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Geometrical variability of esophageal tumors and its implications for accurateradiation therapy

Jin, P.

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Citation for published version (APA):Jin, P. (2019). Geometrical variability of esophageal tumors and its implications for accurateradiation therapy.

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9Dosimetric benefits of mid-position compared

with internal target volume strategy for esophagealcancer radiation therapy

P. Jin, M. Machiels, K.F. Crama, J. Visser, N. vanWieringen, A. Bel,M.C.C.M. Hulshof, and T. Alderliesten

A version of this chapter has been accepted for publication in

International Journal of Radiation Oncology * Biology * Physics. 2018; In press

DOI: 10.1016/j.ijrobp.2018.09.024


Chapter 9

Abstract

Purpose

Both mid-position (MidP) and internal target volume (ITV) strategies can take the respiration-induced target motion (RTM) into account. This study aimed to compare these two strategies interms of clinical target volume (CTV) coverage and dose to organs at risk (OARs) for esophagealcancer radiation therapy (RT).

Materials and methods

Fifteen esophageal cancer patients were retrospectively included for neoadjuvant RT planning.Per patient, a 10-phase 4D-CT was acquired with CTV and OARs delineated on the 20% phase.TheMidP-CTwas reconstructed based on deformable image registration (DIR) between the 20%phase and the other nine phases; thereby the CTV and OARs delineations were propagated andan ITVwas constructed. BothMidPand ITV strategieswere used for treatment planning, yieldingthe planned dose. Next, these plans were applied to the 10-phase 4D-CT to calculate the dose dis-tribution for each phase of the 4D-CT. Based on theDIR, these calculated dose distributionswerewarped and averaged to yield the accumulated 4D-dose. Subsequently, we compared, in terms ofCTV coverage and dose to OARs, the planned dose with the accumulated 4D-dose and also theMidP strategy with the ITV strategy.

Results

The differences between the planned dose and accumulated 4D-dose were limited and clinicallyirrelevant. In 14 patients, both MidP and ITV strategies showed V95%>98% for the CTV. Com-pared to the ITV strategy, the MidP strategy showed a significant reduction of approximately10% in the dose-volume histogram parameters for the lungs, heart, and liver (p


999999999

MidP versus ITV for esophageal cancer RT

9.1 Introduction

Preoperative radiation therapy (RT) with concurrent chemotherapy can improve survival amongpatientswith potentially curable esophageal or gastroesophageal-junction (GEJ) cancer [17]. Theplanning target volume (PTV) is used to encompass the clinical target volume (CTV) in thepresence of tumor delineation and inter-/intrafractional tumor position variations. Respiration-induced targetmotion(RTM) is theprimary sourceof intrafractional uncertainty forRTof esopha-geal or GEJ cancer. This is most pronounced in the cranial–caudal (CC) direction and its averageamplitude is 1–4 mm in the proximal esophagus and 5–8 mm in the distal esophagus and GEJ[165, 210, 214]. However, the interfractional variability of RTM for esophageal and GEJ tumorsis limited (mean variation⩽1.4 mm), therefore a single 4D computed tomography (CT) wouldbe sufficient for estimation and prediction of the RTM over the treatment course [214].

The internal target volume (ITV) is commonly used for taking into account the RTM uncer-tainty in treatment planning, which covers the whole RTM of the CTV [74]. Alternatively, themid-ventilation (MidV) or mid-position (MidP) strategy can be used, where the RTM can be in-cluded as a random positioning error in the probability-based CTV-to-PTV margin [137]. Forthe lung stereotactic body RT (SBRT), liver SBRT, and pancreatic cancer RT, the MidV/MidPstrategy reduced the PTV volume by 25%, 34%, and 14%, respectively compared with the ITVstrategy [127, 202, 227, 228]. Consequently, the mean dose to organs at risk (OARs) was signif-icantly reduced by 0.5–2.0 Gy, which was only reported in a few dosimetry studies of comparingthe two strategies [202, 228]. The use of the MidV/MidP strategy has shown good locoregionalcontrol and overall survival for lung SBRT [129] and the possibility of dose escalation in the grosstumor volume (GTV) for liver SBRT [229].

For esophageal cancer RT, the dosimetric impact of using the MidV/MidP strategy cannot bedirectly derived from the findings in other tumor sites because of the different RTM pattern anddifferent OARs [214]. Most studies on the use of 4D-CT andmotionmanagement in esophagealcancer RT focused on the RTM amplitude [70, 165, 170, 198, 199, 210, 214]. Only few studiesdiscussed the use of ITV for esophageal cancer RT [68, 71, 230] and neither ITVnorMidV/MidPstrategies have yet been analyzed in terms of their dosimetric impacts.

The implementation of an ITV strategy is hindered by the labor-intensive CTV delineation[71], which is also prone to delineation uncertainties especiallywithout the aid of fiducialmarkers[231]. For theMidV/MidP strategy, a region and direction-dependent quantification of the RTMamplitude is required for margin calculation [125, 210, 214]. However, the absence of fiducialmarkers in clinical practice makes this quantification tough [165, 210, 214].

