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Organ motion in radiotherapynada*
1/XXX
Improving clinical brachytherapy: dosimetry &
verification
Frank Verhaegen, Gabriel Fonseca, Murillo Bellezzo, Shane White, Guillaume Landry, Brigitte Reniers
MAASTRO Clinic, Maastricht, the Netherlands
Despite much research: Current status brachytherapy of
dose calculations (5 yrs after publication of TG186)
Real patient Model patient
30 cm
water
Dose calculations based on TG43 protocol
=
all water
Shortcomings of current dose calculation standards (TG43)
From M Rivard
air ≠ water?
tissue ≠ water?
Contrast medium ≠ water?
source superposition?
source shielding?
applicators?
radiation scatter?
How do we verify the dose?
Fat is 40% different
from water!
6 major improvements needed in brachytherapy
1. Heterogeneities in tissues (tissue water)
-problem for low energy photons, is largest source of errors
2. Heterogeneities in sources
-source design and attenuation in sources already in TG43
-intersource attenuation, applicators, shielding, metal imaging markers
3. Dose reporting
-dose-to-water vs dose-to-medium
-known problem in external beam radiotherapy (errors limited to a few %)
4. Dose verification
5. Relative Biological Effectiveness of low energy photons
-everyone uses 1.0, but is 1.0 (especially in low-energy sources)
6. Image guidance
1. Heterogeneities in tissues
An example in breast electronic brachytherapy
TARGIT study: Electronic brachytherapy in breast radiotherapy
• In radiotherapy clinics, physicians (and physicists) think only in terms of dose to
water
• Inter-patient differences are not taken into account
• Dose-response data is unreliable if you think you give all patients the same dose
IntraBeam electronic
brachytherapy source (50 kV)
Inserting x-ray source in breastVaidya et al . Lancet 376: 91–102, 2010
Vaidya et al. Eur J Surg Oncol 28: 447, 2002
Dose vs distance from source
Strong dose heterogeneity due to gold fiducial markers in
prostate (e.g. LDR boost after EBRT)
• Severe underdosing near gold markers
• Clinical relevance?
• Would we adapt our planning strategies?
Methods
• Monte Carlo simulations using GEANT4
– Calculate dose with and without markers
• Virtual water phantom
– Single + multiple 125I sources
– 1 gold marker, various distances from source
• Patient cases with many LDR seeds and several gold markers
– Based on post-implant CT
– Assess magnitude of dose depression and volume of cold spots
OUTCOME: single sources
• Single source scenarios
– Up to 95% dose reduction
– Slight dose enhancement on proximal side of marker
• Multiple sources: Less reduction
125I sourceAu marker
OUTCOME: clinical implants
90Gy
• Up to 50% dose reduction (90 Gy in this example)
• Can modify the 100% isodose contour
• Cold spots (<95%) are observed
• D90 was not affected
(Landry et al. Dose reduction in LDR brachytherapy by implanted prostate gold fiducial markers. Med Phys 39, 1410-7, 2012)
Note: dose reduction due to
interseed attenuation 5%
Define for each voxel: material and density (segmentation)
• Single-energy CT: only electron density e (e–/cm3)
• Dual-energy CT: e and effective atomic number Zeff
• How sensitive is the dose to tissue mis-assignment?
• How well are tissues known?
– Average over population
– In an individual patient?
• With TG-43 we never have this problem (all water)
15/26
Variation of tissue composition
• Human tissues vary from one individual to the other
• Data in literature is scarce and old
• All refs trace back to: (Woodard&White, BJR 1986)
Does any of this matter dosimetrically?
30/52
Sensitivity of dose calcs to tissue composition
• Assess the influence in tissue composition and its variation across
the population on dose calculations
Simple test geometry
• Spherical geometries
• Look at variations of D with distance for various media
20/26
RESULTS
Simulation - breast tissue (adipose + gland)
(Landry et al. Sensitivity of low energy brachytherapy Monte Carlo dose calculations to uncertainties in human tissue composition.Med. Phys. 37, 5188-98, 2010)
• D can differ from TG43 by >80% in 3cm
• Difference due to variation in breast composition
• Different low energy sources behave differently
Simulation – Dose ratio for a breast case (Pd-103)
• Left: From water to average breast, 30%
• Right: Compositional uncertainty (1*) among patients, ±10%
largest effect!
