Radiotherapy and Oncology 154 (2021) 172–178

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Radiotherapy and Oncology

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Original Article

Online adaptive MR-guided radiotherapy for rectal cancer; feasibility of

the workflow on a 1.5T MR-linac: clinical implementation and initial
experience
M.P.W. Intven a, S.R. de Mol van Otterloo a,⇑, S. Mook a, P.A.H. Doornaert a, E.N. de Groot-van Breugel a,
G.G. Sikkes a, M.E. Willemsen-Bosman a, H.M. van Zijp a, R.H.N. Tijssen a,b
a
Department of Radiation Oncology, University Medical Center Utrecht, Utrecht; and b Department of Radiation Oncology, Catharina Hospital, Eindhoven, The Netherlands

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

Article history: Background and purpose: Daily online adaptation of the clinical target volume (CTV) using MR-guided
Received 25 February 2020 radiotherapy enables margin reduction of the planning target volume (PTV). This study describes the
Received in revised form 13 September implementation and initial experience of MR-guided radiotherapy on the 1.5T MR-linac and evaluates
2020
treatment time, patient compliance, and target coverage, including an initial assessment of margin reduc-
Accepted 14 September 2020
Available online 22 September 2020
tion.
Materials and methods: Patients were treated on a 1.5T MR-linac (7MV, FFF). At each fraction a 3D T2
weighted (T2w) MR-sequence was acquired on which the CTV was adapted after a deformable registra-
Keywords:
Radiotherapy
tion of the contours from the pre-planning CT scan. Based on the new contours a full online replanning
Rectal cancer was done after which a new 3D T2w MR-sequence was acquired for position verification. A 5 field
Magnetic resonance imaging Intensity Modulated Radiotherapy (IMRT) plan was delivered.
Image-guided radiation Results: Forty-three patients with rectal cancer were treated with 25 Gy in 5 fractions of which 18 with
Neoadjuvant therapy reduced margins. In total, 204 of 215 fractions were delivered on the MR-linac all of which obtained a
clinically acceptable treatment plan. Median in-room time per fraction was 48 min (interquartile range
8). No fractions were canceled or interrupted because of patient intolerance. CTV coverage after margin
reduction was good on all post-treatment scans but one due to passing gas.
Conclusion: MR-guided radiotherapy using daily full online recontouring and replanning on a 1.5T MR-
linac for rectal cancer is feasible and currently takes about 48 min per fraction.
Ó 2021 The Authors. Published by Elsevier B.V. Radiotherapy and Oncology 154 (2021) 172–178 This is an
open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Patients with intermediate or locally advanced rectal carcinoma
are treated according to international guidelines with neoadjuvant
radiotherapy with or without concurrent chemotherapy followed
by total mesorectal excision surgery [1,2]. Neoadjuvant radiother-
apy leads to a reduction in local recurrence rate but is still associ-
ated with substantial toxicity as large planning volumes are
needed to compensate for inter- and intrafraction movement
[3,4]. Particularly the mesorectum is a nonstationary structure,
with large day-to-day variation as its shape and volume are
affected by both bladder and rectal filling [4–7]. Planning target
⇑ Corresponding author at: Postal Room Q00.311, P.O. Box 85500, 3508 GA
Utrecht, The Netherlands.
E-mail addresses: M.Intven@umcutrecht.nl (M.P.W. Intven), s.r.demolvanotter-
loo-2@umcutrecht.nl (S.R. de Mol van Otterloo), S.Mook-2@umcutrecht.nl
(S. Mook), P.A.H.Doornaert@umcutrecht.nl (P.A.H. Doornaert), E.vanBreugel@umcu-
trecht.nl (E.N. de Groot-van Breugel), G.G.Sikkes@umcutrecht.nl (G.G. Sikkes),
mbosman2@umcutrecht.nl (M.E. Willemsen-Bosman), h.m.vanzijp-2@umcutrecht.
nl (H.M. van Zijp), rob.tijssen@catharinaziekenhuis.nl (R.H.N. Tijssen).
volume (PTV) margins up to 31 mm have been proposed which
results in large volumes that receive irradiation [8–10]. For rectal
cancer patients it is known that margin reduction of the PTV and
reducing the amount of organs at risk (OAR) within these volumes
has the potential to lower toxicity rates [10–15].
Furthermore, studies suggest that dose escalation of the gross
tumor volume (GTV) increases the pathologic complete response
(pCR) rate [16–19]. A higher pCR rate leads to more patients who
are eligible for active surveillance in an organ preservation
approach [20,21]. However, dose escalation of the GTV using large
PTV margins will lead to increased toxicity because of higher doses
to the surrounding OAR. Therefore, high-precision radiotherapy is
needed to enable dose escalation of the tumor.
The MR-linear accelerator (MR-linac) is able to deliver high-
precision radiotherapy and recently became available for rectal
cancer treatment [22,23]. Online recontouring and replanning at
each treatment fraction on this system compensates for interfrac-
tion variation which potentially enables the use of smaller PTV

