Acta Oncologica

ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: http://www.tandfonline.com/loi/ionc20

Dosimetric advantages of a clinical daily adaptive

plan selection strategy compared with a non-
adaptive strategy in cervical cancer radiation
therapy

Agustinus J. A. J. van de Schoot, Peter de Boer, Jorrit Visser, Lukas J. A.

Stalpers, Coen R. N. Rasch & Arjan Bel

To cite this article: Agustinus J. A. J. van de Schoot, Peter de Boer, Jorrit Visser, Lukas J. A.
Stalpers, Coen R. N. Rasch & Arjan Bel (2017) Dosimetric advantages of a clinical daily adaptive
plan selection strategy compared with a non-adaptive strategy in cervical cancer radiation therapy,
Acta Oncologica, 56:5, 667-674, DOI: 10.1080/0284186X.2017.1287949

To link to this article: http://dx.doi.org/10.1080/0284186X.2017.1287949

2017 The Author(s). Published by Informa View supplementary material

UK Limited, trading as Taylor & Francis
Group

Published online: 20 Feb 2017. Submit your article to this journal

Article views: 233 View related articles

View Crossmark data Citing articles: 1 View citing articles

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=ionc20

Download by: [Banaras Hindu University BHU] Date: 19 July 2017, At: 00:03
ACTA ONCOLOGICA, 2017
VOL. 56, NO. 5, 667674
http://dx.doi.org/10.1080/0284186X.2017.1287949

ORIGINAL ARTICLE

Dosimetric advantages of a clinical daily adaptive plan selection strategy

compared with a non-adaptive strategy in cervical cancer radiation therapy
Agustinus J. A. J. van de Schoot, Peter de Boer, Jorrit Visser, Lukas J. A. Stalpers, Coen R. N. Rasch and Arjan Bel
Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

ABSTRACT ARTICLE HISTORY

Background: Radiation therapy (RT) using a daily plan selection adaptive strategy can be applied to Received 30 March 2016
account for interfraction organ motion while limiting organ at risk dose. The aim of this study was to Accepted 20 January 2017
quantify the dosimetric consequences of daily plan selection compared with non-adaptive RT in cer-
vical cancer.
Material and methods: Ten consecutive patients who received pelvic irradiation, planning CTs (full
and empty bladder), weekly post-fraction CTs and pre-fraction CBCTs were included. Non-adaptive
plans were generated based on the PTV defined using the full bladder planning CT. For the adaptive
strategy, multiple PTVs were created based on both planning CTs by ITVs of the primary CTVs (i.e.,
GTV, cervix, corpus-uterus and upper part of the vagina) and corresponding library plans were gener-
ated. Daily CBCTs were rigidly aligned to the full bladder planning CT for plan selection. For daily plan
recalculation, selected CTs based on initial similarity were deformably registered to CBCTs. Differences
in daily target coverage (D98% > 95%) and in V0.5Gy, V1.5Gy, V2Gy, D50% and D2% for rectum, bladder and
bowel were assessed.
Results: Non-adaptive RT showed inadequate primary CTV coverage in 17% of the daily fractions. Plan
selection compensated for anatomical changes and improved primary CTV coverage significantly
(p < 0.01) to 98%. Compared with non-adaptive RT, plan selection decreased the fraction dose to rec-
tum and bowel indicated by significant (p < 0.01) improvements for daily V0.5Gy, V1.5Gy, V2Gy, D50% and
D2%. However, daily plan selection significantly increased the bladder V1.5Gy, V2Gy, D50% and D2%.
Conclusions: In cervical cancer RT, a non-adaptive strategy led to inadequate target coverage for indi-
vidual patients. Daily plan selection corrected for day-to-day anatomical variations and resulted in
adequate target coverage in all fractions. The dose to bowel and rectum was decreased significantly
when applying adaptive RT.