(Landry et al. Sensitivity of low energy brachytherapy Monte Carlo dose calculations to uncertainties in human tissue composition.Med. Phys. 37, 5188-98, 2010)
This means most of the accuracy will be gained by replacing
water average breast tissue
Patient Study: electronic brachytherapy for breast
• AXXENT (Xoft) mini x-ray source
– Isotope-free brachy source
– 0-50 kV, low energy x-rays
– Tunable dose distributions
Prototype #001
Source in scintillation liquidTomato-shaped dose
distribution
16
Detailed Monte Carlo modelling of Axxent source
-bremsstrahlung and characteristic photons produced by electron interactions in target and support
-target (W): 87%
-support (Y): 7%
-rest: 1%
-missing 5%: photo-electric characteristic photons in Yttrium support
Support (Y)W-Targetvacuum
e-
e-
water
catheter
Primary
electrons
Support (Y)W-Targetvacuum
e-
e-
water
catheter
Geant4 model
Primary
electrons
EGS++ Monte Carlo model
tip
Thin transmission target
Liu et al. Phys. Med. Biol. 53, 61-75, 2008
Electronic brachytherapy for breastS White et al, Comparison of TG-43 and TG-186 in breast irradiation using a low energy electronic brachytherapy
source, Med Phys, 41/6, 061701-12, 2014
balloon
applicator
gland
adiposePTV
Dose ratios: heterogeneous/TG43 or
heterogeneous/(water-air model)
Ref=TG43
Ref=water+air
model
Loss of backscatter
Large differences
between Dwm and Dmm
Differences in
PTV close to skin
Conclusions from EBT breast study
TG-43 overestimates dose to certain regions e.g. skin
may permit dose escalation
TG-43 underestimates dose in e.g. ribs
These changes are dependent on the dose reporting method
(Dwm vs Dmm; see further)
Better ways to distinguish tissues?
Dual-energy CT (DECT)
• Use dual energy CT to extract (e , Z) directly from CT images
• Many tissues have similar e, but different Z
• Use Z to distinguish the tissues
6.0 6.5 7.0 7.5 8.00.90
0.92
0.94
0.96
0.98
1.00
1.02
1.04
1.06
1.08
1.10
rela
tive
ele
ctr
on
den
sity
effective atomic number
Breast and prostate phantoms
theory
simulation
corrected simulation
DECT segmentation vs. SECTG Landry et al, Simulation study on potential accuracy gains from dual energy CT tissue segmentation for low energy
brachytherapy Monte Carlo dose calculations. Phys. Med. Biol. 56, 6257-78, 2011
Reference SECT DECT
Many tissues missassigned
RESULTS
Dose errors
• TG43 = large errors
• 103Pd is very sensitive
• DECT performs the
best
Green means
correct dose
2. Heterogeneities in sources/applicators
New dose calculation algorithms
– Model-Based Dose Calculation Algorithms (MBDCA)• Stochastic methods: Monte Carlo (none in commercial TPS)
• Deterministic approaches: GBBS (Acuros, Varian)
• Primary/Scatter separation: CCC (Elekta-Nucletron)
Monte Carlo simulation of an
HDR Ir-192 source
Monte Carlo simulation of an
LDR I-125 seed
MC based dose calculation system: AMIGOBrachy (A Medical Image-based Graphical platfOrm, G Fonseca)
AAPM Task Group TG-186 (2012)
Mandate: Provide user guidance through multiple calculation models,
issues on patient geometry, patient heterogeneity:
“Model-based dose calculation techniques in
brachytherapy: Status and clinical requirements for
implementation beyond the TG-43 formalism”
L Beaulieu, A Carlsson, J-F Carrier, S Davis, F Mourtada, M Rivard, R Thomson, F Verhaegen, T Wareing, J Williamson.