Due to the potentially reduced dose to OARs with possibly lower toxicity [50–53, 56] andthe need of dose escalation [48, 49] as shown in other tumor sites [129, 228, 229], it is essentialto investigate the implementation and dosimetric impact of using the MidV/MidP strategy foresophageal cancer RT. In this study, we therefore aimed to apply the MidP strategy in treatment

135


Chapter 9

planning for free-breathing esophageal cancer RT and to compare it with the ITV strategy in termsof PTV volumes, CTV coverage, and dose to the OARs, using 4D-dose accumulation based ondeformable image registration (DIR).

9.2 Materials andmethods

Patients, imaging data, and manual delineations

We retrospectively included 15 patients with esophageal cancer, who were consecutively treatedbetween December 2015 and May 2016 (Table 9.1). The requirement of additional ethical ap-proval for human subject involvement was waived by the local medical ethics review committee.

Per patient, one planning 4D-CT was acquired (LightSpeed RT 16; General Electric, Wauke-sha,WI)with patients breathing freely in head-first supine position using an armand knee support(CIVCOMedical Solution, Coralville, IA). All 4D-CT scans were sorted into 10 breathing phases(phase binning, 0–90%) and the average intensity projectionCT (AIP-CT)was automatically de-rived (Advantage 4D software; General Electric). The in-plane pixel size was 1.0 mm or 1.3 mmdepending on the field of view. The slice thicknesswas 2.5mm. No serious artifacts were observedin the 4D-CT scans.

Per patient, the gross target volume (GTV) was retrospectively delineated on the 20% phaseof the 4D-CT by an experienced radiation oncology resident with the aid of all available diagnos-tic information including diagnostic positron emission tomography and/or CT scans, endoscopy,and endoscopic ultrasound. We chose the 20%phase as reference due to its proximity to theMidP,which may result in less effort to propagate the delineations to the other phases than when usingone of the other phases as reference. The CTV was generated by extending the GTV in the CCdirection with a 20-mm margin in the cardiac region or a 35-mm margin above the GEJ and pe-ripherally with coverage of the para-esophageal fatty tissue and involved lymph node stations.

The OARs (i.e., lungs, heart, liver, kidneys, and spinal cord) were delineated initially on theAIP-CT by the radiation therapists as part of the clinical treatment planning. By performing DIRbetween the AIP-CT and the 20% phase of the 4D-CT, the OAR delineations were propagated tothe 20% phase of the 4D-CT. All DIRs in the present study were done using ADMIRE version 2.0(Elekta AB, Stockholm, Sweden), which applies a non-linear block-matching method with block-wise normalized-sum-of-squared-differences metric.

MidP-CT reconstruction

Per patient, a MidP-CT was reconstructed based on DIR, in line with the approach introducedfor lung cancer RT [232]. First, the 20% phase was deformably registered with each of the othernine phases, which yielded nine deformation vector fields (DVFs). These DVFs consisted of the

136


999999999


Table9.1:

Patie

nt in

form

atio

n an

d re

spira

tion-

indu

ced

mot

ion

ampl

itude

of s

ub-v

olum

es o

f the

CTV

.

Patie

ntSe

xAge

Tum

orlo

catio

nan

dty

peVo

lum

eof

CTV

[cm

3 ]

Res

pira

tion-

indu

cedm

otio

nam

plitu

deof

CTV

[mm]

