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Original Article
Dosimetric feasibility of hypofractionation for metastatic bone/bone
marrow lesions from paediatric solid tumours
Sophie C. Huijskens
a,1
, Filipa Guerreiro
a,1
, Mirjam Bosman
a
, Geert O. Janssens
a,b
, Bianca A. Hoeben
a,b
,
Raquel Dávila Fajardo
a,b
, Petra S. Kroon
a,2
, Enrica Seravalli
a,
⇑
,2
a
Department of Radiation Oncology, University Medical Center; and
b
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
article info
Article history:
Received 15 December 2020
Received in revised form 16 April 2021
Accepted 28 April 2021
Available online 5 May 2021
Keywords:
Paediatric Radiotherapy
Sarcoma
Neuroblastoma
Metastases
Hypofractionation
SBRT
abstract
Background and purpose: The aim of this study was to determine the feasibility of hypofractionated
schedules for metastatic bone/bone marrow lesions in children and to investigate dosimetric differences
to the healthy surrounding tissues compared to conventional schedules.
Methods: 27 paediatric patients (mean age, 7 years) with 50 metastatic bone/bone marrow lesions (n=26
cranial, n= 24 extra-cranial) from solid primary tumours (neuroblastoma and sarcoma) were included.
The PTV was a 2 mm expansion of the GTV. A prescription dose of 36 and 54 Gy EQD2
a
/b=10
was used
for neuroblastoma and sarcoma lesions, respectively. VMAT plans were optimized for each single lesion
using different fractionation schedules: conventional (30/20 fractions, V
95%
99%, D
0.1cm
3
107%) and
hypofractionated (15/10/5/3 fractions, V
100%
95%, D
0.1cm
3
120%)
.
Relative EQD2 differences in OARs
D
mean
between the different schedules were compared.
Results: PTV coverage was met for all plans independently of the fractionation schedule and for all lesions
(V
95%
range 95.5–100%, V
100%
range 95.1–100%), with exception of the vertebrae (V
100%
range 63.5–91.0%).
For most OARs, relative mean reduction in the D
mean
was seen for the hypofractionated plans compared to
the conventional plans, with largest sparing in the 5 fractions (< 43%) followed by the 3 fractions schedule
(< 40%). In case of PTV overlap with an OAR, a significant increase in dose for the OAR was observed with
hypofractionation.
Conclusions: For the majority of the cases, iso-effective plans with hypofractionation were feasible with
similar or less dose in the OARs. The most suitable fractionation schedule should be personalised depend-
ing on the spatial relationship between the PTV and OARs and the prescription dose.
Ó2021 The Author(s). Published by Elsevier B.V. Radiotherapy and Oncology 160 (2021) 166–174 This is
an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Approximately 20% of the paediatric patients with solid
tumours present with distant metastases at diagnosis. Children
with metastatic disease generally have a poor prognosis and over-
all survival rates are on average 35% (range 5–95%), depending on
histology and the number of lesions [1–3].
A recent survey across leading European paediatric radiother-
apy centres unveiled both consistencies and differences regarding
the radiotherapy approach with curative intent on metastatic sites,
especially regarding patient selection and treatment characteris-
tics [4]. A growing interest in hypofractionation was noticed, but
prescription doses and fractionation schedules are currently
mainly based on local experience and institutional protocols [4].
Moreover, in current European paediatric solid tumour protocols,
hypofractionation is sporadically recommended [5–8]. Across the
respondents of the survey, an urgent need for consensus on the
total and fraction dose per site, age group and disease category
was expressed [4].
With hypofractionation, a highly conformal dose can be deliv-
ered to the target in a limited number of fractions, resulting in
steep dose gradients and a potential dose reduction to the organs
at risk (OARs) in the vicinity of the target [9]. In adults, the current
radiotherapy approach for oligometastatic disease is strongly
focused on hypofractionation and outcomes are associated with
favourable local tumour control and limited toxicity for lesions
within the bone, lymph nodes and soft tissue [10–13]. In contrast,
the available literature on hypofractionation in children is mainly
limited to retrospective and case studies for both cranial and
extra-cranial metastatic disease [14–16]. In these studies, dose
and fractionation schedules varied widely (total dose range
20–60 Gy in 1–10 fractions, dose per fraction range 5–20 Gy).
https://doi.org/10.1016/j.radonc.2021.04.020
0167-8140/Ó2021 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/).
