Radiotherapy and Oncology 171 (2022) 37–42

Contents lists available at ScienceDirect

Radiotherapy and Oncology

journal homepage: www.thegreenjournal.com

Original Article

Online adaptive radiotherapy of urinary bladder cancer with

full re-optimization to the anatomy of the day: Initial experience
and dosimetric benefits
Lina M. Åström a,b,⇑, Claus P. Behrens a,b, Lucie Calmels a, David Sjöström a, Poul Geertsen a,
Lene Sonne Mouritsen a, Eva Serup-Hansen a, Henriette Lindberg a, Patrik Sibolt a
a
Department of Oncology, Copenhagen University Hospital – Herlev and Gentofte, Copenhagen; and b Department of Health Technology, Technical University of Denmark, Roskilde,
Denmark

a r t i c l e i n f o a b s t r a c t

Article history: Background and purpose: Online adaptive radiotherapy (oART) potentially reduces the dose to organs at
Received 24 August 2021 risk (OARs) as the planning target volume (PTV) margins are reduced compared to a non-adaptive
Received in revised form 14 March 2022 approach (non-ART). This study evaluates the feasibility and dosimetric impact of cone-beam computed
Accepted 24 March 2022
tomography (CBCT)-guided oART of urinary bladder cancer for the first patients treated, using patient-
Available online 28 March 2022
specific margins.
Materials and methods: Sixteen consecutive patients with muscle-invasive bladder cancer received two or
Keywords:
more (median = 23) fractions as oART, and remaining fractions as non-ART. The non-ART fractions were
Online adaptive radiotherapy
Bladder cancer
delivered with standard population-based margins, while reduced patient-specific margins based on
Re-optimization intra-fractional variations extracted from 2-4 fractions were applied to the primary PTV (PTV-T) during
Artificial intelligence the oART fractions. Target volume and coverage, and dose to OARs were compared between non-ART
Cone-beam CT and oART plans, and the oART procedure time was recorded.
Image-guided Radiotherapy Results: In total, 297/512 fractions were delivered as oART with full re-optimization to the anatomy of
the day. The median (interquartile range, IQR) oART procedure time, measured from the end of CBCT gen-
eration to completion of plan review, and quality assurance was 13.9 (11.9;16.6) min. The median (IQR)
volume reduction in PTV-T volume was 33.9 (24.2;45.0)%, comparing oART and non-ART plans, resulting
in median (IQR) reductions in bowel bag V45Gy of 18.8 (12.7;27.9)% and rectum V50Gy of 70.7 (35.9;94.8)%.
By re-optimizing the plan to the daily anatomy, full target coverage was achieved at all oART fractions.
Conclusions: oART resulted in large reductions in treatment volumes and doses to OARs, compared to
non-ART, while ensuring target coverage. This indicates potential reductions in gastrointestinal toxicity.
Ó 2022 The Author(s). Published by Elsevier B.V. Radiotherapy and Oncology 171 (2022) 37–42 This is an
open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

To account for uncertainties related to tumor localization, delin-
eation, physical beam parameters, and anatomical variations, mar-
gins are added to the clinical target volume (CTV) to create a
planning target volume (PTV). Optimizing the PTV coverage
ensures an acceptable probability of CTV coverage during radio-
therapy [1,2]. However, the added margins also result in irradiation
of large volumes of normal tissue. Technology advancements have
demonstrated that a reduction in the irradiated volume can
decrease the toxicity related to irradiation of organs at risk (OARs).
Examples of this include stepping from three-dimensional confor-
Abbreviations: oART, Online adaptive radiotherapy.
⇑ Corresponding author at: Copenhagen University Hospital – Herlev and
Gentofte, Radiotherapy Research Unit (52AA), Department of Oncology, Borgmester
Ib Juuls vej 7, DK-2730 Herlev, Denmark.
E-mail address: lina.frida.moeller.andersson@regionh.dk (L.M. Åströ.
mal radiotherapy (CRT) to the more conformal intensity-
modulated radiotherapy (IMRT) for several tumor sites, such as
lung [3–8], head and neck [9–12], and urinary bladder [13]. Despite
the efficiency of conforming the dose to the PTV, the CTV-PTV mar-
gins still account for a large part of the irradiated volume. Reducing
the margins may have equal or larger effect on the irradiated vol-
ume and toxicity as the implementation of IMRT [9,13]. By using
image-based monitoring of geometrical and anatomical variations,
it is possible to adapt the treatment to fit the anatomy of the day
and account for inter-fractional variations. Implementation of
adaptive radiotherapy (ART) has been limited in success due to
e.g. technical limitations, but studies have demonstrated its bene-
fits in irradiated volume and target coverage. The adaptive strate-
gies in pelvic radiotherapy have evolved from offline re-planning

https://doi.org/10.1016/j.radonc.2022.03.014
0167-8140/Ó 2022 The Author(s). Published by Elsevier B.V.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
oART of bladder cancer: initial experience and dosimetric benefits Radiotherapy and Oncology 171 (2022) 37–42

