Academic Medical Accelerators Revised2

Accelerators for Medicine
Maurizio Vretenar, CERN
Academic Training, 12 June 2018

12/6/2018 M. Vretenar, Accelerators for Medicine 2
Accelerator and Society
Over 30’000 Research 6%
particle Particle Physics 0,5%
accelerators Nuclear Physics, solid state, materials 0,2 - 0,9%
are in Biology 5%
operation Medical Applications 35%
world-wide.
Diagnostics/treatment with X-ray or 33%
electrons
Only ~1% are
used for Radio-isotope production 2%
fundamental Proton or ion treatment 0,1%
research. Industrial <60%
Applications
Medicine is Ion implantation 34%
the largest Cutting and welding with electron beams 16%
application
Polymerization 7%
with more
Neutron testing 3.5%
than 1/3 of all
accelerators. Non destructive testing 2,3%

Accelerators for medicine
Number of
operating
accelerators
worldwide
protons proton therapy
Hadron ≈ 75
Primary beam
ions ion therapy therapy
(low en.) IORT Inter Operation
Radiation Therapy >300
electrons (high en.)
VHEE Very High Energy
Electron Therapy 0
Accelerator Secondary beam
X-rays Radiation Therapy ≈ 14’000
Target
neutrons neutron therapy 7
PET Positron
Radioisotopes imaging Emission Tomography ≈ 1’500
theragnostics
therapy Targetd Alpha 0
Therapy, others
Total: ≈ 16’000 particle accelerators operating for medicine

The potential of accelerators
 All these systems share the vision of a bloodless surgery and imaging:
penetrate into the human body to treat diseases and to observe internal
organs without using surgical tools.
 Particle beams (primary and secondary) precisely deliver large amounts of
energy to small volumes, penetrate in depth (different from lasers) and
interact with cells, molecules, and atoms (electrons and nuclei).
 Particles beams can activate the nuclei generating radiation that can destroy
cancerous cells or can be detected from outside.
For a U.S. population of over Nuclear medicine:

application of radioactive substances in the
300 million people, there are
diagnosis and treatment of disease
some 16 million nuclear
medicine procedures per year. Radiation therapy:
therapy using ionizing radiation, generally as part of
cancer treatment to control or kill malignant cells

Medicine at the first accelerators
The idea of using accelerators for treating diseases is
almost as old as accelerators are!
 90 years ago in 1928 Rolf Wideröe invents the
modern radio-frequency accelerator (for his PhD
Thesis at Aachen).
 In 1929 Ernest O. Lawrence in Berkeley adds cyclic
acceleration and develops the cyclotron, the first
high-energy accelerator, producing 1.1 MeV
protons in 1931.
 In 1936, the new Berkeley 37-inch cyclotron was
producing isotopes for physics, biology and
medicine – in parallel to the time devoted to
discoveries in nuclear physics.
 Starting in 1937, Lawrence’s brother John was the
pioneer of injecting radioisotopes produced at the
cyclotron to cure leukemia and other blood
diseases.
 In 1938 starts direct irradiation of patients with
neutrons from the new 60-inch cyclotron.

Particle beam treatments – from neutrons to protons
First direct irradiation of a patient, 20 November
1939 (from left: Dr. R. Stone, J. Lawrence,
patient R. Penny) in a special treatment room on
the new 60-inch cyclotron
Lawrence’s priority was to promote his science and to build
larger and larger cyclotrons. He considered medical
applications as a formidable tool to show the public the
potential of this new technology and to raise more funding for
his projects.
During the 30’s, more than 50% of beam time was devoted to
producing isotopes for medicine and other applications, to the
disappointment of the physicists that were using the cyclotron
beams to lay the ground of modern nuclear physics.
In 1946, Robert Wilson proposed to use protons to treat cancer, profiting

of the Bragg peak to deliver a precise dose to the tumour (Wilson had been
working at Berkeley, then moved to Harvard and finally founded Fermilab).
First treatment of pituitary tumours took place at Berkeley in 1956.