https://doi.org/10.1016/j.radonc.2020.09.024
0167-8140/Ó 2021 The Authors. Published by Elsevier B.V.
This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
M.P.W. Intven, S.R. de Mol van Otterloo, S. Mook et al.
margins [24,25]. Furthermore, high precision online MR-guided
radiotherapy (MRgRT) potentially enables safe dose escalation
without increasing toxicity in rectal cancer patients.
On the MR-linac, MR-guided online recontouring and replan-
ning during each fraction requires a detailed yet concise workflow
[26]. This study describes the clinical introduction and initial expe-
rience of MRgRT on a 1.5T MR-linac at our institution by evaluating
treatment time, patient compliance, and target coverage.
Materials and methods
Patients
As this study aims to estimate the clinical feasibility of MRgRT
in the general rectal cancer population, it was decided that all
patients referred for short course radiotherapy, i.e. 5 times 5 Gy
in accordance with the Dutch guidelines, were eligible for treat-
ment on a 1.5T MR-linac (Elekta Unity, Elekta AB, Stockholm, Swe-
den). Patients with orthopedic implants in the pelvic region were
excluded from treatment as a careful assessment of the geometric
fidelity in the vicinity of orthopedic implants had not yet been con-
ducted at the time of the study. Further exclusion criteria were
general contraindications for 1.5T MRI, an inability to tolerate a
45-minute treatment, and an expected cranio-caudal length of
the clinical target volume (CTV) of >18 cm due to limitations in
maximum field size on the MR-linac. Patients consented to, either
or both, the Dutch Prospective Data Collection Initiative on
Colorectal Cancer (PLCRC) and the MOMENTUM study
(NCT04075305), which both have been approved by the Medical
Research Ethics Committee of the University Medical Centre
Utrecht in the Netherlands [27–29].
Pre-treatment imaging
Pre-treatment imaging consisted of a planning CT scan (Philips,
Brilliance Big Bore CT) and MR-sim (1.5T Philips Ingenia MR-RT). In
accordance with the MRI scan protocol, the minimum imaging
requirements consisted of a 3D T2 weighted (T2w) scan and diffusion
weighted imaging (DWI). Both scans were acquired in head-first
supine treatment position with arms on the chest and a knee sup-
port. This patient set-up was indexed to a special table overlay used
for CT acquisition as described by Werensteijn-Honing (2019) et al.
[26]. Furthermore, patients were administered tattoo skin marks.
Delineation and PTV margins
The planning CT scan and planning MRI images were co-
registered based on bony anatomy. The GTV, the mesorectal CTV
(CTVmeso), CTV of the elective lymph node regions (CTVn), and
OAR were delineated on the CT with visual support of the regis-
tered MRI scan. OAR were contoured as avoidance structures. All
volumes, including the OAR, were delineated by a radiation oncol-
ogist sub-specialized in colorectal tumors in accordance with con-
sensus delineation guidelines. PTV margins were created conform
the margins employed during conventional linac treatment: 1 cm
isotropically around the mesorectum and 8 mm around the elec-
tive nodal regions [27]. After 25 patients, PTV margins for the
mesorectum were reduced to 4 mm in lateral and dorsal direction
and 6 mm in craniocaudal and ventral direction. The elective
lymph node margins were reduced to 4 mm in both lateral and
ventro-dorsal direction and 6 mm craniocaudally. These reduced
margins were determined after analysis of the intrafraction motion
of 6 patients by comparing the CTVmeso and CTVn delineations on
the first and last acquired 3D T2w scan for each fraction. First we
applied an anisotropic margin around the delineated CTVmeso
and CTVn on the first 3D T2w scan. Thereafter we quantified the
173
Radiotherapy and Oncology 154 (2021) 172–178
amount of overlapping volume of the same structures on the last
3D T2w scan of the fraction. The reduced PTVmeso margins cov-
ered >95% of the CTVmeso for the selected cases. The reduced PTVn
margins covered 99% of the CTVn for the selected cases. Therefore,
intrafraction motion was deemed minimal and we were confident
enough with these plans to reduce PTV margins in the latter
patients.
Planning
The pre-treatment plan was generated using the Monaco
5.40.01 (Elekta AB, Stockholm, Sweden) treatment planning sys-
tem, which included the main magnetic field. Plan parameters
were: 5 field Intensity Modulated RadioTherapy (IMRT) with fixed
beam angles, maximum number of segments = 50, grid
size = 4 mm, statistical uncertainty = 1%. The dosimetric criteria
used for this study are summarized in Table 1. All pre-treatment
plans were measured on film as standard QA procedure before
the first treatment fraction.
Patient positioning on the MR-linac
Prior to each treatment, patients were positioned on the patient
couch in the predefined supine index position with the help of an
in-room laser system using the tattoo skin marks. Two four-
channel receive arrays were used for imaging. The posterior coil
was positioned under the patient couch, while the anterior coil
was placed on an indexed coil bridge as close to the patient as pos-
sible to maximize the signal-to-noise. No bladder-filling protocol
was used as the first patients were unable to adhere to the proto-
cols due to the duration of the treatment.
Online adaptive workflow
All patients were treated using the online adapt to shape work-
flow provided by the vendor [25]. The different steps of the work-
flow are visualized in Fig. 1. These steps were timed by a
radiotherapy technologist (RTT) throughout the entire procedure.
The total time per fraction, or total fraction time, was defined as
the time between the patient leaving the dressing room until
returning to the dressing room after the procedure.
Online adaptation of contours and replanning
