Towards a UK Charged Towards a UK Charged Particle Research FacilityParticle Research Facility

Bleddyn Jones MDBleddyn Jones MDGray Institute for Radiation Oncology and Gray Institute for Radiation Oncology and

Biology,Biology, University of OxfordUniversity of Oxford

And James Martin School Institute of And James Martin School Institute of Particle Therapy Cancer Research Particle Therapy Cancer Research

Institute, Wilkinson Building, Oxford Institute, Wilkinson Building, Oxford PhysicsPhysics

Bleddyn.Jones@rob.ox.ac.ukBleddyn.Jones@rob.ox.ac.uk

0.000001

0.00001

0.0001

0.001

0.01

0.1

1

0 1 2 3 4 5 6 7 8 9 10

Dose (Gy)S

urv

ivin

g F

ract

ion

1 x 10Gy

2 x 5Gy

5 x 2Gy

10 x 1Gy

Effect of fractionation on critical normal tissue.

Density of ionisation (LET)Density of ionisation (LET)

RBE, relative biological efficiency RBE, relative biological efficiency or effect, is ratio of doses of high or effect, is ratio of doses of high

LET and low LET radiation for same LET and low LET radiation for same bio-effectbio-effect

Survival curves of mammalian cells after single exposure or fractionated irradiation, Survival curves of mammalian cells after single exposure or fractionated irradiation, from E.Hall; Lippincott Co, 1994from E.Hall; Lippincott Co, 1994

Example of altered radiobiological Example of altered radiobiological behavior with high LET radiation: behavior with high LET radiation:

effect of growth rateeffect of growth rate

Neutron RBE vs Neutron RBE vs photons RBE photons RBE according to according to the doubling the doubling

time of human time of human lung lung

metastasis. metastasis. Battermann et Battermann et al. al. Eur J CancerEur J Cancer

17:539-48, 17:539-48, 19811981

High LET High LET radiations and radiations and hypoxic cellshypoxic cells

Human renal cells T1, Human renal cells T1, hypoxia, hypoxia, normoxi normoxiaa; ;

fromfrom Broerse Broerse && Barendsen, IJRB, 13:559, 1967 Barendsen, IJRB, 13:559, 1967

N2

02

LET, OER & RBE (EBR en France)LET, OER & RBE (EBR en France)

Tubiana, Dutreix et Wambersie, Hermann ed, 1986Tubiana, Dutreix et Wambersie, Hermann ed, 1986

LET and LET and RBERBE

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 1 2 3 4 5 6 7 SB 0 1 1 2 2 1 0

Fit to Barendsen’s kidney T cell data using mono-energetic particles using a UK Poisson statistical model

200 400 600 800LET

2

4

6

8

10

EB

R

m0.065,alphalow0.62per Gy, RBE 17%

Zone where High LET questionable

by estimating initial slope and max value, entire LET – RBE relationship can be predicted

PCT to treat a wide spectrum of PCT to treat a wide spectrum of cancers using cancers using protons and lightprotons and light ions ions

Depth in tissue range 2 – 30 cmDepth in tissue range 2 – 30 cm Higher dose rates than previously Higher dose rates than previously

achieved with synchrotrons that might achieved with synchrotrons that might allow rapid scanning Bragg peak allow rapid scanning Bragg peak frequency with small spot sizes 1mm+frequency with small spot sizes 1mm+

Energy selectionEnergy selection Compact size, shielding and costCompact size, shielding and cost Controllability in a hospital settingControllability in a hospital setting

NHS requirementsNHS requirements Some proton therapy Some proton therapy

centres (? by 2013) will centres (? by 2013) will probably use conventional probably use conventional accelerator technology accelerator technology

High throughputHigh throughput Acceptable cost/benefit Acceptable cost/benefit

ratio compared with ratio compared with conventional radiotherapy conventional radiotherapy and per life year of benefitand per life year of benefit

Competition from entire Competition from entire health budgethealth budget

Implications on other parts Implications on other parts of service…diagnostic of service…diagnostic radiology, pathology, radiology, pathology, medical physics etcmedical physics etc

