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ApplicationApplication ofof HadronHadron BeamsBeamsinin CancerCancer RadiotherapyRadiotherapy
Michael Waligórski
The Skłodowska-Curie Memorial Centre of Oncology, Kraków Divisionand
Institute of Nuclear Physics, Polish Academy of Sciences, Kraków, POLAND
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NORMAL TISSUE CELL INITIATION
An initiating eventcreates a mutation in one of the basal cells
DYSPLASIA
More mutations occurred.The initiated cell hasgained proliferativeadvantages. Rapidly dividing cells begin to accumulate within the epithelium.BENIGN TUMOUR
More changes withinthe proliferative cell line
leads to full tumour development.
MALIGNANT TUMOUR
The tumor breaks troughthe basal lamina. The cells are irregularlyshaped and the cell line is immortal. They have an increased mobilityand invasiveness.
METASTASIS
Cancer cells break troughthe wall of a lymphatic vessel or blood capillary.They can now migratethroughout the body and
potentially seed new tumours
SCHEMATIC DEVELOPMENT OF NEOPLASTIC DISEASE
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METHODS OF TREATING CANCER
The basic modern approaches to cancer therapy are: • surgery,• radiotherapy, • chemotherapy and immunotherapy.Radiotherapy, applied alone or in combination withother techniques, is of basic importance in cancertreatment.Over 50% of all cancer patients are nowadays treatedwith ionising radiation. This results from the major advances in the technology of clinical equipment madein the last decades (medical accelerators, radioactivesource technology, diagnostic equipment, imagingtechniques, computer technology).
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RADIOTHERAPY TECHNIQUESThe basic techniquesof modern radiotherapy are:
• teleradiotherapy,
• brachytherapy,
• systemic radiotherapy(radioisotope therapy).
Intracavitary brachytherapy
Medical accelerator(4-23 MV photons &
4-23 MeV electrons)Interstitial brachytherapy
Selectron brachytherapyunit (Cs-137)
Medical Physicist
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CONFORMAL RADIOTHERAPY WITH PHOTON BEAMS
The aim ofradiotherapy is to achieve the best(conformal) distribution ofdelivered dose overthe target volume(tumour volume) independently of itsshape, in order to protect thesurrounding healthytissues and criticalvolumes.
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The technique of irradiadion affects thewidth of the „therapeutic window”
Tumour Control ProbabilityNormal Tissue ComplicationsCure = TCP (1 – NTCP)
Two opposingbeams
CONFORMALTECHNIQUE
Four beams
Source: W. Schlegel & A. Mahr, Eds. 3D Conformal Radiation TherapyA multimedia introduction to methods and techniques, Springer Electronic Media http://www.springer.de
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Intensity Modulated RadioTherapy (IMRT) offers new possibilities of dose conformation
PTV
OR
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DOSE OF X-RAYS
In a typical external radiotherapybeam treatment, a total dose ofabout 60 Gy is applied to thetumour volume in 30 fractions of2 Gy given each weekday
Assuming that about ½ of thenumber of cells exposed to 2 Gysurvive, a fraction of about(½ )30 ~ 10-10 survives after a dose of 60 Gy.
There are some 1010 cellsin 1 cm3 of tissue.
FRACTIONATED RADIOTHERAPY
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HOW DOES RADIATION AFFECT CELLS?
Radiotherapy is designed to cause cell death in the target (tumour) volume while sparing healthy tissues and critical organs
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The Cell Survival Curve(cell cultures in vitro)
Survival curve formulae:
αD + βD2 m - target
Note that „high-LET” (i.e. densely ionising radiation, such as neutrons or heavy ions) are more effective cell killers per dose – as given by Relative Biological Effectiveness (RBE)
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The Oxygen EffectCells deprived of oxygen (anoxic or hypoxic) are generally more resistant
to photon radiation than are aerobic (oxygenated) cells. Thus, neighbouring healthy tissues are more likely to be damaged than tumourcells which proliferate rapidly and may lack oxygen supply. From analysisof survival curves the Oxygen Enhancement Ratio (OER) may be found.
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The standard procedures of radiotherapy
• Clinical workout, therapy decision• Choice of patient immobilisation technique• Diagnostic & topographic imaging• Tumour localisation• Computer Therapy Planning• Patient setup• Patient irradiation• Treatment verification & Evidence
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Patient ImmobilisationSince the patient has to be repeatedly irradiated (typically 30 times when 2-Gy fractions are delivered), his/her body should not move during irradiation andhis/her positioning should be repeatable with an accuracy of 0.5-3 mm, depending on site irradiated.
Individual vacuum couch with positioningframe (for prostate treatment)
Immobilisation of patient’s headwith respect to treatment chair(proton beam eye therapy)
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OpticalOptical system for system for verifyingverifying patientpatient positioningpositioning3D surface scanning (Laser-based, LCD based)
Advantage: Anatomical information
Challenge: Not yet real-time (1-2 seconds / image)
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Problem Problem –– movementmovement ofof targettarget volumevolume
E Rietzel
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Respiratory movement of the target volumein the lung - (a study of 3D Carbon RT)
Approximation: All fields delivered simultaneously
E Rietzel
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18F-FDG PET 123I-IMT SPECT
MRI (T1) MRI (T2) CT
Imaging
(recurrent astrocytoma in the left temporal lobe )
Application of different imagingtechniques (CT, MRI, PET) provides the diagnosis andenables the target volume to be determined.