First hospital-based proton treatment center at Loma Linda (US) in 1990.
Early idea of curing cancer with particle accelerators

Impact of cancer on world population
Cancer is the second leading cause of death globally, and was responsible for
8.8 million deaths in 2015. Globally, nearly 1 in 6 deaths is due to cancer (WHO).
Increase of cancer cases
due to:
 Increasing age of
population
 Aggressive
environmental and
living conditions in
developing countries.
Nowadays, the standard
protocol for treatment of
most cancers is based on:
1. Surgery
2. Radiotherapy
(accelerator-based)
3. Chemiotherapy
(courtesy M. Dosanih) 4. (Immunotherapy)

Accelerators for cancer diagnosis and treatment
There are today about 16’000 accelerators in hospitals or working for hospitals, but we
have to consider that the requirements for a medical accelerator are very different from
those of a scientific accelerator:
 The beam must be perfectly known, stable and reliable.
 The accelerator (as the radiopharmaceutical unit in case of production of isotopes)
have to follow strict Quality Assurance procedures.
Example: factor 4 in the complexity and cost of the control system for a medical
accelerator as compared to a scientific one.
The role of the medical physicist is essential in planning the treatment and in guaranteeing
the delivered dose.
IntegraLab® PLUS combined radiopharmaceutical production

centre from IBA.
The accelerator is the small box in the upper right corner, all the
rest is what is needed to shield the accelerators and to provide
radiopharmaceuticals compliant with quality control procedures
(purity, sterility, etc.).

Medical exposure – a critical issue
Radiation management and control is a key issue in nuclear
medicine.
- important doses are delivered to patients (comparison risk-
benefit)
- the dose to medical personnel has to be limited to legal limits.
CERN limits
Up to 2000 mSv highly

targeted dose in
conventional radiotherapy !
Source: S. Liauw et
al., Translational
Medicine, 5, 173
1. Radiation therapy
Hadron
Primary beam
Radiation Therapy
VHHE Very High Energy
Electron Therapy

X-rays Radiation Therapy
Target
neutrons neutron therapy
PET Positron
Radioisotopes imaging Emission Tomography
theragnostics
therapy Targetd Alpha
Therapy, others

The most successful accelerator
Electron Linac (linear accelerator) for
radiotherapy (X-ray treatment of cancer)
5 – 25 MeV e-beam
Tungsten target
14,000 in operation
worldwide!
Modern radiotherapy
X-rays are used to treat cancer since last century. The introduction of the
electron linac has made a huge development possible, and new developments
are now further extending the reach of this treatment.
Accurate delivery of X-rays
to tumours
To spare surrounding tissues

and organs, computer-
controlled treatment methods
enable precise volumes of
radiation dose to be delivered.
The radiation is delivered from
several directions and
transversally defined by multi-
leaf collimators (MLCs).
Combined imaging and therapy
Modern imaging techniques (CT computed tomography, MRI magnetic

resonance imaging, PET positron emission tomography) allow an
excellent 3D (and 4D, including time) modelling of the region to be treated.
The next challenge is to combine imaging and treatment in the same
device.

Inside a radiation therapy linac
The Side Coupled Linac structure was invented at Los

Alamos in the late 60’s for the 800 MeV LA meson
facility.
Because of its robustness, stability, reliability and low
cost since the 70’s it has been used – in a 3 GHz
version – to produce X-rays for radiation therapy
A great example of technology transfer from basic science to society

Radiation therapy worldwide
(courtesy ENLIGHT Network)

Radiation therapy nowadays relies mostly on linear accelerators, which in developed
countries have replaced the old «cobalt bombs».
Many countries with an expected increasing cancer rate are not covered.

The ICEC Initiative for a new linac design
Today the radiation therapy linac market is in the hands of 2 large companies –
and two smaller «niche» producers.
Equipment is expensive, requires maintenance and a stable operating
environment (electricity, humidity, dust, etc.) → this has reduced the access of
low and middle income countries to radiation therapy.
A collaboration led by the NGO International Cancer

Expert Corps with the participation of STFC and
CERN has started the development of a new
radiotherapy linac specifically aimed at low and
medium income countries.

