Proton therapy, yesterday, today and tomorrow
Opening of the BNEN 14th Academic Year 2015-2016
Mol, September 21 2015
Yves Jongen (Founder, CRO)
IBA Group
yves.jongen@iba-group.com
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1
Cancer, we are all concerned
33M
80M
1/2
of population
will get cancer
cancers in 2012
cancers in 2030
of people
survive cancer
21/10/2015
1/3
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2
Proton therapy
Precise dose delivery, fewer side effects
Precise dose delivery, fewer side effects
Why protons?
 Deliver maximum energy within a precisely controlled range
 Deposit a high and conformal dose
 Deposit very low entry dose and no exit dose – sparing healthy
tissue
 Reduce unnecessary dose to the critical structures like heart
while treating a lung cancer reduced by 5X
 Risk of growth abnormality for children: dramatically reduced
Expanding list of key Indications
 Head & neck, Spinal cord, Eyes, Orbits, Pelvis, Prostate, Lung,
Pediatric cancers,…
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 Reduce risk of secondary cancers
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The benefits
4
RHABDOMYOSARCOMA
TREATMENT WITH DOUBLE SCATTERING
X-Rays
Proton Therapy
“Fractionated proton radiotherapy is
superior to 3D conformal photon radiation
in the treatment of orbital RMS (…) Proton
radiation therapy minimizes long-term side
effects” (*)
Images Courtesy Torunn I Yock, MD Burr Proton Therapy Center Boston USA – (*) Yock, T. et al; « Proton radiotherapy for orbital
rhabdomyosarcoma: clinical outcome and a dosimetric comparison with photons. », Int J Radiat Oncol Biol Phys. 2005 Nov 15;63(4):11618. Epub
2005 and
Jun Save
13 Lives
-5Protect,
Enhance
Lecture outline

How did we get here?

Proton therapy today

Rapidly developing medical evidence

Two accelerator technologies
Limited importance of accelerator
World market of PT equipment



Future trends
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How it started…
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First idea by Robert Wilson in 1946
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The early days

1946; Bob Wilson suggested the possible use of the Bragg peak of
high energy ions in the radiotherapy of cancer ("Radiological Use of
Fast Protons" , Radiology 1946:47:487-91)

2 decades later: clinical use of particle beam therapy in cancer
treatment

1950s/60s; 1st patient treatments at LBNL, Uppsala University, HCL

Berkeley; heavy ions. Harvard; protons
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The Harvard Synchrocyclotron
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HCL contributions to present day PT

Dr. Herman Suit’s team at MGH and the HCL constitute the base of
today’s proton therapy physics and technology;
Michael Goitein, Bernie Gottschalk, Andy Koehler, Janet Sisterson, Miles
Wagner, Skip Rosenthal and Ken Gall

This team played an important consulting role in the design of the IBA
system at MGH
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Andy Koehler and Jason Burns in the MCR (1989)
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The next step: Hospital based facilities

Success at HCL suggested that the technology belonged in hospitals vs. labs

In 1983, Proton Therapy Cooperative Group (PTCoG) was formed to develop
hospital based PT facilities (35 members)

PTCoG has evolved to >700 people meeting annually

The 54th PTCoG meeting will organized in San Diego (USA) on May 18-23
2015 (http://ptcog54.org/)
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Loma Linda

Pr. James (Jim) Slater at Loma Linda University Medical Center
(LLUMC) was the first to raise the funds needed to build a hospital
based PT facility

Accelerator development was subcontracted by LLUMC to Fermilab;
Synchrotron technology was selected

Gantry development was subcontracted to SAIC
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Massachusetts General Hospital (MGH) (1)

1992, MGH obtained the budget needed to build an in hospital PT
facility from NCI and private donors. An international tender was
launched

After a first selection, 3 groups remained in the race:




Varian, allied with Maxwell-Brobeck proposed a synchrotron based system
Siemens proposed 2 solutions; a synchrotron and a superconducting
isochronous cyclotron (designed by Pierre Mandrillon from CERN & Nice)
IBA, allied with General Atomics, proposed a solution based on a resistive
isochronous cyclotron of 230 MeV
IBA was selected by MGH with contract signature in 1994 and with the
goal to treat the first patient in 1998
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Massachusetts General Hospital (MGH) (2)
At the end of the MGH tender, one observer noted:
« This tender may well cause the end of 3 good accelerator companies: perhaps
for the companies which did not get the contract, but certainly for the company that got
it »




IBA encountered problems too.



