Radiotherapy and Oncology 127 (2018) 68–73

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Radiotherapy and Oncology

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Prostate cancer radiotherapy

Optimal image guided radiation therapy strategy for organs at risk

sparing in radiotherapy of the prostate including pelvic lymph nodes
A. van Nunen ⇑, P.P.G. van der Toorn, T.C.G. Budiharto, D. Schuring
Department of Radiotherapy, 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: Purpose of this study was to quantify the OAR dose for different position correc-
Received 21 December 2017 tion strategies, and to determine which strategy is most optimal for treating patients on the prostate and
Received in revised form 9 February 2018 pelvic lymph nodes.
Accepted 11 February 2018
Materials and methods: For 30 patients, four different treatment plans were made reflecting different cor-
Available online 2 March 2018
rection strategies: online correction on bony anatomy; offline correction on bony anatomy; online correc-
tion on the prostate fiducials; using 1 cm margins around both CTVs. The dose to the PTVs and OARs was
Keywords:
quantified and a pairwise statistical analysis was performed.
Prostate and pelvic lymph nodes
OAR sparing
Results: No statistically significant differences were observed in the dose to the PTVs, ensuring that any
Image guided radiotherapy OAR sparing is not caused by differences in PTV coverage. Dose to the rectum and anal canal was lowest
Treatment planning when applying an online correction on prostate fiducials, although the total PTV volume was higher. Dose
Simultaneous integrated boost to the small bowel bag and femoral heads was slightly higher compared to online correction on bony
structures, but well within clinically acceptable limits.
Conclusion: Although the total PTV volume is higher when applying an online correction on the prostate,
this strategy leads to the most optimal sparing of relevant OARs, at the cost of a slightly higher dose to the
femoral heads and small bowel bag.
Ó 2018 The Authors. Published by Elsevier B.V. Radiotherapy and Oncology 127 (2018) 68–73 This is an
open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

The treatment for lymph node positive prostate cancer, often the prostate, but this will lead to larger PTV margins around the
consists of radiotherapy combined with Androgen Deprivation PLN. In a similar study, Kershaw et al. recently quantified the
Therapy (ADT). The target volume includes the pelvic lymph nodes prostate motion in relation to the PLN and SV to define the setup
(PLN), prostate and seminal vesicles (SV). margins [9]. They concluded that neither a prostate or bone regis-
Ensuring that the target volume receives the planned dose can tration is optimal, and that further research is required to deter-
be a challenge due to the fact that the PLN and prostate can move mine which strategy results in the lowest OAR doses. A number
with respect to each other due to changes in rectal filling [1–3]. of studies have investigated the coverage of the target volumes
Different correction strategies can be chosen to ensure either for a given PTV margin, but did not report on OAR dose [1,10,11].
correct positioning of the prostate or the pelvic nodes, resulting Hsu et al., Rossi et al. and Eminowicz et al. investigated different
in different CTV-PTV margins for both target volumes. Larger correction strategies, but also focused on target coverage. A dosi-
margins and treatment volumes results in higher OAR dose and metric analysis of these different correction strategies quantifying
higher toxicity [4,5]. In a previous study, the required setup the OAR dose has not been published yet. The purpose of this study
margins for different correction strategies were calculated based was to determine which setup correction strategy leads to the low-
on pre-treatment CBCT images of 20 patients [6]. Calculation was est OAR dose, and consequently, the lowest toxicity.
based on the Van Herk formula [7,8]. This study showed that when
a patient setup correction is performed on a match of the bony Materials and methods
anatomy, larger margins are required for the prostate to account
for baseline shifts with respect to the PLN. These baseline shifts Patients
can be accounted for by applying an online setup correction on
30 consecutive patients with lymph node positive prostate
cancer were included retrospectively. All patients received a lymph
⇑ Corresponding author at: Department of Radiotherapy, Catharina Hospital, node dissection and were eligible for radiotherapy when a maxi-
Michelangelolaan 2, 5623 EJ Eindhoven, The Netherlands. mum of 3 micro-metastases or 2 macro-metastases in the PLN
E-mail address: aniek.v.nunen@catharinaziekenhuis.nl (A. van Nunen). were found.

https://doi.org/10.1016/j.radonc.2018.02.009
0167-8140/Ó 2018 The Authors. Published by Elsevier B.V.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
 A. van Nunen et al. / Radiotherapy and Oncology 127 (2018) 68–73 69