⇑
Corresponding author at: Department of Radiation Oncology, University
Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands.
E-mail addresses: s.c.huijskens-2@umcutrecht.nl (S.C. Huijskens), e.seraval-
li@umcutrecht.nl (E. Seravalli).
1
Shared first co-authorship.
2
Equal contribution.
Radiotherapy and Oncology 160 (2021) 166–174
Contents lists available at ScienceDirect
Radiotherapy and Oncology
journal homepage: www.thegreenjournal.com
Nevertheless, high local control rates (> 85%) and no acute or late
toxicities of grade 3 or higher were observed.
Between children and adults, the radical radiotherapy approach
for metastatic disease differs in several aspects. While radical
treatment in adults mostly results in postponing disease progres-
sion, treatment of metastatic sites in children intents to cure
patients. Moreover, treatment of primary metastatic disease in
paediatric patients is often part of the upfront treatment approach,
concurrent with conventional irradiation of the primary tumour,
while in adults treatment is mostly given in a metachronic setting.
Additionally, performing hypofractionation in paediatric patients
may be more challenging than in adults due to the developing
character of the normal tissues and the risk of asymmetric bone
growth caused by the steep dose fall-off of stereotactic plans. In-
silico planning feasibility studies can shed some light on these
issues.
Therefore, the aim of this dosimetric study was to investigate a
range of fractionation schedules and related dose constraints for
different metastatic bone/bone marrow lesions in paediatric
patients, leading to a better understanding of the feasibility of
hypofractionation in children.
Methods
Patient data
After institutional review board approval (WAG/
mb/17/500028), data from 27 paediatric patients with 50 meta-
static bone/bone marrow lesions from solid primary tumours (neu-
roblastoma, n= 21; rhabdomyosarcoma (RMS), n= 2; Ewing
sarcoma, n= 3; osteosarcoma, n= 1) who received radiotherapy
at the University Medical Centre Utrecht (UMCU) between June
2015 and January 2020 was included. The age of the patients (10
female, 17 male) at the start of treatment was on average 7 years
(range, 1–18 years). Cranial metastatic lesions (n= 26, all neurob-
lastoma lesions) were located in the orbital bones (n= 16) or else-
where in the skull (n= 10) while extra-cranial metastatic lesions
(n= 24, 13 neuroblastoma and 11 sarcoma lesions) were located
in the ribs (n= 3, 2 neuroblastoma and 1 sarcoma lesions), verte-
brae (n= 6, 3 neuroblastoma and 3 sarcoma lesions), pelvis
(n= 4, 3 neuroblastoma and 1 sarcoma lesions) and in the extrem-
ities (n= 11, 5 neuroblastoma and 6 sarcoma lesions).
Treatment planning
The gross tumour volume (GTV) and OARs, as delineated by the
paediatric radiation oncologists, were used in this study. The plan-
ning target volume (PTV) in this study was a homogeneous 2 mm
expansion of the GTV for all patients, in line with clinical practice
in adults undergoing stereotactic body radiation therapy (SBRT) for
oligometastatic disease in the bone/bone marrow at our depart-
ment. The PTV was on average (± standard deviation) 11.0 ± 10.4
cm
3
for the orbita, 11.6 ± 11.9 cm
3
for the skull, 15.7 ± 18.9 cm
3
for the ribs, 42.5 ± 45.9 cm
3
for the vertebrae, 20.5 ± 30.3 cm
3
for the pelvis and 108.1 ± 119.7 cm
3
for the extremities metastatic
lesions.
All treatment plans were optimised for each single lesion using
Monte Carlo dose algorithm and a uniform 2 mm grid spacing
(Monaco v5.11.02, Elekta AB, Stockholm, Sweden). The volumetric
modulated arc therapy (VMAT) plans consisted of two partial non-
coplanar arcs for the cranial lesions and two partial co-planar arcs
for the extra-cranial lesions, according to our institution’s protocol.
