Treating Cancer with Charged
Particles
Claire Timlin
Particle Therapy Cancer Research Institute, Oxford Martin School,
University of Oxford
Slides are a PTCRi group effort.
Contents
• Introduction to Charged Particle Therapy
• Production and Delivery of Medical Proton Beams
• Introduction to the Particle Therapy Cancer Research Institute
• Research Projects
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Malignant Induction Modelling
Virtual Phantoms
Data Recording and Sharing
Biological Effectiveness of Particle Beams
Clinical Ethics of Charged Particle Therapy
• Proton Therapy in the UK
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Introduction to Charged Particle
Therapy
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Development of Radiotherapy
• 1895: Wilhelm Conrad Rontgen discovers Xrays
• 1896: First x-ray treatment 3 months later!
• 1898: The Curies discover radium
• 1905: First Curie therapy
– birth of brachytherapy
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The Evolution of External Beam Radiation Therapy
1950’s
The First
Cobalt Therapy
Unit and Clinac
1970’s
Cerrobend Blocks
Electron Therapy
Standard Collimator
5Slide courtesy of Prof. Gillies McKenna
1980’s Computerized 3D
CT Treatment
Planning
1990’s
Multileaf Collimator Dynamic MLC
and IMRT
High resolution
IGRT
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Particle
Therapy
2000’s?
Functional
Imaging
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History of Proton Therapy
• 1946:
– Therapy proposed by Robert R. Wilson,
Harvard Physics
• 1955:
– 1st Proton Therapy at Lawrence Tobias
University of California, Berkeley
• 1955-73:
– Single dose irradiation of benign CNS
lesions
Proton Therapy Centres
Worldwide
http://www.uhb.nhs.uk/ProtonsBirmin
gham/background/facilities.htm
• 2010:
– > 67 000 patients had been treated with
protons worldwide
– 29 proton therapy centres operating
worldwide
– ~ 20 more planned or under construction
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Low vs. High Linear Energy Transfer Radiation
Sparsely ionising radiation (low-LET)
e.g. -rays, -particles
Low concentration
of ionisation events
electron tracks
Densely ionising radiation (high-LET)
e.g. -particles
C6+ ions
High concentration
of ionisation events
7Slide courtesy of Dr Mark Hill
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DNA
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Radiation Induced Damage
• Central Nervous System
– blindness, deafness, paralysis, confusion, dementia, chronic tiredness
• Bowel
– colostomy, chronic bleeding.
• Lung
– shortness of breath
– pneumonias
• Kidney
– renal failure and hypertension
• Reproductive organs
– sterility
• Everywhere:
– severe scarring in medium to high dose regions
– possible increase in induced cancers in low-medium dose regions
• Therefore must avoid dose to normal tissues..........
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Conformal Radiotherapy
• Advantages
– Reduced dose to organs at risk
• Fewer complications
– Increased tumour dose
• Higher probability of tumour control
• Disadvantages
– Requires precise definition of
target
– Complicated planning and
delivery therefore expensive!
– Large volumes of lowintermediate dose (e.g. IMRT) ->
secondary cancers
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Photon vs. Proton/Ion Depth-dose Curve
Photons
Dose
Protons
Carbon
Ions
Depth
• High energy photons
favoured over low energies
due to skin sparing
• Dose falls off but not to zero
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• Density of ionizations
increase as the particles
slow down -> peak in dose
• No dose past peak
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The Spread Out Bragg Peak
Incident energy is
modulated to form spread
out Bragg Peaks the cover
the tumour
Unnecessary dose
Skin sparing
Unnecessary dose
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Combining Fields
80
60
50
150
0
0
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X-Rays
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150
Protons/Ions
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IMRT vs. Proton Therapy
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Medulloblastoma in a Child
X-rays
100
60
With Xrays
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With Protons
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Orbital Rhabdomyosarcoma
Protons/Ions
X-Rays
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Courtesy T. Yock, N. Tarbell, J. Adams
Proton Therapy in Action
Anaplastic Ependymoma Brain Tumour
http://news.bbc.co.uk:80/1/hi/england/7784003.stm
15th Dec
http://news.bbc.co.uk/1/hi/england/7795909.stm
19th Dec
http://news.bbc.co.uk/1/hi/england/7906084.stm
23rd Feb
Pre-treatment
During-treatment
Post-treatment
CPC, Friedmann, NEJM, 350:494, 2004
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Slide courtesy of Prof. Gillies McKenna
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Production and Delivery of Medical
Proton Beams
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Beam Acceleration
HIT, Germany
• Cyclotron
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• Synchrotron
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Protons up to ~250 MeV
Requires degraders
High current
Small(ish)
Simple(ish)
Main Manufacturers
• IBA ,Varian
Carbon up to 400MeV/
Dynamic energy change
Lower current
Bigger
More complicated
Main Manufacturers
• Hitachi, Siemens
– Best choice for protons at
present?