Prox

imal

esop

hagu

sM

iddl

eeso

phag

usDistale

soph

agus

Car

dia

LR-L

LR-R

AP-

AAP-

PCC

LR-L

LR-R

AP-

AAP-

PCC

LR-L

LR-R

AP-

AAP-

PCC

LR-L

LR-R

AP-

AAP-

PCC

172

MDistalA

C10

4.88

1.5

1.2

1.7

0.4

2.3

0.8

0.7

1.5

0.6

3.1

3.1

1.7

3.1

2.4

4.2

--

--

-2

60F

DistalA

C11

0.53

--

--

--

--

--

2.0

3.0

2.2

0.5

5.5

2.1

1.5

3.4

2.1

10.9

355

MDistalA

C36

0.46

1.3

3.0

2.1

0.4

3.8

1.1

1.3

1.3

0.4

6.9

1.6

1.8

2.8

0.6

7.4

2.4

1.7

5.9

1.0

8.3

469

MDistalA

C15

6.35

--

--

--

--

--

2.2

1.7

2.6

0.5

5.8

1.3

1.7

4.7

1.4

7.6

561

FM

iddl

eSC

C56

.62

--

--

-1.4

0.8

1.6

0.7

3.3

2.7

1.4

3.0

1.2

6.3

--

--

-6

76M

DistalA

C14

8.39

--

--

--

--

--

1.7

1.6

2.9

1.7

5.2

1.7

1.4

4.0

3.1

7.2

748

MDistalA

C14

0.61

--

--

--

--

--

2.8

1.7

3.2

0.4

4.8

2.6

1.7

3.6

2.9

5.7

846

MDistalA

C11

1.11

--

--

--

--

--

2.3

2.7

3.4

1.4

8.0

2.3

2.4

4.6

2.1

11.0

984

MDistalS

CEC

100.63

--

--

-2.5

3.1

3.1

0.9

7.9

3.6

1.9

5.1

0.6

8.6

3.2

2.4

7.1

6.7

19.5

1059

MDistalS

CC

41.72

1.1

1.2

1.6

0.9

1.8

1.1

0.9

1.9

1.1

2.9

1.5

2.1

2.4

1.8

3.1

--

--

-11

61M

DistalA

C19

1.85

--

--

-1.5

1.5

2.0

0.5

5.3

3.9

1.9

3.5

0.4

4.6

1.4

1.2

5.3

2.1

5.2

1255

MDistalA

C41

2.55

0.9

2.0

1.4

1.2

1.6

1.0

2.6

2.0

1.1

3.6

2.0

1.4

3.4

1.3

5.3

3.2

1.7

5.6

6.2

6.7

1375

MDistalA

C23

2.42

--

--

--

--

--

3.1

1.9

3.4

0.3

3.9

2.5

1.1

5.8

0.6

4.4

1467

MDistalA

C18

2.50

--

--

--

--

--

3.6

2.4

3.3

1.4

4.9

2.0

2.4

5.1

4.4

4.9

1562

MDistalA

C20

4.68

1.0

2.9

2.7

0.4

4.8

1.9

2.4

1.9

0.4

6.6

2.4

4.3

2.8

0.5

7.9

3.8

2.1

4.5

4.8

8.4

Abb

reviations

:M=

male,

F=

female;

AC

=ad

enoc

arcino

ma,

SCC

=sq

uam

ousc

ellc

arcino

ma,

SCEC

=sm

allc

elle

soph

agea

lcarcino

ma;

CTV

=clin

ical

targ

etvo

lum

e;LR

-L=

left–

right

amplitu

deat

them

ostleft

side,

LR-R

=left–

right

amplitu

deat

them

ostr

ight

side,

AP-

A=

anterio

r–po

ster

iora

mplitu

deat

them

osta

nter

iors

ide,

AP-

P=

anterio

r–po

ster

iora

mplitu

deat

them

ostp

osterio

rsid

e,CC

=cran

ial–ca

udal.

137


Chapter 9

3D voxel displacements from the 20% phase to the other nine phases of the 4D-CT. Next, thenine DVFs were averaged to calculate a mean DVF indicating the 3D voxel displacement fromthe 20% phase to a time-averaged MidP. Subsequently, 10 DVFs from the MidP to all 10 phaseswere calculated (Fig. 9.1a). Using these 10 DVFs, the 10 phases of the 4D-CT were warped andthen averaged in intensity, resulting in the MidP-CT (Fig. 9.1b). The MidP-CT reconstructionwas done using in-house developed software based on the Insight Toolkit (ITK version 4.12).

4D-C

T M

idP-

CT

0% 30% 80%

30%

60%

90%10%

70%MidP

50%40%

80%

20%

0%

30%

60%

90%10%

70%MidP

50%40%

80%

20%

0%

=mean( ) = +

(a)=inverse( )

0% 30% 80%M

idP-

CTDV

F

(b)

DVFs

P

A

RL

Cranial

Caudal

(c)

LR amplitude

CC

am

plitu

de

AP a

mpl

itude

CTV

CTV sub-volume

at the most left side = mean( ) at the most right side = mean( )

LR amplitude:

at the most anterior side = mean( ) at the most posterior side = mean( )

AP amplitude:

CC amplitude = mean( )CT transverse slice

Fig. 9.1: (a) Illustration of mid-position (MidP) reconstruction based on the deformation vector fields (DVFs) derivedfrom deformable image registration between the 20% phase and the other nine phases of four-dimensional (4D) com-puted tomography (CT). (b) Example of DVFs from MidP to three phases and those phases of 4D-CT overlaid on theMidP-CT. (c) Schematic drawing of quantifying the respiration-induced target motion amplitudes in the left–right (LR),anterior–posterior (AP), and cranial–caudal (CC) directions for a sub-volume of the clinical target volume (CTV).

Based on these DIRs, the CTV and OARs delineations on the 20% phase were thereby auto-matically propagated to the other nine phases and the MidP-CT.The envelope of all 10 CTVs onthe 10-phase 4D-CT was taken to yield the ITV on the MidP-CT (Monaco version 5.19; ElektaAB).

Margin recipe

TheCTV-to-PTV and ITV-to-PTVmargins were calculated based on themargin recipe proposedin [125, 137] to ensure that 95% of the prescribed dose is received by 90% of the population. ThePTV for esophageal cancer RT is located in a mixed anatomical environment (i.e., mix of lungand soft tissue); it is however complicated to embed different penumbras in one margin recipe.

138


999999999


Instead, we applied the simplified formula: 2.5Σ + 0.7σ, where Σ and σ are the square roots ofthe quadratic sum of systematic and random errors, respectively. Assuming online cone-beamCT (CBCT)-based bony anatomy setup verification, for the ITV strategy, the systematic and ran-dom errors consisted of the delineation variation (Σdelineation) and the interfractional target posi-tion variation relative to bony anatomy, i.e., the residual errors after the rigid CBCT-based bonyanatomy registration (Σinter and σinter). For theMidP strategy, in addition toΣdelineation, Σinter, andσinter, we included the RTMas a random error (σRTM). The rotational setup errors were neglectedin the present study.