Introduction approaches, have been investigated [4,5]. The most widely

Locally advanced cervical cancer patients are generally
treated using external beam radiation therapy (EBRT) with
concomitant chemotherapy, followed by brachytherapy [1].
Radiation therapy (RT) with concurrent hyperthermia is the
recommended treatment strategy for patients with a contra-
indication for chemotherapy [2]. Intensity-modulated RT
(IMRT) or volumetric modulated arc therapy (VMAT) allows
highly conformal dose distributions and is most effective
when combined with adequate online image guidance.
However, large interfraction anatomical changes limit the effi-
cacy of these advanced treatment techniques [3]. Despite
drinking instructions for cervical cancer patients, the bladder
volume varies between treatment fractions and contributes
to an increased risk of target underdosing [3].
Adaptive RT (ART) has the potential to anticipate on anatom-
ical changes during fractionated EBRT by adapting the radiation
delivery during the treatment course based on pre-fraction
imaging. Several adaptive strategies, both offline and online
reported approach for pelvic EBRT is the plan-library based
plan-of-the-day strategy [68]. Prior to treatment, a patient-spe-
cific plan library is defined by generating multiple treatment
plans corresponding to different target volumes. Each treat-
ment day the library plan best fitting the anatomy as observed
on pre-fraction cone-beam CT (CBCT) imaging is selected in
order to anticipate on interfraction anatomical changes.
Despite the use of large population-based margins added
to the clinical target volume (CTV) to form the planning tar-
get volume (PTV), the interfraction anatomical changes in
cervical cancer EBRT might still induce target underdosing.
Furthermore, these large safety margins increase the dose to
surrounding healthy tissues, which results in the enhance-
ment of radiation-induced toxicity. Recently, several adaptive
strategies in cervical cancer were investigated to anticipate
on anatomical changes during the course of RT [9,10]. Next
to the description of a clinically implemented adaptive strat-
egy [7], most studies reported on tools to support or

CONTACT Agustinus J. A. J. van de Schoot a.j.schootvande@amc.uva.nl Department of Radiation Oncology, Academic Medical Center, University of
Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
Supplemental data for this article can be accessed here.
2017 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/),
which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.
668 A. J. A. J. VAN DE SCHOOT ET AL.

automate adaptive workflows [9,1113]. However, actual Table 1. Patient characteristics.

dosimetric improvements of ART compared with previously Clinical treatment Treatment
applied non-adaptive approaches in terms of target coverage Patient FIGO stage strategy position No. of ITVs
and organ at risk (OAR) sparing are still unknown. 1a IB2 non-ART prone 1
2b IIB non-ART prone 3
To investigate the dosimetric consequences of ART and 3a IB2 non-ART prone 3
determine the area of improvement, differences in dose 4b IIA non-ART prone 3
delivery between an adaptive and non-adaptive strategy 5b IIB non-ART supine 3
6a IIA non-ART prone 2
need to be assessed. Therefore, the purpose of this 7b IIB non-ART prone 3
study was to quantify the potential dosimetric advantages 8b IIB non-ART supine 3
of a daily adaptive plan selection treatment strategy com- 9a IB1 ART supine 2
10a IB1 ART supine 3
pared with a non-adaptive treatment approach in cervical
ART: adaptive radiation therapy; FIGO: International Federation of Gynecology
cancer RT. and Obstetrics; ITV: internal target volume; non-ART: non-adaptive radiation
therapy.
a
Both planning CTs acquired with LightSpeed RT16, General Electric Company,
Material and methods Waukesha WI.
b
Full bladder planning CT acquired with Gemini TF, Philips Medical Systems,
Patients and imaging Eindhoven, the Netherlands and empty bladder planning CT acquired with
LightSpeed RT16, General Electric Company, Waukesha WI.
In this retrospective study, ten consecutive cervical cancer
patients who received pelvic irradiation and additional CT