2 – Hadron therapy

Hadron
Primary beam
Radiation Therapy
Electron Therapy

Target
PET Positron
theragnostics
Therapy, others

The beauty of the Bragg peak
Bethe-Bloch equation of ionisation energy loss by charged particles
2 Different from X-rays
dE 4p nz 2
æ e ö 2
é æ 2mec2 b 2 ö ù
- = . 2 .ç . ê ln ç 2 ÷
-b ú
2 or electrons, protons
dx mec b
2
è 4pe 0 ÷ø ë è I.(1- b ) ø û (and ions) deposit
their energy at a
Spread-Out
Bragg Peak
given depth inside
(SOBP) the tissues,
minimising the dose
to the organs close
to the tumour.
Required energy
(protons) about 230
MeV, corresponding to
33 cm in water.
Small currents: 10 nA
for a typical dose of 1
accelerators-for-society.org Gy to 1 liter in 1 minute.

Comparing proton and X-ray therapy
The results of irradiating a nasopharyngeal carcinoma

by X-ray therapy (left) and proton therapy (right),
showing the potential reduction in
dose outside the tumour volume that is possible with
proton treatment.
(Z. Taheri-Kadkhoda et al., Rad. Onc., 2008, 3:4 – from
APAE Report, 2017).

The rise of particle therapy
• First experimental treatment in 1954 at Berkeley.
• First hospital-based proton treatment facility in
1993 (Loma Linda, US).
• First treatment facility with carbon ions in 1994
(HIMAC, Japan).
• Treatments in Europe at physics facilities from
end of ‘90s.
• First dedicated European facility for proton-
carbon ions in 2009 (Heidelberg).
• From 2006, commercial proton therapy
cyclotrons appear on the market (but Siemens
gets out of proton/carbon synchrotrons market in
2011).
• Nowadays 3 competing vendors for cyclotrons,
one for synchrotrons (all protons).
• More centres are planned in the near future.
A success story, but …

• many discussion on effectivness, cost and
benefits.
• Some negative experiences from some running
centers (lack of patients, increasing costs,…)

Particle therapy centers in Europe
Austria Med-AUSTRON, Wiener S 250 1 gantry, 2 hor., 2017
Neustadt 1 vertical
From 8 centres in 2000 we are
Czech Republic PTC Czech s.r.o, Prague C 230 3 gantries, 2012 now to 20 in operation plus 10
(scan) 1 horizontal
United Kingdom Clatterbridge C 62 1 horizontal. 1989 in construction (4 centres
France CAL, Nice C165 1 horizontal 1991
offering as well ion therapy)
France CPO, Orsay S 250 1 gantry, 1991 https://journals.aps.org/prab/pdf/10.1
103/PhysRevAccelBeams.19.124802
2 horizontal
Germany HZB, Berlin C 250 1 horizontal 1998
Germany RPTC, Munich C 250 4 gantries, 2009
(scan) 1 horizontal.
Germany HIT, Heidelberg S 250 2 horizontal, 2009, 2012
(scan) 1 gantry
Germany WPE, Essen C 230 4 gantries, 2013
(scan) 1 horizontal
Germany PTC, Uniklinikum C 230 1 gantry 2014
Dresden (scan)
Germany MIT, Marburg S 250 3 horizontal, 2015
(scan) 1 45 degrees
Italy INFN-LNS, Catania C 60 1 horizontal 2002
Italy CNAO, Pavia S 250 3 horizontal, 2011
1 vertical - Protontherapy is rapidly
Italy APSS, Trento C 230 2 gantries, 2014 developing: more than 65'000
(scan) 1 horizontal
Poland IFJ PAN, Krakow C 60 1 horizontal 2011 patients treated worldwide, 5
Russia ITEP, Moscow S 250 1 horizontal 1969 companies offer turn-key solutions.
Russia St. Petersburg S 1000 1 horizontal 1975
Russia JINR 2, Dubna C 200 1 horizontal 1999
Sweden The Skandion C 230 2 gantries 2015 - Carbon ions have been used to
Clinic,Uppsala (scan) treat about 6000 patients
Switzerland CPT, PSI, Villigen C 250 2 gantries, 1984, 1996,
(scan) 1 horizontal. 2013 worldwide
Adapted from PTCOG data, May 2016 –
from APAE Report
The difficulties of particle therapy
 Cost: a commercial single-room proton therapy system has a price starting from 30
M€, to be compared with 2-3 M€ of a X-ray radiotherapy system. A complex proton
and ion therapy centre has a cost of 150-200 M€.
 Effectiveness: there is no or little evidence for a different effectiveness between
protons and X-rays. They have the same radiobiological effect and when the same
dose is applied, the effect is the same.
 Quality of life: protons and ions are superior in sparing the surrounding tissues
thus reducing risk of secondary cancer and improving quality of life after
treatment. But while survival rates are easy to measure and compare, quality of life
is not an easily measureable parameter. Only recently studies have been started,
but will take years.
 Optimisation: the effect of protons and ions is not as known as that of X-rays, and
optimisation of treatment is still ongoing. Biological tests are needed to compare
the loss of energy (Bragg peak) to the effect on the cells – not necessarily linear.
 Centralisation of medicine: the high cost of particle treatment calls for large
centralised units that have difficulties in attracting patients from other hospitals.