Since the delineation variation, interfractional target position variation, and RTMwere foundto be most pronounced in the CC direction and in the distal esophagus [176, 210, 214, 231], weapplied an anisotropic and region-specific (proximal, middle, distal esophagus, and cardia) mar-gin. For this, the CTV/ITV was divided into 2–4 sub-volumes depending on how many regionswere covered by theCTV/ITV(example: Fig. 9.2). An anisotropic region-specificmarginwas ap-plied in each sub-volume to construct a regional PTV (Fig. 9.3). By taking the union of all regionalPTVs, the PTV with region-specific margins was then constructed (Monaco).

Fig. 9.2: Illustration of the four sub-volumes of the clinical target volume (CTV) in patient 12 on one sagittal mid-positioncomputed tomography slice.

Although neither the ITV nor the MidP strategy requires an implementation of markers, weassumed thatmarkerswere implanted in all patients to use a reduceddelineationuncertainty in themargin recipe, basedonanearlier studyquantifying the inter-observerdelineationvariation [231].We set Σdelineation at 3.0 mm and 5.0 mm in the CC direction for the most cranially and caudallylocated sub-volumes, respectively, and 1.6mm in the left–right (LR) and anterior–posterior (AP)directions. For Σinter and σinter, values from an earlier study [176] were applied (Table 9.2).

For the MidP strategy, the σRTM is approximated by 0.358 times the RTM amplitude [125].To this end, we used the DVFs derived from the DIR between the 20% phase and the other ninephases to quantify the RTM amplitude of each voxel on the CTV surface. Per CTV sub-volume,the amplitude of RTMwas calculated as illustrated in Fig. 9.1c.

139


Chapter 9

PTVMidP-RTM PTVITV-only PTVMidP-full PTVITV-full

0 5 10 15 20

05

10

15

20

25

30

LR

0 5 10 15 20

05

10

15

20

25

30

CC

0 5 10 15 20

05

10

15

20

25

30

AP

Pro

xim

al esophagus

0 5 10 15 20

05

10

15

20

25

30

0 5 10 15 200

510

15

20

25

30

0 5 10 15 20

05

10

15

20

25

30

Mid

dle

esophagus

0 5 10 15 20

05

10

15

20

25

30

0 5 10 15 20

05

10

15

20

25

30

0 5 10 15 20

05

10

15

20

25

30

Dis

tal esophagus

0 5 10 15 20

05

10

15

20

25

30

0 5 10 15 20

05

10

15

20

25

30

0 5 10 15 20

05

10

15

20

25

30

Card

ia

Respiration-induced motion amplitude [mm]

PT

V m

arg

in [m

m]

Fig. 9.3: Planning target volume (PTV) margin versus respiration-induced target motion (RTM) amplitude in the left–right(LR), cranial–caudal (CC), and anterior–posterior (AP) directions and in four regions in the esophagus for four differentPTVs: incorporating the RTM uncertainties only, using the mid-position (MidP) strategy (PTVMidP-RTM) and the internaltarget volume (ITV) strategy (PTVITV-only); incorporating all region-specific and anisotropic geometrical uncertainties,using the MidP strategy (PTVMidP-full) and the ITV strategy (PTVITV-full).

PTV determination and treatment planning

For theMidP and ITV strategy, the respectivePTVswere denoted as PTVMidP-full andPTVITV-full,in which the margin included all above specified uncertainties (Fig. 9.4). However, these twoPTVs were only suitable for comparison of the dose to OARs because no other uncertainties butthe RTMwas simulated in the present study. Consequently, for the CTV-coverage evaluation weapplied another two PTVs per patient: PTVMidP-RTM, PTVITV-only (Fig. 9.4). The PTVMidP-RTMwas determined by extending the CTV with a margin incorporating σRTM only; the PTVITV-onlywas identical to the ITV.These twoPTVswere only used to investigate theCTV coverage for bothMidP and ITV strategies.

Based on the four PTVs, four plans with prescribed dose of 41.4 Gy in 23 fractions were cor-respondingly made on the MidP-CT with a 6-MV single-arc (356°) volumetric-modulated arctherapy (VMAT) technique (Oncentra VMAT version 4.3; Elekta AB). The planned doses were

140


999999999


Table 9.2: Systematic and random errors (i.e., Σinter and σinter) of the interfractional target position variation relative tobony anatomy used in the margin recipe.