imaging were included. All patients, treated between January guidelines. The bladder wall was created using a 3 mm
2014 and August 2015, gave written informed consent after inwards expansion of the delineated bladder [16].
local medical ethical approval for additional CT imaging ini- The library of target structures for the adaptive strategy
tially acquired for a study on adaptive proton therapy [14]. was created based on the planning CTs acquired with an
Besides two planning CTs (i.e., full and empty bladder), all empty and a full bladder. After bony registration of both
patients received pre-fraction CBCT imaging (Synergy plat- planning CTs, corresponding primary CTVs (pCTVs) which
form, Elekta AB, Stockholm, Sweden) and weekly CT imaging encompassed the GTV, cervix, corpus-uterus and upper part
in treatment position directly after irradiation. Weekly post- of the vagina were registered using a structure-based
fraction CT imaging resulted in a unique set of on average 7 deformable image registration (DIR) algorithm [17]. The
CTs per patient with varying anatomy. Regarding the pre- patient-specific full-range primary internal target volume
fraction imaging, five out of the 230 CBCTs were acquired (pITV) was divided in pITV subranges by scaling the deform-
with a limited field of view or limited number of projections ation vectors (Supplementary Figure A1). According to our
resulting in poor image quality and were excluded from ana- clinically implemented adaptive strategy, the full-range pITV
lysis. For tumor localization on CBCT, fiducial markers (24 was divided into one (pITV0-100), two (pITV0-50, pITV50-100) or
per patient, Visicoil, 0.35 mm diameter, IBA Dosimetry GmbH, three (pITV0-33, pITV33-67, pITV67-100) subranges when the top
Schwarzenbruck, Germany) were implanted in the cervix dur- of corpus-uterus displacement was below 10 mm, between
ing the pre-treatment examination under anesthesia. 10 mm and 20 mm or above 20 mm, respectively. For each
Six patients were treated in the recommended prone pos- pITV subrange, a primary PTV was generated by enlarging
ition using a belly board device and for four patients the the part of the pITV including the corpus-uterus with an
supine position was applied since the prone position was not 8 mm isotropic margin and the part of the pITV including the
possible due to comfort and stability issues. Aiming at irradi- cervix and vagina with a margin of 8 mm, 8 mm and 13 mm
ations with a full bladder, patients were instructed to empty in left right, superiorinferior and anteriorposterior direc-
their bladder, to drink 0.5 liter of water, and to refrain from tion, respectively. The extended margin in anteriorposterior
voiding 1.5 h prior to each treatment fraction. As a result of direction was derived clinically and introduced to anticipate
the clinical introduction of ART at our department in April on possible large inter- and intrafraction rectum filling. The
2015, two out of the ten included patients were actually lymph nodes were enlarged with an 8 mm isotropic margin
treated according to the adaptive strategy. For these two and PTVs were created by combining primary PTVs with the
patients, the non-adaptive strategy was simulated. The other expanded lymph nodes.
patients were clinically treated according to the non-adaptive In our non-adaptive strategy, target definition was based
strategy while the adaptive strategy was simulated for this on only the full bladder planning CT using associated delin-
analysis (Table 1). eations. The pCTV, encompassing the GTV, cervix, corpus-ute-
rus and upper part of the vagina was expanded with an
isotropic margin of 10 mm. Also, the lymph nodes were
Target and OAR definition expanded with an 8 mm isotropic margin and combined with
According to clinical guidelines [15], the gross tumor volume the expanded pCTV to form the PTV.
(GTV), corpus-uterus, cervix, upper part of the vagina and
lymph nodes were delineated on all CTs (i.e., planning CTs
Treatment planning
and weekly repeat CTs) by an experienced radiation oncolo-
gist. Also, rectum, bladder and bowel cavity, as a surrogate In the adaptive strategy, plans based on the defined
for small bowel, were delineated according to RTOG PTVs were created to form the plan library and for the