Advantages of proton therapy
The main recognised advantage of
proton therapy are for:
- Pediatric tumours, where
surrounding tissues are more
delicate and the risk of secondary
tumours is higher.
- Tumours close to vital organs:
base of skull, central nervous
system, head and neck.
Source: IBA, state of proton therapy

market entering 2017
Source: IBA proton therapy fact-sheet,

Proton therapy accelerators: cyclotrons
At present, the cyclotron is the best
accelerator to provide proton therapy
reliably and at low cost (4 vendors on
the market).
Critical issues with cyclotrons:

1. Energy modulation (required to
adjust the depth and scan the
tumour) is obtained with degraders
(sliding plates) that are slow and
remain activated.
2. Large shielding
ProteusOne and
ProteusPlus turn-
key proton
therapy solutions
from IBA
(Belgium)

Proton therapy accelerators: synchrotrons
 The Loma Linda Medical Centre in US (only protons) and the ion therapy centres in
Japan have paved the way for the use of synchrotrons for combined proton and ion
(carbon) therapy).
 2 pioneering initiatives in Europe (ion therapy at GSI and the Proton-Ion Medical
Machine Study PIMMS at CERN) have established the basis for the construction of 4
proton-ion therapy centres: Heidelberg and Marburg Ion Therapy (HIT and MIT)
based on the GSI design, Centro Nazionale di Terapia Oncologica (CNAO) and Med-
AUSTRON based on the PIMMS design.
CNAO
HIT Heidelberg

Alternative solutions: the linear accelerator
The TERA Foundation launched and directed by U. Amaldi is
promoting accelerators for cancer therapy since 1992. It has
launched in 1995 a collaboration with CERN for the
development of a proton therapy linac operating at high
frequency (3 GHz) and high gradient (30-50 MV/m) reaching 230
MeV in 25 meters.
The LIBO
The development is now continued by ADAM (an AVO company) prototype
structure and
Advantages of a LINAC:
accelerating
- High repetition frequency with pulse-to-pulse energy variability
cells (CERN)
- Small emittance, no beam loss.
The TULIP concept using CLIC The LIGHT linac by ADAM (being assembled
high-gradient cavities – 15 meters and built in a CERN test area) – 25 meters
The CERN Radio Frequency Quadrupole
CERN has developed and built a «mini-RFQ» (Radio Frequency Quadrupole) at
750 MHz, extending to higher frequencies and applications outside science the
experience of the Linac4 RFQ
Radio Frequency Quadrupole (the first element of any ion acceleration chain) at high frequency –
targeted at low current applications requiring small dimensions, low cost, low radiation emissions, up
to portability
The prototype unit (5 MeV protons) has been built at the CERN Workshops and is now
used in front of the LIGHT prototype linac of ADAM.
Ion therapy: advantages
Heavy ions are more effective than protons or X-rays in attacking cancer.
The particle (or X-ray) breaks the DNA; multiple breaks kill the tumour
cell. However, the key mechanism is DNA self-repair by the body cells.
 Protons and X-rays cause single-strand breaks that are easy to repair.
 Ions produce more ionisations per length and may cause double-
strand breaks that are much more difficult to repair.
Heavy ions allow for lower doses, are effective with radio-resistant
tumours (low oxygen content), and might reduce metastasis that are the
main cause of mortality.
So far, 2/3 of cases treated at the mixed facilities (CNAO, etc.) are with
carbon.
Fragmentation is what makes
ions more effective in treating
cancer
Radio Biological
Effectiveness (RBE) is
higher for Carbon than for
protons.
1.1 for protons
3 for C ions
(reference 1 for Co X-rays)