Travel and Travel and accommodationaccommodation

Research RequirementsResearch Requirements Relative roles of protons and ionsRelative roles of protons and ions Choice of various ions, He, Ne etc in terms of Choice of various ions, He, Ne etc in terms of

physical and biological propertiesphysical and biological properties Integration with other forms of cancer Integration with other forms of cancer

treatment…surgery, drug therapies, treatment…surgery, drug therapies, ultrasonics, laser, etc [combinations give best ultrasonics, laser, etc [combinations give best results]results]

Optimum fractionationOptimum fractionation Optimum safety, use of RBE, Optimum safety, use of RBE, Patient selection: biological predictive assaysPatient selection: biological predictive assays Physics dose computation……across UKPhysics dose computation……across UK Patient experiencePatient experience Quality of life /cure /cost outcomesQuality of life /cure /cost outcomes

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

GantriesGantries Angles criticalAngles critical Patients can be rotated on vertical Patients can be rotated on vertical

axis only on flat couch; horizontal axis only on flat couch; horizontal axis rotation leads to long delays and axis rotation leads to long delays and possible inaccuraciespossible inaccuracies

Various combinations fixed and Various combinations fixed and movable gantriesmovable gantries

Isocentric concept: 4-6 fields in 10-20 Isocentric concept: 4-6 fields in 10-20 minutes using Linear acceleratorsminutes using Linear accelerators

A cost effective solution is proton A cost effective solution is proton gantries + fixed fields for C gantries + fixed fields for C ions….but +/- 20ions….but +/- 2000 shifts required to shifts required to reduce skin entrance dose esp. for reduce skin entrance dose esp. for large dose per fraction.large dose per fraction.

Can more flexible fixed beams with Can more flexible fixed beams with variable geometry be designed; variable geometry be designed; insert additional insert additional magnet/change/reversal or magnet/change/reversal or modification of electromag. field at modification of electromag. field at final portion ???final portion ???

Three fixed fields

Versatile ‘fixed’ field

Couch rotation allowed

Isocentricity: use constant distance from Isocentricity: use constant distance from treatment source to isocentre –a defined {x, y, treatment source to isocentre –a defined {x, y,

z} point within tumour targetz} 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

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

nervesnerves

New indications? Kidney Cancer : Stage I, New indications? Kidney Cancer : Stage I, TIa N0 M0TIa N0 M0

National Institute of Radiological Sciences, National Institute of Radiological Sciences, Chiba, Japan carbon ions, 80GyE / 16fr. Chiba, Japan carbon ions, 80GyE / 16fr.

/4wks/4wks

New indications? Kidney Cancer : Stage I, New indications? Kidney Cancer : Stage I, TIa N0 M0TIa N0 M0

National Institute of Radiological Sciences, National Institute of Radiological Sciences, Chiba, Japan carbon ions, 80GyE / 16fr. Chiba, Japan carbon ions, 80GyE / 16fr.

/4wks/4wks

治療前 1 year3 years

4 years5 years

Can radical surgery be avoided?

Better cancer screening might create extra need to use physics solutions

Some possible Gantry combinationsSome possible Gantry combinations1. not possible to transfer between rooms for same 1. not possible to transfer between rooms for same treatment fraction (time elapsed for DNA repair) treatment fraction (time elapsed for DNA repair) 2. phases allowed where volumes change, room changes 2. phases allowed where volumes change, room changes then permitted.then permitted.3. e.g. start with 2 fixed fields, finish later with 3 or 4 3. e.g. start with 2 fixed fields, finish later with 3 or 4 angled fieldsangled fields4. Second cancers (due to radiation) should depend on 4. Second cancers (due to radiation) should depend on reduction of volume of low dose exposure in patientreduction of volume of low dose exposure in patient

Option 1Option 1 Option 2Option 2 Option 3Option 3

Room1Room1 G 360G 36000 G 360G 36000 G 360G 36000

Room 2Room 2 G 360G 36000 G 240G 24000 2 Fixed 2 Fixed fields APfields AP

Room 3Room 3 G 360G 36000 G 180G 18000 2 Fixed 2 Fixed fields A+Lfields A+L

Imaging : need verification of beam Imaging : need verification of beam placementplacement

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

Nuclear activation detection Nuclear activation detection sensitivity and specificitysensitivity and specificity

Should detectors increase is sensitivity, it Should detectors increase is sensitivity, it may be possible not only to confirm tumour may be possible not only to confirm tumour position relative to beam, but also study position relative to beam, but also study temporal changes in tumour temporal changes in tumour physiology….e.g. oxygen content, volume, physiology….e.g. oxygen content, volume, blood flow and if deposition of heavy metals blood flow and if deposition of heavy metals has occurred [Pl, Gad, Au, In ].has occurred [Pl, Gad, Au, In ].