non-adaptive strategy, a single treatment plan was generated
based on the corresponding PTV. Treatment plans using a
dual-arc VMAT technique (356
per arc, 10 MV, 20
collimator
angle) were created (Oncentra, Elekta AB, Stockholm,
Sweden) with a prescribed PTV dose of 46 Gy (23  2 Gy). All
plans were optimized on a uniform 3 mm dose grid with the
beam isocenter set to the PTV center of mass using the full
bladder planning CT. Plan optimizations were performed
using the clinically used set of planning objectives in order
to minimize OAR dose while maintaining ICRU-based PTV
coverage (D98% > 95%, D2% < 107%).
Daily dose calculation
Since CBCT Hounsfield units (HU) are inaccurate, CBCT
images are not directly suitable for dose calculation. To
enable daily dose distribution calculation, CT HU were
mapped to CBCT images by registering selected CTs to
CBCT images deformably (VelocityAI, version 3.1.0, Varian
Medical Systems, Inc., Palo Alto, CA) [18]. For each pre-frac-
tion CBCT image, one of the planning CTs or weekly
repeat CTs best representing the daily pelvic anatomy (i.e.,
the CT with the highest initial anatomical similarity) was
selected in order to maximize DIR accuracy. After rigid
alignment based on bony anatomy, selected CTs with
accurate HU were deformed to represent CBCT images.
The performances of CT-to-CBCT deformable registration in
the pelvic area using the VelocityAI software were vali-
dated previously and accurate DIR results were reported
[19,20]. Additionally, an experienced observer visually
assessed the DIR results to verify plausible HU modification
for CBCT-based dose calculation.
Daily plan selection was simulated according to the clin-
ical adaptive protocol. The deformed CTs representing daily
anatomy were rigidly aligned with the full bladder planning
CT based on bony anatomy. Next, patient-specific PTVs were
projected on the daily image and the PTV encompassing the
target with the implanted fiducial markers inside the PTV
was selected.
The library plan corresponding to the selected PTV and
the non-adaptive plan were recalculated to obtain daily
adaptive and non-adaptive dose distributions, respectively.
Data analysis
Potential dosimetric advantages of ART were determined by
comparing fraction dose distributions obtained using the
adaptive and non-adaptive strategy. For evaluation purposes,
original structures were deformed after DIR in order to match
the deformed CT. Although plausible delineation deformation
was obtained due to the high initial anatomical similarity
between CBCTs and selected CTs combined with the
reported high DIR accuracy, possible deformation inaccura-
cies are present in both strategies and will not affect the out-
come when comparing both strategies. Supplementary
Figure A2 shows a typical example of the DIR procedure
including deformed delineations. Dose-volume histograms
(DVHs) of daily dose distributions were calculated for the
ACTA ONCOLOGICA 669
pCTV, lymph nodes, CTV, bladder, bladder wall, bowel cavity
and rectum. For the target structures, the fraction dose to
98%, 50% and 2% of the volume (D98%, D50%, D2%) were cal-
culated and differences between ICRU-based coverage
(D98%>95%) were tested pairwise for significance (McNemar
chi-square test). Besides the median (D50%) and near-max-
imum (D2%) fraction dose, the V0.5Gy, V1.5Gy and V2Gy for OARs
were extracted from daily DVHs and tested pairwise for sig-
nificance using a non-parametric statistical test (Wilcoxon
signed-rank test).
Results
Large (>20 mm) pre-treatment displacements of the corpus-
uterus top were observed in seven out of the ten patients,
resulting in plan libraries consisting of three plans. For two
patients, the plan library consisted of two plans and a one-
plan library was generated for one patient. Compared with
the average PTV volume for the non-adaptive strategy of
1601 cm3, the average volume of all generated PTVs was
decreased to 1487 cm3 in the adaptive strategy.
Figure 1(a) shows the selected adaptive plans per patient.
For most of the patients, in the majority of fractions the
selected adaptive plan corresponded to the target position
related to a full bladder (PTV67-100, PTV50-100). However, des-
pite drinking instructions, the preferred irradiation with a full
bladder was not achieved for all fractions and library plans
were selected corresponding to target positions related to
low or intermediate bladder volumes. For patients with a
three-plan library, the selection frequency of the adaptive
plan with the target position related to a full bladder (PTV67-
100) was on average 50% and 57% for the prone and supine
treatment position, respectively (Figure 1(b)).
Figure 2 shows a typical example of fraction DVHs for the
target structures of one patient and overall results are pre-
sented in Figure 3. Although 24 (11%) and 38 (17%) fractions
in the non-adaptive approach showed inadequate coverage
(D98% < 95%) for, respectively, the CTV and pCTV, daily plan
selection resulted in adequate target coverage in 225 (100%)
and 220 (98%) fractions for the CTV and pCTV, respectively
(Figure 3(a,b)). Compared with non-ART, ART significantly
(p < 0.01) improved daily coverage (D98% > 95%) for both the
pCTV and CTV. The overall inadequate target coverage is
largely caused by three patients and thereby illustrates the
potential benefit of the adaptive strategy for individual
patients (Figure 3(c,d)).
As an example, for one patient also fraction DVHs for
OARs are shown (Figure 2). Supplementary Figures B1B10
show fraction DVHs of target volumes and OARs for each
patient. Compared with non-adaptive RT, daily plan selection
reduced the dose to rectum and bowel cavity indicated by
significant improvements (p < 0.01) of all DVH parameters of
interest (Figure 4). However, the D50%, V1.5Gy and V2Gy for
bladder were increased significantly (p < 0.05) when applying
the adaptive strategy instead of the non-adaptive approach.
Supplementary Table A1 presents the mean DVH parameter
values for the OARs and the absolute and relative differences
between non-adaptive and adaptive RT.
670 A. J. A. J. VAN DE SCHOOT ET AL.

