1. Treating Cancer with Charged Particles
Claire Timlin
Particle Therapy Cancer Research Institute, Oxford Martin School, University of Oxford
Slides are a PTCRi group effort.

2. Contents Introduction to Charged Particle Therapy
Production and Delivery of Medical Proton Beams
Introduction to the Particle Therapy Cancer Research Institute
Research Projects
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
PP Seminar
30/11/2010

3. Introduction to Charged Particle Therapy
PP Seminar
30/11/2010

4. Development of Radiotherapy
1895: Wilhelm Conrad Rontgen discovers X-rays
1896: First x-ray treatment 3 months later!
1898: The Curies discover radium
1905: First Curie therapy
birth of brachytherapy
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30/11/2010

5. The Evolution of External Beam Radiation Therapy
1950’s
The First Cobalt Therapy Unit and Clinac
Computerized 3D CT Treatment Planning
1990’s
2000’s?
1980’s
1970’s
Key points to make:
Completely new carriage and leaf design to
Other improvements made:
Reduced Head Diameter by 10 cm from previous “Standard” MLC
Functional
Imaging
Cerrobend Blocks Electron Therapy
Multileaf Collimator
Dynamic MLC
and IMRT
Standard Collimator
High resolution IGRT
Particle
Therapy
Slide courtesy of Prof. Gillies McKenna
PP Seminar
30/11/2010

6. History of Proton Therapy
1946:
Therapy proposed by Robert R. Wilson, Harvard Physics
1955:
1st Proton Therapy at Lawrence Tobias University of California, Berkeley :
Single dose irradiation of benign CNS lesions
2010:
> patients had been treated with protons worldwide
29 proton therapy centres operating worldwide
~ 20 more planned or under construction
Proton Therapy Centres Worldwide
PP Seminar
30/11/2010

7. 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
DNA
Slide courtesy of Dr Mark Hill
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30/11/2010 7

8. 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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30/11/2010

9. 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 low-intermediate dose (e.g. IMRT) -> secondary cancers
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30/11/2010

10. Photon vs. Proton/Ion Depth-dose Curve
Photons
Protons
Carbon
Ions
Dose
Depth
High energy photons favoured over low energies due to skin sparing
Density of ionizations increase as the particles slow down -> peak in dose
Dose falls off but not to zero
No dose past peak
PP Seminar
30/11/2010

11. 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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30/11/2010

12. Combining Fields X-Rays Protons/Ions 80 50 150 60 150 40 PP Seminar60
150 40
X-Rays
Protons/Ions
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13. IMRT vs. Proton Therapy
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14. Medulloblastoma in a Child
X-rays
100 60 10
With Xrays
With Protons
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15. Orbital Rhabdomyosarcoma
Protons/Ions
X-Rays
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30/11/2010
Courtesy T. Yock, N. Tarbell, J. Adams

16. Proton Therapy in Action Anaplastic Ependymoma Brain Tumour th Dec Dec Feb
Pre-treatment
During-treatment
Post-treatment
CPC, Friedmann, NEJM, 350:494, 2004
Slide courtesy of Prof. Gillies McKenna
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30/11/2010

17. Production and Delivery of Medical Proton Beams
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30/11/2010

18. Beam Acceleration Cyclotron Synchrotron Protons up to ~250 MeV
HIT, Germany
Cyclotron
Synchrotron
Protons up to ~250 MeV
Carbon up to 400MeV/
Requires degraders
Dynamic energy change
High current
Lower current
Small(ish)
Bigger
Simple(ish)
More complicated
Main Manufacturers
IBA ,Varian
Hitachi, Siemens
Best choice for protons at present?
Only viable choice for heavy ion therapy at present?
Hydrogen gas
Plasma created via interaction with electrons form cathode
Future accelerators that do the job better? e.g FFAG, Laser Driven?
PP Seminar
30/11/2010

19. Beam Transport Gantries Fixed Beams Clinical Indications Flexibility
Space
Cost
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20. Beam Delivery - Scanning
Parallel proton pencil beams are used (~3mm σ )
Sweeper magnets scan the target volume in transverse plane (steps of 4mm)
One litre target volume typically spots are deposited in less than 5min.
Beam direction
Target
Patient
parallel proton pencil beams are used (~3mm σ )
position and dose of each spot is chosen by the computer in the treatment planning system, individually for each spot
sweeper magnets are used to scan the target volume in transverse plane (steps of 4mm)
scanning depth is controlled by changing beam energies.
for one litre target volume typically spots are deposited in less than 5min.
dose distributions of complex shapes can be constructed with less entrance dose
Beam direction
Target
Patient
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30/11/2010