DIGITAL RADIOGRAPHYRECONSTRUCTION (DRR)
PET
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Determination of tumour volume Scans
CT
MRI
From a sequence of tomography scans (CT +MRI) it is possible to determine the targetvolumes, critical volumes and patienttopography for therapy planning purposes.
Source: W. Schlegel & A. Mahr, Eds. 3D Conformal Radiation TherapyA multimedia introduction to methods and techniques, Springer Electronic Media http://www.springer.de
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Computer radiotherapy planning – optimising theplacement of photon beams required to model the
spatial distribution of dose
projections:„beam’s eye view” (BEV) geometrical projection
Source: W. Schlegel & A. Mahr, Eds. 3D Conformal Radiation TherapyA multimedia introduction to methods and techniques, Springer Electronic Media http://www.springer.de
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Computer radiotherapyplanning – viewing andoptimising the 3D dosedistribution
Izodoses
Dose distribution in the target volumeand in critical volumes
Source: W. Schlegel & A. Mahr, Eds. 3D Conformal Radiation TherapyA multimedia introduction to methods and techniques, Springer Electronic Media http://www.springer.de
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VerificationVerification ofof thethe irradiationirradiation fieldsfields((dynamicdynamic MLC)MLC)
A sequence of fluence maps is shown for five photon beams providing the optimum individual treatment plan for the prostate.
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The future medical linear accelerator ?
Key features:
+„true” 3D mobility,
+ Pencil beam (6MV)conformality
+ DRR patient positioning
+ On-line organ tracking
? Dose delivery algorithm
? „true” IMRT
? „true” 3D Radiotherapyplanning….
Is this the standard against which Hadron RT should compete?
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What new elements are introduced by Hadron Radiotherapy?
• conformity of dose (well-defined range, charged particles)
• Bragg Peak at distal end of ion range
• RBE (Relative Bological Effectiveness) > 1
• OER (Oxygen Enhancement Ratio) ~ 1
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0
20
40
60
80
100
120
0 5 10 15 20 25 30
Głębokość [cm]
Moc
daw
ki [%
]
Conformity of dose (well-defined range, charged particles)Ion Beams („high-LET”) Conventional Radiotherapy (‘low-LET”
Co-60
6 MV photons
ElectronBeams
(4-20 MeV)
Percent dose-depth distributions
Ion tracks in nuclear emulsion
RBE?
Note: no effect of Bragg peak in ion tracks!
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Data: Furusawa et al. Radiat. Res. 154, 485-496 (2000)
Survival of V79 cells in vitro vs. LET of a Carbon-12 beam:Aerated cells Anoxic cells
RBE (Relative Bological Effectiveness) > 1 OER (Oxygen Enhancement Ratio) ~ 1
How does cell survival depend on ion LET (-dE/dX)?
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0 2 4 6 8 10 121E-3
0.01
0.1
1
Data: Tilly et al, 1999 * Stenerlöw et al, 1995
Model Parameters:m = 2.14E0 = 2.13*104 erg/cm3
σ0 = 5.15*10-7 cm2
κ = 1100
Katz ModelCo 60 & N-ions, V79 cells
Sur
viva
l
Dose (Gy)
Co 60 N 76.6 eV/nm N 121 eV/nm* N 159 eV/nm
1 10 100 1000 100000
1
2
3
4
5
6
7
8
9
Data: Tilly et al, 1999 * Stenerlöw et al, 1995
Model Parameters:m = 2.14E0 = 2.13*104 erg/cm3
σ0 = 5.15*10-7 cm2
κ = 1100
Katz ModelRBE0.1, V79 cells
Track Segment
RBE
0.1
LET (MeV/cm)
H He RBE for He* B N RBE for N Ar Fe
RBE (Relative Biological Effectiveness) > 1
Fractionation is less effective for high-LET RT, but RBE may then be higher
Conclusion: Fewer fractions needed inheavy-ion radiotherapy…..
High-LET survival & RBE can be modelled
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Entrance dose Bragg Peak dose
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ION PARAMETERS (BEAM DATA)ION PARAMETERS (BEAM DATA)
The CSDA range of all ion beams is R = 26.0 cm, in water
Values at Beam Entrance (range straggling)
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0 5 10 15 20 25 260,01
0,1
1
10
100
1000
Dose 0.25 Gy 1 Gy
V79 cells12C
Survival
RBES
LET
Su
rviv
al, R
BE S, L
ET (k
eV/μ
m)
Depth in tissue (cm)
DEPTH DISTRIBUTIONS OF LET, SURVIVAL AND RBES
Depth distributions of ion LET, cell survival and RBES for V79 and AA cells in a beam of 12C ions of initial energy 385.2 MeV/amu, delivering an entrance dose of 1.0 Gy.
