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 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

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

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 PP Seminar 30/11/2010

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

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 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 PP Seminar 30/11/2010

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 PP Seminar 30/11/2010 7

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.......... PP Seminar 30/11/2010

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 PP Seminar 30/11/2010

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

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 PP Seminar 30/11/2010

Combining Fields X-Rays Protons/Ions 80 50 150 60 150 40 PP Seminar 60 150 40 X-Rays Protons/Ions PP Seminar 30/11/2010

IMRT vs. Proton Therapy PP Seminar 30/11/2010

Medulloblastoma in a Child X-rays 100 60 10 With Xrays With Protons PP Seminar 30/11/2010

Orbital Rhabdomyosarcoma Protons/Ions X-Rays PP Seminar 30/11/2010 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 Slide courtesy of Prof. Gillies McKenna PP Seminar 30/11/2010

Production and Delivery of Medical Proton Beams PP Seminar 30/11/2010

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

Beam Transport Gantries Fixed Beams Clinical Indications Flexibility Space Cost PP Seminar 30/11/2010

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 10000 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 10000 spots are deposited in less than 5min. dose distributions of complex shapes can be constructed with less entrance dose Beam direction Target Patient PP Seminar 30/11/2010

Beam Delivery - Scattering Courtesy of T. Lomax, PSI, Switzerland. PP Seminar 30/11/2010

Introduction to the Particle Therapy Cancer Research Institute PP Seminar 30/11/2010

The Particle Therapy Cancer Research Institute PTCRi PP Seminar 30/11/2010

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: http://www.ptcri.ox.ac.uk/people/ PP Seminar 30/11/2010

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. PP Seminar 30/11/2010

Novel Accelerator and Gantry Design PP Seminar 30/11/2010

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

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

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

Advantages and Challenges of Laser Driven Ion Acceleration 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… PP Seminar 30/11/2010

Malignant Induction Modelling PP Seminar 30/11/2010

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

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

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

Virtual Phantoms PP Seminar 30/11/2010

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

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 30/11/2010

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

Data Recording and Sharing PP Seminar 30/11/2010

EU Projects: ENLIGHT and PARTNER http://enlight.web.cern.ch http://partner.web.cern.ch Slide courtesy of Faustin Roman PP Seminar 30/11/2010 40 40

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

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) PP Seminar 30/11/2010

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

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

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. http://www.nature.com/nm/journal/v16/n7/full/nm0710-744.html 30/11/2010 PP Seminar Slide courtesy of Faustin Roman

Biological Effectiveness of Particle Beams PP Seminar 30/11/2010

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

RBE vs. Dose for Protons Where does the 1.1 come from? Paganetti et al.: Int. J. Radiat. Oncol. Biol. Phys. 2002; 53, 407 PP Seminar 30/11/2010

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 PP Seminar 30/11/2010

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 30/11/2010

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

Clinical Ethics of Charged Particle Therapy PP Seminar 30/11/2010

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

Proton Therapy in the UK PP Seminar 30/11/2010

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

Proton Therapy in UK – Where Next? 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............ PP Seminar 30/11/2010

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

Thank you for listening..... ......any questions? PP Seminar 30/11/2010

Back up slides PP Seminar 30/11/2010

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

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

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

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. PP Seminar 30/11/2010

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

Can we do better? Slide courtesy of Ken Peach Dose The Bragg Peak Proton Proton PP Seminar Slide courtesy of Ken Peach 30/11/2010

PP Seminar 30/11/2010

Proton Therapy PP Seminar 30/11/2010