21. Beam Delivery - Scattering
Courtesy of T. Lomax, PSI, Switzerland.
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22. Introduction to the Particle Therapy Cancer Research Institute
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23. The Particle Therapy Cancer Research Institute
PTCRi
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24. The PTCRi Collaborators
Also work closely with (not an exhaustive list!):
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:
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30/11/2010

25. Challenges in Charged Particle Therapy
Which particle (, p, C)?
Radiobiology
Cost-effectiveness
Which clinical indications?
Clinical ethics
Treatment Planning and Delivery
MC vs. treatment planning algorithms
Biological heterogeneity
Uncertainty in radiological models and parameters
Organ Motion
Recording and sharing clinical data
Late effects e.g. carcinogenesis
Accelerator design
Radiobiological modelling validated with existing cell, small animal and clinical data
New, improved radiobiological experiments on cells (and small animals)?
Prostate study with Maastro
Investigating equipoise and clinical utility in collaboration with ETHOX.
Oxford PT centre or collaboration?
Voxelised virtual phantom
Database for multiple parallel radiobiological calculations (with Jim Loken) -> sensitivity analyses
At treating centres
EU Projects: ULICE, PARTNER, ENLIGHT.
Radiobiological modelling validated with existing cell, small animal and clinical data.
FFAG (PAMELA), laser driven accelerators.
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30/11/2010

26. Novel Accelerator and Gantry Design
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30/11/2010

27. 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
PP Seminar
30/11/2010

28. FFAG Gantry
Conventional Carbon Gantry at Heidelberg
A PAMELA NS-FFAG Gantry conceptual design
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
PP Seminar
30/11/2010

29. Laser Driven Ion Acceleration+ - e-
ions
Pulsed
laser
Contaminant layer
metal foil
plasma sheath
(Target Normal Sheath Acceleration-TNSA)
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
PP Seminar
30/11/2010

30. Advantages and Challenges of Laser Driven Ion Acceleration
Extreme laminarity: rms emittance <  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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31. Malignant Induction Modelling
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32. Radiation Action on Cells
Direct DNA damage
DNA dsb
Repair
Mis-repair
Mutation
Transformation
No repair
Cell survival
Cell death
Slide courtesy of Prof. Boris Vojnovic
PP Seminar
30/11/2010

33. Induction and cell kill
What is the form of the induction function? Linear, quadratic?
Induction
Cell killing
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 transforming a cell
Risk needs to be
accurately modelled
confirmed experimentally
taken into account when deciding on the optimal treatment plan
Probability of inducing a potentially malignant mutation
PP Seminar
30/11/2010

34. Voxelised 3D Calculations of Biological Endpoints
Model and parameter sensitivity analyses
Validation with clinical data on secondary malignancies
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30/11/2010

35. Virtual Phantoms
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36. Virtual Phantoms
Virtual phantom provides an anthropomorphic reference geometry for Monte Carlo particle transport
Two flavours:
Nowadays have the memory and processing power to deal with megavoxels
Computationally intensive
voxellised phantoms
(3D equivalent of pixels)
Geometrically simple
mathematical phantoms
(cylinders, spheres, cones, etc...)
PP Seminar
30/11/2010

37. 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
PP Seminar
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38. 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.
PP Seminar
30/11/2010

39. Data Recording and Sharing
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40. EU Projects: ENLIGHT and PARTNER
Slide courtesy of Faustin Roman
PP Seminar
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41. 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
PP Seminar
30/11/2010

42. European Heavy Ion Centres
Centres in Europe treating with heavy ions
NRoCK
(Kiel)
RKA
(Marburg)
Connect centres ...
... and make most of available data!
HIT
(Heidelberg)
MedAustron
(Wiener Neustadt)
ETOILE
(Lyon)
protons better target conformity than photons
Common treatment for certain cancers
Many centres operational worldwide
„heavy ions“ e.g. Carbon, higher RBE, until last year only two clinical centres in Japan and a few research institutes in Europe
...centres
Relatively new treatment, not fully understood -> data needed -> connect centres with coherent IT infrastructure
Motivate why this information sharing is important
CNAO
(Pavia)
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30/11/2010