(a) (b)

100
I III III III III II III III II III I II III II III

I: oneplan library
PTV0 100
Selected library plans (%)
75

II: twoplan library

PTV0 50
PTV50 100
50

III: threeplan library

PTV0 33
PTV33 67
PTV67 100
25
0

P P P P S P P S S S (N=1) (N=1) (N=4) (N=1) (N=3)

1 2 3 4 5 6 7 8 9 10 Prone Supine
Patient #
Figure 1. (a) Frequency of the selected library plans during the course of treatment for each patient. The number on top of each bar represents the number of
available library plans and the character in the figure (P; S) represents the used treatment position (prone; supine). (b) Average percentage of selected library plans
during the course of treatment for both the prone and supine treatment position. The number on top of each bar represents the number of available library plans.
100

100
80

80
Volume (%)

Volume (%)

nonART
60

60

ART
40

40
20

20

CTV pCTV
0

0
100

100
80

80
Volume (%)

Volume (%)
60

60
40

40
20

20

Bladder Bladder wall

0

0
100

1500
80

Volume (cm3)
Volume (%)

1000
60
40

500
20

Rectum Bowel cavity

0

0.0 0.5 1.0 1.5 2.0 0.0 0.5 1.0 1.5 2.0
Dose (Gy)
Figure 2. For patient 3, DVHs of recalculated fraction dose distributions are shown for target volumes (CTV, pCTV) and OARs (bladder, bladder wall, rectum, bowel
cavity) based on the non-adaptive (non-ART; solid lines (red)) and adaptive (ART; dotted lines (blue)) treatment strategy. The intersection of the 2 thin solid lines
(black) in the DVHs for target structures indicates V95% 98%.
 ACTA ONCOLOGICA 671

(a) * (c)

2
1.75

nonART nonART
ART ART
1.5
Fraction dose (Gy)

primary CTV primary CTV D98%

(b) * (d)
2
1.75
1.5

CTV CTV D98%

D98% D50% D2% 1 2 3 4 5 6 7 8 9 10

Patient #
Figure 3. Overall and patient-specific results of the recalculated fraction dose distributions based on the primary CTV (upper) and the CTV (lower), with the dotted
gray horizontal lines indicating 95% and 107% of the prescribed fraction dose. (a,b) The boxplots of daily dose parameters over all analyzed fractions of all included
patients are shown for both the non-adaptive (non-ART) and the adaptive (ART) strategy. Boxes represent upper and lower quartiles (IQR), the band inside the box
the median value and the whiskers the highest (lowest) value within 1.5 IQR of the upper (lower) quartile. Horizontal lines including an asterisk indicate statistical
significant difference (p < 0.01). (c,d) Patient-specific coverage of the primary CTV and CTV (D98%) for all analyzed fractions are shown for both the non-ART and
ART strategy.

Discussion important next step to optimize the presented adaptive strat-

In this first realistic dosimetric analysis on ART in cervical can-
cer, we investigated the potential advantages of a daily plan
selection strategy compared with a non-adaptive approach in
cervical cancer RT. A plan-library based plan-of-the-day strat-
egy was used to adapt for day-to-day anatomical variations
and dose distributions according to the adaptive as well as
the conventional non-adaptive treatments were calculated
using pre-fraction CBCT imaging. Compared with non-adap-
tive RT, a daily plan selection adaptive strategy allowed us to
anticipate on anatomical changes and consequently
improved fraction-based target coverage significantly.
Additionally, daily plan selection reduced the dose to rectum
and bowel significantly; however, the clinical relevance of the
limited dose differences has to be investigated prospectively.
Previously conducted research on cervical cancer ART
focused either on the quantification of inter- and intrafrac-
tion anatomical changes [11], the optimization of various
adaptive strategies [9,10,21], tools to guide or automate
adaptive workflows [12,13] or the clinical implementation [7].
However, the actual benefit of ART in terms of delivered
dose while taking into account day-to-day anatomical varia-
tions is essential to further improve current adaptive strat-
egies. Our recalculated daily adaptive and non-adaptive dose
distributions based on pre-fraction imaging resulted in a rep-
resentative comparison in terms of differences in target
coverage and OAR sparing. Therefore, this study is an
egy in cervical cancer RT.
The simulated adaptive strategy resulted in a significant
improvement on daily target coverage (D98% > 95%) while
the daily dose to rectum and bowel decreased significantly.
However, the anticipation on anatomical changes by plan
selection resulted in an increased dose to the adjacent blad-
der, indicated by the V2Gy, V1.5Gy and D50% bladder parame-
ters. Since adaptive target volumes were created based on
bladder volume variations, bladder sparing in ART was
expected to be less [22]. Besides considering CTV-to-PTV mar-
gin reductions to avoid the increase of bladder dose during
ART, target volume definitions could be optimized based on
magnetic resonance imaging (MRI) by excluding the healthy
part of the corpus-uterus from the target volume [23,24].
There are limitations to this study. Firstly, our dosimetric
analysis was performed based on a relatively small patient
population of ten patients because prospectively collected
data from a previous study was used [14]. All included
patients received additional CT imaging during the treatment
course, resulting in a unique set of on average 7 CTs per
patient with varying anatomy. Unfortunately, patients who
received para-aortic lymph nodes irradiation were unsuited
for the presented analysis. Due to the limited field of view of
CBCT imaging, volumes of interest were not completely
visualized on pre-fraction CBCTs. The majority of patients (i.e.,
eight patients) were treated using the non-adaptive
approach. For these patients, we simulated adaptive
672 A. J. A. J. VAN DE SCHOOT ET AL.

