19 Novembre 2009

1

Hadrontherapy

An Overiew

Roberto Orecchia

Chair of Radiation Oncology at Milan University

Co-Scientific Director and Chief of Department

of Imaging and Radiological Science at IEO, Milan

Scientific Director at CNAO, Pavia

Jornadas Oncologicas Internationales

Madrid, 5 Junio 2014

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

Alternative:

heavy particles radiotherapy

particle therapy

neutrontherapy,

protontherapy

CIRT (Carbon Ion RT),

….

Protons

• Proposed by 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 Loma Linda University (CA)

• First hospital-based

proton-therapy centre

• First patient: 1992

7m synchrotron

IBA

Mitsubishi

Hitachi

Varian

Protontherapy: a market exists …

Coming up: single room facility

250 MeV synchrocyclotron rotating around the patient

MEVION S250

Superconducting SC

Diameter 1.8 m

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

The Hyogo ‘dual’ Centre

Mitsubishi: turn-key system

500 carbon patients

carbon

proton

29 m

linac

The Gunma University centre

R&D = NIRS + KEK + RIKEN

Construction: Mitsubishi

20 m

Protontherapy is booming

(www.ptcog.psi.ch)

0

5,000

10,000

15,000

20,000

25,000

30,000

35,000

40,000

45,000

1950 1960 1970 1980 1990 2000 2010

0

5

10

15

20

25

30

35

40

4540,000 patients

22 PT centers

Research centres

Hospitals

In the next years there will be about 15 centres opened.

Five will offer both proton and C-ion therapy

Dual System C12/P+:

Heidelberg (D) open

Pavia (I) open

Marburg (D) ????

Med Austron (A) October 2015

Etoile (F) ????

Europe

HIT ad

Heidelberg

Ion-

Sources

LINAC

Synchrotron

Treatment halls by

Siemens Medical

High Energy Beam Transport Line

Quality

Assurance

Gantry

Working Group

2003, 2008, 2009Estimated 15.000 new eligible patients

in Italy for protons

High priority

Chordoma

Chondrosarcoma

Eye Melanoma

Paediatric

solid tumors

Italy

Working Group

2003, 2008, 2009Estimated 7.000 patients with “radioresistant tumors” in

Italy

About 20% of these tumors

should be treated by ions

High priority

Italy

Head&Neck

adenocarcinoma

Soft tissue and bone

sarcomas

Prostate

Liver and Pancreas

CNAO (National Center for Oncological

Hadrontherapy) Syncrotron

P+ (60-250 MeV)

C-12 (400 MeV/n)

42 centres with protons

(USA 14, Europe 12, Japan 8, …..)

6 centres with carbon ions

(Japan 3, Europe 2, China 1)

3 dual centres (p+ C-12)

27 new centres planned

Some numbers …..

(www.ptcog.psi.ch, March 2014)

107,792 treated patients

(93,452 with p+, 10753 with C-12)

+ 46,000 in the past 5 years

≈ 10,000 patients per year

>20,000 treated with neutrons

Some numbers …..

(www.ptcog.psi.ch, March 2014)

Hadron Therapy:

A long debate

EBM ?

Cost ?

Radiosurgery Hadrontherapy

HadrontherapyIMRT

Physical Selectivity

- Inverted depth dose profile (Bragg peak)

- Defined penetration depth

- Less lateral scattering (1H ≠ C12)

- Reduction of integral dose

9 children primary CNS malignancies

Choclea:

average mean of 25 ± 4% of the prescribed dose from PRT; 75 ± 6% from photons

Temporal lobe:

40% of temporal lobe volume was completely excluded using protons; with photons 90% of the temporal lobe received 31% of the dose

Advantage of Protons

X-ray IMRT Proton

CTV 90% 90% 90%

Heart 18.2 17.4 0.1

Right lung 3.5 21.9 0.1

Esophagous 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

Protons in pediatric tumors

Protons

Photons

Integral Dose

3 times higher

for all

photon’s

techniques

Weber DC et al, Radiat Oncol, 2009; 4:34

Reference Institution Pts Histo-

logy

RT GTV Dose , mean

(CGE)

% LC F-up

(Months)

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

290 C X+p NA 72

(70 – 75.6)

5 yrs: 73 (C)

41

(1-254 )

5 yrs: 98 (CS)229 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 100 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%