Left–Right [mm] Cranial–Caudal [mm] Anterior–Posterior [mm]

Σinter σinter Σinter σinter Σinter σinter

Proximal esophagus 1.5 1.3 4.1 1.5 1.9 1.2Middle esophagus 3.1 1.5 2.9 2.0 3.2 2.3Distal esophagus 1.9 1.9 4.2 2.5 1.9 1.4Cardia 5.4 4.3 4.9 3.2 1.9 2.4

Four plans made on MidP-CT

PTVMidP-RTM PTVITV-only PTVMidP-full PTVITV-full

4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

4D-CT =

10×3D-CT

MidP-CT

(3D)

Applied to

Planned dosesP

TV

Mid

P-R

TM

PT

VIT

V-o

nly

PT

VM

idP

-full

PT

VIT

V-fu

ll

Calculated 4D-doses

PTVMidP-RTM

PTVITV-only

PTVMidP-full

PTVITV-full4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

4D-CT =

10 × 3D-

CT

10×3D-

DVF

Warped 4D-doses

PTVMidP-RTM

PTVITV-only

PTVMidP-full

PTVITV-full

Accumulated 4D-doses

PTVMidP-RTM

PTVITV-only

PTVMidP-full

PTVITV-full

CTV CTV CTV CTV

Margin for respiration-

induced target motion

(RTM) using mid-position

(MidP) strategy

Internal target volume (ITV) Margin for delineation

variation, interfractional

position variation, and

RTM using MidP strategy

Margin for delineation

variation and

interfractional position

variation using ITV strategy

Dose

comparison

CTV

Dose

comparison

OARs

Fig. 9.4: Schematic view of the four planning target volumes (PTVs) and calculation of the planned dose and accu-mulated four-dimensional (4D) dose based on the deformation vector fields (DVFs). Abbreviations: CT = computedtomography; 3D = three-dimensional; CTV = clinical target volume, OARs = organs at risk.

calculated using the collapsed cone algorithm with a dose grid size of 2 mm. For comparison be-tween the different plans, the D99% (minimum dose to 99% of the volume) in the PTV was nor-malized to 95%of the prescribed dose. Theplanning objectives in dose-volume histogram (DVH)parameters are listed in Table 9.3.

4D-dose calculation and accumulation

To simulate theRTM-induced blurred dose distribution, for each of the four planswe recalculatedthe dose on all 10 phases of the 4D-CT (Oncentra). For each plan, the resulting 10 3D-doses (i.e.,

141


Chapter 9

Table 9.3: Planning objectives.

Region of interest Dose-volume histogram parameter Constraint

PTV V95% Volume [% of the total volume] receiving⩾ 95% of the prescribed dose, i.e., 39.33 Gy =99%*D2% Near-maximum dose


999999999


(patients 1, 2, 3, 10, and 13), the propagated CTVs were compared with the manually delineatedCTVs on the nine phases of 4D-CT in terms of the Dice coefficient and the average distance be-tween the vertices of the propagatedCTVmesh and the triangular faces of themanually delineatedCTV mesh (i.e., average vertex-to-face distance). The manual delineation of the CTVs was doneindependently by the radiation oncology resident (i.e., without the presence of the propagatedCTVs). The five patients were selected to create a group of diversity in tumor extent, location, andRTM. In addition, the geometrical accuracy of DIR was validated using the lung 4D-CT datasetand manually labelled landmarks, according to the guideline of American Association of Physicsin Medicine (AAPM) RadiationTherapy Committee Task Group No. 132 [235].

9.3 Results

Table 9.1 shows for each patient which of the four esophageal regions were covered by the CTVand gives per covered region the RTM amplitude of the CTV in the LR, CC, and AP directions.The mean± standard deviation (SD) of RTM amplitudes in the CC direction was 4.7± 2.0 mmand7.6±4.0mmfor themost cranially andcaudally located sub-volumesof theCTV, respectively.

PTVMidP-RTM volumes were smaller than PTVITV-only volumes: mean± SD reduction of 6.5± 3.5% for PTVMidP-RTM compared to PTVITV-only. Compared to the PTVITV-full, the volume ofPTVMidP-full was reduced by 12.0± 2.2%.

A linearly decreasing relationship (R2⩾0.82) was found between the RTM amplitude of thecaudal sub-volume of the CTV and the overall passing rate of 3%/3-mm gamma analysis whichrepresented thedifferencebetween theplanneddose and accumulated4D-dose (Fig. 9.5). Mostly,the pass ratewas high (>98%)when theRTMamplitudewas⩽11.0mm. Thedifferences betweenthe planned doses and accumulated 4D-doses, which did not meet the 3%/3-mm tolerance, weremostly located in the caudal regions of the PTVswhere the RTMwasmost pronounced (Fig. 9.5).

Although theV95% of the planned dose in theCTVwas always>98% for both strategies (Table2), for the accumulated4D-dose thatwasonlynot the case for patient 9whenusing thePTVMidP-RTM-based plan (V95% = 95.7%). The region receiving a dose below 95% of the prescribed dose(i.e., 39.33 Gy) was mainly located in the caudal part of the CTV (Fig. 9.6). The reason for thiscould be that patient 9 had an average respiration-induced motion amplitude of the cardiac sub-volume of the CTV of 19.5 mm in the CC direction (Table 9.1), resulting in an up to 10-mmdifference in the CC direction between the most caudal slices of PTVITV-only and PTVMidP-RTM.Overall, the V95%, Dmean, and D2% of the accumulated 4D-doses in the CTV were, albeit signif-icantly, only


Chapter 9

Table9.4:Planning objectives.

