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Towards a UK Charged Particle Research Facility Bleddyn Jones MD Gray Institute for Radiation Oncology and Biology, University of Oxford University of Oxford And James Martin School Institute of Particle Therapy Cancer Research Institute, Wilkinson Building, Oxford Physics

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Density of ionisation (LET)

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RBE, relative biological efficiency or effect, is ratio of doses of high LET and low LET radiation for same bio-effect Survival curves of mammalian cells after single exposure or fractionated irradiation, from E.Hall; Lippincott Co, 1994

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Example of altered radiobiological behavior with high LET radiation: effect of growth rate Neutron RBE vs photons RBE according to the doubling time of human lung metastasis. Battermann et al. Eur J Cancer 17:539-48, 1981

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High LET radiations and hypoxic cells Human renal cells T1, hypoxia, normoxia; from Broerse & Barendsen, IJRB, 13:559, 1967 N2N2 0202

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LET, OER & RBE (EBR en France) Tubiana, Dutreix et Wambersie, Hermann ed, 1986

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LET and RBE initially increases linearly with LET, increased probability of strand breakage, many of which will lead to a lethal event, As ionisations become closer, yield of Strand Breaks (SB) reduces, and same principles apply at higher levels e.g. chromosomal damage track SB

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Fit to Barendsen’s kidney T cell data using mono-energetic particles using a UK Poisson statistical model Zone where High LET questionable by estimating initial slope and max value, entire LET – RBE relationship can be predicted

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PCT to treat a wide spectrum of cancers using protons and light ions Depth in tissue range 2 – 30 cm Depth in tissue range 2 – 30 cm Higher dose rates than previously achieved with synchrotrons that might allow rapid scanning Bragg peak frequency with small spot sizes 1mm+ Higher dose rates than previously achieved with synchrotrons that might allow rapid scanning Bragg peak frequency with small spot sizes 1mm+ Energy selection Energy selection Compact size, shielding and cost Compact size, shielding and cost Controllability in a hospital setting Controllability in a hospital setting

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NHS requirements Some proton therapy centres (? by 2013) will probably use conventional accelerator technology Some proton therapy centres (? by 2013) will probably use conventional accelerator technology High throughput High throughput Acceptable cost/benefit ratio compared with conventional radiotherapy and per life year of benefit Acceptable cost/benefit ratio compared with conventional radiotherapy and per life year of benefit Competition from entire health budget Competition from entire health budget Implications on other parts of service…diagnostic radiology, pathology, medical physics etc Implications on other parts of service…diagnostic radiology, pathology, medical physics etc Travel and accommodation Travel and accommodation

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Research Requirements Relative roles of protons and ions Relative roles of protons and ions Choice of various ions, He, Ne etc in terms of physical and biological properties Choice of various ions, He, Ne etc in terms of physical and biological properties Integration with other forms of cancer treatment…surgery, drug therapies, ultrasonics, laser, etc [combinations give best results] Integration with other forms of cancer treatment…surgery, drug therapies, ultrasonics, laser, etc [combinations give best results] Optimum fractionation Optimum fractionation Optimum safety, use of RBE, Optimum safety, use of RBE, Patient selection: biological predictive assays Patient selection: biological predictive assays Physics dose computation……across UK Physics dose computation……across UK Patient experience Patient experience Quality of life /cure /cost outcomes Quality of life /cure /cost outcomes

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HIMAC : Treatment Room Small peripheral T1, T2 stage lung cancer now treated in single session in NIRS Japan with < 7% loss in respiratory function vital capacity/Tco

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Gantries Angles critical Angles critical Patients can be rotated on vertical axis only on flat couch; horizontal axis rotation leads to long delays and possible inaccuracies Patients can be rotated on vertical axis only on flat couch; horizontal axis rotation leads to long delays and possible inaccuracies Various combinations fixed and movable gantries Various combinations fixed and movable gantries Isocentric concept: 4-6 fields in minutes using Linear accelerators Isocentric concept: 4-6 fields in minutes using Linear accelerators A cost effective solution is proton gantries + fixed fields for C ions….but +/ shifts required to reduce skin entrance dose esp. for large dose per fraction. A cost effective solution is proton gantries + fixed fields for C ions….but +/ shifts required to reduce skin entrance dose esp. for large dose per fraction. Can more flexible fixed beams with variable geometry be designed; insert additional magnet/change/reversal or modification of electromag. field at final portion ??? Can more flexible fixed beams with variable geometry be designed; insert additional magnet/change/reversal or modification of electromag. field at final portion ??? Three fixed fields Versatile ‘fixed’ field Couch rotation allowed