To prevent treatment planning diversity between patients, a com-
mon dose was prescribed for all lesions of the same primary
tumour cohort. Thus, a prescription dose of 36 Gy EQD2
a
/b=10
was selected for neuroblastoma metastatic lesions while a pre-
scription dose of 54 Gy EQD2
a
/b=10
was used for sarcoma meta-
static lesions. For each neuroblastoma lesion, four fractionation
schedules were applied: conventional (20 fractions) and hypofrac-
tionated (10/5/3 fractions) (Table 1). For each sarcoma lesion, with
exception of the vertebral metastases, three fractionation sched-
ules were used: conventional (30 fractions) and hypofractionated
(10/5 fractions) (Table 1). Due to spinal cord and cauda equina dose
constraints (Table 2), only two fractionation schedules were
applied for the vertebral sarcoma metastases: conventional (30
fractions) and hypofractionated (15 fractions) (Table 1).
Target coverage for the conventional plans was aimed for at
least 99% of the PTV to receive 95% of the prescription dose
(V
95%
99%). For the hypofractionated plans, at least 95% of the
PTV was targeted to receive the total prescription dose
(V
100%
95%). The allowed maximum dose (D
0.1cm
3
) in the PTV
was 107% for conventional and 120% for hypofractionated sched-
ules. Dose constraints for all OARs were assessed using an
a
/
b= 3, with exception of the spinal cord for which an
a
/b= 2 was
used. An overview of the selected dose constraints/objectives for
each fractionation schedule is denoted in Table 2. For all lesions
with exception of the vertebrae, coverage of the PTV was priori-
tised. To minimise the risk of bone fracture, a D
0.1cm
3
<70Gy
EQD2
a
/b=3
dose constraint was aimed for all metastatic lesions
[17]. For the vertebral lesions, isotoxic planning was performed
in order to respect the dose constraints on the spinal cord and
cauda equina. In addition, to minimise the risk of asymmetric bone
growth, a homogeneous left–right dose gradient (< 3–5 Gy) or
alternatively a minimum dose of 36 Gy EQD2
a
/b=3
on the vertebrae
primary ossification centres (in case of a prescription dose > 40 Gy)
was aimed for all vertebral metastatic lesions [17].
Plan quality evaluation
Target coverage in the conventional and hypofractionated plans
was evaluated as the PTV percentage receiving at least 95% of the
prescription dose (V
95%
) and 100% of the prescription dose
(V
100%
), respectively. Additionally, for the evaluation of the confor-
mity/quality of the hypofractionated plans the following metrics,
as described in the NRG-BR001 phase 1 trial [18,19], were used:
Homogeneity Index ðHIÞ¼ PD
D
0:1cm
3
;0:6HI 0:9;ð1Þ
with PD defined as the dose received by 95% of the PTV.
Volume ratio of 100%prescription isodose to PTV ðR100%Þ¼VPD
VPTV
;
<1:5;ð2Þ
Volume ratio of 50%prescription isodose to PTV ðR
50%
Þ
¼V
PD=2
V
PTV
;<3:77:5;ð3Þ
D
2cm
¼maximum dose at 2cm from the PTV
PD ;
<57%94%;ð4Þ
with acceptance values for R
50%
and D
2cm
dependent on the PTV
(Supplementary Table 1).
Conventional and hypofractionated plans were considered clin-
ically feasible if all dose constraints/objectives in Table 2 were met.
In addition, hypofractionated plans needed to meet all four of the
conformity/quality parameters (HI, R
100%
,R
50%
and D
2cm
).
For the OARs in close proximity to the PTV, the relative differ-
ences in mean dose (D
mean
) between hypofractionation schedules
compared to the conventional were evaluated for each metastatic
lesion. For the body, the percentages of the body volume receiving
S.C. Huijskens, F. Guerreiro, M. Bosman et al. Radiotherapy and Oncology 160 (2021) 166–174
167
more than 95% of the prescription dose (V
>95%
), 80% of the prescrip-
tion dose (V
>80%
), 5 Gy EQD2
a
/b=3
(V
>5Gy
) and 2 Gy EQD2
a
/b=3
(V
>2Gy
)
were evaluated for all fractionation schedules and metastatic
lesions.
Statistical data analysis
All statistical analysis were performed using R version 1.1.456
(RStudio: Integrated Development for R. RStudio, USA). Since not
all data for the plan quality parameters fitted the normal distribu-
tion (tested with the Shapiro-Wilk’s test for normality), the non-
parametric Friedman test was used to assess differences in the plan
conformity/quality parameters between the hypofractionation
schedules for all metastatic lesions. Since the 15 fractions schedule
was used exceptionally for 3 sarcoma lesions, resulting in only
three data points for each metric, data was insufficient to include
in the statistical test. Therefore, differences in plan conformity/
quality parameters were only evaluated between the 10, 5 and 3
fractions schedules.
