treating cancer with charged particles
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
Treating Cancer with Charged Particles
Claire TimlinParticle Therapy Cancer Research Institute, Oxford Martin School,
University of OxfordSlides are a PTCRi group effort.
2 PP Seminar 30/11/2010
• 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
Contents
3 PP Seminar
Introduction to Charged Particle Therapy
30/11/2010
4 PP Seminar
Development of Radiotherapy
30/11/2010
• 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
5 PP Seminar
The Evolution of External Beam Radiation Therapy
30/11/2010
High resolution
IGRT
Multileaf CollimatorDynamic MLCand IMRT
1950’s
1970’s 1980’s 1990’s 2000’s?
Cerrobend Blocks Electron Therapy
Functional
Imaging
The First Cobalt Therapy Unit and Clinac
Computerized 3D CT Treatment Planning
Standard Collimator
ParticleTherapy
Slide courtesy of Prof. Gillies McKenna
6 PP Seminar
History of Proton Therapy
30/11/2010
• 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
• 2010:– > 67 000 patients had been treated
with protons worldwide– 29 proton therapy centres operating
worldwide– ~ 20 more planned or under construction
Proton Therapy Centres Worldwide
http://www.uhb.nhs.uk/ProtonsBirmingham/background/
facilities.htm
7 PP Seminar
Low vs. High Linear Energy Transfer Radiation
30/11/2010
Sparsely ionising radiation (low-LET)e.g. -rays, -particles
Low concentrationof ionisation events
Densely ionising radiation (high-LET)
e.g. -particlesC6+ ions
High concentrationof ionisation events
DNA
electron tracks
Slide courtesy of Dr Mark Hill
8 PP Seminar
Radiation Induced Damage
30/11/2010
• 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..........
9 PP Seminar
Conformal Radiotherapy
30/11/2010
• 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
10 PP Seminar
Photon vs. Proton/Ion Depth-dose Curve
30/11/2010
• High energy photons favoured over low energies due to skin sparing
• Dose falls off but not to zero
• Density of ionizations increase as the particles slow down -> peak in dose
• No dose past peak
Dose
Depth
Photons Protons Carbon Ions
11 PP Seminar
The Spread Out Bragg Peak
30/11/2010
Incident energy is modulated to form spread out Bragg Peaks the cover
the tumour
Unnecessary dose
Unnecessary dose
Skin sparing
12 PP Seminar
40
80
60 150
50
0
0
X-Rays Protons/Ions
150
Combining Fields
30/11/2010
13 PP Seminar
IMRT vs. Proton Therapy
30/11/2010
14 PP Seminar
100
60
10
X-rays
With Protons
Medulloblastoma in a Child
30/11/2010
With Xrays
15 PP Seminar Courtesy T. Yock, N. Tarbell, J. Adams
Orbital Rhabdomyosarcoma
30/11/2010
X-Rays Protons/Ions
16 PP Seminar
Proton Therapy in ActionAnaplastic 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
30/11/2010
CPC, Friedmann, NEJM, 350:494, 2004
Pre-treatment
During-treatment Post-treatment
Slide courtesy of Prof. Gillies McKenna
17 PP Seminar
Production and Delivery of Medical Proton Beams
30/11/2010
18 PP Seminar
Beam Acceleration
30/11/2010
• Cyclotron– Protons up to ~250 MeV– Requires degraders– High current– Small(ish)– Simple(ish)– Main Manufacturers
• IBA ,Varian– Best choice for protons at present?
• Synchrotron– Carbon up to 400MeV/– Dynamic energy change– Lower current– Bigger– More complicated– Main Manufacturers
• Hitachi, Siemens– Only viable choice for heavy ion
therapy at present?Future accelerators that do the job better? e.g FFAG, Laser Driven?
HIT, Germany
19 PP Seminar
Beam Transport
30/11/2010
• Gantries
• Fixed Beams• Clinical Indications
• Flexibility• Space• Cost
PP Seminar
Beam Delivery - Scanning
30/11/201020
• 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 10000 spots are deposited in less than 5min.