[14–17] towards increased utilization of online adaptive radiother-
apy (oART) using a plan selection approach [18–21].
Patients with urinary bladder cancer often display large inter-
fractional variations in volume and shape of the CTV [22–24],
why ART is of interest. While the plan selection approach has been
the primary oART method for these patients [25,26], it is not adapt-
ing fully to the anatomy of the day. Taking the full leap to online
adaptation based on targets and OARs delineated on the daily anat-
omy may further reduce the margins as the inter-fractional varia-
tions are accounted for [27]. However, as the intra-fractional
anatomical variations are large [27–29], a time-efficient treatment
procedure is crucial for safe margin reduction without compromis-
ing target coverage.
The aim of this study was to investigate the feasibility and dosi-
metric impact of oART and compare it to the standard non-
adaptive cone-beam computed tomography (CBCT) guided (non-
ART) approach, for patients with urinary bladder cancer. This paper
reports on target volume reductions, OAR sparing, and timing
achieved for the first patients treated with a novel commercial
solution for artificial intelligence (AI)-driven, CBCT-guided oART
with full re-optimization to the anatomy of the day.
Material and methods
This study included 16 consecutive patients with muscle-
invasive urinary bladder cancer treated with curative-intended
radiotherapy in 32 fractions between September 2019 and Febru-
ary 2021 (Table 1). All patients received oART for two or more (me-
dian = 23) fractions, with remaining fractions delivered as non-
ART. A total dose of 64 Gy was delivered to the primary CTV
(CTV-T). If indicated according to Danish national guidelines [30],
50 Gy and 64 Gy were simultaneously delivered to pelvic lymph
nodes (CTV-E) and positive lymph nodes (CTV-N), respectively.
All patients provided informed written consent and treatments
were delivered under institutional approval.
The Ethos Therapy system (Varian Medical Systems, VMS) used
for AI-driven, CBCT-guided oART has been described elsewhere
[31–33]. A brief description of the oART workflow as well as
non-ART workflow is included in Appendix A. Supplementary
material.
Simulation and contouring
Reference computed tomography (ref-CT) and magnetic reso-
nance (ref-MR) scans were acquired in supine position approxi-
mately one week prior to treatment. The patients emptied their
bladder and used rectal laxatives prior to the reference scans as
well as treatments if needed. They were furthermore instructed
to avoid consuming fluids two hours prior to the oART treatments
to reduce the intra-fractional variation.
CTV-T was defined as the entire bladder and, when indicated,
other involved organs such as the prostate or seminal vesicles.
The CTV-T non-ART delineation strategy was changed during the
inclusion period to consolidate the delineation procedures of
non-ART and oART, while the strategy for oART was the same for
all patients. For 13 of the patients, the bladder part of the CTV-T
non-ART was defined as the union of the bladder on ref-CT and
ref-MR; for the remaining patients it was defined in the same
way as the CTV-T oART, i.e. CT-based with MR-guidance in caudal
parts where the visibility on CT was limited and the bladder filling
had little impact on its shape. CTV-E included the pre-sacral nodes
from S1-S3, external iliac, internal iliac, and obturator nodes. OARs
were delineated on the ref-CT and included rectum, bowel bag, and
femoral heads. Rectum was contoured from the anal canal to the
recto-sigmoid transition. Bowel bag was delineated as the peri-
toneal space from the most caudal slice with visible bowel to at
least the most cranial slice with any PTV structure.
Initial contouring was conducted in Eclipse treatment planning
system (TPS (VMS)) and segmentations were imported to Ethos
TPS (VMS) for treatment planning.
Margins and initial treatment planning
Non-ART treatment plans followed institutional standard and
were based on population-based margins. The bladder part of
CTV-T was expanded 10 mm in cranial and caudal (CC) directions
and 6 mm in left and right (LR) as well as anterior and posterior
(AP) directions to generate primary internal target volume (ITV-
T), from which muscles and bones were excluded. An anisotropic
margin of 5 mm (8 mm CC) was added to ITV-T and the non-
bladder part of CTV-T (if any) to generate PTV-T. Similarly, an ani-
sotropic margin of 5 mm (8 mm CC) was added to CTV-E to create
PTV-E.
Adaptive reference plans were generated using patient-specific
CTV-T-to-PTV-T margins and reducing the CTV-E-to-PTV-E margin
to 3 mm LR and AP while keeping 8 mm CC, due to uncertainties in
the target deformation during the oART procedure and experience
from simulations prior to implementation [31]. The patient-
specific margins were calculated extracting the maximum intra-
fractional bladder variation as observed on pre- and post-
treatment CBCTs during two to four non-ART fractions prior to
the start of oART, with an extra 5 mm isotropic margin added.

Table 1
Patient characteristics, including sex, age in years, whether the patient had a CTV-E, whether supplementary ref-MR images were acquired, number of oART fractions (fx), and
additional comments.