– Only viable choice for heavy ion
therapy at present?
Future accelerators that do the job better? e.g FFAG, Laser Driven?
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Beam Transport
• Gantries
• Fixed Beams
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•Clinical Indications
•Flexibility
•Space
•Cost
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Beam Delivery - Scanning
•
Parallel proton pencil beams are used (~3mm σ )
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Sweeper magnets scan the target volume in transverse plane (steps of 4mm)
•
One litre target volume typically 10000 spots are deposited in less than 5min.
Beam
direction
Target
Patient
Beam
direction
Target
Patient
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Beam Delivery - Scattering
Courtesy of T. Lomax, PSI, Switzerland.
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Introduction to the Particle Therapy
Cancer Research Institute
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The Particle Therapy Cancer Research Institute
PTCRi
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The PTCRi Collaborators
• Also work closely with (not an exhaustive list!):
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Oxford Radcliffe Hospitals Trust
CERN
Mayo Clinic, Minnesota, USA
RAL
Ethox, University of Oxford
Maastro, Maastrict, Netherlands
Electa-CMS, Germany
• For more info on the PTCRi team see:
http://www.ptcri.ox.ac.uk/people/
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Challenges in Charged Particle Therapy
Radiobiological modelling
validated with existing cell, small
animal and clinical data
Investigating equipoise and clinical
utility in collaboration with ETHOX.
Oxford PT centre or collaboration?
• Which particle (, p, C)?
– Radiobiology
– Cost-effectiveness
New, improved radiobiological
experiments on cells (and small
animals)?
• Which clinical indications?
– Clinical ethics
• Treatment Planning and Delivery
Database for multiple parallel
radiobiological calculations (with
Jim Loken) -> sensitivity analyses
EU Projects: ULICE, PARTNER,
ENLIGHT.
– MC vs. treatment planning algorithms
– Biological heterogeneity
– Uncertainty in radiological models and
parameters
At treating centres
– Organ Motion
• Recording and sharing clinical data
• Late effects e.g. carcinogenesis
FFAG (PAMELA), laser driven
accelerators.
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Voxelised virtual phantom
Radiobiological modelling
validated with existing cell,
small animal and clinical data.
• Accelerator design
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Novel Accelerator and Gantry Design
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FFAG Accelerator
Fixed Field Alternating Gradient synchrotrons,
FFAGs, combine some of the main advantages of
both cyclotrons and synchrotrons:
• Fixed magnetic field – like a cyclotron
‒ fast cycling
‒ high acceptance
‒ high intensity
‒ easy maintenance
‒ high reliability
• Strong focussing – like a synchrotron
‒beam extraction at any energy
‒higher energies or ion acceleration
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FFAG Gantry
A PAMELA NS-FFAG Gantry conceptual design
Conventional Carbon Gantry at Heidelberg
•Gantry is a beam delivery system which can rotate around the patient in 3600
•Delivering beams, avoiding critical organs and minimal transverse irradiation
•Consists of bending magnets, focusing magnets, beam scanning system
•Only one C- ion gantry existing at present , weighs ~600 tons
•Use of FFAG technique is expected to reduce the size considerably
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Laser Driven Ion Acceleration
plasma
sheath
metal foil
Pulsed
laser
-++
-++--+++-++---+
+
--
eions
(Target Normal Sheath Acceleration-TNSA)
Contaminant
layer
•High intensity (>1019 Wcm-2) laser irradiate thin foil (~10μm)
•Laser electric field is higher than atomic electron binding energy (~1016 Wcm-2) and the surface will be
instantly ionised and plasma is created.
•Laser electric field and magnetic field drive plasma electrons into the target with relativistic energies
•Some of the energetic electrons escapes through the rear side of the target (non irradiated surface) and
large space charge is generated on the rear surface.