Knowledge of rate of change/directionality Knowledge of rate of change/directionality rather than absolute values would be useful.rather than absolute values would be useful.

Confirmation of dose/inaccuracies…..and Confirmation of dose/inaccuracies…..and their subsequent (non-linear) correction their subsequent (non-linear) correction

Chemotherapy pulses

protons

These plots represent two extremes: there will inevitably be intermediate rates of change in perfusion

C ion

Post operative radiationPost operative radiation Treatment to a zone of risk, defined Treatment to a zone of risk, defined

anatomically and not to a distinct anatomically and not to a distinct cancercancer

?Where is the cell……….where is the electron ? Probabilities….back to Schroedinger et al.

New accelerator technologies e.g. NS- FFAG New accelerator technologies e.g. NS- FFAG and lasers capable of very high dose rates and lasers capable of very high dose rates and different spot scanning dose painting and different spot scanning dose painting

patterns/methodspatterns/methods Statistics of obtaining reliable Statistics of obtaining reliable

reproducible dose reproducible dose distributions/overlaps/smaller spot distributions/overlaps/smaller spot sizes/over and underdose. sizes/over and underdose.

Over dose allowed in tumour; not in Over dose allowed in tumour; not in NT /OARNT /OAR

Mobile tumours; probability of miss Mobile tumours; probability of miss enhanced or reduced?enhanced or reduced?

RadiobiologyRadiobiology

Some Basic Radiation Some Basic Radiation BiologyBiology

Expected Lethal Expected Lethal events per cell=events per cell=

Surviving Surviving Fraction=Fraction=

Tumour cure Tumour cure probability=probability=

Repopulation termRepopulation term

].2ln

[.[ 2

TdRdRnExpCExp

][ 2dRdRnExp

2dRdRn

]2ln

[factor repop

2ln;2

];[.

0

0

tExp

kN

Nwhen

ktExpNN

t

t

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

BED - The ConceptBED - The Concept Represents total dose if given in Represents total dose if given in

smallest fraction sizesmallest fraction size

/1

E dndBED

)( 2ddnE

ndE

ndE

ndndd

2,0

BED equations for high LET radiationsBED equations for high LET radiations

L

HMAXH

dRBEDBED

L

HMINMAXH

dRBERBEDBED

2

Low doses or if changes very little with increasing LET relative to

Assuming that high LET changes in are relevant at high doses

L

HMINH

L

HMAXH

HLHLHHHH

RBEd

RBEd

ddddE

,

,0

22

The RBE at low dose

The RBE at high dose

Jones, Carabe and Dale BJR 2006 – adapted for treatment interruption calculations

RBE is dL/dH

High LET radiobiology – general principlesHigh LET radiobiology – general principles

Using BED equation with RBEmax and RBEmin;

low

RBE ≈ 1 or 1.1 RBE >> 1-5

Neutrons

MV X-rays and protons > 100 MV

C ions

Fractionation Fractionation (according to Newton or (according to Newton or Liebniz)Liebniz)

T T f(n-1), where f is average inter-fraction f(n-1), where f is average inter-fraction interval;interval;

TKdRdRnE .2

/1

;/

1d

d

BEDn

dndBED

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

0)/(.2)/(

)/( 2

fKzfgKzg

dt

dzLATE

TUM

LATE

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

High LET optimum dose per fractionHigh LET optimum dose per fraction

Even for protons, treatments might be accelerated;

Germany 19#

Japan 16, 10, 4, 1 #

Space flights and large doses Space flights and large doses per fraction !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 2nd, 3rd hits

Cell experiment range

Modelling range ?