Patient Sex Age CTV-E ref-MR # oART fx Comments

1 M 78 Yes Yes 29 Prostate included in CTV-T, Urinary catheter
2 M 57 Yes Yes 26 Urinary catheter
3 M 80 Yes Yes 8 Prostate included in CTV-T
4 F 71 No Yes 6
5 M 76 No No 32 Hernia with bladder extending into scrotum, Urinary catheter
6 F 62 Yes Yes 3 CTV-N along right iliac vessel, Urinary catheter
7 M 73 Yes Yes 4
8 M 63 Yes Yes 2 Nephrostomy catheter
9 F 67 Yes No 19 Nephrostomy catheter
10 F 81 Yes Yes 15
11 F 71 No No 26
12 F 72 Yes Yes 28
13 F 61 No Yes 24
14 M 50 Yes Yes 22
15 F 72 No Yes 28 Urinary catheter
16 M 83 Yes Yes 25 Prostate and seminal vesicles included in CTV-T

38
L.M. Åström, C.P. Behrens, L. Calmels et al.
The intra-fractional bladder variation was measured in all six
directions using anatomical landmarks (e.g. symphysis, femoral
heads, and spinal column) as reference measuring points. Three
patients received oART from the first fractions; for one patient,
the intra-fractional variation was measured from an additional
ref-CT acquired 12 min after the standard ref-CT; for two other
patients, initial CTV-T-to-PTV-T margins were derived from mar-
gins of previous oART patients.
Non-ART plans were generated in either Ethos v1.0 (12/16
patients) or Eclipse v15.6 (4/16 patients) TPS, while all adaptive
reference plans were generated in Ethos TPS. All dose calculations
were carried out using AcurosXB algorithm (VMS), calculating dose
to medium, with plan normalization to achieve a PTV-T mean dose
of 100% of the prescribed dose as per institutional standard. The
offline (non-ART and adaptive reference) and online (adapted and
scheduled) generated treatment plans used a calculation resolu-
tion of 2.5 and 3 mm, respectively; the sparser resolution for online
plans was used to reduce the calculation time. Plans were evalu-
ated in accordance with constraints and priorities in Table 2.
Plan-specific quality assurance (QA) was conducted prior to treat-
ment using an independent dose calculation software (Mobius3D
and MobiusAdapt, VMS).
Online adaptation
oART treatments were carried out on the Ethos system v2.0
(VMS), with bladder and rectum as so-called influencers, and tar-
gets and OARs re-generated at each fraction. The influencers are
a set of system-defined structures in the closest proximity to the
target, influencing the deformation of it (see Appendix A. Supple-
mentary material for details on the oART workflow). A CBCT image
was acquired after the adaptive procedure but before treatment
delivery the first three oART fractions and thereafter whenever
indicated (e.g. due to patient movement as observed on a monitor
or pro-longed oART procedure) to verify that the bladder was cov-
ered by the PTV-T, hence validating the margins. If necessary, to
ensure CTV coverage, the treatment couch was shifted before treat-
ment delivery.
In addition to the radiotherapy technicians conducting the oART
workflow, a physicist was present at all oART fractions and a physi-
cian was present whenever needed (at all fractions for the first
patients and at least at the first four fractions for the latter
patients).
Evaluation parameters and statistical analysis
Adapted, scheduled, adaptive reference and non-ART plans gen-
erated in Ethos TPS were exported and transferred to Eclipse TPS.
Data extracted from Eclipse TPS were evaluated in Matlab
(R2019a, The MathWorks, Inc.). Differences in target volumes and
clinically relevant dose-volume parameters of OARs (Table 2)
between the non-ART plan and the oART plans (adaptive
reference-, scheduled- and adapted plan) were analyzed in a
non-accumulated, fraction-wise manner, with each plan scaled to
Table 2
Dose constraints and priorities on target coverage and OARs.
Priority Structure Constraint
1 PTV-T V95%  99%
1 PTV-T Dmax  107%
1 PTV-E V95%  99%
2 Rectum V50Gy  25%
2 Rectum V40Gy  50%
2 Bowel bag V45Gy < 300 cm3
2 Bowel bag V30Gy < 600 cm3
2 Femoral heads Dmax < 52 Gy
39
Radiotherapy and Oncology 171 (2022) 37–42
32 fractions. Target coverage was compared between scheduled
and adapted plans, and the plan selected for treatment was
recorded. The plan quality was retrospectively evaluated using
conformity index (CI) (CI = (V95%,PTV-T)2/(VPTV-T  V95%,Body), where
V95%,PTV-T and V95%,Body is the volume of PTV-T and body, respec-
tively, receiving 95% or more of the prescribed dose, and VPTV-T is
the volume of PTV-T) [34,35], and homogeneity index (HI)
(HI = (D2% D98%)/D50%, where D2%, D98%, and D50% is the dose
received by 2%, 98%, and 50% of the volume, respectively) [2]. Wil-
coxon signed-rank tests were used to test whether data of sched-
uled and adapted plans came from different distributions, at a
Bonferroni adjusted significance level of 1.25% (=5%/4). oART pro-
cedure durations were extracted from treatment records.
Results
In total, 297 out of 512 fractions were delivered as oART, with
remaining fractions delivered using the non-ART plan (Table 1).
Because of limited number of trained staff, the COVID-19 pandemic
and downtime due to maintenance and upgrade of the system, the
number of oART fractions varied among the patients. As experience
was gained over the delivered oART fractions, a workflow and
adaptive margin calculation procedure was established.
All oART fractions except one (patient 1), due to technical issues
in session reconstruction, were exported from Ethos TPS, resulting
in 296 analyzed oART fractions. Treatment records of 282/296 frac-
tions were extracted; remaining fractions could not be extracted
due to technical issues and were therefore not included when eval-
uating the oART procedure duration.
The median (IQR) oART procedure duration measured from the
end of CBCT generation to completion of plan review and QA was
13.9 (11.9;16.6) minutes. Influencer review and edit had a median
(IQR) duration of 7.3 (5.9;9.6) minutes while target review and
edit, and plan selection and QA took 1.2 (0.9;1.5) and 4.9
(4.2;6.1) minutes, respectively (Fig. 1). None of the oART treat-
ments were discontinued due to added time spent on the oART
procedure.
The seminal vesicles were added as an influencer for patient 16
after eight oART fractions to improve the propagation of CTV-T
which included the seminal vesicles. For the same reason, the blad-
der was excluded as an influencer for patient 7. As patient 7 was
radically prostatectomized, the position of the bladder deviated,
which degraded the AI-driven auto-generation of the bladder
influencer.
The adapted plan was selected for treatment in 292/296 frac-
tions, with target coverage being the major reason. The CI and HI
of adapted plans were superior to scheduled plans (p < 0.001 for
both), and similar to non-ART and adaptive reference plans
(Table 3).
All plan-specific QA resulted in gamma passing rates (3%/3mm,
global gamma, 20% dose threshold) above the clinical tolerance
(>95%), with acceptable differences (within 3%) in target and OAR
dose-volume parameters.
Plan Selection
& QA 36%
4.9 (4.2;6.1) min Influencer review
55% 7.3 (5.9;9.6) min
9%
Target review
1.2 (0.9;1.5) min
Fig. 1. Median (IQR) duration of the different steps in the oART procedure and the
distribution between them.
oART of bladder cancer: initial experience and dosimetric benefits Radiotherapy and Oncology 171 (2022) 37–42