•This sheath field is of the order of ~1012 Vm-1, ionises rear surface and accelerate ions to MeV energies
(generally present in the form of contaminants)
•Any ion species can be accelerated
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Advantages and Challenges of Laser Driven Ion Acceleration
Advantages
•Extreme laminarity: rms emittance < 0.002  mm-mrad
•Short duration source: ~ 1 ps
•High brightness: 1011 –1013 protons/ions in a single shot (> 3 MeV)
•High current : kA range
•minimal shielding and expensive magnets are not required
Challenges
•Clinical energies are not achieved yet (~65MeV proton at present)
•Energy spread, repetition rate, neutron contamination, beam stability…
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Malignant Induction Modelling
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Radiation Action on Cells
Direct DNA damage
DNA dsb
Repair
No repair
Mis-repair
Mutation
Cell survival
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Slide courtesy of Prof. Boris Vojnovic
Transformation
PP Seminar
Cell death
30/11/2010
Induction and cell kill
What is the form
of the induction
function? Linear,
quadratic?
Probability of
transforming a cell
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Cell killing
Induction
Form of cell killing
function known with
some certainty at clinical
energies, the parameters
are tissue dependent
and can have large
uncertainties.
Probability the cell
survives
Probability of inducing a
potentially malignant mutation
Risk needs to be
•accurately modelled
•confirmed experimentally
•taken into account when deciding on the optimal
treatment plan
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Voxelised 3D Calculations of Biological Endpoints
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Model and parameter sensitivity analyses
Validation with clinical data on secondary malignancies
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Virtual Phantoms
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Virtual Phantoms
• Virtual phantom provides an anthropomorphic reference
geometry for Monte Carlo particle transport
• Two flavours:
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Computationally
intensive
voxellised
phantoms
Geometrically
simple
mathematical
phantoms
(3D equivalent of
pixels)
(cylinders, spheres,
cones, etc...)
• Nowadays have the memory and processing power to deal
with megavoxels
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Virtual Phantoms
• ICRP Reference Man consists of 7 million voxels (3D
pixels)
• Each voxel assigned an organ type that specifies
density, elemental composition, etc.
• Size and masses typical of average man
• Female phantoms also exist, children being developed
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PTCRi Phantom work
• ICRP man has been converted to a simulated CT scan
– can be input into treatment planning software
• Enables assessment of TPS accuracy by comparison to
Monte Carlo:
– Accuracy of the TPS method of mapping CT number (x-ray
linear attenuation coefficient) to proton stopping power
– Effect of air cavities and tissue boundaries on the range and
profile of proton beams
• Also interested in examining the second cancer
induction risk due to scatter from the beam head.
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Data Recording and Sharing
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EU Projects: ENLIGHT and PARTNER
http://enlight.web.cern.ch
40 Slide courtesy of Faustin Roman
http://partner.web.cern.ch
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EU Project: ULICE
• ULICE: Union of Light Ion Centres in Europe
• Aims:
– Transnational access to particle radiotherapy facilities
– Facilitating joined up research across Europe
– Addressing efficacy and cost-benefits for CPT
• Methods:
‒ developing and recommending standards for key observations
and measurements in CPT
‒ facilitate data sharing and reuse through pan-European
collaborative groups
‒ at the point at which key European centres are
commissioning facilities
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European Heavy Ion Centres
Centres in Europe
treating with heavy ions
NRoCK
(Kiel)
RKA
(Marburg)
HIT
MedAustron
(Heidelberg)
(Wiener Neustadt)
ETOILE
(Lyon)
Connect centres ...
... and make most of
available data!
CNAO
(Pavia)
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Data Sharing and Interpretation - Challenges
Platform for translational research
Medical
Users
Doctor
and clinical practiseclinicians
(1/2)
from multiple disciplines
with specific views on data
researchers
Biologist
across Europe
with different levels of
technical knowledge
Statistician
data owners
Chemist
Physicists
with different privileges
Common access
point
Data
from multiple disciplines
with specific terminologes
stored across Europe
In various independent
repositories
with different ethical and
legal requirements
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GRID? : Coordinated resource sharing and problem solving in
dynamic, multi-institutional virtual organizations… (I. Foster et al)
Hadrontherapy Information Sharing Platform (HISP)
Prototype connecting:
• Users
• Data sources
with
• Grid resources
• Security framework
• Data integration services
by
• Portals
• Interfaces
30/11/2010
Slide courtesy of Faustin Roman
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USECASES:
1. REFERRAL 2.RESEARCH
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A patient opinion…
http://www.nature.com/nm/journal/v16/n7/full/nm0710-744.html
30/11/2010
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Slide courtesy of Faustin Roman
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Biological Effectiveness of Particle
Beams
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Relative Biological Effectiveness
• Photons and protons (at clinical energies) have similar
biological effects
– Clinically a modifier (RBE) of 1.1 is applied to physical dose for protons
• For heavier ions (e.g. C) RBE has large uncertainties
• RBE needed* to calculate physical dose to administer to
achieve prescribed biological dose
*maybe there is a better way?