Report of the Task Group 186 on model-based dose calculation methods in brachytherapy beyond the TG-43 formalism:
Current status and recommendations for clinical implementation. Med Phys 39, 6208-36, 2012
Guidelines of Task Group 186 (AAPM)
Recommendations in TG186:
• Define for each voxel: material and density (segmentation)
• Define the dose scoring medium
• Provide guidelines for commissioning complex dose calcn algorithms
Aims:
• Must maintain inter-institution consistency (as in TG43)
• Avoid chaos due to increased complexity
• Should improve estimates of outcome studies
• May allow better estimate of radiobiological parameter /
Work group on TG186
Comparing modelling of applicators for 192Ir
Monte Carlo codes: ALGEBRA, BrachyDose, Geant4, MCNP5, MCNP6, Penelope2008
Grid Based Boltzmann Solver (Varian): BrachyVision ACUROS
Collapsed−cone superposition/convolution (Elekta): Oncentra Brachy Advanced Calculation Engine (ACE)
Results
Differences between MC codes
are small but not zero!
Differences between Acuros
and ACE (up to 10%)
Recent work of the Work Group
Differences Geant4-MNCP6 Differences ACE-MNCP6
3. Difference in reporting dose to water or medium
• MBDCA result in Dose to the real medium
• Three different ways of dose reporting
– Transport photons in water, score in water: Dw,w (TG43)
– Transport photons in medium, score in medium: Dm,m (natural way for MBDCA)
– Transport photons in medium, score in water: Dw,m
• In EBRT this is not a problem
TG43
Difference in reporting dose to water or medium:
example of breast brachytherapy
Left: Dw,m and Dm,m in mean adipose tissue (103Pd, 125I, Axxent 50 kV)
Right: Ratio Dw,m/Dm,m
differences up to 70%
slightly dependent on source, varies slightly with distance from source
(Landry et al. The difference of scoring dose to water or tissues in Monte Carlo dose calculations for low energy brachytherapy
photon sources. Med. Phys. 38, 1526-33, 2011)
Dose reporting method may influence clinical practiceWhy do we need 3 different dose reporting methods (Dw,w ; Dw,m ; Dm,m)?
• Most people agree we should transport photons in
medium, but score in what?
• Arguments for Dm,m
– Natural scoring method in Monte Carlo
– Outcome correlates better with this natural quantity?
• Arguments for Dw,m
– All clinical practice is based on dose to water
– Most measurements are water based
– Cells are mostly made of water (embedded in matrix of
other media)
103Pd breast implant
Different dose reporting methods and conversion methods
Cavity theory G Fonseca et al, Dose specification for 192Ir high dose rate brachytherapy in terms of dose to
water in medium and dose to medium in medium. Phys Med Biol 60, 4565-79, 2015)
Large Cavity Theory (LCT) uses (μen/)w,m, assuming charged particle equilibrium (CPE)
for the cavity
Small Cavity Theory (SCT) uses (S/)w,m, for Bragg-Gray cavities with dimensions much
smaller than the secondary electron ranges
Strong variation
with energy
Weak variation
with energy
A head&neck brachy case G Fonseca et al, Dose specification for 192Ir high dose rate brachytherapy in terms of dose to water in medium and dose to
medium in medium. Phys Med Biol 60, 4565-79, 2015
Variation of mean photon
energy with distance from
implant (192Ir)
Dm,m / Dw,m(LCT) Dw,m(LCT) / Dw,m(SCT)
But what is a large/small cavity?
Burlin cavity theory (mix of small/large cavity)
Value of ‘d’ to be used in the
cavity theory, as function of
photon energy and cavity
chord
192Ir
SmallLarge
125I
4. Dose verificationUsing an imaging panel to capture photon fluence outside patient
Imaging
Plan
Treatment
Goal - Real Time Dosimetry
AMIGOBrachy
EPID Dosimetry
Additional
Steps
Using a robotic arm with position sensors for accurate brachy experiments
Using RAMBO (Robotic Arm for Measurements in Brachytherapy
and Other applications) to calibrate EPID panel
39/45
Meet RAMBO (Robotic Arm for Measurement in Bachytherapy and Other