The Brobeck division of Maxwell was closed
The “special projects” division of Siemens was closed. It was purchased by the
managers and restarted business under the name of ACCEL. ACCEL sold a proton
therapy cyclotron to PSI, and a protontherapy system in Munich. ACCEL was eventually
acquired by Varian
The cyclotron, beam lines and gantries came on spec, on time and on budget.
We significantly underestimated badly effort and methodology needed for the software
development.
The first patient was treated in 2001, 7 years after the contract!
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1995-2000: Japan active

1995 to 2000, the public authorities of Japan, financed the construction of 4 PT
facilities and one carbon/proton facility by 3 Japanese companies; Hitachi,
MELCO and SHI

1991, IBA and SHI signed an agreement to jointly develop a proton therapy
system; NCC in Kashiwa

1st patient treatment in 1998

After 2000, orders for PT facilities around the world began to grow
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Proton therapy
today
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Unprecedented Growth of Operational PT Rooms
Observed number of PT rooms in operation, patients treated with PT and medical publications
Total number of rooms worldwide, patient evolution index based on number of rooms
Patients Treated
# rooms in operation
# rooms sold
160000
250
120000
100000
200
150
80000
60000
40000
100
50
20000
0
0
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140000
19
Treatment Room Potential
Treatment Room Potential
North America
53
339
South America
1
198
Europe incl. Russia
43
658
Asia
44
1 307
World
141
2 671
Source : IBA internal modeling based on Netherlands Model Based Approach
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Current number of
treatment rooms
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Region
20
Unique product offering with Multi-room & Compact
Proteus®PLUS
Proteus®ONE*
360 m²
At comparable scope, it
represents a saving of
> 30% for the hospital
1800 m²
*Proteus®ONE & Proteus®Plus features PBS and Cone Beam CT
*Subject
to review by Competent Authorities (FDA, European Notified Bodies, et al.) before being put on the market.
IBA – Leading the Installed Base
Proton Centers Sold Share
Varian
16%
SHI
8%
AVO
0%
Mevion
5%
Hitachi
13%
IBAIBA
52%
Hitachi
15%
Varian
18%
Pronova
1%
SHI
5%
MELCO
11%
IBA
43%
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ProNova
1%
Mevion
3%
MELCO
6%
AVO
1%
Total Room Sold Market
Share
22
IBA’s Three Key Areas of Focus in PT
Clinical Relevance
Affordability
Technology
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Increasing potential to grow the niche from 1% to 20% of RT
23
Clinical
Relevance
Exponential Growth in PT Publications
500
452
450
418
Publications per year
400
350
314
300
230
222
200
176
157
154
145
139
150
100
50
106
80888687
7071
58
433949354339 50
34
33
2822 28
253033
1615211721 17
13 13
7
12124535767 8 7
0
233
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261
250
Year
Number of publications up to July 2015
24
Clinical
Relevance
Growth in Prospective Clinical Studies
2009
2015
Randomized studies
10
20
Worldwide prestigious cancer institutes as Principle
Investigators leading the clinical studies
Non-randomized
comparison studies
13
29
PI Institutes
Total number of prospective
studies
58
122
30
20
15
9
1
3 10 2 8 3
17
5
13
8
7
7
2
3
6
2
1
3
0
7 6
6
8
ocular
spine
pancreas
prostate
bone soft tissues
breast
pediatric
planning study
10
17 17
16
7 1
18
head and neck
liver
esophagus, gastric, anal
uterus, cervix
lung
brain, skullbase
lymphoma, hodgkins
others
Source: www.clinicaltrials.gov
3
2
1
1
2
1
1
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Ongoing clinical trial Total
122
25
25
25
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GROWING INTERNATIONAL RECOGNITION OF PT BENEFITS
UK Government - Oct, 2012
Dutch Government - Dec, 2009
“The Government
recognises that ensuring
patients have access to
high quality modern
radiotherapy techniques
such as Proton Beam
Therapy (PBT) will
support improved
outcomes, increase cure
rates and improve
patient experience by
minimising long-term
side effects of
treatment.”
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“A substantial number of
Dutch cancer patients
could potentially benefit
from future treatment with
proton radiotherapy,
resulting in less clinically
relevant side effects,
improvement of local
tumour control, and
prevention of secondary
cancers.”
Two accelerator technologies