New treatment regimes requiring new methods of
optimisation?
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RBE vs. Dose for Protons
Where does the 1.1 come from?
Paganetti et al.: Int. J. Radiat. Oncol. Biol. Phys. 2002; 53, 407
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RBE vs. Dose for Protons
More data is required to
determine magnitude of
proton RBE variation with
dose for a variety of tissues
Where? CERN?
V79 Cells. Wouters et al.: Radiat Res 1996
vol. 146 (2) pp. 159-70
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Modeling RBE vs. Dose for Carbon
RBE increases with decreasing dose
Analysis of 77keV Data from Suzuki et al, IJRBP, Vol. 48, No. 1, pp. 241–250, 2000
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RBE – The Solution?
• Radiobiological experiments
– GSI, Germany
– Gray Institute for Radio-oncology and Biology
– Future – CERN?
• Validated (or at least validatable!)
radiobiological models
– Mechanistic vs. empirical?
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Clinical Ethics of Charged Particle
Therapy
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Ethical Issues in CPT
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Controversy among the medical community about CPT
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Few Randomised Control Trials (RCTs), the “gold standard” for evidence of clinical
effectiveness
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Dose distributions obtained with CPT mostly superior conventional radiotherapy
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RCTs are unethical if they lack “equipoise”
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Biological dose uncertainties enough to restore equipoise?
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Limited number of centres
– What is the optimal use?
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Paper to discuss issues
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Workshop next year
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Proton Therapy in the UK
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Proton Therapy in UK - Clatterbridge
• World First: hospital based
proton therapy at
Clatterbridge, near Liverpool
• >1700 patients with ocular
melanoma; local control ~97%.
• Targets the cancer
• Avoids key parts of eye (optic
nerve, macula, lens)
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Proton Therapy in UK – Where Next?
•
http://www.bbc.co.uk/news/uk-england-11519263
•
Decision of Department of Health - 17th September 2010
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“The three potential trial sites are the Christie NHS Foundation Trust in
Manchester, University College London Hospital and University Hospitals
Birmingham NHS Foundation Trust.”
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Research and treatment centre at Oxford?
•
Centres should:
– Treat patients currently eligible for treatment abroad
– Optimise treatment regimes
– Expand indications
– Research biological effectiveness of protons and heavier ions
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– Train staff............
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Summary
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CPT is a rapidly expanding field
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Many challenges still to be tackled
– Optimal treatments for protons
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Fractionation schemes
Dose delivery
– Heavy Ions
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Radiobiological uncertainties
Treatment planning and delivery uncertainties
Organ motion
Cost-effectiveness
Clinical ethics
Achieved by
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Which ions?
For which indications?
Accelerator development
Radiobiological modelling and experiments
Advanced treatment planning and delivery techniques e.g. MC, proton radiography
Consistent data recording and data sharing
Clinical studies with long-term follow-up
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• Thank you for listening.....
......any questions?
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• Back up slides
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Contributions to the Proton Bragg Peak
Coulomb interactions with atomic electrons
Energy spread and energy loss differences
Nuclear interactions with atomic nuclei
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Illustrations courtesy of M. Goitein
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ULICE - Work Package 7
• seeks to provide automatic support for the management
and use of these standards
– customise components of information systems and
analysis engines from the definition of the data
– better documentation and design leads to
transparency and reliability of results
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Contributions to the Proton Bragg Peak
Coulomb interactions with atomic electrons
Energy spread and energy loss differences
Nuclear interactions with atomic nuclei
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Illustrations courtesy of M. Goitein
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The combined effect (in water)
Used for
imaging
Credit:
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Historically Currently
used in
used in
radiotherapy radiotherapy
Figure by MIT OpenCourseWare.
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Transferred
to charged
particles
Scattered
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Curing Cancer with X-rays
Dose
Linac
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Slide
courtesy of Ken Peach
30/11/2010
Can we do better?
Dose
The Bragg Peak
Proton
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Slide
courtesy of Ken Peach
30/11/2010
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Proton Therapy
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