Beam direction
Beam direction
Patient
Patient
Target
Target
21 PP Seminar
Courtesy of T. Lomax, PSI, Switzerland.
Beam Delivery - Scattering
30/11/2010
22 PP Seminar
Introduction to the Particle Therapy Cancer Research Institute
30/11/2010
The Particle Therapy Cancer Research Institute
30/11/201023 PP Seminar
PTCRi
The PTCRi Collaborators
30/11/201024 PP Seminar
• 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:http://www.ptcri.ox.ac.uk/people/
25 PP Seminar
Challenges in Charged Particle Therapy
30/11/2010
• 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 MaastroInvestigating equipoise and clinical utility in collaboration with ETHOX.Oxford PT centre or collaboration?
Voxelised virtual phantomDatabase for multiple parallel radiobiological calculations (with Jim Loken) -> sensitivity analyses
At treating centres
EU Projects: ULICE, PARTNER, ENLIGHT.
FFAG (PAMELA), laser driven accelerators.
Radiobiological modelling validated with existing cell, small animal and clinical data.
26 PP Seminar
Novel Accelerator and Gantry Design
30/11/2010
27 PP Seminar
FFAG AcceleratorFixed 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
30/11/2010
28 PP Seminar
FFAG Gantry
•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
Conventional Carbon Gantry at Heidelberg A PAMELA NS-FFAG Gantry conceptual design
30/11/2010
29 PP Seminar
Laser Driven Ion Acceleration
+++++++
-------
---------
+++-----
e-
ionsPulsedlaser
Contaminant layer
metal foil
+
plasma sheath
•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
(Target Normal Sheath Acceleration-TNSA)
30/11/2010
30 PP Seminar
•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
Advantages
•Clinical energies are not achieved yet (~65MeV proton at present)•Energy spread, repetition rate, neutron contamination, beam stability…
Advantages and Challenges of Laser Driven Ion Acceleration
30/11/2010
31 PP Seminar
Malignant Induction Modelling
30/11/2010
32 PP Seminar
Radiation Action on Cells
Direct DNA damage
DNA dsbRepair No repair
Cell deathCell survival
Mis-repair
Mutation
Transformation
30/11/2010Slide courtesy of Prof. Boris Vojnovic
PP Seminar
Induction and cell kill
30/11/201033
Induction Cell killingWhat is the form of the induction function? Linear,
quadratic?
Form of cell killing function known with
some certainty at clinical energies, the parameters
are tissue dependent and can have large
uncertainties.
Risk needs to be• accurately modelled • confirmed experimentally • taken into account when deciding on the optimal
treatment plan
Probability of transforming a cell
Probability of inducing a potentially malignant mutation
Probability the cell survives
34 PP Seminar
Voxelised 3D Calculations of Biological Endpoints
30/11/2010
• Model and parameter sensitivity analyses• Validation with clinical data on secondary malignancies
35 PP Seminar
Virtual Phantoms
30/11/2010
36 PP Seminar
Virtual Phantoms
30/11/2010
• 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
Geometrically simple
mathematical phantoms
(cylinders, spheres, cones, etc...)
Computationally intensivevoxellised phantoms
(3D equivalent of pixels)
37 PP Seminar
Virtual Phantoms
30/11/2010
• 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
38 PP Seminar
PTCRi Phantom work
30/11/2010
• 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.
39 PP Seminar 30/11/2010
Data Recording and Sharing
40 PP Seminar
EU Projects: ENLIGHT and PARTNER
30/11/201040
http://enlight.web.cern.ch http://partner.web.cern.ch
Slide courtesy of Faustin Roman
EU Project: ULICE
30/11/201041 PP Seminar
• 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
Centres in Europe treating with heavy ions
European Heavy Ion Centres
30/11/201042 PP Seminar
Connect centres ...... and make most of available data!