Imaging and delineation A standard set of objectives was used for optimising the treat-
ment plans. The objectives were adapted for the individual patient
All patients received a planning CT scan (Philips Healthcare,
to achieve an optimal treatment plan. Dose criteria that should
Best, The Netherlands) in supine position, with a slice thickness
minimally be achieved for both the PTVs and OARs are summarised
of 3 mm. Patients were immobilised using a knee and ankle sup-
in Table 2 [5]. For the PTVs, 95% of the PTV volume must be covered
port. To reduce chance of systematic errors due to prostate shifts
by at least 95% of the prescription dose (V95% 95%). Care was
on the planning CT, patients were instructed to empty their blad-
taken that the PTV coverage was identical for all plans. All gener-
der and defecate one hour before scanning and each treatment
ated treatment plans were reviewed by the same expert medical
fraction and after that to drink 500 mL of water. If a large rectal fill-
physicist and radiation oncologist. Priority was given to reducing
ing was observed, the planning CT was repeated after the defeca-
the rectum and anal canal dose, followed by the SBB, as this is clin-
tion. The CT scan was imported in the RayStation TPS (version
ically most relevant. Sparing of the femoral heads and bladder was
5.0.2.35, Raysearch Laboratories, Stockholm, Sweden). The CTV of
considered to be less important.
the prostate (CTVp) consists of the entire prostate gland and the
SV were included in this CTV. Delineation of the CTV of the PLN
(CTVPLN) was based on consensus recommendations from the
RTOG [12]. Bladder, small bowel bag (SBB), femoral heads, rectum Data collection and analysis
and anal canal were delineated. The SBB was defined as the peri- The dose criteria given in Table 2 were evaluated. In addition,
toneal space in which the small bowel can move. The rectum the absolute volumes of the different PTVs (PTVp, PTVPLN and
was contoured from the ischial tuberosities to the rectosigmoid PTVtotal), the maximum and the mean dose to the PTVs, rectum
junction and the anal canal was defined from anus to the musculus and bladder were evaluated. All parameters were automatically
puborectalis. Femoral heads were defined up to and including the retrieved using the scripting functionality.
trochanter minor. For data analysis, SPSS was used. A Shapiro–Wilk test was per-
formed to check if the data were normally distributed. If data were
normally distributed, the mean and standard deviation were calcu-
CTV-PTV margins
lated. Otherwise the median including minimum and maximum
The CTV-PTV margins used in this study are shown in Table 1 value was determined. A pairwise statistical analysis was per-
and depend on the position correction strategy: formed on the data to see if a statistically significant difference
in OAR dose could be observed between the different strategies,
A. online correction on bony anatomy; using a repeated measurements ANOVA test or a Friedman test,
B. offline Shrinking Action Level (SAL) correction protocol on depending on the normality of the data. When a Friedman test
bony anatomy (n = 3, a = 10) [13]; was used and a significant difference was obtained, a Wilcoxon
C. online correction on the prostate fiducials; Signed Rank test was applied to point out between which correc-
D. CTV-PTV margin of 1 cm around both CTVp and CTVPLN tion strategies the dose was statistically significant different. A
Bonferroni correction was applied to correct for multiple testing.
The setup margins were determined in a previous study, and
account for translational patient setup errors as well as baseline
shifts between the prostate and PLN [6]. Depending on the correc- Results
tion strategy, this results in either larger margins to the prostate or
the PLN to account for these baseline shifts. An additional margin Four treatment plans with margins reflecting different correc-
was included to account for rotation and delineation uncertainties. tion strategies were optimised. Patient characteristics are sum-
For a bony anatomy match, both an online and offline correction marised in Table 3. The mean or median values of the evaluated
was included as the positional errors in the pelvis are usually parameters obtained from the treatment plans and the results of
small, however an offline strategy will lead to a reduced online the pairwise statistical analysis are summarised in Table 4.
workload and a decreased imaging frequency. The CTVs and PTVs Differences in the average PTV volumes are statistically signifi-
for all evaluated strategies are visualised in Fig. 1. cant between the four strategies (p < 0.001). An online correction
on the prostate results in the smallest PTVp volume (average 129
cc), while an offline correction on the bony anatomy results in
Treatment planning
the largest PTVp volume (average 192 cc). The PTVPLN volume is
For each patient, one treatment plan was made for each of the smallest for online correction on bony anatomy and largest for
four PTV margins reflecting the different correction strategies. All online correction on prostate fiducials (average 606 cc versus
plans were created for an Elekta linac with an Agility MLC (Elekta, 940 cc). The average volume of PTVtotal varied between 762 cc
Crawley, UK) using a single VMAT beam with a full gantry rotation when performing an online correction on bony anatomy and
and a beam energy of 10 MV. The isocentre was placed in the geo- 1108 cc when using the standard margin of 1 cm. No statistically
metric centre of the total PTV volume (PTVp + PTVPLN). The pre- significant differences were observed in the coverage and mean
scribed dose was 50.4 Gy to PTVPLN and 67.2 Gy to PTVp in 28 dose to the PTVs, ensuring that any OAR sparing is not caused by
fractions using a simultaneous integrated boost (SIB) technique. differences in PTV dose.