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Isocentricity: use constant distance from treatment source to isocentre –a defined {x, y, z} point within tumour target Set up P1 X cm Distance of P1, P2 and P3 to isocentre is constant = x cm Set up accuracy better than previous system of constant source to skin distance; also faster. P2 P3 % Depth dose inversely proportional to source skin distance for divergent beams, so before computers used in depth calculation a constant source skin distance was preferred

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Adenoidcystic Ca Lacrimal Gland – 72 CGE – dose tracking of cranial nerves

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New indications? Kidney Cancer : Stage I, TIa N0 M0 National Institute of Radiological Sciences, Chiba, Japan carbon ions, 80GyE / 16fr. /4wks 治療前 1 year 3 years 4 years 5 years Can radical surgery be avoided? Better cancer screening might create extra need to use physics solutions

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Some possible Gantry combinations 1. not possible to transfer between rooms for same treatment fraction (time elapsed for DNA repair) 2. phases allowed where volumes change, room changes then permitted. 3. e.g. start with 2 fixed fields, finish later with 3 or 4 angled fields 4. Second cancers (due to radiation) should depend on reduction of volume of low dose exposure in patient Option 1 Option 2 Option 3 Room1 G Room 2 G G Fixed fields AP Room 3 G G Fixed fields A+L

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Imaging : need verification of beam placement X-ray film or image intensifier screen bone 3-D CT/MRI fusion has made this easier, with recognisable reconstructions of anatomy, but more challenges in proton/ion therapy…use proton radiography, soft x-rays, MV x-rays, nuclear activation and PET analysis? X-rays Optical systems with same divergence geometry can be used as far as skin Simple x-ray systems can be used to determine daily set up w.r.t bony anatomy Low Voltage XRays better bone definition MV beams poor bone definition

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Nuclear activation detection sensitivity and specificity Should detectors increase is sensitivity, it may be possible not only to confirm tumour position relative to beam, but also study temporal changes in tumour physiology….e.g. oxygen content, volume, blood flow and if deposition of heavy metals has occurred [Pl, Gad, Au, In ]. Should detectors increase is sensitivity, it may be possible not only to confirm tumour position relative to beam, but also study temporal changes in tumour physiology….e.g. oxygen content, volume, blood flow and if deposition of heavy metals has occurred [Pl, Gad, Au, In ]. Knowledge of rate of change/directionality rather than absolute values would be useful. Knowledge of rate of change/directionality rather than absolute values would be useful. Confirmation of dose/inaccuracies…..and their subsequent (non-linear) correction Confirmation of dose/inaccuracies…..and their subsequent (non-linear) correction

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Chemotherapy pulses protons These plots represent two extremes: there will inevitably be intermediate rates of change in perfusion C ion

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Post operative radiation Treatment to a zone of risk, defined anatomically and not to a distinct cancer Treatment to a zone of risk, defined anatomically and not to a distinct cancer ? Where is the cell……….where is the electron ? Probabilities….back to Schroedinger et al.

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New accelerator technologies e.g. NS- FFAG and lasers capable of very high dose rates and different spot scanning dose painting patterns/methods Statistics of obtaining reliable reproducible dose distributions/overlaps/smaller spot sizes/over and underdose. Statistics of obtaining reliable reproducible dose distributions/overlaps/smaller spot sizes/over and underdose. Over dose allowed in tumour; not in NT /OAR Over dose allowed in tumour; not in NT /OAR Mobile tumours; probability of miss enhanced or reduced? Mobile tumours; probability of miss enhanced or reduced? Radiobiology Radiobiology