Table 3 CTV-T and PTV-T coverage comparing adapted and scheduled plans
Median (IQR) conformity (CI) and homogeneity index (HI) for the different treatment both gave p < 0.001.
plans.
oART resulted in median (IQR) reductions of rectum V50Gy and
Plan CI HI V40Gy of 6.6 (1.5;11.6) percentage points and 12.4 (4.0;21.4) per-
Non-ART 0.89 (0.88;0.91) 0.04 (0.04;0.05) centage points, respectively, compared to non-ART (Fig. 2). This
Adaptive reference 0.89 (0.87;0.92) 0.05 (0.04;0.05) corresponds to relative reductions of 70.7 (35.9;94.8)% and 38.8
Scheduled 0.75 (0.68;0.79) 0.15 (0.10;0.28) (14.9;57.2)%. The reductions in bowel bag V45Gy and V30Gy were
Adapted 0.87 (0.85;0.90) 0.04 (0.04;0.06)
78.8 (48.1;103.5) cm3 and 67.4 (30;103.5) cm3, respectively, corre-
sponding to 18.8 (12.7;27.9)% and 12.6 (6.0;18.8)% (Fig. 2). The
maximum dose to the femoral heads was below 52 Gy for all plans.
Applying patient-specific margins resulted in CTV-T-to-PTV-T
margins ranging from 8-13 mm, 5–10 mm, 5–8 mm, and 5–
Discussion
10 mm in cranial, caudal, LR, and AP directions, respectively. The
median (IQR) volume reductions in PTV-T and PTV-E were 33.9
One major finding in this study was a 33.9% median volume
(24.2;45.0)% and 7.1 (4.5;10.3)% during the oART fractions com-
reduction in the PTV-T, comparing oART to non-ART. As demon-
pared to corresponding non-ART volumes (Fig. 2, graphical exam-
strated by the lack of PTV-T coverage in the scheduled plans, the
ples in Appendix A. Supplementary material, Fig. A3). Besides the
large margin reductions often required full re-optimization to the
margin reduction, the PTV-T volume was affected by variations
anatomy of the day to ensure target coverage (Fig. 3); target cover-
in the CTV-T, i.e. the bladder (Fig. 2). The variations in bladder vol-
age was primarily evaluated based on PTV-T rather than CTV-T due
ume and shape resulted in lack of PTV-T coverage (V95% < 99%) in
to intra-fractional bladder variations. Since the scheduled plan
89.5% of all scheduled plans, while re-optimization regained cover-
often was ruled out based on PTV coverage, evaluation of the dose
age in 99.7% of all adapted plans (Fig. 3). Similarly, CTV-T coverage
to OARs added little value to the selection of plan. This was further-
was lacking (V95% < 99%) in 19.6% of the scheduled plans and in
more demonstrated by the superior CI and HI of adapted plans
none of the adapted plans. The Wilcoxon signed-rank tests for
compared to scheduled plans (Table 3).