MedAustron(Wiener
Neustadt)ETOIL
E(Lyon)
CNAO
(Pavia)
HIT(Heidelberg
)
RKA(Marburg
)
NRoCK
(Kiel)
Data Sharing and Interpretation - Challenges
30/11/2010
43
PP Seminar
Platform for translational research and clinical practise (1/2)
Data
stored across Europe
In various independent repositories
from multiple disciplines with specific terminologes
with different ethical and legal requirements
Users
from multiple disciplines with specific views on data
with different levels of technical knowledge
across Europe
with different privileges
clinicians
researchers
data ownersMedical Doctor
Biologist
Physicists
Statistician
Chemist
CONFIDENTIAL
CONFIDENTIAL
Common access point
GRID? : Coordinated resource sharing and problem solving in dynamic, multi-institutional virtual organizations… (I. Foster et al)
Hadrontherapy Information Sharing Platform (HISP)
USECASES:1. REFERRAL 2.RESEARCH
PP Seminar
Prototype connecting:• Users• Data sourceswith• Grid resources• Security framework• Data integration servicesby• Portals• Interfaces
30/11/2010 44Slide courtesy of Faustin Roman
A patient opinion…
http://www.nature.com/nm/journal/v16/n7/full/nm0710-744.htmlPP Seminar
4530/11/2010Slide courtesy of Faustin Roman
46 PP Seminar 30/11/2010
Biological Effectiveness of Particle Beams
47 PP Seminar
Relative Biological Effectiveness
30/11/2010
• 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?
48 PP Seminar
RBE vs. Dose for Protons
Paganetti et al.: Int. J. Radiat. Oncol. Biol. Phys. 2002; 53, 407
Where does the 1.1 come from?
30/11/2010
49 PP Seminar
RBE vs. Dose for Protons
V79 Cells. Wouters et al.: Radiat Res 1996 vol. 146 (2) pp. 159-70
More data is required to determine magnitude of proton
RBE variation with dose for a variety of tissuesWhere? CERN?
30/11/2010
50 PP Seminar
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, 200030/11/2010
51 PP Seminar
RBE – The Solution?
30/11/2010
• Radiobiological experiments– GSI, Germany– Gray Institute for Radio-oncology and Biology– Future – CERN?
• Validated (or at least validatable!) radiobiological models– Mechanistic vs. empirical?
52 PP Seminar 30/11/2010
Clinical Ethics of Charged Particle Therapy
53 PP Seminar
Ethical Issues in CPT
30/11/2010
• 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
54 PP Seminar 30/11/2010
Proton Therapy in the UK
55 PP Seminar
Proton Therapy in UK - Clatterbridge
30/11/2010
• 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)
56 PP Seminar
Proton Therapy in UK – Where Next?
30/11/2010
• http://www.bbc.co.uk/news/uk-england-11519263
• 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............
57 PP Seminar
Summary
30/11/2010
• 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
58 PP Seminar 30/11/2010
• Thank you for listening.....
......any questions?
59 PP Seminar 30/11/2010
• Back up slides
60 PP Seminar
Contributions to the Proton Bragg Peak
30/11/2010
Coulomb interactions with atomic electrons Energy spread and energy loss differences
Nuclear interactions with atomic nuclei
Illustrations courtesy of M. Goitein
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 61PP Seminar
62 PP Seminar
Contributions to the Proton Bragg Peak
30/11/2010
Coulomb interactions with atomic electrons Energy spread and energy loss differences
Nuclear interactions with atomic nuclei
Illustrations courtesy of M. Goitein
63 PP Seminar
The combined effect (in water)
30/11/2010Credit: Figure by MIT OpenCourseWare.
Historically used in
radiotherapy
Currently used in radio-
therapy Transferred to charged particles
Scattered
Used for imaging
64 PP Seminar
Curing Cancer with X-rays
30/11/2010
Dose
Linac
Linac
Linac
Linac
Linac
Linac
Linac
Linac
Linac
Linac
Linac
Slide courtesy of Ken Peach
65 PP Seminar
Can we do better?
30/11/2010
Dose
Proton
Proton
The Bragg Peak
Slide courtesy of Ken Peach
66 PP Seminar 30/11/2010
67 PP Seminar
Proton Therapy
30/11/2010