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Some Basic Radiation Biology Expected Lethal events per cell= Expected Lethal events per cell= Surviving Fraction= Surviving Fraction= Tumour cure probability= Tumour cure probability= Repopulation term Repopulation term

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How can we picture BED ? DOSE Surviving Fraction Imagine the dose to be given in infinitely small fractions with no curvature to slope BED Single fraction Dose for same effect in single fraction Dose for same effect in four fractions Iso-effect level

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BED - The Concept Represents total dose if given in smallest fraction size Represents total dose if given in smallest fraction size

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BED equations for high LET radiations Low doses or if changes very little with increasing LET relative to Assuming that high LET changes in are relevant at high doses The RBE at low dose The RBE at high dose Jones, Carabe and Dale BJR 2006 – adapted for treatment interruption calculations RBE is d L /d H

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High LET radiobiology – general principles Using BED equation with RBEmax and RBEmin; low

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RBE ≈ 1 or 1.1 RBE >> 1-5 Neutrons MV X-rays and protons > 100 MV C ions

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Fractionation (according to Newton or Liebniz) T f(n-1), where f is average inter-fraction interval; Eliminate n and T in Then differentiate and solve (dE/dT)=0 to give max cell kill for constant level of normal tissue side effect defined by the BED. Also for more sparing forms of radiation d=gz, where z is dose to tumour and d to normal tissue

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The solution when plotted shows that z’ : Increases as g is reduced, as with a better dose distribution Reduces as f is shortened, Increases with K (for rapidly growing tumours) Increases as / of cancer approaches that of the normal late reacting tissues [OAR]. With an increase in RBE, z falls, but all above features the same

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High LET optimum dose per fraction Even for protons, treatments might be accelerated; Germany 19# Japan 16, 10, 4, 1 #

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Space flights and large doses per fraction ! Prospects for long term survival of humans/cells in space will depend on improved knowledge of low and high LET radiation effects and their reduction. Poissonian modification of LQ model to compensate for 2 nd, 3 rd hits Cell experiment range Modelling range ?

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LEM-local effect model Calculates lesion number in a region of nanometre scale Calculates lesion number in a region of nanometre scale Amorphous track structure model assumed Amorphous track structure model assumed Uses low LET survival curve (LQ model) Uses low LET survival curve (LQ model) Assumes straight line survival curve for low LET at high dose Assumes straight line survival curve for low LET at high dose

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MKM-microdosimetric kinetic model Modified dual radiation action theory by Hawkins Modified dual radiation action theory by Hawkins SF=exp[-( 0 + .z* 1D )D - D 2 ] SF=exp[-( 0 + .z* 1D )D - D 2 ] z* 1D Dose mean specific energy corrected by saturation effect [can be measured by a Rossi counter] z* 1D Dose mean specific energy corrected by saturation effect [can be measured by a Rossi counter] 0 the radiosensitivity at LET~0. 0 the radiosensitivity at LET~0. Use Kiefer-Chatterjee track structure model. Use Kiefer-Chatterjee track structure model.

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MKM and LEM are roughly equivalent in LET regions used in heavy ion therapy and for fractionated (low) doses Both refer to surviving fractions down to Both refer to surviving fractions down to This is the range of in vitro survival curves This is the range of in vitro survival curves Tumour control needs to range Tumour control needs to range Further extension required to both models Further extension required to both models GSI fractionation has so far been 19 fractions in 19 days – but now dooing boosts of 1-4 fractions after IMRT. GSI fractionation has so far been 19 fractions in 19 days – but now dooing boosts of 1-4 fractions after IMRT. Japanese experience showed anomalous results at 1 fraction. Japanese experience showed anomalous results at 1 fraction.

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Clinical Cancer sites Breast Breast Prostate Prostate Lung Lung Oesophagus Oesophagus Brain & Spine Brain & Spine Head, neck Head, neck Thyroid Thyroid Gynaecology Gynaecology Liver upper/Abdomen Liver upper/Abdomen Limbs Limbs Palliation of metastatic cancer Palliation of metastatic cancer See Jones B, Clinical Oncology, 2008 Large research portfolio on clinical applications, relationship with other cancer therapies etc particularly possibilities of priming a cancer with drugs prior to elimination of cancer cell population by particle therapy

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Models of Tumour Hypoxia – iterative Quiescent Hypoxic cells Repopulating Oxic cells Cell death Radiosensitivities modified by hypoxia Radiosensitivities not modified by hypoxia Daily Flux of cells Modified from Scott (1988); alternative is to use analytical models with integration of effective OER with time to give average values. Results very similar. Initial conditions and variables: hypoxic fraction, reoxygenation rate, OER, repopulation rates, radiosensitivities and mean inter- fraction interval. Model repeats every day until TCP > 0.05.