Fig. 2. The boxplots present CTV-T volume (top left), PTV-T volume (top right), bowel bag V45Gy (bottom left), and rectum V50Gy (bottom right) variations during oART
fractions for the 16 patients analyzed. The dash-dotted lines represent the value achieved in the adaptive reference plan; the dotted lines represent the corresponding values
achieved in the standard non-ART approach; the dashed line (bottom left and right) represent the clinical constraint for the OAR (Table 2). The inner line of the boxes denotes
the median value, the box the inter-quartile range (IQR), and the whiskers indicate the range of data within (1.5  IQR). The outliers are presented as single markers and
defined as values greater than (P75 + 1.5  IQR) or smaller than (P25 + 1.5  IQR), where P75 and P25 are the 75th and 25th percentile.

40
L.M. Åström, C.P. Behrens, L. Calmels et al.
Fig. 3. The boxplots present CTV-T (left) and PTV-T (right) coverage (V95%) for
adapted and scheduled plans. The dotted lines represent the corresponding values
achieved in the standard non-ART approach. The inner line of the boxes denotes the
median value, the box the inter-quartile range (IQR), and the whiskers indicate the
range of data within (1.5  IQR). The outliers are presented as single markers and
defined as values greater than (P75 + 1.5  IQR) or smaller than (P25 + 1.5  IQR),
where P75 and P25 are the 75th and 25th percentile.
Inter-fractional volume variations in PTV-T oART and lack of its
coverage were primarily a result of variations in the CTV-T, i.e. the
bladder (Fig. 2), which varied among the patients. For some, offline
re-planning with reduced CTV-to-PTV-margins might be a suffi-
cient option. However, with less frequent adaptation, one might
not dare to decrease the margins in the same extent as for oART.
PTV-T reductions achieved in this study correspond to previ-
ously reported simulation studies [36,37]. Both Vestergaard et al.
and Kong et al. report on the superiority of the re-optimization
approach using the same CTV-T-to-PTV-T margin for all patients
compared to the plan selection approach. In contrast, this study
used patient-specific margins to account for intra-fractional varia-
tions, giving a range of CTV-T-to-PTV-T margins. As all patients,
including those with catheter, showed intra-fractional variations
in the bladder, the PTV-T margin was larger than 5 mm in all direc-
tions for all patients. Nevertheless, the dose to both rectum and
bowel bag were lower compared to the non-ART approach for all
patients. Moving from non-ART to oART resulted in more plans ful-
filling the bowel bag V45Gy < 300 cm3 constraint, which is an impor-
tant dose-volume parameter related to gastrointestinal toxicity
[38,39]. Søndergaard et al. [13] demonstrated a reduction of peak
acute gastrointestinal morbidity (CTCAE v.4.0) grade  2 diarrhea
from 56% to 30% when comparing CRT to IMRT for patients with
bladder cancer. The obtained PTV volume and OAR dose reductions
achieved in this study thus indicate promising potential toxicity
reductions.
Clinical use of the re-optimization approach has until recently
been limited due to the cumbersome re-delineation and treatment
planning. There are limitations in other studies reporting on clini-
cal experience and timing with this treatment approach for bladder
cancer patients [31]. This study demonstrated a median oART pro-
cedure of 13.9 min, which is vastly faster than that reported for
MR-guided oART of rectal cancer of 43 min from first MR-image
to end of treatment [40], even if 2–5 min is added for treatment
delivery. The procedure time presented in this study is representa-
tive for the added steps of the oART workflow and should be com-
pared to the time for online image registration and evaluation in a
41
Radiotherapy and Oncology 171 (2022) 37–42
non-ART workflow. In addition to anatomical site, affecting which
influencers and targets are involved, the oART procedure time
depends on e.g. the staff’s experience and patient characteristics.
In accordance with Intven et al. [40], recontouring was the most
time-consuming step of the oART procedure. In the present study,
more than half of the procedure time was spent on editing influ-
encers to ensure correct target propagation, and the variety in
characteristics among the patients (Table 1) required different
extent of editing. At the time of this study, the version of the sys-
tem had difficulties defining influencers in cases for which the AI