The daily online procedure started with acquiring a 3D T2w
scan. This scan was registered to the pre-treatment CT scan using
rigid registration. Subsequently, the pre-treatment CT scan con-
tours of target and OAR were automatically propagated by deform-
able registration to the online planning MRI. Then a stratified
synthetic CT scan was generated with 3 electron density (ED)
levels: soft tissue (ED = 1), femoral bones (ED = the average ED
from the pre-treatment CT), and (external) air (ED = 0). Gaseous
regions within the body contour were set to ED = 1 and support
structures (e.g., the patient couch and MR receive arrays) were
Table 1
Target dosimetric criteria and criteria for online evaluation.
Structure Target Criteria Online Evaluation Criteria
CTVmeso V95% (23.75 Gy) >99% >99%
CTVn V95% (23.75 Gy) >99% >99%
PTV_total V95% (23.75 Gy) >99% >97%
V107% (26.75 Gy) <2 cc <5 cc
V110% (27.50 Gy) <0.5 cc <0.5 cc
Abbreviations: CTVmeso (clinical target volume of the mesorectum), CTVn (clinical
target volume of the elective lymph node regions), PTV (planning target volume),
IQR (interquartile range) and RTT (Radiotherapy technologists).
Online adaptive MR-guided radiotherapy for rectal cancer; feasibility of the workflow on a 1.5T MR-linac: clinical implementation and initial experience
Fig. 1. The online workflow. Abbreviations: Calculation (calc.), Position verification (PV).
taken into account. Thereafter we adapted the deformed contours
of the CTVmeso and CTVn. For the first twelve patients the con-
tours where adapted by a radiation oncologist. From patient 13
onwards, we started training RTTs to adapt the deformed contours
under direct supervision of a radiation oncologist. Thereafter the
trained RTTs adapted the contours with supervision on request
and offline revision by a radiation oncologist. The deformed con-
tours of the OAR were not manually adapted but used as an avoid-
ance structure in the replanning. Based on the new contours, a full
plan re-optimization was performed on the planning MRI using the
‘optimize weights and shapes from fluence’ option with the same
planning parameters that were used to generate the pre-
treatment plan [25]. During phase 2 (segment optimization) of
the treatment planning process, a position verification (PV) scan
was acquired with identical parameters to those of the pre-
treatment 3D T2w scan.
Plan evaluation, motion management and dose delivery
The radiation oncologist and the physicist evaluated the new
treatment plan based on the traffic light procedure as provided
in online Monaco using online plan evaluation criteria (Table 1).
This system displays a green light if the plan optimization reached
the target criteria, an orange light if the plan optimization reached
the online evaluation criteria, and a red light when these con-
straints were not met. For this study, plans that generated an
orange light were only accepted after evaluation by a physicist,
while plans with a red light were only accepted after consent of
both the physician and physicist.
Concurrently, the PV scan was overlaid onto the first MRI for
analyses of motion that occurred during the recontouring and
recalculation phase by visual inspection of the CTV contours.
Meanwhile, a medical physicist assessed the complexity of the
treatment plan by comparing the total number of monitor units,
number of segments, beam irregularity, and beam modulation to
the pre-treatment plan. Additionally, a second planning system
(Oncentra, Elekta AB, Stockholm, Sweden) performed an indepen-
dent 3D dose check without the B0 field effect. All metrics were
recorded to establish tolerance levels.
174
Two 3D T2w scans were acquired during treatment delivery and
one 3D T2w scan was acquired after the treatment for offline
assessment of intrafraction target coverage. Intrafraction motion
was assessed by visually comparing the target volumes on the
post-treatment scan with the volumes on the pre-treatment scan.
We did not deploy a gating strategy as the system did not support
gating methods. Radiotherapy was delivered using 7 MV FFF IMRT.
Statistics
Descriptive statistics were generated to give an overview of the
patient characteristics, treatment time, and planning details of the
patients. Patient, tumor, and treatment characteristics were pre-
sented as means with standard errors, median with interquartile
range or as frequencies with percentages depending on their distri-
bution. Data were visualized using Statistical Package for Social
Sciences (SPSS) version 25 (Released 2017. IBM SPSS Statistics for
Windows, Version 25.0. Armonk, NY: IBM Corp.).
Results
Forty-three rectal cancer patients were selected for treatment
on the MR-linac between November 2018 and March 2020. Patient
and tumor characteristics are summarized in Table 2. Most
patients were diagnosed with intermediate risk rectal cancer
located in the middle or distal rectum. Seven patients were treated
for a metastasized rectal tumor, with palliative short course radio-
therapy followed by systemic therapy. One patient with a cT2N0
tumor was treated with short course radiotherapy per an organ
preservation protocol.
The timeline of the online adaptive workflow before and after
trained RTTs performed online recontouring is presented in Table 3.
The median total time per fraction was 48 min with a minimum of
32 min and a maximum of 73 min due to a technical failure. The
time for recontouring increased from 9 min (IQR 7) to 13 min
(IQR 11) when trained RTTs performed the contour-adaptation.
In total, 94.9% (204/215) of all fractions were delivered on the
MR-linac. Six fractions (2.8%) were delivered on a conventional
accelerator because of logistical reasons. Three fractions (1.4%)
M.P.W. Intven, S.R. de Mol van Otterloo, S. Mook et al. Radiotherapy and Oncology 154 (2021) 172–178