DVH

parameter

Reference

valuePlanned

doseAccum

ulated4D

-dose

MidP

ITV

Difference

p-valueM

idPIT

VDifference

p-value

PTVMidP-RTM-based or

PTVITV-only-basedplan

V95%

[%]

>98%

99.7±

0.299.9

±0.1

0.2±

0.20.015

99.0±

1.199.9

±0.1

0.9±

1.1<

0.001

CTV

Dm

ean[%

]-

98.9±

0.899.2

±0.7

0.4±

0.40.003

98.7±

0.999.2

±0.7

0.5±

0.3<

0.001

D2%

[%]

<107%

100.7±

1.0101.2

±0.9

0.5±

0.60.004

100.4±

1.1100.9

±0.9

0.5±

0.50.001

PTV

V95%

[%]

-99.0

±0.0

99.0±

0.00.0

±0.0

-95.8

±3.7

96.3±

2.80.5

±0.9

0.015

PTVMidP-full-based or PTVITV-full-based plan

V95%

[%]

>98%

100.0±

0.0100.0

±0.0

0.0±

0.00.789

100.0±

0.0100.0

±0.0

0.0±

0.00.584

CTV

Dm

ean[%

]-

101.3±

0.7101.5

±1.0

0.2±

0.80.303

101.2±

0.9101.3

±1.1

0.2±

0.90.359

D2%

[%]

<107%

103.2±

1.0103.3

±1.2

0.0±

1.10.599

103.1±

0.9103.1

±1.2

0.0±

1.00.421

PTV

V95%

[%]

-99.0

±0.0

99.0±

0.00.0

±0.0

-97.6

±1.3

97.6±

1.20.1

±0.4

0.561

V10G

y [%]

<50%

44.4±

19.448.4

±19.8

4.1±

2.1<

0.00144.3

±19.6

48.3±

19.94.0

±2.0

<0.001

LungsV

20Gy [%

]<

30%9.8

±6.8

11.2±

7.61.4

±0.9

<0.001

9.8±

7.011.2

±7.7

1.4±

1.0<

0.001

Dm

ean[G

y]<

16Gy

10.0±

3.310.6

±3.4

0.6±

0.2<

0.00110.0

±3.3

10.6±

3.40.6

±0.2

<0.001

Heart

V30G

y [%]

<30%

15.9±

5.017.8

±5.4

2.0±

1.1<

0.00115.9

±5.2

17.9±

5.51.9

±1.1

<0.001

LiverD

mean

[Gy]

<26

Gy

12.8±

5.513.5

±5.7

0.8±

0.5<

0.00112.8

±5.5

13.6±

5.60.8

±0.5

<0.001

Leftkidney

V18G

y [%]

<33%

1.5±

2.82.0

±3.6

0.5±

0.90.018

1.5±

2.52.0

±3.4

0.5±

0.90.030

Rightkidney

V18G

y [%]

<33%

0.2±

0.60.3

±1.2

0.1±

0.61.000

0.1±

0.50.3

±1.0

0.1±

0.51.000

SpinalcordD

2cm3[G

y]<

50Gy

25.3±

3.325.4

±2.6

0.1±

1.40.934

25.3±

3.325.4

±2.6

0.1±

1.40.934

Abbreviations:

DVH

=dose-volum

ehistogram

;MidP

=m

id-position,ITV

=internaltargetvolum

e;CTV

=clinicaltargetvolum

e,PTV

=planning

targetvolume;RT

M=

respiration-induced

targetmotion.

Note:Th

ePT

VV

95%ofthe

planneddose

wasalw

ays99%because

theplanned

dosewasnorm

alizedforallcases.Th

ePT

VV

95%ofthe

accumulated

4D-dose

wasnotused

forevaluationdue

tothe

simulation

ofRTM

.Therefore,no

referencevalue

wasgiven.Th

elistofD

VH

parametersforthe

CTV

usingthe

PTV

MidP-full -orPT

VIT

V-full -basedplan

isnotintendedforC

TV

coverageevaluation.Itisonly

usedto

verifythe

faircomparison

onthe

DVH

parametersin

theorgansatrisk

between

theM

idPand

ITV

strategies.

144


999999999


9596

9798

9910

00 4 8 12 16 20

R2 = 0.83PTVMidP-RTM

9596

9798

9910

0

0 4 8 12 16 20

R2 = 0.86PTVITV-only

9596

9798

9910

0

0 4 8 12 16 20

R2 = 0.84PTVMidP-full

9596

9798

9910

00 4 8 12 16 20

R2 = 0.82PTVITV-full

Amplitude [mm]

Pass

rate

[%]

γ>1:

Acc

umul

ated

4D-

dose

—

Plan

ned

dose

P2: Pass rate = 99.05% P9: Pass rate = 97.03%

PTVMidP-RTMCTV PTVITV-onlyγ

PTVMidP-RTM-based plan PTVITV-only-based plan

(a)

(b)

Fig. 9.5: (a) Correlation (R2: coefficient of determination) between the respiration-induced target motion (RTM) am-plitude at the most caudally located sub-volume of the clinical target volume (CTV) and the pass rate of the gammaanalysis comparing the planned dose and accumulated four-dimensional (4D) dose based on all four planning targetvolumes (PTVs) using mid-position (MidP) and internal target volume (ITV) strategies. (b) Region of γ>1 comparingthe planned dose and accumulated 4D-dose for patients 2 (P2) and 9 (P9).

ters in the lungs, heart, and liver were significantly reduced by approximately 10%on average, witha mean dose reduction up to 1.0 Gy, 1.7 Gy, and 1.9 Gy, respectively, using the PTVMidP-full-basedplan compared with the PTVITV-full-based plan (p4.0 Gy) between the two strategies weremostly found in the most cranially and caudally located regions of the PTVs (e.g., in the tracheaand intestines) (Fig. 9.7).