Table 1
CTV-PTV margins for different correction strategies.

Strategy Prostate margins (cm) Lymph node margins (cm)

LR SI AP LR SI AP
A 0.6 0.9 1.1 0.5 0.5 0.7
B 0.8 1.1 1.2 0.8 0.7 0.9
C 0.5, with 0.8 to apex prostate and around SV [2] 0.6 1.0 1.2
D 1.0 1.0 1.0 1.0 1.0 1.0
70 Radiotherapy for prostate and lymph nodes

Fig. 1. Visualisation of CTVs and PTVs for different correction strategies (light blue: CTVPLN and CTVSV, blue: CTVp, red: PTV with the standard margin of 1 cm. (a): PTV for
correction strategy A (b): PTV for strategy B, (c): PTV for strategy C).

Table 2 Table 3
Dose criteria for the treatment plans. Patient characteristics.

PTVs Number of patients n = 30

PTVp V95%  95%
Age (years) 69 (57–77)
PTVPLN V95%  95%
Gleason score
PTVtotal Dmax < 107%
6/7/8/9/10 1/10/8/9/2
OARs PSA (ng/ml) 20 (2–70)
Rectum Dmax,0.5cc < 70 Gy T stage
V69 Gy < 5% 1/2/3/4 2/8/19/1
V66 Gy < 15% N stage
V58 Gy < 40% 0/1 0/30
V30 Gy < 75% M stage
Anal canal Dmean < 36 Gy 0/1 30/0
Small bowel bag Dmax,2cc < 52 Gy
V45 Gy < 195 cc
Femoral heads Dmax,0.5cc < 50 Gy

Strategy B generally leads to the highest rectum dose, except for

the low dose region (V30Gy). The mean anal canal dose was lowest
The evaluated parameters for rectum and anal canal for the dif- when applying strategy C and highest for strategy B (average 16.1
ferent strategies are visualised in Fig. 2. For all parameters except Gy versus 23.5 Gy). The largest dose reduction for the rectum and
the volume receiving 69 Gy, an online correction on the prostate anal canal was achieved by performing strategy C, online correc-
leads to the largest reduction in rectum dose. No statistically sig- tion on prostate fiducials.
nificant differences were found in the mean rectum dose for the The lowest mean bladder dose is achieved for strategies A and C
other strategies (averages varying between 37.5 Gy and 37.9 Gy). (average 44.8 Gy and 44.3 Gy) and the highest dose for strategies B
For strategy C, the average mean rectum dose was 31.9 Gy. and D (average 46.3 Gy and 46.2 Gy), as displayed in Fig. 2.
 A. van Nunen et al. / Radiotherapy and Oncology 127 (2018) 68–73 71

Table 4
Summary treatment planning results: dose and volume parameters in PTVs and OAR for evaluated strategies.

M: mean; SD: Standard Deviation; MDN: median; Min: minimum value; Max: maximum value.
*
p < 0.001 for all six pairwise comparisons.
#
p < 0.05 for all six pairwise comparisons.
a–e: p > 0.05 in subgroups (when a pairwise comparison was not significant, this pair is noted by for example a – a in superscript).
Green value represents the significant lowest value of all evaluated strategies.

Strategy A results in the lowest SBB dose and strategies C and D PTV volumes depend on the setup correction strategy as this
result in the highest dose. The median maximum dose in 0.5 cc of determines the required CTV-PTV margins. Online correction on
the SBB was 49.9 Gy for strategy A and 50.8 Gy – 50.7 Gy for strate- prostate fiducials (strategy C) results in the smallest PTVp volume
gies C and D. The median absolute volume of the SBB which and a larger PTVtotal volume due to larger margins around the
received 45 Gy was 11 cc for strategy A and 18 cc for strategies C PLN to account for misalignments between prostate and PLN. This
and D. The largest dose reduction for the small bowel bag was leads to a larger overlap between PTVPLN and the bladder, femoral
achieved by performing strategy A. heads and SBB. Online correction on bony anatomy (strategy A)
Compared to the standard 1 cm PTV margin, all strategies lead results in the smallest PTVtotal volume, but in an increase in the
to a statistically significant reduction in the maximum dose to PTVp volume. This results in a larger overlap between PTVp and
the femoral heads. Strategy A results in the lowest maximum dose the bladder, rectum and anal canal. Similar results were found by
to the femoral heads, with an average maximum dose of 36.6 Gy Kershaw et al. [9]. They concluded that neither correction strategy
for the left femur head and 36.3 Gy for the right femur head. was optimal, and that the dosimetric consequences should be fur-
ther investigated. As different dose levels are prescribed to the
Discussion prostate and PLN, it is difficult to directly translate the differences
in overlap to their influence on the OAR dose.
The aim of this study was to quantify the OAR dose for different Although online correction on the prostate fiducials is resulting
position correction strategies and their corresponding PTV mar- in a higher PTVtotal volume compared to correction on PLN, the
gins, and to determine which strategy is most optimal for treating most optimal sparing of the clinically relevant OARs can be
patients with lymph node positive prostate cancer. achieved with this strategy. The smaller overlap between the PTVp
72 Radiotherapy for prostate and lymph nodes