For the OARs related to the cranial metastatic lesions, as data
was normally distributed (tested with the Shapiro-Wilk’s test for
normality), a one sample t-test was performed to compare the rel-
ative differences in D
mean
for each hypofractionation schedule
compared to the conventional schedule. For the OARs related to
the extra-cranial metastatic lesions, a limited number of data
points were available per organ as a result of the large variability
in the metastases location. Thus, no statistical tests were per-
formed for these OARs.
For the body dose measurements (V
>95%
,V
>80%
,V
>5Gy
and V
>2Gy
)
for all metastases, data did not fit a normal distribution, thus mea-
surements for each hypofractionation schedule (10/5/3 fractions)
were compared to the conventional schedule using a non-
parametric paired Wilcoxon test. Similarly to the plan confor-
mity/quality parameters, body dose measurements for the 15 frac-
tion schedule were only available for 3 metastatic lesions and
therefore not included in the statistical test. For all statistical tests,
p-values < 0.05 were considered significant.
Results
For all metastatic lesions with exception of the vertebrae, the
PTV coverage was fulfilled for both conventional and hypofraction-
ated plans (V
95%
range 95.5–100%, V
100%
range 95.1–100%). For 5
out of 6 lesions (n= 2 neuroblastoma, n= 3 sarcoma) located in
the vertebrae, target coverage was not met (V
100%
range 63.5–
91.0%) with hypofractionation (Fig. 1; underdosage even when
excluding the spinal cord volume from the PTV).
For 39 out of 50 lesions, plans were optimized without violating
the OAR dose constrains, with exception of the plans for 11/15
orbital lesions where the lacrimal gland overlapped with the PTV
(Fig. 1). Consequently, the D
0.1cm
3
in the lacrimal gland exceeded
the allowed dose (Table 2) for 5 out of 15 lesions in the conven-
tional plans and 7, 9 and 11 out of 15 lesions in the 10, 5, 3 fraction
schedules, respectively.
An overview of the plan quality parameters is given in Fig. 2.No
significant differences were found between the different hypofrac-
tionation schedules for any of the considered parameters (p>0.05).
For the 36 Gy-equivalent and 54 Gy-equivalent plans, all plan qual-
ity parameters for each hypofractionated plan were met for 29/39
and 5/11 lesions, respectively. For the remaining lesions, either one
or two parameters were not fulfilled.
For all OARs (with exception of the lacrimal gland and spinal
cord), a reduction in the D
mean
on average less than 3 Gy EQD2
a
/b=3
Table 1
Prescription doses used for each fractionation schedule. Dose criteria for 15, 10, 5 and 3 fractions (fx) were calculated using the linear-quadratic (LQ) model with an
a
/b= 10 and
without correction for overall treatment time.
Prescription
dose
Conventional 15 fx 10 fx 5 fx 3 fx
36 Gy
equivalent
20 1.8 Gy = 35.4 Gy
EQD2
a
/b=10
–103.2 Gy = 35.2 Gy
EQD2
a
/b=10
55.5 Gy = 35.5 Gy
EQD2
a
/b=10
38 Gy = 36.0 Gy
EQD2
a
/b=10
54 Gy
equivalent
30 1.8 Gy = 53.1 Gy
EQD2
a
/b=10
15 3.2 Gy = 52.8 Gy
EQD2
a
/b=10
10 4.5 Gy = 54.4 Gy
EQD2
a
/b=10
57.0 Gy = 49.6 Gy
EQD2
a
/b=10
-
Table 2
Clinical dose criteria used in the optimisation and evaluation of the conventional and hypofractionated treatment plans according to the NRG-BR001 phase 1 trial
a
and in-house
b
guidelines. Dose constraints/objectives were determined for each fractionation schedule using an
a
/b= 10 for the target and an
a
/b= 3 for all OARs, with exception of the spinal
cord (
a
/b= 2).
