radiotherapy

- Alone or Combined

- with surgery

- with drugs

- with both

Who?

Main Goal: OARs Sparing

Carotid artery

Optic nerve

Mandibular bone

Brain Stem

Rectum, Bowel,

Nerve roots

Comparison of dose distribution between IMRT and IMPT in T4N0 OPSCC

Gregoire V et al, JC0 2015

Constrictor muscles sparing

Swallowing muscles dose-volume 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

A

Cervical spine osteosarcoma

Before

64 GyE/16 fx/4

weeks

Patch technique

7 years

after (Imai, Lancet Oncology 2006)

CIRT at NIRS

UVEAL MELANOMA

More than 12,000 patients treated

(MGH/HCL Boston, PSI Villingen, Nice & Orsay,

Clatterbridge, ……………)

5-y LC rate

> 95%

Eye

preservation

90%

Visual acuity

>45%

Helium ions vs

iodine125 plaque

Brachytherapy

• Improved LC

He 100% and 98%,

BRT 84% and 79%

at 5- and 12-y

• Improved DFS

• No difference in OS

Metanalysis

(Wang Z et al, IJROBP 2013)

Protontherapy vs

Brachytherapy

Lower recurrence

rate (OR=0.22)

N.

pts

Type RT GTV Dose ,

mean

(Geq)

% LC

F-up

(Month

s)

Hug et al,

1999

LLUMC 58 C (33)

CS (25)

X+p (9%): 0 to ≤15 mL

(12%): >15 to ≤25 mL

(79%): >25 Ml

71.9

(66.6-79.2)

3 yrs: 67 (C)

5 yrs: 59

33

(7-75)

5 yrs: 79 (CS)

Munzenrider

et al,

1999

MGH

29

0

C X+p NA 72

(70 – 75.6)

5 yrs: 73 (C)

41

(1-254 )

5 yrs: 98 (CS)22

9

CS

Igaki et al,

2004

Tsukuba 13 C X+p

(5)

P

only

(8)

33.7 mL (3.3–88.4) Median

72.0

(63.0 -95.0)

3 yrs: 67.1 (C)

5 yrs: 46.0

69.3

(14.6-

123.4)

Noel et al,

2005

CPO 10

0

C X+p 23 cm3

(1 - 125 cm3)

Median

67.0

(60.0-71.0)

2 yrs: 86 (C)

4 yrs: 53

31

(0-87)

Noel et al,

2004

CPO 26 Cs X+p NA Median

67.0

(22-70)

3 yrs: 91 (CS) 34

(3-74)

Ares C et al,

2009

PSI 42 C (42)

CS (22)

p ≤25 mL

n=24 (C) , n= 15 (CS)

> 25 mL

n=18 (C) , n= 7 (CS)

73.5 for C

(67-74)

3yrs: 87 (C)

5yrs: 81

38

(14-92)

68.4 for CS

(63-74)

3 yrs: 94 (CS)

5 yrs: 94

PT in Skull Base Chordomas and Chondrosarcomas

5-y Local Control

Chordoma 59-81%

Chondrosarcoma 79-98%

Protons in pediatric tumors

Protons

Photons

X-ray IMRT Proton

CTV 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

Right kidney 3.3 29.8 0.1

Transvers colon 2.6 18.0 0.1

Reduction of

radiation-

induced risk

for second

cancer

Kralik SF et al, IJROBP 2017

Radiation-inducedlarge vessel

cerebralvasculopathy

70‘s

80‘s

90‘s

Hadrontherapy:„the clinical evidence“

“Rare Diseases” –

“established indications”

34

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

10. Pediatric solid tumors2017

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 36Weber DC, … Orecchia R,…. et al, Radiother Oncol 2017

Prostate. 1982-1995, T3-T4, 67.2 Gy vs 75.6 Gy

Shipley, IJROBP, 1995

MGH

Boston

First (and only) Phase III

randomized trial

I

I

I

I

I

I

I

Prostate. Protontherapy

More than 2500 patientsearly, 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