Cyclotrons;




beam is accelerated in a spiral path in a fixed magnetic field. The
beam is generally accelerated up to the maximum energy, corresponding to the deepest
range in patient, and is decelerated outside of the cyclotron to the required energy by an
energy degrader.
Cyclotrons come in two varieties: isochronous cyclotrons (continuous) and
synchrocyclotrons (pulsed)
Synchrotrons;




the beam is accelerated on a fixed path, the magnetic field increases during the beam
acceleration.
beam can be extracted at the energy needed for the treatment. After acceleration, the
magnetic field needs to be lowered to accept the next bunch of particles.
The beam of the synchrotron is therefore not continuous.
Synchrotrons require an injector accelerator, generally a proton linac.
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IBA superconducting synchrocyclotron
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IBA 230 MeV resistive isochronous cyclotron
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Hitachi Proton Therapy Synchrotron
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The limited importance of accelerators in PT


Accelerator, while important is < 20% of the budget and footprint of a large PT
system.
Key technologies which define the quality of a proton therapy system are:
 Beam delivery technology: what method is available: Scanning?
Scattering? Both? What are the technical specifications in each mode? The
speed of treatment?
 HW and SW tools to position accurately and reproducibly the target in the
proton beam (positioning the target is not the same as positioning the body)
 All the tools for Image Guided Proton Therapy (Digital X-Ray, CBCT,
Fluoro, Optical patient anatomy monitoring etc.)
 Seamless integration of the proton therapy workflow into the radiation
oncology department
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Emerging trends for
the future
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Emerging trends

Shift from big multiroom systems toward one and two rooms systems

New, superconducting designs

IMPT using spot scanning

Reduction of the neutron dose to the patient

Image Guided Proton Therapy (IGPT)

Range verification in vivo and in real time
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Emerging trends 1: one and two room systems

Most PT systems today have 3- 5 treatment rooms; lowest cost/room

Patient recruitment for larger system can be challenging

Smaller hospitals with more limited patient base, want PT

Most active manufacturers are considering today the development of smaller,
less expensive one or two room systems
Compact, reasonably priced one (or two) room systems will probably
dominate sales in the future
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IBA Proteus®ONE
• 70% volume reduction
• Footprint of a tennis cour t
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* CBCT and 220°Compact Gantry are ongoing developments.
The marketing approval will be subject to review by competent authorities (FDA, Notified bodies, et al…)
IBA ProteusONE treatment room
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Emerging trends 2: superconducting systems

Magnetic rigidity of 230 MeV protons is 2.33 T m


Resistive magnets are limited to 2T for cyclotrons, 1.6 T for beam line magnets.


If you want smaller systems, you need smaller radii, and this means higher magnetic fields.
If you want to go to higher magnetic fields, you need superconducting magnets.
SC magnets technology is mature for fixed field magnets (like cyclotrons).

For variable field magnets, like beam lines or synchrotrons, there is more to do.