100
*

2
80
Volume (% )
60

Dose (Gy)
1.5
40
20 ** *
nonART

1
ART
Bladder
0
100

**

2
**
80
Volume (% )

**
60

Dose (Gy)
1.5
40

** **
20

1
Rectum
0

2
2000

**
1.5
Volume (cm3)
1500

**
Dose (Gy)

**
1
1000

0.5
500

**
Bowel cavity
**
0

V0.5Gy V1.5Gy V2Gy D50% D2%

Figure 4. For the non-adaptive (non-ART) and adaptive (ART) strategy, boxplots of fraction DVH parameters over all analyzed fractions of all patients are shown for
bladder (upper), rectum (middle) and bowel cavity (lower). For the meaning of box, whiskers and dots: see Figure 3. Horizontal lines including asterisks indicate
statistical significant difference (p < 0.05; p < 0.01).

treatments according to the clinically implemented daily plan
selection strategy. For the two patients actually treated using
the adaptive strategy, non-adaptive treatments were simu-
lated to fairly quantify dosimetric differences compared with
the adaptive strategy. Although we illustrated the benefit of
ART for individual patients, based on this data it is difficult to
estimate the number of patients that will actually benefit
from ART. Therefore, a study including a larger number
of patients is required to provide definitive information on
target coverage improvements, maximum achievable
OAR sparing and the percentage of patients that will benefit
from ART.
Secondly, possible consequences of intrafraction anatom-
ical changes are not represented by our recalculated dose
distributions since we used pre-fraction CBCT images for
both plan selection and dose recalculation. Intrafraction
organ motion during cervical cancer irradiation can be con-
siderable (e.g., passing rectal gas) and may affect dose deliv-
ery [11]. However, the reported intrafraction motion is based
on pre- and post-fraction CBCT imaging with a relatively
large interval time of 20.8 minutes [11]. Our clinical experi-
ence indicated that all operations between pre-fraction CBCT
imaging and the end of dose delivery, including patient posi-
tioning, library plan selection and VMAT dose delivery, is
determined to take up to at most 7 min. Consequently, the
intrafraction variation present in our patient population is
assumed to be smaller compared with the reported intrafrac-
tion displacements. In addition, the use of ITVs in our adap-
tive strategy also compensates for possible intrafraction
target motion induced by intrafraction bladder filling. Hence,
dosimetric uncertainties induced by intrafraction anatomical
changes in cervical cancer RT are assumed to be limited.