LEM-local effect modelLEM-local effect model Calculates lesion number in a region Calculates lesion number in a region

of nanometre scaleof nanometre scale Amorphous track structure model Amorphous track structure model

assumedassumed Uses low LET survival curve (LQ Uses low LET survival curve (LQ

model)model) Assumes straight line survival curve Assumes straight line survival curve

for low LET at high dosefor low LET at high dose

MKM-microdosimetric kinetic MKM-microdosimetric kinetic modelmodel

Modified dual radiation action theory Modified dual radiation action theory by Hawkinsby Hawkins

SF=exp[-(SF=exp[-(00++.z*.z*1D1D)D - )D - DD22]] z*z*1D 1D Dose mean specific energy corrected Dose mean specific energy corrected

by saturation effect [can be measured by by saturation effect [can be measured by a Rossi counter]a Rossi counter]

0 0 the radiosensitivity at LET~0.the radiosensitivity at LET~0. Use Kiefer-Chatterjee track structure Use Kiefer-Chatterjee track structure

modelmodel..

MKM and LEM are roughly equivalent in MKM and LEM are roughly equivalent in LET regions used in heavy ion therapy LET regions used in heavy ion therapy and for fractionated (low) dosesand for fractionated (low) doses

Both refer to surviving fractions down to 10Both refer to surviving fractions down to 10--

44.. This is the range of in vitro survival curvesThis is the range of in vitro survival curves Tumour control needs 10Tumour control needs 10-8-8 to to 1010-10 -10 rangerange Further extension required to both modelsFurther extension required to both models GSI fractionation has so far been 19 GSI fractionation has so far been 19

fractions in 19 days – but now dooing boosts fractions in 19 days – but now dooing boosts of 1-4 fractions after IMRT.of 1-4 fractions after IMRT.

Japanese experience showed anomalous Japanese experience showed anomalous results at 1 fraction.results at 1 fraction.

Clinical Cancer sitesClinical Cancer sites BreastBreast ProstateProstate LungLung OesophagusOesophagus Brain & SpineBrain & Spine Head, neckHead, neck ThyroidThyroid GynaecologyGynaecology Liver upper/AbdomenLiver upper/Abdomen LimbsLimbs Palliation of metastatic cancerPalliation 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

Models of Tumour Hypoxia Models of Tumour Hypoxia – –

iterativeiterative

Quiescent Hypoxic cells

Repopulating Oxic cells

Cell death

Radiosensitivities modified by hypoxia

Radiosensitivities not modified by hypoxia

DailyFlux 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.

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^2 + 0.693 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

Modelled dose responses for 250 different tumours with initial hypoxic fraction of 15% and 1% reoxygenation per dayA : 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

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

Full Economic CostFull Economic Cost Cost of treatment per fraction (n) + fixed costs of Cost of treatment per fraction (n) + fixed costs of

treatment planning etctreatment planning etc Cost of treatment failure, where failure probability Cost of treatment failure, where failure probability

= (1-TCP)= (1-TCP) Cost other salvage therapies and or supportive careCost other salvage therapies and or supportive care Studies done for breast, head and neck and Studies done for breast, head and neck and

medulloblastoma, chordoma.medulloblastoma, chordoma. SCOPE for modelling optimum dose per fraction or SCOPE for modelling optimum dose per fraction or

fraction number in context of particle therapy, fraction number in context of particle therapy, taking into account RBE, normal tissue sparing etc.taking into account RBE, normal tissue sparing etc.

Effect of changing dose-rate on critical normal tissue

0.000001

0.00001

0.0001

0.001

0.01

0.1

11 2 3 4 5 6 7 8 9 10 11

Dose (Gy)

Su

rviv

ing

fra

cti

on

0.25Gy/h

0.5Gy/h

2Gy/h

240Gy/h

Dose rate effect modellingDose rate effect modelling

1)(,0

11

2)(

.10 2

)(

)(.22

tftas

t

e

ttf

hrtfort

tf

tftrrtE

t

•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 .

Dose rate effects on tissuesDose rate effects on tissuesDepends on tissue/cells as to where saturation of effect occurs. Also, some earlier work back in 1960 -70s 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!

20 30 40 50 60 70 80 90TOTAL DOSECo Eq Gy

20

40

60

80

100PERCENTAGE CURES

1# 4# 9# 18#

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

Model accounts for single fraction deviation from present Japanese model

Malignant Induction Malignant Induction Probabilities with compensation Probabilities with compensation for fractionation and high LETfor fractionation and high LET

)(2max

2max).()1( ddRxneddRnxMIP

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

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

?