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?

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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!