43. Data Sharing and Interpretation - Challenges
Platform for translational research
and clinical practise (1/2)
Medical Doctor
Statistician
data owners
Users
clinicians
from multiple disciplines with specific views on data
researchers
Biologist
across Europe
Chemist
with different levels of technical knowledge
Physicists
with different privileges
Data
Common access point
from multiple disciplines with specific terminologes
Problem of connecting users to data
Users -> from several disciplines
Data –> as well
Implies distinct views on data
Different institutes use different standards, e.g. For tumour staging
Different disciplines may use different terminologies for the same concept
Need way to annotate data with meaning to make it interoperable in this environment
distributed across Europe
Levels of technical knowledge -> common easy to use access point
Which has to conform to certain ethical and legal requirements since data is confidential
stored across Europe
In various independent repositories
CONFIDENTIAL
CONFIDENTIAL
with different ethical and legal requirements
PP Seminar
30/11/2010

44. Hadrontherapy Information Sharing Platform (HISP)
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
To answer all the challenges and requirements of the Hadron Therapy community we are building a prototype software platform based on Grids and here is the conceptual view of it. The HISP role is to connect users with data sources.
Conceptually consists of:
A grid middleware for basic services like data storage
A security layer to enforce ethical and legal aspects of medical data
A data integration and access service for semantic linking of data.
A portal for various usecases: cross-border patient referral and research - RTDB will be presented further.
All these linked by open and standard interfaces
USECASES:
1. REFERRAL 2.RESEARCH
30/11/2010
PP Seminar
Slide courtesy of Faustin Roman

45. A patient opinion…
Stressing again the need of sharing data by showing you a patient opinion.
Medicine has a slow pace in using new technologies for a good reason.
But also looking at the advantages of knowledge sharing could bring a big change for patients, clinicians and researchers alike.
30/11/2010
PP Seminar
Slide courtesy of Faustin Roman

46. Biological Effectiveness of Particle Beams
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47. 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?
PP Seminar
30/11/2010

48. 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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49. 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
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50. Modeling RBE vs. Dose for Carbon
RBE increases with decreasing dose
RBE maximises at low doses because charged particles create more irrepairable damage
Analysis of 77keV Data from Suzuki et al, IJRBP, Vol. 48, No. 1, pp. 241–250, 2000
PP Seminar
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51. Radiobiological experiments
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?
PP Seminar
30/11/2010

52. Clinical Ethics of Charged Particle Therapy
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53. Ethical Issues in CPT
Controversy among the medical community about CPT
Few Randomised Control Trials (RCTs), the “gold standard” for evidence of clinical effectiveness
Dose distributions obtained with CPT mostly superior conventional radiotherapy
RCTs are unethical if they lack “equipoise”
Biological dose uncertainties enough to restore equipoise?
Limited number of centres
What is the optimal use?
Paper to discuss issues
Workshop next year
PP Seminar
30/11/2010

54. Proton Therapy in the UK
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55. 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)
PP Seminar
30/11/2010

56. Proton Therapy in UK – Where Next?
Decision of Department of Health - 17th September 2010
“The three potential trial sites are the Christie NHS Foundation Trust in Manchester, University College London Hospital and University Hospitals Birmingham NHS Foundation Trust.”
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
Train staff
PP Seminar
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57. Summary CPT is a rapidly expanding field
Many challenges still to be tackled
Optimal treatments for protons
Fractionation schemes
Dose delivery
Heavy Ions
Which ions?
For which indications?
Radiobiological uncertainties
Treatment planning and delivery uncertainties
Organ motion
Cost-effectiveness
Clinical ethics
Achieved by
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
PP Seminar
30/11/2010

58. Thank you for listening.....
......any questions?
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59. Back up slides
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60. 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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30/11/2010
Illustrations courtesy of M. Goitein

61. 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
30/11/2010
PP Seminar

62. Contributions to the Proton Bragg Peak
Coulomb interactions with atomic electrons
Energy spread and energy loss differences
Nuclear interactions with atomic nuclei
PP Seminar
30/11/2010
Illustrations courtesy of M. Goitein

63. The combined effect (in water)
Used for imaging
Historically used in radiotherapy
Currently used in radio-therapy
Transferred to charged particles
Scattered
Credit: Figure by MIT OpenCourseWare.
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64. Curing Cancer with X-rays
Dose
Linac
Linac
Linac
Linac
Linac
Linac
Linac
Linac
Linac
Linac
Linac
PP Seminar
Slide courtesy of Ken Peach
30/11/2010

65. Can we do better? Slide courtesy of Ken Peach Dose The Bragg Peak
Proton
Proton
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Slide courtesy of Ken Peach
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66. PP Seminar
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67. Proton Therapy
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