The automatically propagated delineations of the CTV and OARs were approved by our radi-ation oncology resident and radiation therapist, respectively. Comparing the propagated CTVswith the manually delineated CTVs, the mean ± SD(range) of Dice coefficients were 0.92 ±0.02(0.84–0.97); themean±SD(range)of the average vertex-to-facedistanceswere1.2±0.4(0.5–

145


Chapter 9

Fig. 9.6: Isodose lines of accumulated four-dimensional dose calculated based on the planning target volume (PTV)with margin incorporating the respiration-induced target motion (RTM) uncertainty only (PTVMidP-RTM) on two coronalslices of mid-position (MidP) computed tomography for patient 9. The clinical target volume (CTV) and internal targetvolume (ITV, i.e., PTVITV-only) are also plotted.

2.4) mm. Based on the approach recommended by the AAPMTask Group No. 132, the mean±SD(maximum) of the absolute errors of the DIR using ADMIRE was 0.5± 0.5(6.7) mm, 0.8±0.9(7.6)mm, and 0.6± 0.9(12.4)mm, in the LR,CC, andAPdirection, respectively. Only in fourout of 300 landmarks in the superior and inferior lobes of the lungs we found the absolute errors>5.0 mm in at least one direction.

9.4 Discussion

This study is the first to apply the MidP strategy and to compare it with the ITV strategy in treat-ment planning of esophageal cancer RT. Further, for the first time an anisotropic and region-specific safety margin for esophageal cancer RT is proposed and successfully applied. Comparedto the ITV strategy, the MidP strategy ensures adequate CTV coverage and a statistically signifi-cant reduction in the dose to the most relevant OARs.

Considering other published results onDIR accuracy [236], intra-observer variation inmanualdelineation, and the voxel spacing in the 4D-CT, the DIR algorithm in ADMIRE is affirmed to behighly accurate in the target and the lungs for our patient group based on the validation. The visualapproval of the automatically propagated delineations by both the radiation oncology resident andradiation therapist indicated that the performance of DIRs in these regions was trustworthy.

For patients with an RTM amplitude⩽11.0 mm, the difference between the planned dose andaccumulated 4D-dose was limited irrespective of the MidP or ITV strategy. This implies that forRT planning of esophageal cancer inmost patients, a 4D-dose accumulation usingDIR is not nec-essary. Moreover, we chose to use the MidP-CT for treatment planning, because it has a betterimage quality than the AIP-CT and single-phase scan [232] for the purpose of a voxel-to-voxelcomparison between the planned dose and accumulated 4D-dose. Although the blurred AIP-CTmight be more commonly used for dose calculation due to breathing-induced density variation,

146


999999999


Heart (H) Liver (Lr) Lungs (Ls) Left kidney (LK) Right kidney (RK) Spinal cord (S) CTV (C)

ITVMidP

►

◄

◄ ◄

0 10 20 30 40

0

20

40

60

80

100

Vol

ume

[%]

P2

CHLr

Ls

LK

S

RK

►

◄

◄ ◄

0 10 20 30 40

P9

CHLr

Ls

LK

S

RK

►

◄

◄ ◄

0 10 20 30 40

P12

CHLr

Ls

LK

S

RK

Dose [Gy]

Dose difference [%]:Dose difference [Gy]:

PTVMidP-fullCTV PTVITV-full

-20%-8.28

-15% -6.21

-10% -4.14

-5% -2.07

5% 2.07

10% 4.14

20%8.28

15% 6.21

P2 P9 P12

Isod

ose:

PTV

ITV-

full-b

ased

− P

TVM

idP-

full-

base

d ac

cum

ulat

ed 4

D-do

se

P2: Pass rate = 50.27% P9: Pass rate = 71.05% P12: Pass rate = 68.01%

γ>1:

PTV

ITV-

full-b

ased

− P

TVM

idP-

full-

base

d ac

cum

ulat

ed 4

D-do

se

PTVMidP-fullCTV PTVITV-fullγ

(a)

(b)

(c)

Fig. 9.7: Example of accumulated four-dimensional (4D) dose for patient 2 (P2), 9 (P9), and 12 (P12). (a) Dose-volumehistogram for clinical target volume (CTV) and organs at risk with reference value of CTV V95% (▶), lung V10Gy and V20Gy(◀), and heart V30Gy (◀). (b) Region of γ>1 comparing the accumulated 4D-doses using the mid-position (MidP)and internal target volume (ITV) strategies based on planning target volumes (PTVs) incorporating all uncertainties(PTVMidP-full and PTVITV-full). (c) Dose difference between the PTVMidP-full- and PTVITV-full-based accumulated 4D-doses.

our 4D-dose accumulation results imply a high accuracy of using theMidP-CT for treatment plan-ning. This is in line with the findings for lung (SB)RT [237–240].