… in a population of more than 100 million

patients….. (Waddle MR et al, IJROBP 2017)

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 wasextremely low compared with that

of conventional RT

The number of pediatric patientsaccounted 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 allpatients, 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

Lung cancer

Mohan R, Grosshans D, Adv Drug Deliv Rev 2017

• 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

Phase I/II study T1-T3N0 medically inoperable

5-y LR free: 85.0%5-y RR free: 89.2%

PneumonitisG2: 11.4%G3: 2.9%

Chang JY, Radiother Oncol 2017

PBT and concurrent CTPhase II study

Unresectable Stage III

5-y PFS: 22.0%5-y LRR free: 72.0%

PneumonitisG2: 16.0%G3: 12.0%

Esophagitis G4 2%

Chang JY, JAMA Oncol 2017

PTCOG Subcommitte.

Consensus guidelines for

implementing pencil-

beam canning Proton

therapy for thoracic

malignancies

Chang JY et al, IJROBP 2017

Lung cancer

Durante M, Orecchia R, Loeffler JS, 2017

Study Institution Condition

R03CA188162

IMPT versus IMRT MDACC Houston Oropharynx

NCT01617161

P+ versus IMRTMGH Boston Low Risk & Intermediate Risk

prostate

NCT01512589

IMPT versus IMRTMDACC Houston Oesophagus

RADCOMP (NCT02603341)

P+ versus X-rays

Penn University PMRT stage II-III breast

NRG 1542

P+ versus SBRT

NRG Oncology Hepatocellular

P+ ongoing randomized trials

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 toxicities18/787 patients (<2%)

Igaki H et al, Int J Clin Oncol 2017

Hepatocellular carcinoma

Yearly number of patients treated in JapanA) PBT; B) CIRT

gray (liver); other sites (black)

SBRT/Proton based liver mets

MGH/BostonPhase II study

Importance of tumor genotype

MGH/BostonPhase II study

Importance of tumor genotype

HystologySize

Hong TS et al, J Natl cancer Inst 2017)

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

• … 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

X-e X-e

IMRT 1 IMRT 1IMRT 2 IMRT 2

P+ P+

Breast cancer. Protontherapy

Orecchia R et al, Curr Opinion Oncol 2015

Partial BreastIrradiation

LocoregionalIrradiation

Left BreastIrradiation

Durante M, Orecchia R, Loeffler JS, 2017

www.cnao.it

CNAO in Pavia

dual center

active scanning

Protons /Carbon Ions

1

32 4

experimental room (2017)

Synchrotron P-C 400 meV/u

http://folder.cnao.it

serviziomedico@cnao.it

in room 3D imaging

Experimental Phase

133 patients up to

December 2013

Clinical Phase

(National Health System)

Started since January 2014

Study Institution Condition

NCTO1182753

p+ versus C-12 Heidelberg

Skull base low- and

intermediate-grade

chondrosarcoma

NCTO1182779

p+ versus C-12

Heidelberg Skull base Chordoma

ETOILE NCTO2838602

C-12 versus IMRT

Lyon/CNAO

/HIT

H&N adenoid cystic

carcinoma and sarcomas

BAA-N01CM51007-51

C-12 versus IMRTNCI/Shanghai

Phase I/III

Locally advanced

pancreatic cancer

CIPHER: C-12

versus IMRT (+ CT)

Dallas/NIRS/

CNAO

Locally advanced

pancreatic cancer

C-12 ongoing randomized trials

www.cnao.it

CTV1 : Main tumor＋N2 nodes and plexus 9 fractions, prone position, 2 fields

43.2 Gy RBE in 9 fx

CTV2 ( Main tumor)3 fractions, 1 field, rolled position

14.4 Gy RBE in 3 fx

Pancreas cancer

In the future, we could

use targeted particles

exactly as now we are

using targeted drugs .......

Molecular Imaging

& Biology driven

studies

Grazie !!!!!!