Transcript Kundrat - CERN Indico

Hadron Radiotherapy
Pavel Kundrát
Institute of Physics, Academy of Sciences of the Czech Republic, Prague
[email protected]
Outline
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Introduction
Hadron radiotherapy
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Principles
Technical requirements
Existing centres
Treatment planning, mathematical modelling
Introduction
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Cancer:
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2nd major cause of death
A form of cancer is diagnosed
to every 3rd person
Czech Rep.: 60 000 new
tumours/year (10 mil.
inhabitants)
Cure rate: 45 – 50% only
Surgery, radiotherapy,
chemotherapy
Strategies:
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Early detection, improved
diagnostics
Improved local treatment
Improved systemic treatments
surgery
22%
chemotherapy
5%
paliative
treatment
37%
radiotherapy
12%
surgery +
radiotherapy 6%
loco-regional
failure 18%
Radiotherapy
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Biological effects of ionizing radiation
Aim: tumour eradication, minimal risk of complications
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Inactivate clonogenic tumour cells
Spare normal tissues & cells
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Lethal tumour dose
Tolerance doses of healthy tissues
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Dose conformity
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100
90
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Fractionation
80
Probability [%]
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70
tumour control
60
normal tissue complications
50
w ithout complications
40
tumour control w ithout complications
30
20
10
0
Applied dose D
Conventional radiotherapy
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Photons, electrons (60Co, linac)
Decreasing depth-dose curves
Multiple-field irradiation
IMRT: Intensity Modulated RT
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E. Pedroni (2000)
Non-homogeneous
intensity profile
High dose to target
volume
Normal tissue burden
distributed to a larger
area
Dose escalation
Hadron radiotherapy
Hadron radiotherapy
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Protons, ions
(60-250 MeV, 100-400 MeV/amu)
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Bragg peak
→ excellent conformation
Bragg peak position
given by particle energy
Beam modulation
Increased biological
effectiveness
(RBEion=Dx/Dion)
Diminishing oxygen effect
(OER=Dhypoxic/Doxic)
Fractionation
Online monitoring PET
Photons
Protons
Beam modulation:
Passive spreading
Beam modulation:
Active scanning
Hadron radiotherapy vs. IMRT
Photon IMRT
Target volume: nasopharynx + lymph nodes
(yellow)
Organs at risk: brainstem, parotid glands (red)
Protons – IMPT
(active scanning, 4 fields)
E.Pedroni, Europhysics News 31, 2000
Hadrontherapy: Technical requirements
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Range in tissue
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Protons
Ions
220 – 250 MeV
up to 400 MeV / amu
Shift in Bragg peak position (1 – 3 mm)
→ energy shifts (0.5 – 1 MeV)
Field size
Dose rate → particle fluence
Accelerators
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2 – 3.5 cm
2 – 10 cm
2 – 25 cm
Energy
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Eye tumours
Head & neck tumours
Deep seated tumours
Cyclotron (IBA, Accel)
Synchrotron (PIMMS, PRAMES, Optivus, Mitsubishi, Hitachi)
Fixed beams (horizontal, vertical), gantry
Beam modulation - passive spreading, active scanning
Hadrontherapy worldwide
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Nuclear physics centres
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head & neck tumours
eye tumours
NSCLC lung cancer
prostate cancer
Berkeley, Harvard (USA),
Dubna, Moscow (Russia),
PSI (Switzerland),
Nice, Orsay (France)
→ medical facilities
Loma Linda (CA, USA) 1991
HIMAC Chiba (Japan) 1994
NCC Kashiwa (Japan) 1998
NPTC Boston (USA) 2001
Wan Jie PTC (China) 2004
RPTC Munich (Germany) 2006
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Approx. 25 centres + 20 in planning
(USA, Europe, Japan)
Almost 50000 patients
(protons + ions)
Potential patients:
1000-3000 per year / 10 mil. inhabitants
Main indications:
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Clinical results:
5 yrs. local control
chordomas
chondrosarcomas
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photon vs. hadron RT
17-50% vs. 73-83%
50-60% vs. 90-98%
Costs:
initial costs 70-120 mil. € (1000 pt/y)
about 20 000 € / patient
approx. 2-3x more expensive than photon RT,
about the same as surgery, by far less expensive
than chemotherapy
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Particle Therapy Co-Operative Group
(PTCOG)
http://ptcog.web.psi.ch/
Proton therapy
facilities (1)
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NPTC Boston 2001
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IBA proton cyclotron, 230 MeV
Compact design (6m diameter)
Fixed energy + energy degrader
Kashiwa, Japan 1998
Wan Jie PTC, China 2004
MPRI Bloomington, USA 2006
Florida PT Inst, USA 2006
Beijing, China 2007
NCC, Seoul, Korea 2006
[NPTC Boston, 2001]
[IBA]
Proton therapy
facilities (2)
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RPTC Munich
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Superconducting cyclotron Accel, 250 MeV
protons
4 gantries (Schär AG), 1 fixed beam
Plan: 4000 patients / year
Tests & commissioning; operating in 2006?