Ion therapy: cost and perspectives
For practical and historical reasons, all ion accelerators operate with fully
stripped Carbon ions.
Bethe energy loss goes as z2, z=charge of the incident particle → the
energy loss is higher for ions → we need a higher energy (per atomic mass
unit) to fully penetrate inside the body → around 440 MeV/u.
The accelerator is more complex than for protons: magnetic rigidity at full
energy is 2.76 times that of proton at full treatement energy.
Br [T .m] = 3.3356 × pc[GeV ]
For a given
magnet field, in a
medical ion
synchrotron with
respect to a proton
one accelerator
and gantries have
to be almost 3
times larger. All existing ion medical accelerators are
large synchrotrons.
The HIT gantry
Cyclotrons cannot be easily used because of
has a mass of 600
tons for a dipole the dimensions and complexity (needs
bending radius of superconductivity) and because of the
3.65 m. complexity of ion extraction from cyclotrons.
Alternative ions are being considered and extensive studies are ongoing
New developments in particle therapy
 Pencil Beam Scanning (PBS): (or Intensity-Modulated Particle Therapy IMPT)
scanning through the tumour of a small pencil beam, to reduce even more the dose
to surrounding organs.
 Motion Management: following the movements of the patients (breathing, etc.)
with the movement of the beam. It is often called 4-D scanning.
 Adaptive image guided therapy (IGPT): combining proton therapy and MRI.
 Imaging from secondary emission: imaging during treatment is possible by
monitoring secondary emission from the particle beam.
 Use of other ions: intermediate ions like e.g. Helium seem to have similar properties
than Carbon, while being easier to accelerate. Oxygen and Argon are also
considered. More clinical studies and accelerator design effort are needed.
 Particle beams for other diseases than cancer: interest for cardiac arrhythmia and
other applications.
 Compact gantries: the gantry is a critical element of particle therapy centres, in
terms of cost, dimensions and limitation to scanning speed. Options being
considered are superconducting magnets, FFAG, full accelerators on gantries, etc.

3 – electrons and neutrons

Hadron
Primary beam
Radiation Therapy
VHEE Very High Energy
Electron Therapy

Target
PET Positron
theragnostics
Therapy, others

Electrons: IORT and VHEE
Inter Operational Radiation Therapy (IORT) – (5-20 MeV):
Technique derived from radiation therapy, where a compact electron linac is
not used to produce X-rays, but to send the electrons directly on the tissues.
It delivers a concentrated dose of radiation therapy to a tumour bed during
surgery. This technology may help kill microscopic diseases, reduce
radiation treatment times, preserve more healthy tissue.
Very High Energy Electrons (50-

250 MeV) for radiotherapy:
Proposed as a lower-cost
alternative to hadron therapy, treat
deep seated tumours with high-
energy electron beams. High dose
deposition, less sensitive to errors,
good sparing of healthy tissues.
Made possible by recent advances
in high-gradient NC linac
technology (CLIC, etc.).

Neutrons: fast neutron therapy and BNCT
Fast Neutron Therapy (> 1 MeV): High RBE but difficulty in controlling and directing the neutral
particles. Only 7 centres in the world proposing fast neutron treatement, with beams generated by a
proton beam (50 MeV) on target or by a nuclear reactor.
Boron Neutron Capture Therapy

The (normal) stable version of boron,
boron-10, captures slow neutrons to
give boron-11. This then decays into
lithium-7 and alpha particles, which kill
any surrounding malignant tissue.
A boron-containing drug designed to
localise in cancerous cells is injected
into the patient, and a beam of low-
energy neutrons shaped to optimise
capture by the injected boron is
directed at the cancerous sites.
Two-stage creation of the delivered
dose, particularly effective with some
difficult-to-treat cancers such as brain
A BNCT centre is in operation in Tokyo, a first
tumours or malignant melanoma.
commercial unit installed at Helsinki,
Neutron production requires intense experimentation progressing in several centres.
proton beams (e.g. 3 MeV, >1 mA CW)
with problems of heat load, activation,
M. Vretenar, Accelerators for Medicine 33
target (usually solid lithium).12/6/2018
4- Radioisotopes - imaging