Zenda S et al, IJROBP, 2011

The potential benefit of radiotherapy with protons in head and neck

cancer with respect to normal tissue sparing: a systematic review of

literature

TA van de Water et al, The Oncologist, 2011, 16: 366-377

Groningen & Maastricht, The Netherlands

• 14 in silico planning comparative (ISPC) studies

• Protons have the potential for a significantly lower normal tissue dose,

while keeping similar or better target coverage

• Probability of reducing >25% salivary flow with IMRT

is 22% , and with IMPT 9%

• Probability of reducing grade 2-4 swallowing dysfunction

is reduced by 8.8% with IMRT, and by 17.2% with IMPT

The results of these ISPC studies should be confirmed in properly designed clinical trials

10 – 20 keV/mm = 100 – 200 MeV/cm =

20 – 40 eV/(2 nm)

Biological Effectiveness (C12)

Up-regulated

oncogenes

Which tumors might

benefit of high LET

particles?

Radioresistant

for genetic alteration

Mutated tumor

suppresor genes

Dis-regulated

apoptosis

Radioresistant

for intratumoral

micromilieau

Deprivation

of oxigen

Up-regulated

defense system

High angiogenetic

potential

Radioresistant

for proliferation status

High content

of quiescent

cell clones

Slow

proliferation

activity

Carbon ion RT at NIRS

5 –year LC rate

Overall 68 %

MMM 75 %

ACC 73 %

Adenoca. 73 %

Papillary 61 %

Adenoca.

SCC 61 %

Sarcomas 24 % (with Max 64 GyE)

Mizoe J et al, Radiother Oncol, 2012

Bone and soft-tissue

sarcoma

70.4 GyE/16f./4 wksPre RT 5 years

Carbon ion RT at NIRS

Jingu K et al IJROBP, 2012

Carbon ion RT at NIRS

Author No. Tumor location Treatment modalities 5-year OS

Gilligan 28 Sinonasal Radiotherapy 18

Shibuya 28 Upper jaw Radiotherapy +/– surgery 25

Shah 74 Head and neck Surgery +/– radiotherapy 22

Chaudhry 41 Head and neck Surgery+/– radiotherapy+/– chemotherapy 17

Lund 58 Sinonasal Surgery+/– postoperative radiotherapy+/

–chemotherapy (BCG, melphalan) 28

Pandey 60 Head and neck Surgery+/– radiotherapy+/– chemotherapy 28*

Chang 163 Head and neck Surgery+/– radiotherapy+/– chemotherapy 32

Patel 59 Sinonasal and oral Surgery +/– postoperative radiotherapy+/

–chemotherapy 35

Stern 42 Sinonasal and oral Surgery+/– radiotherapy+/– chemotherapy+/

–immunotherapy 40

Guzzo 48 Head and neck Surgery+/– radiotherapy+/– chemotherapy+/

–immunotherapy 21

Wada 31 Head and neck Surgery+/– radiotherapy+/– chemotherapy 33*

NIRS-1(9602) 100 Head and neck Carbon ion radiotherapy 36

NIRS-2(0007) 82 Head and neck Carbon ion radiotherapy+ chemotherapy 62

Malignant mucosal melanoma in head and neck

Hadron Therapy:

What is happenning

at CNAO?

Presented to:

- Italian Ministry of Health

- Lombardy Region

Main Tasks:

- Dosimetry characterisation

- Radiobiology characterisation

- Patient treatment

Proton Radiobiology

3 cell lines: HSG (human salivary gland tumour), T98G (human

glioblastoma), V79 (Chinese hamster lung fibroblast)

(16 energies)

Field10x10 cm2,

33x33 spots,

scanning step 3 mm

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

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

22 September 2011

Chondrosarcoma G2

Contouring with image fusion TC/RM

T1 post gadolinium

sequences in T2

Dose distribution

RBE value 1.1

Optical & X-ray tracking

systems

for set-up verification

44

Cell Survival vs Depth

Dose uniformity

Carbon Ion Radiobiology

Group Leader: Yoshiya Furusawa, NIRS, Chiba Carbon ions

Animals

Horizontal beam, direction ventral - dorsal

3 animals per field

Set-up

Comparison of RBE results

(CNAO vs GSI \ NIRS)

Prescription doses (GyE)(16 fractions, 4 fractions per week)