Structure 30 fx 20 fx 15 fx 10 fx 5 fx 3 fx
PTV 36 Gy equivalent
b
–V
34.2Gy
99%
D
0.1cm
3
< 38.5 Gy
–V
32Gy
95%
D
0.1cm
3
< 38.4 Gy
V
27.5Gy
95% D
0.1cm
3
<33Gy V
24Gy
95%
D
0.1cm
3
< 28.8 Gy
PTV 54 Gy equivalent
b
V
51.3Gy
99%
D
0.1cm
3
< 57.8 Gy
–V
48Gy
95%
D
0.1cm
3
< 57.6 Gy
V
45Gy
95%
D
0.1cm
3
<54Gy
V
35Gy
95%
D
0.1cm
3
<42Gy
-
Brainstem
a
–D
0.1cm
3
<51Gy - D
0.1cm
3
<40Gy D
0.1cm
3
<31Gy D
0.1cm
3
<23Gy
Cochlea
b
–D
mean
<24Gy - D
mean
<20Gy D
mean
<17Gy D
mean
<14Gy
Eye
b
–D
0.1cm
3
<44Gy - D
0.1cm
3
<35Gy D
0.1cm
3
<27Gy D
0.1cm
3
<22Gy
Lacrimal Gland
b
–D
0.1cm
3
<40Gy - D
0.1cm
3
<32Gy D
0.1cm
3
<25Gy D
0.1cm
3
<20Gy
Lens
b
–D
0.1cm
3
<10Gy - D
0.1cm
3
< 9 Gy D
0.1cm
3
< 8 Gy D
0.1cm
3
<7Gy
Optic Nerve
b
–D
0.1cm
3
<52Gy - D
0.1cm
3
<40Gy D
0.1cm
3
<30Gy D
0.1cm
3
<25Gy
Pituitary
b
–D
mean
<22Gy - D
mean
<19Gy D
mean
<15Gy D
mean
<13Gy
Oesophagus
a
D
0.5cm
3
<60Gy D
0.5cm
3
<54Gy D
0.5cm
3
<48Gy D
0.5cm
3
<42Gy D
0.5cm
3
<32Gy D
0.5cm
3
<25Gy
Heart
a
D
0.5cm
3
<54Gy D
0.5cm
3
<48Gy D
0.5cm
3
<43Gy D
0.5cm
3
<38Gy D
0.5cm
3
<29Gy D
0.5cm
3
<26Gy
Spinal Cord
b
D
0.1cm
3
<54Gy D
0.1cm
3
<46Gy D
0.1cm
3
<42Gy D
0.1cm
3
<36Gy D
0.1cm
3
<27Gy D
0.1cm
3
<22Gy
Spinal Cord PRV (2 mm)
b
D
0.1cm
3
<60Gy D
0.1cm
3
<52Gy D
0.1cm
3
<47Gy D
0.1cm
3
<40Gy D
0.1cm
3
<30Gy D
0.1cm
3
<23Gy
Liver
b
D
mean
<34Gy D
mean
<31Gy D
mean
<29Gy D
mean
<25Gy D
mean
<20Gy D
mean
<17Gy
Spleen
b
D
mean
<15Gy D
mean
<14Gy D
mean
<14Gy D
mean
<12Gy D
mean
<10Gy D
mean
<9Gy
Contralateral Kidney
a
D
mean
<11Gy D
mean
<10Gy D
mean
<10Gy D
mean
< 9 Gy D
mean
< 8 Gy D
mean
<7Gy
Vertebrae
b
D
0.1cm
3
<67Gy D
0.1cm
3
<59Gy D
0.1cm
3
<54Gy D
0.1cm
3
<46Gy D
0.1cm
3
<35Gy D
0.1cm
3
<28Gy
Cauda Equina
a
D
0.1cm
3
<57Gy D
0.1cm
3
<53Gy D
0.1cm
3
<48Gy D
0.1cm
3
<42Gy D
0.1cm
3
<32Gy D
0.1cm
3
<24Gy
Dosimetric feasibility of hypofractionation for metastatic bone/bone marrow lesions from paediatric solid tumours
168
Fig. 1. Conventional (20 fractions (fx)) and hypofractionated (10/5/3 fx) transversal dose maps for six metastatic bone/bone marrow lesions from different neuroblastoma
patients located in the skull (a), orbita (b), humerus (c), rib (d), vertebra (e) and pelvis (f). The PTV is shown in white, the lacrimal gland in green, the eye in pink, the spleen in
black, the kidneys in yellow, the spinal cord in light blue and the spinal cord PRV in dark blue. The allowed maximum dose shown in dark red was 107% for the 20 fx and 120%
for the 10/5/3 fx plans.