Hadron
Primary beam
Radiation Therapy
Electron Therapy

Target
PET Positron
theragnostics
Therapy, others

Radioisotope-based tomographies
 A radioisotope (radiotracer) is produced by an
accelerator (usually a cyclotron) and attached to
a normal chemical compound, usually a glucose,
in a radiopharmaceutical unit.
 The compound is injected to the patient and
accumulates in tissues with high metabolic
activity, as tumours – and metastasis.
 When the radioisotope decays, the emitted
particles are detected by a scanner allowing a
precise mapping of the emitting areas.
 In SPECT (single photon emission computed
(source: Huntsman Cancer Institute) tomography) is used Technetium-99 (6 hours
half-life) that emits a photon. 99-Te is generated
in the hospital by Molybdenum-99 (66 hours
half-life) produced at a nuclear plant.
 In the much more precise PET (Positron Emission
Tomography) is used Fluorine-18 (1h50’ half-life)
attached to Fludeoxyglucose (FDG) molecules,
90% of PET scans are
in clinical oncology
which emits positrons that annihilates with
electrons producing 2 gamma rays in opposite
directions.
The isotope production and distribution scheme
Isotopes and radiochemical drugs are

produced in large centres equipped with (courtesy Robert Hamm)
a commercial cyclotron.
After production, the drugs are shipped • Sales in 2015 - US$165M (~ 60 units sold
per year).
by road or air to the hospital (FDG half- • Top 5 manufacturers sell more than 50 units
life 1h50’). per year.
This scheme works well in Europe and • PET sales dominate market (> 95% of all PET
procedures use FDG.
US (good transport networks, shows • Sales flat (saturated?) in North America and
limits in Asia and rest of world). Europe due to FDG distribution model.
• Sales increasing in Asia and rest of the world.
Isotope production in hospitals
Alternative accelerator systems under study to extend the reach of PET
imaging to areas far from the large production centres and to the use of
alternative isotopes with shorter half-life (e.g. 11C, 20 min). 11C is more
effective than 18F for some cancer imaging and reduces the dose to the patient.
AMIT superconducting cyclotron

for isotope production in hospitals The CERN design of a 2-stage HF-
(CIEMAT, Spain, with CERN RFQ system to 10 MeV.
contribution) Only the production target is shielded
(by layers of steel and borated
polyethilene). Footprint: 15m2
SPECT isotopes from accelerators
Accelerator Production of
Technetium-99 (half-life 6 h)
Source: Nature, 2013
SPECT isotopes are now produced in nuclear • 30 MeV cyclotron

reactors (Molybdenum-99 generators, 66 hrs., • Photo-fission of U
converted to Technetium-99 in the hospital). • Neutron-spallation of Mo
Source: Government of Canada 2009 shortage crisis

5 – Radioisotopes, treatment

Hadron
Primary beam
Radiation Therapy
Electron Therapy

Target
PET Positron
theragnostics
Therapy, others

Targeted Alpha Therapy
Alpha-emitting therapeutic isotopes as an example of therapeutic isotopes
Injected radiolabeled antibodies accumulate in cancer tissues and selectively deliver their
dose. Particularly effective with alpha-emitting radionuclides (minimum dose on
surrounding tissues).
Advanced experimentation going on in several medical centres, very promising for solid
or diffused cancers (leukaemia).
Potential to become a powerful and selective tool for personalised cancer treatment.
If the radioisotope is also a gamma or beta emitter, can be coupled to diagnostics tools to
optimise the dose (theragnostics)
Alpha particles: very high RBE (up to 1’000)