Table 2 The propagated CTV contours were manually adapted for each
Patient and tumor characteristics. fraction. Average CTVmeso volume was 284 cc (SD 78 cc), CTVn
N = 43 volume 153 cc (SD 36 cc), and PTV volume 815 cc (SD 202 cc). Daily
Sex Male 30 (70%) volume differences in CTVmeso, CTVn and PTV were 17 cc (SD
Female 13 (30%) 34 cc), 8 cc (SD 15 cc), and 36 cc (SD 52 cc) respectively (Fig. 2).
Age 63.9 (43.4–83.3) Average PTV volumes with and without reduced margins were
cT-stage 1 0 (0%) 650 cc (SD 139 cc) and 923 cc (SD 160 cc).
2 12 (28%)
3 29 (67%)
Total CTV coverage was above 99% in all treatment fractions
4 2 (5%) (Fig. 3). In 3/215 (1,4%) fractions the PTV coverage was below the
MRF status <1 mm 4 (9%) target coverage of 97%. However, this was deemed acceptable upon
>1 mm 39 (91%) visual inspection as the underdosage was located at the periphery
cN-stage 0 8 (19%)
of the PTV in all cases. In one fraction (0,5%) the V26.75 Gy was
1 33 (77%)
2 2 (5%) above 5 cc, which was accepted after visual inspection of the loca-
cM-stage 0 36 (84%) tion of the hotspot. V27.5 Gy < 0.5 cc was respected in all treatment
1 7 (16%) fractions. For patients treated with reduced margins, post-
MRI distance from anal-rectal junction 0–5 17 (40%) treatment fraction evaluation showed that the CTVmeso was cov-
5–10 20 (47%)
ered by the PTVmeso in 80 of 81 (98.8%) of fractions. In one fraction
>10 6 (14%)
in one patient the target coverage was less because of the passing
of rectal gas during treatment delivery.
were scheduled on the MR-linac but delivered on a conventional
Additional to pre-treatment plan QA, the first online adapted
accelerator due to MR-linac downtime. Also, the final 2 scheduled
plan of each patient was measured on film. Gamma analysis pass
fractions (0.9%) of one patient were not delivered due to a severe
rates for a criterion of 3%/3mm with a low-dose threshold value
infectious disease. Patients tolerated treatment on the MR-linac
of 10% were 97.3% ± 7.3% for the pre-treatment plans and 97.7%
well; no treatment fractions were canceled or interrupted due to
± 10.3% for the online adaptive plans.
problems with patient comfort on the MR-linac.