Thirdly, daily dose distributions were calculated based on
deformed CTs after CT-to-CBCT DIR for HU modification using
the implemented algorithm in VelocityAI [18]. The algorithm
performance for CT-to-CBCT registration in the pelvic area
was previously evaluated in terms of registration errors and
small errors across the whole pelvic area (mean: 1.9 mm)
were reported [19,20]. However, only the reported registra-
tion error for bladder was relatively large (mean: 4.6 mm) due
to the initial large bladder volume differences in their study
[19]. In our study, registration errors were further minimized
by selecting one of the planning CTs or weekly repeat CTs
best representing the daily pelvic anatomy (i.e., the CT with
the highest initial anatomical similarity). Next to the reported
DIR accuracy and the high initial similarity between CBCTs
and selected CTs, deformed CTs were visually inspected by
an experienced observer to ensure correct HU modification
for reliable dose calculation. Moreover, Onozato et al. [20]
evaluated the accuracy of dose calculation for pelvic anatomy
after CT-to-CBCT DIR and reported average dose uncertainties
of 1.2%. Furthermore, deformed CTs including possible
deformation inaccuracies are used in both strategies and will
not affect the outcome when comparing both strategies. The
effect of residual deformation errors on our results was there-
fore expected to be negligible.
Besides HU modification, DIR between pre-fraction CBCTs
and selected CTs with a high initial anatomical similarity was
also used to deform original delineations in order to match
deformed CTs. Next to the earlier mentioned justification (i.e.,
reported DIR accuracy, high initial similarity between images,
negligible dose uncertainties induced by HU modification),
deformed delineations were also visually inspected by an
experienced observer to ensure plausible delineation deform-
ation. Although the deformed delineations could include
small deformation errors, these delineations were used for
both the non-adaptive and the adaptive strategy.
Consequently, possible small deviations are included in an
identical way in both strategies and will not affect our out-
come when comparing both strategies. Given the previously
evaluated DIR accuracy [19], the reported negligible dose
uncertainties induced by HU modification [20], the high initial
similarity between pre-fraction CBCTs and selected CTs, delin-
eation deformation validation by an experienced observer
and the use of identical deformed delineations for both strat-
egies, we consider our presented dose differences realistic
and definitely representative for advantages of cervical
cancer ART.
The presented adaptive strategy is designed to anticipate
on day-to-day anatomical variations using pre-treatment pre-
dicted deformations. However, anatomical changes not repre-
sented by the library plans (e.g., changing bowel or rectum
volume) can limit the efficiency of our adaptive strategy. To
overcome this problem, a motion-robust backup plan with
very generous margins can be added to the plan library.
Heijkoop et al. [7] selected such a motion-robust backup
plan in 17.5% of all fractions to cover unpredicted variations,
resulting in limited OAR sparing while adequate target cover-
age was ensured.
In this study, the potential dosimetric benefit of a daily
plan selection adaptive approach was retrospectively
ACTA ONCOLOGICA 673
investigated by comparing adaptive and non-adaptive frac-
tion dose distributions. The definitive dosimetric gain of ART
will be determined when comparing accumulated dose distri-
butions; however, reliable dose accumulation requires accur-
ate voxel-to-voxel correspondence. Despite the reported DIR
accuracy for anatomical borders, the limited soft-tissue con-
trast in CBCT imaging prevents accurate correspondences
within structures. Specific structure-based algorithms are
developed to overcome this limitation [17]; however, the
accuracy of such algorithms for dose accumulation is
unknown and first need to be derived in an independent
study. Also, a prospective evaluation of ART based on a large
number of patient is required to determine the actual benefit
of ART in terms of tumor control and toxicity.
In future, our adaptive procedure will be optimized to
reduce clinical workload and minimize OAR dose. Also, the
use of online plan adaptations based on daily MRI will be
implemented [25]. First of all, MRI guidance can be intro-
duced to avoid plan selection difficulties due to limited CBCT
image quality or to implement additional boost techniques
based on tumor response. Moreover, the clinical introduction
of MRI-guided RT allows online plan adaptations and could
be the next step in online ART in cervical cancer [25].
In conclusion, an adaptive strategy using daily plan selec-
tion allows to correct for day-to-day anatomical variations in
cervical cancer RT. Compared with the conventional non-
adaptive strategy, significant improvements in target cover-
age were found when applying the adaptive strategy.
Additionally, a significant reduction in dose to bowel and rec-
tum was observed with a yet unclear clinical relevance.
Acknowledgements
The authors would like to thank Dr M. Hoogeman (Erasmus MC,
Rotterdam, the Netherlands) for making the Erasmus RTStudio, an appli-
cation of the Erasmus MatterhornRT Software Development Platform,
available.
Disclosure statement
The authors report no conflict of interest. The authors alone are respon-