The DIR-based quantification of the RTM amplitude confirmed that the RTM amplitude dif-fers per region of the esophagus as shown in previous studies using rigid registration on fidu-cial markers [165, 210, 214]. This also provided an alternative approach to quantify the patient-specific and region- and direction-dependent RTM amplitude when no fiducial markers are avail-able. Moreover, combined with the dependence of interfractional tumor position variation ondirection and region [176], this signifies the necessity of using an anisotropic and region-specificPTVmargin.

147


Chapter 9

Clinically, when the patient is freely breathing and online bony anatomy-based setup verifica-tion is used during the treatment, the full PTV margin should be used, in which the RTM is onecomponent [125, 137]. In this study, we only simulated the presence of RTM and ignored thepresence of other uncertainties such as interfractional tumor position variation relative to bonyanatomy. However, since the full PTV margin was designed to cover all the uncertainties, theCTV coverage is expected to also be adequate if all the uncertainties were simulated with the aidof DIR and daily CBCTs. In this case, the dose to OARs might slightly deviate from the resultsin the present study, possibly dominated by the interfractional tumor position variation relativeto bony anatomy as shown in liver SBRT [241]. For the present study, further dosimetric eval-uation on all the uncertainties, however, would not change the qualitative results regarding thecomparison between the two strategies accounting for RTM.

Due to the quadratic sum of all random errors in the PTVMidP-full margin calculation, using thePTVMidP-RTM overestimated the influence of RTM (Fig. 9.8). For patients with an RTM ampli-tude ⩽11.0 mm, this overestimate was ⩽1.7 mm, which is negligible compared to the CT slicethickness of 2.5 mm and the dose grid size of 2.0 mm. Although we could use the PTVMidP-full-based plan to evaluate the target coverage based on a full PTV excluding the RTM uncertaintyto avoid this overestimate, the inevitable inclusion of lung tissue in such a target can result in anunderestimate of target coverage due to the dose attenuation. Therefore, the evaluation of targetcoverage based on the CTV is appropriate in the present study.

The full margin including delineation variation, interfractional position variation, and respiration-induced target motion (RTM)

2.5 Σdelineation

2+ Σ

inter

2+ 0.7 σ

inter

2+ σ

RTM

2

The contribution by RTM in the full margin

0.7 σinter

2+ σ

RTM

2− 0.7σ

inter

The margin including RTM only

0.7σRTM

The overestimate of RTM contribution

0.7 σRTM

− σ'()*+

2+ σ

RTM

2− σ

'()*+( )

CTV CTV

PTVMidP-full PTVMidP-RTM

Delineation + interfractional position

variation

Fig. 9.8: Illustration of the overestimation of the respiration-induced target motion (RTM) contribution for the mid-position (MidP) strategy when the planning target volume (PTV) includes the RTM only, i.e., PTVMidP-RTM, compared tothe RTM contribution in the actual full margin including other uncertainties, i.e., PTVMidP-full. Σdelineation is the systematicdelineation variation; Σinter is the systematic component of the interfractional target position variation; σinter is therandom component of the interfractional target position variation; σRTM is the random error induced by RTM, which is0.358 times the RTM amplitude. Abbreviation: CTV = clinical target volume.

Albeit many studies showed that the DVH parameters can predict the risk of a particular end-point (e.g., pneumonitis and cardiotoxicity), it is difficult to conclude the clinical benefits in num-bers due to the different predictive values among different population groups and endpoints [50–

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52, 54–57]. However, it is fair to state that a dose reduction toOARs can result in a lower incidenceof certain clinical endpoints. For the heart toxicity, it was found that rates ofmajor coronary eventsincreased linearly with the mean dose to the heart by 7.4% per Gy [242]. Consequently, the sta-tistically significant reductions in dose to the lungs, heart, and liver as found in the present studyfor theMidP strategy compared to the ITV strategymight be considered potentially clinically rel-evant.

Apart from theOARs,more pronounceddose reductionswere observed in the upper abdomen(Fig. 9.7), resulting fromthe largerPTVmargin in the caudal part using the ITVstrategy comparedwith the MidP strategy. Although the dose in this region is normally far below the tolerance, it ispreferred to keep the dose as low as possible to reduce the risk of toxicity [243].

Only in one patient (patient 9) we found a slightly inadequate CTV coverage, which could bedue to the extremely large RTM amplitude (19.5 mm) in the CC direction. However, the approx-imation of σRTM by 0.358 times the RTM amplitude was designed under the condition of RTMamplitude


Chapter 9

a breath-hold. In addition, there could be substantial motion and inter-breath-holding positionvariation in the upper abdomen, especially for the inhalation breath-holds [131, 132]. Hence, thefeasibility of implementing breath-hold in the clinical practice of esophageal cancer RT requiresfurther research.

In conclusion, using aMidP strategy in treatmentplanningof esophageal cancerRT is beneficialfor patients with moderate RTM in terms of an approximately 10% dose reduction in the OARswithout compromising the target coverage. When an accurate DIR software is available in clinicalpractice, we recommend using the MidP strategy with anisotropic and region-specific margins intreatment planning of esophageal cancer RT.

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