Table 3
Overview of timing of the online workflow before and after trained RTTs performed online recontouring. Abbreviations: IQR (interquartile range). Radiotherapy technologists
(RTT).

Minutes in median (IQR)

Patient 1–25 Patient 26–43 Total
Online recontouring by Radiation Oncologist RTT in training or trained RTT Radiation Oncologist,RTT in-training or trained RTT
Total Fraction time* 48 (8) 50 (9) 48 (9)
1st MRI – end treatment 41 (7) 45 (7) 43 (9)
Recontouring 9 (7) 18 (5) 13 (11)
Planning 5 (1) 4 (1) 5 (1)
Dose Delivery 7 (1) 7 (1) 7 (1)
*
Total fraction time is defined as time between the patient leaving the dressing room until returning to the dressing room after the procedure.

Fig. 2. Box plot of daily variation of target volumes compared to the reference plan*. Abbreviations: CTVmeso (clinical target volume of the mesorectum), CTVn (clinical target
volume of the elective lymph node regions) and PTV (planning target volume). The outliers (O) indicate a volume difference of 1.5*3rd quartile  median  1,5*1st quartile.
The asterisk (*) indicates a volume difference of greater than ( )3*IQR. *The extreme outliers in the graphs, indicated by an asterisk (*), refer to volume differences of one
patient with a relative small rectal volume on the pre-treatment scan (630 cc) compared to later imaging (730–893 cc).

175
Online adaptive MR-guided radiotherapy for rectal cancer; feasibility of the workflow on a 1.5T MR-linac: clinical implementation and initial experience

Fig. 3. Overviews of achieved planning targets after online plan optimization. Abbreviations: the CTVmeso (clinical target volume of the mesorectum), CTVn (clinical target
volume of the elective lymph node regions) and PTV (planning target volume). The outliers (O) indicate a volume or percentage of 1.5*3rd quartile  median  1,5*1st
quartile. The asterisk (*) indicates a volume percentage of greater than (( )3*IQR)*median.