sible for the content and writing of the manuscript.
References
[1] Eifel PJ, Winter K, Morris M, et al. Pelvic irradiation with concur-
rent chemotherapy versus pelvic and para-aortic irradiation for
high-risk cervical cancer: an update of Radiation Therapy
Oncology Group trial (RTOG) 90-01. J Clin Oncol. 2004;22:
872880.
[2] Franckena M, Stalpers LJA, Koper PCM, et al. Long-term improve-
ment in treatment outcome after radiotherapy and hyperthermia
in locoregionally advanced cervix cancer: an update of the Dutch
Deep Hyperthermia Trial. Int J Radiat Oncol Biol Phys.
2008;70:11761182.
[3] Jadon R, Pembroke CA, Hanna CL, et al. A systematic review of
organ motion and image-guided strategies in external beam
radiotherapy for cervical cancer. Clin Onco. 2014;26:185196.
[4] Stewart J, Lim K, Kelly V, et al. Automated weekly replanning for
intensity-modulated radiotherapy of cervix cancer. Int J Radiat
Oncol Biol Phys. 2010;78:350358.
674 A. J. A. J. VAN DE SCHOOT ET AL.
[5] Vestergaard A, Sndergaard J, Petersen JB, et al. A comparison of
three different adaptive strategies in image-guided radiotherapy
of bladder cancer. Acta Oncol. 2010;49:10691076.
[6] Lutkenhaus LJ, Visser J, de Jong R, et al. Evaluation of delivered
dose for a clinical daily adaptive plan selection strategy for blad-
der cancer radiotherapy. Radiother Oncol. 2015;116:5156.
[7] Heijkoop ST, Langerak TR, Quint S, et al. Clinical implementation
of an online adaptive plan-of-the-day protocol for nonrigid
motion management in locally advanced cervical cancer IMRT. Int
J Radiat Oncol Biol Phys. 2014;90:673679.
[8] Meijer GJ, van der Toorn P-P, Bal M, et al. High precision bladder
cancer irradiation by integrating a library planning procedure of 6
prospectively generated SIB IMRT plans with image guidance
using lipiodol markers. Radiother Oncol. 2012;105:174179.
[9] Bondar L, Hoogeman M, Mens JW, et al. Toward an individualized
target motion management for IMRT of cervical cancer based on
model-predicted cervix-uterus shape and position. Radiother
Oncol. 2011;99:240245.
[10] Ahmad R, Bondar L, Voet P, et al. A margin-of-the-day online
adaptive intensity-modulated radiotherapy strategy for cervical
cancer provides superior treatment accuracy compared to clinic-
ally recommended margins: a dosimetric evaluation. Acta Oncol.
2013;52:14301436.
[11] Heijkoop ST, Langerak TR, Quint S, et al. Quantification of intra-
fraction changes during radiotherapy of cervical cancer assessed
with pre- and post-fraction Cone Beam CT scans. Radiother
Oncol. 2015;117:536541.
[12] van de Schoot AJAJ, Schooneveldt G, Wognum S, et al. Generic
method for automatic bladder segmentation on cone beam CT
using a patient-specific bladder shape model. Med Phys.
2014;41:031707.
[13] Bondar ML, Hoogeman M, Schillemans W, et al. Intra-patient
semi-automated segmentation of the cervix-uterus in CT-images
for adaptive radiotherapy of cervical cancer. Phys Med Biol.
2013;58:53175332.
[14] van de Schoot AJAJ, de Boer P, Crama KF, et al. Dosimetric
advantages of proton therapy compared with photon therapy
using an adaptive strategy in cervical cancer. Acta Oncol.
2016;55:892899.
[15] Lim K, Small W, Portelance L, et al. Consensus guidelines for
delineation of clinical target volume for intensity-modulated pel-
vic radiotherapy for the definitive treatment of cervix cancer. Int J
Radiat Oncol Biol Phys. 2011;79:348355.
[16] Wright P, Muren LP, Hyer M, et al. Evaluation of adaptive radio-
therapy of bladder cancer by image-based tumour control prob-
ability modelling. Acta Oncol. 2010;49:10451051.
[17] Bondar L, Hoogeman MS, Vasquez Osorio EM, et al. A symmetric
nonrigid registration method to handle large organ deformations
in cervical cancer patients. Med Phys. 2010;37:37603772.
[18] Veiga C, McClelland J, Moinuddin S, et al. Toward adaptive radio-
therapy for head and neck patients: Feasibility study on using CT-
to-CBCT deformable registration for "dose of the day" calcula-
tions. Med Phys. 2014;41:031703.
[19] Stanley N, Glide-Hurst C, Kim J, et al. Using patient-specific phan-
toms to evaluate deformable image registration algorithms for
adaptive radiation therapy. J Appl Clin Med Phys. 2013;14:4363.
[20] Onozato Y, Kadoya N, Fujita Y, et al. Evaluation of on-board kV
cone beam computed tomography based dose calculation with
deformable image registration using Hounsfield unit modifica-
tions. Int J Radiat Oncol Biol Phys. 2014;89:416423.
[21] Oh S, Stewart J, Moseley J, et al. Hybrid adaptive radiotherapy
with on-line MRI in cervix cancer IMRT. Radiother Oncol.
2014;110:323328.
[22] Bondar ML, Hoogeman MS, Mens JW, et al. Individualized
nonadaptive and online-adaptive intensity-modulated radiother-
apy treatment strategies for cervical cancer patients based on
pretreatment acquired variable bladder filling computed tomog-
raphy scans. Int J Radiat Oncol Biol Phys. 2012;83:16171623.
[23] van de Schoot AJAJ, de Boer P, Buist MR, et al. Quantification of
delineation errors of the gross tumor volume on magnetic reson-
ance imaging in uterine cervical cancer using pathology data and
deformation correction. Acta Oncol. 2014;54:224231.
[24] de Boer P, Adam JA, Buist MR, et al. Role of MRI in detecting
involvement of the uterine internal os in uterine cervical cancer:
systematic review of diagnostic test accuracy. Eur J Radiol.
2013;82:e422e428.
[25] Kontaxis C, Bol GH, Lagendijk JJW, et al. A new methodology for
inter- and intrafraction plan adaptation for the MR-linac. Phys
Med Biol. 2015;60:74857497.