Penetration in tissues only 10’s of mm

Accelerators for Alpha Emitters - Astatine
 In the trial phase, only small quantities of a-emitting radionuclides are needed,
provided by research cyclotrons.
 If this technique is successful, there will be a strong demand of a-emitters that the
accelerator community will have to satisfy.
 One of the most promising a-emitters is Astatine-211, obtained by a bombardment
of a natural Bismuth target (209Bi(α,2n) 211At nuclear reaction).
 At production needs a (q/m=1/2) accelerator; optimum energy 28 MeV (sufficient
yield but below threshold for 210Po), current >10 mA.
 The use of a’s in cyclotrons is limited by extraction losses; linacs have a strong
potential.
 Synergy with low-energy section of carbon therapy linacs (q/m=1/2).
Astatine, an amazing element:

The rarest element on earth (only 25 g at any given time)
The less stable element in the periodic table (<100)
Half life (210At): 7.2 hours

Theragnostics
Theragnostics = integration of diagnostics and therapeutics. Disease identification,
targeting, treatment and monitoring opens a new chapter in precision medicine.
In Molecular Nuclear Medicine, theragnostics consists in using targeting molecules
labeled either with diagnostic radionuclides (e.g., positron or gamma emitters), or with
therapeutic radionuclides (e.g., beta emitters) for diagnosis and therapy of a particular
disease. Molecular imaging and diagnosis can be followed by personalised treatment
utilizing the same targeting molecules. Example: gallium 68 (Ga-68) labeled tracers for
diagnosis, followed by therapy using lutetium Lu-177 to radiolabel the same targeting
molecule for personalized radionuclide therapy.
A recent success story:

Lutathera developed by AAA
(company with old relations
to CERN, based in St.
Genis). AAA now acquired by
Novartis for 3.9 billion $ cash

6 – New CERN initiatives

CERN Medical Initiatives
 Renewed interest at CERN in promoting medical accelerator developments within
the limits set by the «knowledge transfer for the benefit of medical applications»
document approved by Council in March 2017.
 Limited personnel and material budget, to be used as seed funding for
collaborative R&D projects (receiving additional support from EU or other sources),
using technologies and infrastructures that are uniquely available at CERN.
 A proposal is in preparation for a collaborative design study, possibly coordinated
by CERN, for a new generation of compact and cost-effective light-ion medical
accelerators. For the moment this initiative is called «PIMMS2» - as a follow-up of
the old PIMMS.
Funding and
Organisational Structure:
~ 0.1% of the CERN
budget (for P+M),
administered and
controlled by 5
Committees.

PIMMS2 Guidelines
18 years after PIMMS the particle therapy environment has evolved and the situation now is
different from the time when PIMMS was completed:
 Proton therapy is now industrial
 Ion therapy has a clear potential but requires a strong effort in clinical testing to optimize
treatment and in the design of a more compact and possibly more economic accelerator.
PIMMS2 will explore options to design a novel ion accelerator, improving with respect to the
PIMMS(1) generation. It should lead to the design of a multinational research and therapy
facility with ions.
PIMMS2 should be carried on by a wide collaboration involving a large number of partners
and including potential future users of the design. The new programme should be
innovative, build on CERN competences, and not be in competition with industry or national
programmes in the Member States.

The synchrotron option
 Can benefit of the momentum
gained with the BioLEIR
proposal at CERN, recently
discarded.
 Must profit of the experience of
the 4 existing ion therapy
centers + GSI.
 Needs a wide collaboration.
 Some new features to explore:
- Smaller emittances
- Superconducting magnets
- New NC magnet design
- Option of fast extraction
- Multiple ion sources First step: International
- Electron cooling (smaller beam Workshop in June to
size)
explore technical and
- SC gantries
collaboration options

The linac option
Among the alternative options to synchrotrons (SC cyclotron, FFAG, Linear
accelerator), The linear accelerator looks as the most promising in terms of
size, complexity, energy variability potential (pulse to pulse) and match to
CERN competences and experience.
A 430 MeV/u Linac could be about 50 m long, folded in 2 sections. Accelerator
footprint 200 m2.
Continuation of the
ongoing CABOTO linac
design developed by
TERA (U. Amaldi et al.),
with CERN contribution.