was not yet trained, e.g. patients with hernia or catheter, leading
to a more extensive need for influencer editing. Given the dosimet-
ric benefits, the oART procedure was, however, deemed feasible
also for those patients. Implementing a novel system, with limited
experience prior to inclusion of patients furthermore affected the
procedure time. Having staff under training throughout the study
period, and due to the dependence of patient characteristics, no
overall decrease in procedure time was seen over the patients.
The time slot reserved for oART of bladder cancer is currently
30 min per fraction, while corresponding non-ART time slot is
15 min.
One limitation of this study was basing the patient-specific
margins on intra-fractional variation during non-ART fractions,
without taking the added time of the oART procedure into account.
Furthermore, the number of fractions used to calculate the margins
varied. However, by acquiring an extra pre-treatment CBCT image
prior to treatment delivery, the suitability of the margins was ver-
ified, and the target coverage was ensured.
Another limitation was the absence of dose calculation of the
non-ART plan on the daily anatomy and dose accumulation for
both non-ART and oART plans. This study included comparisons
of oART plans calculated on the anatomy of both ref-CT (i.e. adap-
tive reference plan) and daily CBCTs (re-calculated: scheduled
plan, re-optimized: adapted plan) to non-ART plans calculated
solely on ref-CT. Accumulated doses in combination with non-
ART plan calculations on daily anatomy would give a more repre-
sentative picture of the actual dose delivered over the fractions.
However, the relationship between the adaptive reference and
non-ART plans indicates what could be achieved with the two
treatment strategies on the same anatomy and demonstrated great
sparing of OARs.
Conclusions
This study has demonstrated the feasibility and time-efficiency
of CBCT-guided oART of urinary bladder cancer with full re-
optimization to the anatomy of the day, using a novel commercial
AI-driven solution. While oART required additional treatment time
compared to non-ART, it resulted in reductions in treatment vol-
umes and dose-volume parameters of bowel bag and rectum, indi-
cating potential reduction in gastrointestinal toxicity for the
patients.
Conflict of interests
Varian Medical Systems (VMS) provided support and training
during the project reported on here. The authors provided feedback
to VMS on suggestions for improvements and usability of the sys-
tem. Several research projects, including Ethos-related projects at
the Department of Oncology, Copenhagen University Hospital –
Herlev and Gentofte, are sponsored by VMS. None of the authors
have any affiliation with VMS.
oART of bladder cancer: initial experience and dosimetric benefits
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.radonc.2022.03.014.
References
[1] Van Herk M. Errors and Margins in Radiotherapy. Semin Radiat Oncol
2004;14:52–64. https://doi.org/10.1053/j.semradonc.2003.10.003.
[2] Grégoire V, Mackie T, De Neve W, Gospodarowicz M, Purdy JA, van Herk M,
et al. ICRU Report 83. J ICRU 2010;10.
[3] Chun SG, Hu C, Choy H, Komaki RU, Timmerman RD, Schild SE, et al. Impact of
intensity-modulated radiation therapy technique for locally advanced non-
small-cell lung cancer: A secondary analysis of the NRG oncology RTOG 0617
randomized clinical trial. J Clin Oncol 2017;35:56–62. https://doi.org/10.1200/
JCO.2016.69.1378.
[4] Grills IS, Yan D, Martinez AA, Vicini FA, Wong JW, Kestin LL. Potential for
reduced toxicity and dose escalation in the treatment of inoperable non-small-
cell lung cancer: a comparison of intensity-modulated radiation therapy
(IMRT), 3D conformal radiation, and elective nodal irradiation. Int J Radiat
Oncol Biol Phys 2003;57:875–90. https://doi.org/10.1016/S0360-3016(03)
00743-0.
[5] Murshed H, Liu HH, Liao Z, Barker JL, Wang X, Tucker SL, et al. Dose and volume
reduction for normal lung using intensity-modulated radiotherapy for
advanced-stage non-small-cell lung cancer. Int J Radiat Oncol Biol Phys
2004;58:1258–67. https://doi.org/10.1016/j.ijrobp.2003.09.086.
[6] Wu VWC, Kwong DLW, Sham JST. Target dose conformity in 3-dimensional
conformal radiotherapy and intensity modulated radiotherapy. Radiother
Oncol 2004;71:201–6. https://doi.org/10.1016/j.radonc.2004.03.004.
[7] Liu HH, Wang X, Dong L, Wu Q, Liao Z, Stevens CW, et al. Feasibility of sparing
lung and other thoracic structures with intensity-modulated radiotherapy for