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PSI Villigen – PROSCAN
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Synchrotrons – Loma Linda (>10000 pts
since 1991), MD Anderson CC
Optivus, Mitsubishi, Hitachi
[Accel/Schär]
Ion therapy
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Rationale:
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Cyclotrons: ongoing research
(IBA 400 MeV/amu
superconducting cyclotron)
Synchrotrons: PIMMS, HICAT,
Siemens, Mitsubishi
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Pulsed beam
Variable energy
Active scanning
PIMMS: 23 m diameter
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Physical selectivity
Increased biological effectiveness,
diminishing oxygen effects
(→ radioresistant tumours)
Online dose monitoring (PET)
Hypofractionation
Protons 60-250 MeV
Carbon 120-400 MeV/amu
Several projects within the EU
HICAT Heidelberg
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Heavy Ion Cancer Therapy
Centre
p
48-220 MeV
He 72-330 MeV/amu
C
88-430 MeV/amu
O 102-430 MeV/amu
Linac: 5m, 7 MeV/amu
Synchrotron, 20m diameter
Gantry 20m x 13m diameter
(120t), active scanning
Preclinical operation 2006,
clinical - 2007
Other p + ion hadrontherapy centres in Europe
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PIMMS design
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CNAO Pavia (Italy) 2007
ETOILE Lyon (France)
MedAustron Wiener Neustadt (Austria)
Karolinska, Stockholm (Sweden)
Prague?
ENLIGHT network
ENLIGHT
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European Network for Light Ion Hadron Therapy, European Commission,
QLG1-CT-2002-01574, 2002-2005
ESTRO, CERN, EORTC, GSI Darmstadt, DKFZ Heidelberg, GHIP
Heidelberg, TERA, Karolinska Institutet, ETOILE Project, Med-Austron,
FZR Rossendorf, Linköping University, Hospital Virgen de la Macarena,
Charles University in Prague
Workpackages:
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Epidemiology and patient selection
Design and conduct of clinical trials
Preparation, delivery and dosimetry of ion beams
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Preparation of Ion Beams
Dosimetry of Ion Beams
Treatment Planning
Accelerator Technology
Radiation biology
In-situ monitoring with positron emission tomography
Health-Economic Assessment
ENLIGHT++ proposal (2006)
Summary – Hadron therapy
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Excellent dose conformity
Proven clinical benefits in several
tumours/locations
Approx. 1000 – 3000 pts/year/10 mil.
inhabitants would benefit from HT
Ion therapy: radioresistant tumours
Costs: initial ~ 70-120 M€, per pt ~ 20 k€
Biological effects of ionizing radiation:
Mechanism and its modelling
Motivation
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Biological effects are not given by
deposited dose only
Increased biological effectiveness (RBE)
of light ions
RBE=DX/Dion depends on Z, E, D, ...,
cell repair capacity, …
Needs to be integrated into TP systems
Need for detailed biology-oriented
models, reflecting the underlying
mechanisms
Dose
Biological effect
Radiobiological mechanism
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Physical phase
(10-18 – 10-10 s)
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Energy transfer,
excitations, ionizations,
radical formation
Chemical phase
(10-10 – 10-3 s)
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Diffusion, recombination,
chemical reactions,
DNA damage
(base modification, base
loss, cross-link, SSB,
DSB, LMDS)
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Biological phase
(seconds – hours, years)
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Repair processes (BER,
HR, NHEJ), cellular
response, apoptosis,
necrosis;
organ, organism
Probabilistic two-stage model
Kundrát P, Lokajíček M, Hromčíková H (2005)
Phys. Med. Biol. 50 1433-1447
Kundrát P (2006)
Phys. Med. Biol. (in press), arXiv: physics/0509053
 Mono-energetic
particles:
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Number of primary particles, k:
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Transferred energy
DNA damage induction
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Lethal lesions formed by single particles … a
„single-particle“ lesions
Sublethal lesions … b
Lethal if combined from at least 2 particles
„combined“ lesions
Repair processes
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Pk(D) = [(hD)k/k!]exp(-hD)
h~σ/LET
ε ~ LET
Repair success probability … rk
Effect of k particles
k  
qk  1    ki  ai (1  a)k i
i1  
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 
j 2
j
k i j
Cell survival probability s(D) = Σ Pk(D) qk
 General
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k i
 k j i b (1  b)
case:
Transferred energy
Cell survival
π1(ε), πk(ε)= ∫ π1(ε’) πk-1(ε-ε’) dε’
s = Σ Pk ∫qk(ε) πk(ε) dε
1 r 
ab
ij
Detailed analysis of the response of different cell