Synergies: the SEEIIST Initiative
 Following the initiative of H. Schopper and with the
coordination of S. Damjanovic, nuclear physicist and
Minister of Science of Montenegro, 8 Balkan countries
have signed a Declaration of Intent for the creation of
the South-East European International Institute for
Sustainable Technologies.
 Their goal is to foster peace and collaboration in the
area with the creation of a particle accelerator
laboratory, following the example of the SESAME
facility in Middle East.
 In March 2018 the SEEIIST has decided to build a
combined cancer therapy and biomedical research
facility (preferred to a synchrotron light facility).
 Funding (150-200M) primarily from structural and pre-
accession EU funds.
 CERN was asked to host the headquarters of SEEIIST
and the study group, until the site is selected.
 2 years to prepare a TDR.
Conclusions
• Medical accelerators is a vast and promising field, connected to one
of the main technology drivers of XXIst century.
• There is wide space for improvement and for exciting new
developments
• However, the accelerator is only a (small) part of wider facilities
devoted to delivering medicine to patients, which have to comply
with well defined and established procedures and rules.
the MedAUSTRON hall

Thank you for your attention
maurizio.vretenar@cern.ch

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Accelerators for Medicine

Maurizio Vretenar, CERN

Academic Training, 12 June 2018

12/6/2018 M. Vretenar, Accelerators for Medicine 3

Total: ≈ 16’000 particle accelerators operating for medicine

12/6/2018 M. Vretenar, Accelerators for Medicine 4

For a U.S. population of over Nuclear medicine:

12/6/2018 M. Vretenar, Accelerators for Medicine 5

12/6/2018 M. Vretenar, Accelerators for Medicine 6

In 1946, Robert Wilson proposed to use protons to treat cancer, profiting

First treatment of pituitary tumours took place at Berkeley in 1956.

Early idea of curing cancer with particle accelerators

12/6/2018 M. Vretenar, Accelerators for Medicine 7

12/6/2018 M. Vretenar, Accelerators for Medicine 8

IntegraLab® PLUS combined radiopharmaceutical production

12/6/2018 M. Vretenar, Accelerators for Medicine 9

Up to 2000 mSv highly

Accelerator Secondary beam

12/6/2018 M. Vretenar, Accelerators for Medicine 11

To spare surrounding tissues

Combined imaging and therapy

Modern imaging techniques (CT computed tomography, MRI magnetic

12/6/2018 M. Vretenar, Accelerators for Medicine 13

The Side Coupled Linac structure was invented at Los

A great example of technology transfer from basic science to society

(courtesy ENLIGHT Network)

12/6/2018 M. Vretenar, Accelerators for Medicine 15

A collaboration led by the NGO International Cancer

12/6/2018 M. Vretenar, Accelerators for Medicine 16

protons proton therapy

Accelerator Secondary beam

12/6/2018 M. Vretenar, Accelerators for Medicine 17

12/6/2018 M. Vretenar, Accelerators for Medicine 18

The results of irradiating a nasopharyngeal carcinoma

12/6/2018 M. Vretenar, Accelerators for Medicine 19

A success story, but …

12/6/2018 M. Vretenar, Accelerators for Medicine 20

12/6/2018 M. Vretenar, Accelerators for Medicine 22

Source: IBA, state of proton therapy

Source: IBA proton therapy fact-sheet,

12/6/2018 M. Vretenar, Accelerators for Medicine 23

Critical issues with cyclotrons:

12/6/2018 M. Vretenar, Accelerators for Medicine 24

12/6/2018 M. Vretenar, Accelerators for Medicine 25

12/6/2018 M. Vretenar, Accelerators for Medicine 28

12/6/2018 M. Vretenar, Accelerators for Medicine 30

protons proton therapy

Accelerator Secondary beam

12/6/2018 M. Vretenar, Accelerators for Medicine 31

Very High Energy Electrons (50-

12/6/2018 M. Vretenar, Accelerators for Medicine 32

Boron Neutron Capture Therapy

protons proton therapy

Accelerator Secondary beam

12/6/2018 M. Vretenar, Accelerators for Medicine 34

Isotopes and radiochemical drugs are

AMIT superconducting cyclotron

SPECT isotopes are now produced in nuclear • 30 MeV cyclotron

Source: Government of Canada 2009 shortage crisis

12/6/2018 M. Vretenar, Accelerators for Medicine 38

protons proton therapy

Accelerator Secondary beam

12/6/2018 M. Vretenar, Accelerators for Medicine 39