non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2004;58:1268–79.
https://doi.org/10.1016/j.ijrobp.2003.09.085.
[8] Liao ZX, Komaki RR, Thames HD, Liu HH, Tucker SL, Mohan R, et al. Influence of
technologic advances on outcomes in patients with unresectable, locally
advanced non-small-cell lung cancer receiving concomitant
chemoradiotherapy. Int J Radiat Oncol Biol Phys 2010;76:775–81. https://
doi.org/10.1016/j.ijrobp.2009.02.032.
[9] Nutting CM, Morden JP, Harrington KJ, Urbano TG, Bhide SA, Clark C, et al.
Parotid-sparing intensity modulated versus conventional radiotherapy in head
and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled
trial. Lancet Oncol 2011;12:127–36. https://doi.org/10.1016/S1470-2045(10)
70290-4.
[10] Chao KSC, Majhail N, Huang CJ, Simpson JR, Perez CA, Haughey B, et al.
Intensity-modulated radiation therapy reduces late salivary toxicity without
compromising tumor control in patients with oropharyngeal carcinoma: a
comparison with conventional techniques. Radiother Oncol 2001;61:275–80.
https://doi.org/10.1016/S0167-8140(01)00449-2.
[11] Feng FY, Kim HM, Lyden TH, Haxer MJ, Feng M, Worden FP, et al. Intensity-
modulated radiotherapy of head and neck cancer aiming to reduce dysphagia:
early dose-effect relationships for the swallowing structures. Int J Radiat Oncol
Biol Phys 2007;68:1289–98. https://doi.org/10.1016/j.ijrobp.2007.02.049.
[12] Eisbruch A, Ten Haken RK, Kim HM, Marsh LH, Ship JA. Dose, volume, and
function relationships in parotid salivary glands following conformal and
intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol
Biol Phys 1999;45:577–87. https://doi.org/10.1016/S0360-3016(99)00247-3.
[13] Søndergaard J, Holmberg M, Jakobsen AR, Agerbæk M, Muren LP, Hoyer M. A
comparison of morbidity following conformal versus intensity-modulated
radiotherapy for urinary bladder cancer. Acta Oncol (Madr) 2014;53:1321–8.
https://doi.org/10.3109/0284186X.2014.928418.
[14] Yan Di, Ziaja E, Jaffray D, Wong J, Brabbins D, Vicini F, et al. The use of Adaptive
Radiation Therapy to reduce setup error: a prospective clinical study. Int J
Radiat Oncol Biol Phys 1998;41:715–20. https://doi.org/10.1016/S0360-3016
(97)00567-1.
[15] Vanasek J, Odrazka K, Dolezel M, Dusek L, Jarkovsky J, Hlavka A, et al. Searching
for an appropriate image-guided radiotherapy method in prostate cancer -
Implications for safety margin. Tumori 2014;100:518–23. https://doi.org/
10.1177/1660.18168.
[16] Sur RK, Clinkard J, Jones WG, Taylor RE, Close HJ, Chaturvedi A, et al. Changes
in target volume during radiotherapy treatment of invasive bladder
carcinoma. Clin Oncol 1993;5:30–3. https://doi.org/10.1016/S0936-6555(05)
80693-4.
[17] Turner SL, Swindell R, Bowl N, Marrs J, Brookes B, Read G, et al. Bladder
movement during radiation therapy for bladder cancer: implications for
treatment planning. Int J Radiat Oncol Biol Phys 1997;39:355–60. https://doi.
org/10.1016/S0360-3016(97)00070-9.
[18] Xia P, Qi P, Hwang A, Kinsey E, Pouliot J, Roach M. Comparison of three
strategies in management of independent movement of the prostate and
pelvic lymph nodes. Med Phys 2010;37:5006–13. https://doi.org/10.1118/
1.3480505.
[19] Vestergaard A, Muren LP, Lindberg H, Jakobsen KL, Petersen JBB, Elstrøm UV,
et al. Normal tissue sparing in a phase II trial on daily adaptive plan selection
in radiotherapy for urinary bladder cancer. Acta Oncol 2014;53:997–1004.
https://doi.org/10.3109/0284186X.2014.928419.
42
Radiotherapy and Oncology 171 (2022) 37–42
[20] Heijkoop ST, Langerak TR, Quint S, Bondar L, Mens JWM, Heijmen BJM, 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;90:673–9. https://doi.org/10.1016/j.
ijrobp.2014.06.046.
[21] Foroudi F, Pham D, Rolfo A, Bressel M, Tang CI, Tan A, et al. The outcome of a
multi-centre feasibility study of online adaptive radiotherapy for muscle-
invasive bladder cancer TROG 10.01 BOLART. Radiother Oncol
2014;111:316–20. https://doi.org/10.1016/j.radonc.2014.02.015.
[22] Dees-Ribbers HM, Betgen A, Pos FJ, Witteveen T, Remeijer P, Van Herk M. Inter-
and intra-fractional bladder motion during radiotherapy for bladder cancer: a
comparison of full and empty bladders. Radiother Oncol 2014;113:254–9.
https://doi.org/10.1016/j.radonc.2014.08.019.
[23] Yee D, Parliament M, Rathee S, Ghosh S, Ko L, Murray B. Cone beam CT imaging
analysis of interfractional variations in bladder volume and position during
radiotherapy for bladder cancer. Int J Radiat Oncol Biol Phys 2010;76:1045–53.