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Example of iterative loop in ‘Mathematica’ Heterogeneity is included by having long lists of separate tumours each with different , , and w, the cell repopulation parameter. Nox = nox Exp[ - list d- list d^ f / list ] Nhyp = nhyp Exp[ - listd/q- listd^2/q^2]; Ntot = nox + nhyp; Tcp = Exp[-ntot]; n = n+1; Reox = x nhyp; ntot = nox + nhyp; nhyp = nhyp – xnhyp - ynhyp; Nox = nox + reox

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Modelled dose responses for 250 different tumours with initial hypoxic fraction of 15% and 1% reoxygenation per day A : x-rays 2 Gy, 5 times per week, B : x-rays 1.4 Gy, 10 times per week. C : carbon ions (dose equivalent Gray, RBE=3) 5 times per week at 2.1 Gy-equivalent fractions, reduced OER value =1.5 assumed. D : carbon ions delivered in 6 Gy-equivalent fractions SLOW RE-OXYGENATION

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Photons (x-rays) at 2 Gy per fraction Or, carbon ions at 6 Gy per # Or X-rays to 40 Gy in 20 fractions plus 6 Gy carbon X-ray and carbon more ‘effective’ than either alone

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Full Economic Cost Cost of treatment per fraction (n) + fixed costs of treatment planning etc Cost of treatment per fraction (n) + fixed costs of treatment planning etc Cost of treatment failure, where failure probability = (1-TCP) Cost of treatment failure, where failure probability = (1-TCP) Cost other salvage therapies and or supportive care Cost other salvage therapies and or supportive care Studies done for breast, head and neck and medulloblastoma, chordoma. Studies done for breast, head and neck and medulloblastoma, chordoma. SCOPE for modelling optimum dose per fraction or fraction number in context of particle therapy, taking into account RBE, normal tissue sparing etc. SCOPE for modelling optimum dose per fraction or fraction number in context of particle therapy, taking into account RBE, normal tissue sparing etc.

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Dose rate effect modelling Classical dose rate effect is linked to parameter But must also be affected at very high dose rates: G2 repair, relationship between dose rate and low dose radiosensitivity needs investigation LET and RBE produces much greater increase in than in .

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Dose rate effects on tissues Depends on tissue/cells as to where saturation of effect occurs. Also, some earlier work back in s showed local oxygen depletion at very high dose rates; might affect outcomes for protons. ROB could re-look this in a more modern setting Generally speaking at higher LET, the dose rate effect is less significant…the solid curve shown would be almost flat. M=marrow, G=gut, E=skin L=lung…….no error bars!

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UK Carbon ION Modelling Carbon ions for early lung cancer (Japanese experience): using Monte Carlo computer simulation of hypoxic and oxic (repopulating) with re- oxygenation flux, reduced oxygen dependency of ion cell kill and typical RBE. (see chapters on Oxygen Effect and High LET Radiotherapy in Radiobiological Modelling in Radiation oncology: eds Dale and Jones Published by British Insitite of radiology, London, 2007) Model accounts for single fraction deviation from present Japanese model

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Malignant Induction Probabilities with compensation for fractionation and high LET P[malignant ch. break] P[cell survival due to lethal ch. breaks] Let x be proportion of chromosome breaks cell kill, and (1-x) cancer

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Micro-dosimetry Beam – multiple components, elastic, non elastic, nuclear fragmentation, -rays, neutrons [detectors, MC simulations] RBE……….varies between RBEmax at zero dose to RBEmin at very high dose Bio-effect models outcomes Target configurations at sub-cellular level [molecular and cell biology] Dose prescription ?

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