S.C. Huijskens, F. Guerreiro, M. Bosman et al. Radiotherapy and Oncology 160 (2021) 166–174
169
was seen for the hypofractionated compared to the conventional
plans. For cranial lesions located in the orbita, relative differences
in doses to the eye (n= 16) and lens (n= 16) were significantly
lower in the majority of the cases (> 90%) for the hypofractionated
plans (Fig. 3(a)). Relative differences were largest for the 5 fraction
schedule, with a decrease on the D
mean
on average of 28% and 43%
for the eye and lens, respectively (Supplementary Table 2). In con-
trast, in 11 out of 15 lesions, where the lacrimal gland was in close
proximity to or even overlapped with the PTV, an increased D
mean
was noticed for 7 lesions for the 10 fraction schedule and 8 lesions
for the 5 and 3 fraction schedules (Fig. 1,Supplementary Table 2).
For extra-cranial lesions located in or near the vertebrae, rela-
tive differences in D
mean
to the kidneys (n= 6), liver (n= 4), spleen
(n= 3), oesophagus (n= 4) and the spinal cord (n= 6) were evalu-
ated for the hypofractionated plans and compared to the conven-
tional plan (Fig. 3(b)). For the kidneys, liver and spleen, a larger
dosimetric sparing was achieved by reducing the number of frac-
tions (on average 30% reduction in D
mean
compared to the conven-
tional plan). In contrast, the D
mean
of the spinal cord was larger
when using less fractions for 8 out of 13 lesions (Fig. 3 (b)). Never-
theless, constraints to the spinal cord were met in all cases
(D
0.1cm
3
< physical dose constraints listed in Table 2).
Fig. 2. Boxplots of the plan conformity/quality parameters (HI, R
100%
,R
50%
and D
2cm
) for the hypofractionated plans for cranial (n= 26) and extra-cranial (n= 21) lesions in
paediatric patients. Black dots represent lesions from neuroblastoma patients (n= 39) and blue triangles represent lesions from sarcoma patients (n= 11). Boxes: median
value and upper and lower quartiles; whiskers: lowest and highest data point within 1.5x interquartile range, open circles: outliers. Green indicates preferred values, yellow
indicates acceptable values and red indicates values outside of these ranges. R
50%
and D
2cm
acceptance range was dependent on the volume of the PTV (Supplementary
Table 1).
Dosimetric feasibility of hypofractionation for metastatic bone/bone marrow lesions from paediatric solid tumours
170
For the V
>80%
V
>5Gy
and V
>2Gy
body dose measurements, a signif-
icant larger dosimetric sparing was achieved with all hypofraction-
ated compared to the conventional plans (p<0.05)(Fig. 4). For the
V
>95%,
no significant differences were found between the hypofrac-
tionated and the conventional plans (p>0.05).
Discussion
In this study, the feasibility of hypofractionated compared to
conventional radiotherapy schedules for metastatic bone/bone
marrow lesions in neuroblastoma and sarcoma patients was eval-
uated with focus on the target coverage and dose to the healthy
surrounding tissues. Results demonstrated that for the majority
of the paediatric metastases, iso-effective plans with less fractions
could be generated with similar or even significantly less dose
deposition in the surrounding tissues. For cases in which the dose
criteria were not met, the limiting factor was often the presence of
OARs in close proximity or overlapping with the target. Conse-
quently, the most suitable fractionation schedule should be per-
sonalised depending on the spatial relationship between the PTV-
OARs and the prescription dose.
In adults, the current radiotherapy approach for oligometastatic
disease has a strong focus on stereotactic techniques with hypofrac-
tionation [12,13,20]. For the evaluation of hypofractionated sched-
ules, plan conformity/quality parameters (i.e. HI, R
100%
,R
50%
and
D
2cm
) were designed as described in [18,19]. Although these criteria
were developed for adults, in this study the same parameters were
pragmatically used for the evaluation of paediatric hypofraction-
Fig. 3. Relative EQD2 differences (y-axis) in D
mean
of the OARs in close proximity to the target for the different hypofractionation schedules (x-axis) compared to the
conventional fractionation schedules (red dotted line) for cranial (a) and extra-cranial (b) metastatic lesions. Dose criteria for 15, 10, 5 and 3 fractions were calculated using
the linear-quadratic (LQ) model with an
a
/b= 3 for all OARs, with exception of the spinal cord (
a
/b= 2). In (a), * indicates significance difference (p< 0.05). Boxes: median
value and upper and lower quartiles; whiskers: lowest and highest data point within 1.5interquartile range, circles: outliers, diamonds: averages. In (b), each symbol
represents a different patient and symbols in black represent neuroblastoma and in blue sarcoma patients. No statistical test was performed for the extra-cranial lesions due
to the limited number of data points per hypofractionation schedule.