lines to carbon irradiation
Hromčíková H, Kundrát P, Lokajíček M (2005)
14th Symposium on Microdosimetry,
Venezia, Italy; arXiv: physics/0512044
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analysis of survival data for CHO-K1 and
repair-deficient CHO mutant xrs5
irradiated by carbon ions (2.4 – 266.4
MeV/u, 13.7 – 482.7 keV/μm)
equal damage yields, different radiation
sensitivities due to different repair capacities
(rxrs5=0)
qk=[1-(1-(1-a)k)(1-ra)][1-(1-(1-b2)k(k-1)/2)(1-rb)]
Mechanism of cell inactivation by different ions:
damage induction probabilities per single tracks
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p
■, □ 0.57–7 MeV
3He ●, ○ 1.13 – 2.3 MeV/u
12C
▲, Δ 2.4 – 266.4 MeV/u
16O
▼,  1.9 – 396 MeV/u
20Ne ♦,  8.0 – 395 MeV/u
Combined lesions
Single-track lesions
Kundrát P, Lokajíček M, Hromčíková H, Judas L
(2005) 14th Symposium on Microdosimetry,
Venezia, Italy; arXiv: physics/0512028
 Damage probabilities in dependence on LET
and effective charge Zeff2/β2
5.8 – 37.8 keV/μm
58.9 – 105.8 keV/μm
13.7 – 482.7 keV/μm
18 – 754 keV/μm
28 – 452 keV/μm
Towards biology-oriented treatment
planning in hadron radiotherapy
Kundrát P (2005) 14th Symposium on Microdosimetry,
Venezia, Italy; arXiv: physics/0512028
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Bragg peak model
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Energy loss: SRIM-2003
Energy-loss straggling: effective depth straggling,
variance σ[cm] = 0.012 x0.951[cm] A-0.5
Attenuation of primary particle fluence Φ due to nuclear
reactions
Φ = Φ0 exp(– x / λ)
λ - nuclear interaction length, x - depth
Fragmentation, scattering: not represented
Bragg peaks – C, 195 and 270 MeV/u
Radiobiological model
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Effective version, considering unrepaired damage only
Damage induction probabilities per track at given LET
(single-track lesions - a, two-track lesions - b)
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CHO cells – C, 187 MeV/u, 2x107 cm-2
Average damage probability per track along Bragg peak
depth
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Derived from survival data for mono-energetic ions
Weighting over LET spectrum πi(L) (and different ion
species with abundances ρi) at given depth
a = Σi ρi ∫ai(L)πi(L)dL, b = Σi ρi ∫bi(L)πi(L)dL
Survival after the traversal of k particles
qk = (1-a)k [(1-b)k + kb(1-b)k-1]
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Distribution of ion tracks over cell nuclei: Poisson
statistics, mean number of primary particles reduced due
to nuclear reactions
Pk = exp(-h) hk/k! ,
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Survival probability: s = Σk Pk qk
h = σcell nucleus Φ0 exp(– x / λ)
CHO cells – C, 264 MeV/u, 2 and 5x107 cm-2
On the biophysical interpretation of lethal DNA lesions
induced by ionizing radiation
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Numbers of lethal events
 Derived from survival data of V79 cells irradiated by protons,
0.57–5.01 MeV (LET 7.7 – 37.8 keV/µm)
10000
1000
Damage yields [1/Gy/cell]
Kundrát P, Stewart RD (2005) 14th Symposium on
Microdosimetry, Venezia, Italy; arXiv: physics/0512030
DSB
SSB
other lesions
10
mis-repaired
enzymatic DSB
lethal events
1
0.1
0.01
[Belli et al 1998; Folkard et al 1996]
Probabilistic two-stage model [Kundrát et al 2005]
all lesions
100
0
10
20
LET [keV/m]
30
40
1000
Monte Carlo estimated yields of different classes of DNA damage
and the outcome of excision repair of non-DSB lesions
 Initial yields of DSBs, SSBs, base damage
 Enzymatic DSBs through aborted excision repair of SSBs, point
mutations through mis-repair of SSBs and base damage
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DSB total
DSB 10+
lethal events
1
0.1
0.01
Combined MCDS/MCER simulations [Semenenko and Stewart 2004;
Semenenko et al 2005; Semenenko and Stewart 2005]
Clustered lesions play important role in reproductive cell death
Differences in biological effectiveness of radiations of diverse quality
correlate with the differences in the yields of complex DSBs
 Certain subclasses of complex DSBs, e.g. approx. 3 – 5% of
DSB 8+, may be intrinsically unrepairable or are often lethally
mis-rejoined
DSB 4+
DSB 6+
DSB 8+
10
0
10
20
LET [keV/m]
30
40
1
Ratio of lethal events among DSBs
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Damage yields [1/Gy/cell]
100
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0.1
DSB total
DSB 4+
DSB 6+
DSB 8+
0.01
DSB 10+
0.001
0.0001
0
10
20
LET [keV/m]
30
40
Summary – Modelling
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P2S model
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Biology-oriented model
DNA damage & repair
Systematic description of survival curves
→ TCP, NTCP models
Future work
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Relate damage induction to track structure
Interpretation of lethal events
TCP, NTCP models
[email protected]