Fig. 2. Evaluated doses for rectum, bladder and anal canal.

volume and the OARs results in a decrease in the mean rectum position are not correlated to the bony anatomy. As a result, an
and anal canal dose, as well as a reduction in all evaluated online correction on bony anatomy only results in a small reduc-
DVH-parameters for the rectum. The mean bladder dose was tion of the PTV margins compared to an offline correction. An off-
reduced compared to the offline correction strategies and was line strategy could thus be chosen when only correcting on the
similar compared to the online correction strategy on bony anat- bony anatomy to reduce workload and imaging dose to the patient.
omy. Although the larger overlap between PTVtotal and the bladder Online correction on prostate fiducials leads to a much larger
for strategy C, apparently the increased overlap of PTVPLN is reduction in OAR dose and should thus be preferred.
compensated by the (smaller) decrease in overlap with PTVp. Several studies investigated the effect of different correction
When applying an online correction on prostate fiducials, the dose strategies on target coverage [1,3,10,11,14]. These studies focussed
to the SBB and femoral heads was slightly higher compared to on evaluating the target dose for a given PTV margin, reporting
correction on bony anatomy due to the larger margins needed only the target dose without evaluating the OAR doses. The mar-
for the PLN to account for baseline shifts. If the SBB dose is gins used in these studies varied from 5 mm to 10 mm and could
violated in a patient, an online correction on PLN could be sometimes vary from patient to patient depending on the prefer-
chosen to limit this dose at the cost of a higher rectum and anal ence of the radiation oncologist [1,3]. In our study, anisotropic
canal dose. CTV-PTV margins based on an analysis of pre-treatment CBCT
Differences in OAR dose for online versus offline correction on images of 20 patients were used [6]. Compared to the other studies,
bony anatomy were marginal. The random setup errors of the the applied margins were slightly larger in AP direction, and some-
PLN are usually limited, while the larger variations in prostate what smaller in the other directions. Hsu et al., Thörnqvist et al.
 A. van Nunen et al. / Radiotherapy and Oncology 127 (2018) 68–73 73

and Rossi et al. concluded that outliers (specifically due to changes in the PTV margins, and consequently, a further reduction in
in rectal filling) cause a deterioration of the CTV coverage, but for toxicity. An offline adaptive strategy for example can help in deal-
most patients their margins were adequate. The applied margins ing with outliers due to systematic error in the prostate position on
in this study will take care that the CTV coverage is not compro- the planning CT. Further research is needed to quantify the reduc-
mised, even when these outliers occur during the radiotherapy tion in OAR dose using adaptive strategies.
treatment. Using standard CTV-PTV margins of 1 cm might not In conclusion, although the total PTV volume is higher when
always result in an optimal CTV coverage as the required setup applying an online correction strategy on the prostate due to the
margins in anterior–posterior (AP) direction must be larger than larger margins around the PLN, this strategy leads to the most opti-
1 cm [6]. These margins furthermore do not result in the lowest mal sparing of the relevant OARs (rectum, anal canal and bladder),
OAR dose. at the cost of a slightly higher dose to the femoral heads and small
Although there are no studies comparing the OAR doses for bowel bag compared to the other correction strategies. Online
different correction strategies, a number of authors have reported correction on prostate fiducials using CBCT imaging is now used
on OAR dose for this patient group for a fixed PTV margin. Ishii clinically in our hospital.
et al. made a dosimetric comparison between different treatment
techniques (IMRT and VMAT) for patients with high-risk prostate Conflict of interest
cancer [15]. The margins around the prostate in this study were
slightly smaller than those in strategy C, and also smaller margins Regarding our manuscript "Optimal image guided radiation
were used around the PLN. A slightly higher dose was prescribed to therapy strategy for organs at risk sparing in radiotherapy of the
PTVp (70 Gy compared to 67.2 Gy) while the dose to PTVPLN was prostate including pelvic lymph nodes", none of the authors has
identical. When comparing the OAR dose for strategy C of the cur- any conflict of interest to declare.
rent study with the VMAT results of Ishii et al., the mean bladder
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