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DEPTH DISTRIBUTIONS OF LET, SURVIVAL AND RBES
26 10 1 0,1 0,01 1E-3 1E-40,01
0,1
1
10
1 Gy
12C
Survival
RBES
LET
S
urvi
val,
RB
E S
Residual range (cm)
CellsV79 AA
10
100
1000
LET
(keV
/μm
)
Depth distributions of ion LET, cell survival and RBES for V79 and AA cells in a beam of 12C ions of initial energy 385.2 MeV/amu, delivering an entrance dose of 1.0 Gy.
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DEPTH DISTRIBUTIONS OF LET, SURVIVAL AND RBES
Depth distributions of ion LET, cell survival and RBES for V79 and AA cells in a beam of 12C ions of initial energy 385.2 MeV/amu, delivering entrance dose 0.25, 0.5 and 1.0 Gy.
26 10 1 0,1 0,01 1E-31E-4
1E-3
0,01
0,1
1
Dose Cell Lines V79 AA0.25 Gy 0.5 Gy 1 Gy
Survival12C
Sur
viva
l
Residual range (cm )
The FluenceProblem
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1,0 0,8 0,6 0,4 0,2 0,01
2
3
4V79 cells
20Ne
14N12C
11B
7Li4He
1H
1 Gy
RB
ES
Residual range (cm)
DEPTH DISTRIBUTIONS OF RBES(V79 CELLS) FOR LIGHT ION BEAMS
RBES- depth dependences of V79 cells over the last 1 cm of residual ion ranges, for lighion beams of range 26 cm, delivering an entrance dose of 1 Gy. Aerobic V79 cells are represented by parameters fitted to the data of Furusawa et al. (2000)
(is Carbon-12 the best ion for hadron radiotherapy?)
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Protons – Bragg peak or Straggling ?
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Elements of a HadronRadiotherapy Installation
• accelerator (H, C, 250 MeV/u, variable energy, beam sweeping?)
• beam transport system• Gantry (isocentric patient irradiation)
• PET imaging
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Spread-out Bragg peak(SOBP)
• „passive” method• „active” method
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Spreading out the Bragg peak using absorption filters
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Spreading out the Bragg peak using absorption filters
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Compensation Filters (detail)
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Principle of the Active Beam (GSI Darmstadt)
Source: W. Schlegel & A. Mahr, Eds. 3D Conformal Radiation TherapyA multimedia introduction to methods and techniques, Springer Electronic Media http://www.springer.de
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Comparison of treatment techniques
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Transversal cuts through the biologically effective dose distribution planned for a medial tumor of the base of the skull using two nearly opposing fields. Dose values in this color-wash presentations are: dark gray > 0.1% to < 10%; blue < 50%, green < 60%, yellow < 80%, dark yellow < 90%, red >= 90%. The PTV is indicated by red contours, the OARsby yellow (optical chiasm) and green (brain stem, myelon) contours (GSI Darmstadt).
Distribution of „biological dose”or distribution of survival?
Source: W. Schlegel & A. Mahr, Eds. 3D ConformalRadiation TherapyA multimediaintroduction to methodsand techniques, Springer Electronic Media http://www.springer.de
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HIMAC – NIRS, Japan
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Patient chair and X-ray computer tomograph for CTs in seated position at HIMAC
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Gantry (PSI Villigen)
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Proton radiotherapy of eye melanoma
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THE PROTON RADIOTHERAPY OF EYE MELANOMA PROJECT at the Institute of Nuclear Physics (IFJ PAN) in Krakow
Milestones (June 2006):• 55 MeV beam extracted• decision to fund project positive inwestycji• beam measurements (Bragg peak)• initial measurements of spread-out Braggpeak (SOBP)
• beam control electronics assembled EYEPLAN-PC thrapy planning program (AGH+IFJ) (VARIAN-Eclipse)
Bragg peak at IFJ
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THE ENLIGHT PROJECTEuropean Network for Research in Light-IonRadiotherapyNetwork began within the 5th EU FrameworkProgramme, with the following members:
ESTRO (European Society for Therapeutic Radiology andOncology)EORTC (European Organisation for Research in the Treatment of Cancer)ETOILE (Espace de Traitement Oncologique par ions Legers –Lyon (France)Karolinska Institutet – Stockholm (Sweden)GHIP (German Heavy-Ion Project) GSI-Darmstadt & HeidelbergUniversity (Germany)Virgen Hospital – Macarena (Spain)MED-AUSTRON – Wiener Neustadt (Austria)TERA Foundation – Milan (Italy)CERN – Geneve (Switzerland)
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WILL WE HAVE A HADRON RADIOTHERAPY FACILITY IN POLAND?
ENLIGHT and the European projectsENLIGHT and the European projects• GSI project for the University of Heidelberg Clinics• TERA project for CNAO in Pavia• Med-Austron for Wiener Neustadt (partner of PIMMS since 1996)• ETOILE in Lyon• Nordic Centre in Stockholm
Modular PIMMS accelerator(CERN) for European ENLIGHT hadron RT installations