Indication

NIRS dose CNAO dose

Opposed ports Orthogonal ports Single port

q.e. q.e. q.e. MC

Cubes

Spheres Cubes Spheres Cubes Spheres

Head and neck non mesenchymal cancer

3.6 4.2 4.15 4.2 4.15 4.2 4.15 4.19

Skull base chordoma and chondrosarcoma

3.8 4.35 4.3 4.35 4.3 4.35 4.3 4.33

Head and neck non mesenchymal cancer

4 4.5 4.4 4.5 4.45 4.5 4.45 4.47

Spinal chordoma and chondrosarcoma 4.2 4.65 4.6 4.7 4.6 4.7 4.6 4.64

Head and neck sarcoma 4.4 4.8 4.7 4.8 4.7 4.8 4.7 4.75

Bone and soft tissue sarcoma 4.4 4.8 4.75 4.8 4.75 4.8 4.75 4.78

NIRS – CNAO Collaboration

Fossati P et al, Dose prescription in carbon ion radiotherapy: a planning study to compare NIRS and LEM

approaches with a clinically-oriented strategy. Phys Med Biol, 2012

Local recurrence of adenoideocistic carcinoma involving

pterigopalatina fossae, orbital apex, right cavernous sinus

and medium skull

13 November 2012

• Carbon ion

• 12 fractions of 4.1 GyE each, 4 frs x week, 49.2 GyE total

• Boost with 4 additional fractions, same fractionation

• 3 fixed fields by IMPT

Dose distribution

Skin Toxicity

6 December 2012

End od the treatment

12 March 2013

Before After 8 months

Patients treated up to 31 December 2013

Protontherapy: 79 patients

mainly chordomas & condrosarcomas

conventional fractionation

Carbon Ion Therapy: 120 patients

Mainly sarcomas & salivary glands tumors

hypofractionation

Toxicity

G3 mucositis during and at the end:

8/153 (<2%, accepted up to 5%)

Intermediate/late:

2 cases G4 (visual loss)

One complete at 18 months(optic nerve in the field)

One complete at 3 months (progression of disease)

CE Label

Moving to clinical use ….

… At the end of December, the Ministry of Healthgave the full CE label for all the tumor site …..

… At the end of December, Lumbardy Region willgive the tarifs for the Public Health System

… Three different treatment modality:

- Boost (mixed field with X-rays): 12,000 E

- Stereotactic treatment (1 to 3 frs): 18,000 E

- Full cycle (indipendent from frs): 24,000 E

Protocollo Descrizione Protocollo Protoni o

Ioni

Carbonio

Frazioni Trattato In

trattamento

Trattati/in

trattamento

N° previsto

da protocollo

Mancanti per

certificazione

protocollo

Trattato In

trattamento

Trattati/in

trattament

o

CNAO 01/2011 V.2.0

Trattamento con protoni

(adroterapia) di cordomi e

condrosarcomi della base del cranio

P 35-37 30 0 30 30 0 1 8 9

CNAO 02/2011 V.1.0

Radioterapia mediante protoni

(adroterapia) dei cordomi e dei

condrosarcomi del rachide

P 35-37 13 1 14 20 6 0 0 0

CNAO 03/2011 V.2.0

Radioterapia mediante protoni

(adroterapia) dei meningiomi

intracranici

P 30-33 1 0 1 30 29 0 0 0

CNAO S4/2011/P Radioterapia mediante protoni

(adroterapia) dei tumori dell’encefalo P 22-30 0 0 0 40 40 0 0 0

CNAO 05/2011 V.1.0

Radioterapia mediante protoni

(adroterapia) delle recidive di

neoplasie del distretto cervico-cefalico

P n.a. 1 0 1 40 39 0 0 0

CNAO 06/2011 V.2.0

Boost di Radioterapia mediante

protoni (adroterapia) di neoplasie

localmente avanzate del distretto

cervico-cefalico

P 8-15 9 0 9 20 11 0 0 0

CNAO S7/2012/P Radioterapia mediante protoni

(adroterapia) dei gliobastomi P 37 0 0 0 20 20 0 0 0

CNAO S8/2012/P

Ritrattamento mediante radioterapia

con protoni (adroterapia) dei cordomi e

dei condrosarcomi del rachide recidivi

P n.a. 2 0 2 20 18 0 0 0

CNAO S9/2012/C

Radioterapia mediante ioni carbonio

(adroterapia) del carcinoma adenoideo

cistico delle ghiandole salivari

C 16 14 0 14 20 6 0 0 0

CNAO S10/2012/C

Ritrattamento mediante radioterapia

con ioni carbonio (adroterapia) degli

adenomi pleomorfi recidivi

C 16 2 0 2 30 28 0 0 0

CNAO S11/2012/C Reirradiation of ricurrent rectal cancer

using carbon ions C

dose

escalation 0 0 0 20 20 0 0 0

CNAO S12/2012/C Sarcomi (ossei e dei tessuti molli)