applications) &
CARMEN (Cybernetic Arm for Radiotherapy MEasurements and Novel
applications)
Gabriel Fonseca
Dwell time and dwell position verificationG Fonseca et al, Online pretreatment verification of high-dose rate brachytherapy using an imaging panel. Phys Med
Biol, under review, 2017
Dwell time errors detected
in real time
Dwell position errors
detected in real time
5. Relative Biological Effectiveness for low energy photons
Yield of di-centric chromosomal aberrations in human
lymphocytes (Hill, Rad Prot Dosim 112, 471-81, 2004)
AXXENT
Pd-103
I-125
Ir-192
Axxent mini x-ray source (40-50 kV)
increased RBE for lower
energy photons
1m.... from single collisions of 1.3 MeV photons
1m
... from single collisions of 30 keV photons
(Lappa et al. TRION track structure Monte Carlo code)
Track structure calculations from microdosimetry
=Monte Carlo at micron scale (or smaller)
RBE estimate from Monte Carlo modelling
Step 4: Calculate frequency
of SSB and DSB in DNA
Step 6: Fold photon/electron
spectra with damage distributions
Step 7: Calculate RBE
Step 3: Use DNA damage
model MCDS (R Stewart)Step 1: MC model AXXENT
Step 2: Calculate
photon & secondary e-
spectra in media
0
0.05
0.1
0.15
0.2
0 10 20 30 40 50
Primary Electron Energy (keV)
Prim
ary
Ele
ctr
on
Spe
ctr
um
(A
E)
photo-electric effectCompton
Augerwater, 50 kVp
3.9 (a)
75
100
125
150
175
200
0.1 1 10 100 1000
Electron Energy (keV)
SS
B y
ield
(G
y-1 G
bp
-1)
0
5
10
15
20
25
30
DS
B y
ield
(G
y-1 G
bp
-1)
Primary electron spectrum (keV)
Step 5: Analyze complex
DNA damage
50/52
75
100
125
150
175
200
0.1 1 10 100 1000
Electron Energy (keV)
SS
B y
ield
(G
y-1 G
bp
-1)
0
5
10
15
20
25
30
DS
B y
ield
(G
y-1 G
bp
-1)
Calculate SSB and DSB frequencies: MCDS (Monte Carlo
Damage Simulation; Semenenko and Stewart, 2004, 2006)
I) In a DNA segment: randomly distribute expected
# lesions in a cell Gy-1
1) Select nucleotide pair at random from segment: {1,nseg}
2) Select one of 2 DNA strands randomly. If not damaged yet, record damage. Else goto 1
3) sb=sb-1; if sb > 0 goto 1
4) repeat 1)-3) for Bp base damages
II) Subdivide lesions in segments in clustersScore SSB, DSB, complex breaks,
base damage,…
Calculate RBE for Axxent source
Medium SSB
(Gy-1Gbp-1)
DSB
(Gy-1Gbp-1)
RBESSB RBEDSB
Water 161 (189) 14.9 (8.2) 0.89 (0.88) 1.42 (1.49)
Muscle 162 (188) 14.7 (8.4) 0.90 (0.89) 1.40 (1.47)
Breast 161 (188) 15.0 (8.4) 0.89 (0.88) 1.43 (1.50)
Breast+Ca 160 (188) 15.1 (8.4) 0.89 (0.88) 1.44 (1.51)
Bone (0.1 cm) 178 (188) 11.1 (8.4) 0.99 (0.98) 1.06 (1.11)
Bone (1 cm) 176 (188) 11.9 (8.2) 0.98 (0.97) 1.13 (1.19)
RBE with 192Ir (60Co) as reference radiation
50 kV AXXENT source has 40% higher RBEDSB than 192Ir
(50% higher compared to 60Co)
Reniers et al. Calculation of relative biological effectiveness of a low-energy electronic brachytherapy source. Phys. Med. Biol. 53, 7125, 2008
Breast electronic brachytherapy study: RBES White et al, A comparison of the relative biological effectiveness of low energy brachytherapy sources in breast
tissue: A Monte Carlo study. Phys Med Biol, 61, 383-99, 2016
Density map
Mean photon
energy map
Material map
RBE map
SummaryHow to switch from water sphere to real patient geometry
• Low energy brachytherapy dose calcs very sensitive to tissue composition
– Recommendations on tissue segmentation needed
– Recommendations on tissue composition/assignment needed
• Dm,m and Dw,m can be very different
– Be aware of dose prescription
– Conversion needs cavity theory
• Recommendations on further research: tissue typing, imaging modalities
(Dual Energy CT, quantitative MRI), …
• Relative Biological Effectiveness (RBE>1.0) should be taken into account
– Effective dose to target may be underestimated
– Sensitive organ sparing may be overestimated (e.g. Axxent compared to 192Ir)
– Measurement of RBE and related physical quantities (e.g. LET) needed
Brachytherapy needs input from metrology!