https://doi.org/10.1016/j.ijrobp.2009.03.022.
[24] Muren LP, Smaaland R, Dahl O. Organ motion, set-up variation and treatment
margins in radical radiotherapy of urinary bladder cancer. Radiother Oncol
2003;69:291–304. https://doi.org/10.1016/S0167-8140(03)00246-9.
[25] Thörnqvist S, Hysing LB, Tuomikoski L, Vestergaard A, Tanderup K, Muren LP,
et al. Adaptive radiotherapy strategies for pelvic tumors – a systematic review
of clinical implementations. Acta Oncol 2016;55:943–58. https://doi.org/
10.3109/0284186X.2016.1156738.
[26] Kong V, Hansen VN, Hafeez S. Image-guided adaptive radiotherapy for bladder
cancer. Clin Oncol 2021;33:350–68. https://doi.org/10.1016/
j.clon.2021.03.023.
[27] Grønborg C, Vestergaard A, Høyer M, Söhn M, Pedersen EM, Petersen JB, et al.
Intra-fractional bladder motion and margins in adaptive radiotherapy for
urinary bladder cancer. Acta Oncol (Madr) 2015;54:1461–6. https://doi.org/
10.3109/0284186X.2015.1062138.
[28] Nishioka K, Shimizu S, Shinohara N, Ito YM, Abe T, Maruyama S, et al. Analysis
of inter- and intra fractional partial bladder wall movement using implanted
fiducial markers. Radiat Oncol 2017;12. https://doi.org/10.1186/s13014-017-
0778-z.
[29] Vestergaard A, Hafeez S, Muren LP, Nill S, Høyer M, Hansen VN, et al. The
potential of MRI-guided online adaptive re-optimisation in radiotherapy of
urinary bladder cancer. Radiother Oncol 2016;118:154–9. https://doi.org/
10.1016/j.radonc.2015.11.003.
[30] DaBlaCa Danish Bladder Cancer Group. Behandling og opfølgning af
muskelinvasiv blærekræft 2020:1–33. Accessed: Mar. 14, 2022. https://
www.dmcg.dk/siteassets/kliniske-retningslinjer—skabeloner-og-vejledninger/
kliniske-retningslinjer-opdelt-pa-dmcg/blarecancer/
dablaca_muskelinvasiv_1_1_admgodk111120.pdf.
[31] Sibolt P, Andersson LM, Calmels L, Sjöström D, Bjelkengren U, Geertsen P, et al.
Clinical implementation of artificial intelligence-driven cone-beam computed
tomography-guided online adaptive radiotherapy in the pelvic region. Phys
Imaging Radiat Oncol 2021;17:1–7. https://doi.org/10.1016/j.
phro.2020.12.004.
[32] Yoon SW, Lin H, Alonso-Basanta M, Anderson N, Apinorasethkul O, Cooper K,
et al. Initial evaluation of a novel cone-beam ct-based semi-automated online
adaptive radiotherapy system for head and neck cancer treatment – a timing
and automation quality study. Cureus 2020;12. https://doi.org/10.7759/
cureus.9660.
[33] de Jong R, Visser J, van Wieringen N, Wiersma J, Geijsen D, Bel A. Feasibility of
Conebeam CT-based online adaptive radiotherapy for neoadjuvant treatment
of rectal cancer. Radiat Oncol 2021;16:1–11. https://doi.org/10.1186/s13014-
021-01866-7.
[34] Cao T, Dai Z, Ding Z, Li W, Quan H. Analysis of different evaluation indexes for
prostate stereotactic body radiation therapy plans: conformity index,
homogeneity index and gradient index. Precis Radiat Oncol 2019;3:72–9.
https://doi.org/10.1002/pro6.1072.
[35] Riet AV, Mak ACA, Moerland MA, Elders LH, van der Zee W. A conformation
number to quantify the degree of conformality in brachytherapy and external
beam irradiation: application to the prostate. Int J Radiat Oncol Biol Phys
1997;37:731–6. https://doi.org/10.1016/S0360-3016(96)00601-3.
[36] Vestergaard A, Muren LP, Søndergaard J, Elstrøm UV, Høyer M, Petersen JB.
Adaptive plan selection vs. re-optimisation in radiotherapy for bladder cancer:
a dose accumulation comparison. Radiother Oncol 2013;109:457–62. https://
doi.org/10.1016/j.radonc.2013.08.045.
[37] Kong VC, Taylor A, Chung P, Craig T, Rosewall T. Comparison of 3 image-guided
adaptive strategies for bladder locoregional radiotherapy. Med Dosim
2019;44:111–6. https://doi.org/10.1016/j.meddos.2018.03.004.
[38] Kavanagh BD, Pan CC, Dawson LA, Das SK, Li XA, Ten Haken RK, et al. Radiation
dose-volume effects in the stomach and small bowel. Int J Radiat Oncol Biol
Phys 2010;76:S101–7. https://doi.org/10.1016/j.ijrobp.2009.05.071.
[39] McDonald F, Waters R, Gulliford S, Hall E, James N, Huddart RA. Defining bowel
dose volume constraints for bladder radiotherapy treatment planning. Clin
Oncol 2015;27:22–9. https://doi.org/10.1016/j.clon.2014.09.016.
[40] Intven MPW, de Mol van Otterloo SR, Mook S, Doornaert PAH, de Groot-van
Breugel EN, Sikkes GG, et al. Online adaptive MR-guided radiotherapy for
rectal cancer; feasibility of the workflow on a 1.5T MR-linac: clinical
implementation and initial experience. Radiother Oncol 2021;154:172–8.
https://doi.org/10.1016/j.radonc.2020.09.024.