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