del distretto cervico-cefalico C 16 15 0 15 15 0 0 4 4

CNAO S13/2012/C Sarcomi (ossei e dei tessuti molli)

del tronco C 16 15 0 15 15 0 6 2 8

CNAO S14/2012/C Recidive di neoplasie del distretto

cervico-cefalico C 10-30 9 0 9 15 6 0 0 0

CNAO S15/2012/C Melanomi maligni delle mucose delle

prime vie aerodigestive C 16 2 1 3 15 12 0 0 0

CNAO S16/2012/C Carcinoma della prostata ad alto

rischio C 16 3 0 3 20 17 0 0 0

CNAO S17/2012/C Tumori primitivi e secondari dell'orbita C 16 0 1 1 15 14 0 0 0

CNAO S18/2013/C Tumori del pancreas C 12 0 0 0 15 15 0 0 0

CNAO S19/2013/C Neoplasie primitive maligne del fegato C 12 0 0 0 15 15 0 0 0

CNAO S20/2013/C

Ritrattamento mediante radioterapia

con ioni carbonio dei cordomi e dei

condrosarcomi del rachide recidivi

C 12-20 0 1 1 15 14 0 0 0

CNAO S21/2013/C Radioterapia mediante protoni del

melanoma oculare P 4 0 0 0 15 15 0 0 0

CNAO S22/2013/C

SINTART1. Approccio multidisciplinare

per tumori dei seni paranasali operabili

a prognosi sfavorevole: studio di fase II

di trattamento integrato

chemioterapico, chirurgico e

radioterapico (con protoni e/o ioni

pesanti) allo scopo di identificare un

approccio terapeutico più efficace e

con minor tossicità.

P/C n.a. 0 0 0 40 40 0 0 0

CNAO S23/2013/C

SINTART2. Approccio multidisciplinare

per la cura dei tumori dei seni

paranasali non operabili a prognosi

sfavorevole: studio di fase II di

trattamento integrato chemioterapico

e radioterapico (con protoni e/o ioni

pesanti) allo scopo di identificare un

approccio terapeutico più efficace e

con minor tossicità.

P/C n.a. 0 0 0 25 25 0 0 0

Pazienti in sperimentazione 116 4 120 7 14 21

16

Protoni 7

Ioni Carbonio 9

Pazienti in

sperimentazione

Pazienti post

sperimentazione

Pazienti compassionevoli in trattamento/trattati

Protons for chordoma

Dose

74 Gy

(RBE)

Sarcomas. Irradiation with C-12

H&N cancer. Re-irradiation with C-12

One year after

At CNAO 258 patients

(87 with p+, 168 with C-12, 3 mixed)

Sarcomas

Base of the skull

Salivary Glands

“Big Killers”

Children & Eye melanoma

Some numbers …..

UVEAL MELANOMA

• More than 12,000 patients treated

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

Clatterbridge)

• 5y-LC rate >95%

• Eye preservation >90%

• Visual acuity >45%

First patient

treated

with IMPT

ITALIAN NETWORK

CNAO

INTERNATIONAL

NETWORK Norway

French Italian Protocol

ENVISION

European NoVel Imaging Systems

for ION therapy

PARTNER

Particle Training Network

for

European Radiotherapy

Different endpoints,

not only in LC & S,

but in QoL and other

surrogate markers

Multicentric/

Multidisciplinary

ESTRO, EORTC, PTCOG,

National Societies

Some Issues for Innovative Studies

“Difficult” tumors,

not only for dose

distribution,

but for biology

Altered Fractionation

Hypofractionation

High Tech RT

vs Proton

vs Carbon

& Mixed beam

Molecular Imaging

& Biology driven

THANK YOU