Discussion RTTs prolonged the online workflow. However it is expected that

This study provides an MR-guided online adaptive workflow for
neoadjuvant radiotherapy for rectal cancer and shows that daily
adaptive radiotherapy is feasible in rectal cancer patients. The
average time on the treatment couch per fraction was 48 min
(IQR 9). Despite these longer treatment times compared to conven-
tional devices, patients had good compliance; no patient missed a
fraction or switched to conventional treatment due to discomfort.
Performance of the MR-linac system was acceptable. 1,4% (3/215)
of treatment fractions had to be delivered on a conventional accel-
erator due to machine downtime. Initial experience with margin
reduction resulted in considerable smaller PTV volumes and
assessment of coverage was promising.
Currently, daily adaptive radiotherapy is both time- and labor-
intensive requiring daily commitment by in-room presence of per-
sonnel which puts a strain on the department’s recourses. One
essential step in the online adaptive workflow is recontouring. This
time-consuming step in the workflow showed most variation with
an IQR of 11 min for all 43 patients. To bring down the burden on
department logistics RTTs were trained in adapting the propagated
contours. Our study shows that online recontouring by trained
this time will reduce as the RTTs gain more experience. Alterna-
tively, machine learning could speed up this procedure and reduce
the observed variation in time. Currently this is being explored at
our institution using the adapted delineation of treated patients.
Another essential step is the daily plan approval which requires
the presence of both a physicist as well as a physician. For this
study we used the traffic light system provided by the vendor. Cur-
rently, a similar traffic light system is being developed to simplify
and potentially automate the online dose check procedure. We aim
to execute the daily plan approval without presence of the physi-
cist and physician in the near future.
In this study we have mitigated interfraction motion by daily
online plan adaptation, which enabled a considerable reduction
of our PTV margins. However, in this patient cohort we did not
actively control intrafraction motion. Exception gating could be
used in the future to ensure adequate coverage for all given treat-
ment fractions and potentially allow further reduction of PTV mar-
gins [30,31].
The experiences with the introduction of MRgRT on the 1.5T
MR-linac as reported in this study show the feasibility of MRgRT
in rectal cancer patients. The potential of MRgRT with high preci-

176
M.P.W. Intven, S.R. de Mol van Otterloo, S. Mook et al.
sion for rectal cancer is well established [23,32,33]. Compensating
inter-, and ultimately, intrafraction movement might enable inten-
sification of treatment without increasing toxicity and therefore
safely render higher tumor regression grade and tumor response
rates [34–38]. This would in turn increase the number of patients
eligible for an active surveillance strategy in an organ preservation
approach [20,21,39–43]. Another potential advantage of MRgRT is
the visualization of the anatomical treatment response on daily
MR-imaging, which enables identification of non-responders and
could be used for selecting patients that would qualify for treat-
ment intensification. Functional imaging during MRgRT may fur-
ther improve response monitoring and may have a role in
response prediction enabling early identification of patients for
dose escalation treatments [44–49].
An important limitation of this workflow is that the exact OAR
dose was unknown as we used these contours as an avoidance
structure for replanning. We choose not to adapt the OAR like
the target volumes during the online treatment procedure, but to
use the propagated structures for dose planning. As a consequence
the delineated OAR were not the exact OAR on the actual image.
This pragmatic approach was chosen to reduce the time per frac-
tion and because tolerance doses for these structures are higher
than the delivered dose. Even though we cannot calculate the exact
dose to the OARs because these were only partially adapted in the
vicinity of the PTVs, using smaller PTV margins consequently lead
to a lower OAR dose.
In conclusion, an online adaptive workflow with full replanning
for neoadjuvant short course radiotherapy in patients with rectal
cancer on a Unity 1.5T MR-linac is feasible and currently takes
about 48 min per fraction.
Disclosures and/or funding
None.
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