Superconducting cyclotrons (S2C2 or isochronous) will probably be the accelerator
of choice tomorrow. SHI is now following IBA, Varian and Mevion

Superconducting gantries are being designed and prototypes are being tested.

Pronova and IBA are investigating
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Varian superconducting cyclotron
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Mevion superconducting synchrocyclotron
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IBA superconducting synchrocyclotron
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ProNova two rooms layout with SC gantry magnets
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Emerging trends 3: IMPT using spot scanning

While scattering is still favored by some institutions for moving tumors
scattering only allows uniform fields

Intensity Modulated Proton Therapy (IMPT) is made possible by spot scanning,
or pencil beam scanning

There are always treatment cases exceeding the limits of the treatment field
(Medulloblastoma): IMPT allows also much more robust field patching.

Most facilities sold today feature only scanning treatments.


My opinion- the use of scattered beams will progressively disappear
At UPenn, the introduction of PBS has doubled the number of patients for
whom PT was the preferred mode of treatment
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•
Most Advanced
Arc Therapy
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Passive Proton
Therapy : 4 Fields
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Images courtesy of Elekta
•
Pencil Beam
Scanning : 1 Field
Emerging trends 4: IGPT

To stay ahead of classical X-ray therapy, PT needs to develop the
imaging tools, in and out of the treatment room

Although not generalized today, true 3D daily imaging will become
extensively used tomorrow, not only for tumor localization, but also for
daily plan correction

Cone Beam CT (CBCT) and CT on rail are competing technologies in
this field. Both have merits and disadvantages. The future will tell us
which technology becomes preferred

Besides imaging hardware, the treatment image manipulation
software will become increasingly powerful and necessary
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In room CT or CBCT?
CT-on-Rails, Trento, Italy
CBCT, Penn Medicine, USA
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47
Optimum quality CBCT images requires the X-Ray tube to
be far from isocenter – limit of ring-type CBCT’s
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Combining X-Ray modalities in the Proteus One
Fixed Stereoscopic X-ray
CBCT
X-ray tube
Flat panels
X-ray
tube
Flat panel
X-ray tubes
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Flatpanel
Emerging trends 5: Reducing the neutron dose

Proton stopping in the patient body undergo nuclear reactions, causing therefore the emission
of neutrons. There is a minimum neutron dose outside the treatment field which is unavoidable
in proton treatments

We start to see more clinical data validating the relation between the neutron dose given in
proton therapy and the induction of secondary cancers

Therefore, reducing the neutron dose associated by the proton treatment will be increasingly
important, especially for pediatric patients

In an ideal case, the neutron irradiation is limited to the neutrons generated by the protons
stopping in the patient body. This is the case for PBS proton treatment

In contrast, treatments by scattering subject the patient to a much larger neutron flux coming
from other elements such as patient specific apertures, scatterers, range shifters etc.
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PBS Proteus ONE vs. gantry mounted cyclotron with scattering only:
Neutron Dose (Pediatric Medulloblastoma)
20
Scattering
Gantry Mounted
Cyclotron
18
ProteusONE
16
H*(10) (mSv/Gy)
14
Ideal PBS
12
10
8
6
4
2
0
Esophagus Thymus
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Heart
Thyroid
Adrenals
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Liver
Pancreas
Bladder
Kidneys
Brain
Emerging trends 6: precisely measuring the range of the proton
beam in the patient

The range of a proton beam in an actual patient has very large
uncertainties, due to day to day variations in the patient anatomy

Large safety margins on the range are therefore used in the current
practice of PT, cancelling part of the advantage of protons over x-ray

The advantages of protons over photons would be significantly
increased if we could watch in real time the range of the proton pencil
beam in the patient

This can be done if we image the prompt gammas coming from
nuclear reactions caused by the proton beam in the patient
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Concept of prompt gamma camera…
Scintillator +
photodetector
Slit collimator
Proton pencil beam (scan
the tumor, spot by spot, in
X, Y, Z)
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Thank you…
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