Fig. 3 (continued)
S.C. Huijskens, F. Guerreiro, M. Bosman et al. Radiotherapy and Oncology 160 (2021) 166–174
171
ated plans. The guidelines however state that for small gross target
volumes (< 1.8 cm
3
) and/or volumes within 2 cm of the skin, which
was the case for the majority of the metastatic lesions in this study
(43/50 lesions), it may be challenging to meet the criteria for all
plan conformity/quality parameters [19]. Nevertheless, all parame-
ters were fulfilled in all hypofractionated schedules for the majority
of the lesions (34/50 lesions). No significant differences in the plan
quality parameters were noticed between the different fractiona-
tion schedules, indicating that similar iso-effective plans can be
generated either with 10, 5 and/or 3 fractions. In addition, target
and OARs dose constraints/objectives were met for all hypofrac-
tionated plans with exception of lesions in the orbita (n= 11, neu-
roblastoma) and vertebrae (n= 5, 2 neuroblastoma and 3 sarcoma).
For the orbital lesions, where in several cases the PTV overlapped
with the lacrimal gland, a significant dose increase for this OAR
was observed in at least one of the hypofractionated plans com-
pared to the conventional plan. For the vertebral lesions, since the
maximum dose constraint to the spinal cord could not be violated,
an underdosage of the PTV was unavoidable in all hypofractionated
schedules. Thus, when adhering to the spinal cord constraints, per-
forming hypofractionation for these metastases is not feasible for
both neuroblastoma (with 10 fractions and a prescription dose of
36 Gy EQD
2
a
/b=10
) and sarcoma patients (with 15 fractions and a
prescription dose of 54 Gy EQD
2
a
/b=10
). For the remaining lesions,
a significant dose reduction to the surrounding OARs and body
was achieved with all hypofractionation schedules compared to
the conventional schedule. It is clear that the expected benefit of
hypofractionation for the OARs decreases with increasing PTV mar-
gins. Nevertheless, the use of a homogeneous 2 mm GTV-PTV mar-
gin in this in-silico study was in accordance with clinical residual
set-up errors after online patient position correction recorded dur-
ing hypofractionated treatments of oligometastastic bone/bone
marrow disease in literature [21,22].
In paediatrics, literature on hypofractionated radiotherapy and
the radiobiological effect of a higher dose per fraction on the normal
tissue is lacking. Also, as normal tissue complication probability
Fig. 4. Boxplots denoting the body volume receiving more than 95% and 80% of the prescription dose (high dose) (a) and more than 5 and 2 Gy EQD2
a
/b=3
(low dose) (b) for
hypofractionated (10/5/3 fractions (fx)) and conventional (Conv) fractionation schedules for all cranial and extra-cranial metastatic lesions. Black dots represent lesions from
neuroblastoma patients and blue triangles represent lesions from sarcoma patients. Boxes: median value (solid line), average value (dashed line) and upper and lower
quartiles; whiskers: lowest and highest data point within 1.5x interquartile range, circles: outliers. * indicate significant differences between the hypofractionated and the
conventional plans.
Fig. 4 (continued)
Dosimetric feasibility of hypofractionation for metastatic bone/bone marrow lesions from paediatric solid tumours
172
(NTCP) models for hypofractionation and especially for children
still have to be developed, dose constraints in this study were based
on the known tolerance doses for 2 Gy fractionation schedules.
Dose criteria were calculated with an
a
/bof 3 for most OARs, with
exception of the spinal cord (
a
/b= 2) and with an
a
/bof 10 for
the target. For metastatic bone/bone marrow lesions, it is however
debatable which
a
/bis appropriate to use in case of a target volume
and/or an OAR, since for certain lesions the use of hypofractionation
could lead to a higher risk of bone fracture [23]. Nevertheless, all
conventional and hypofractionated plans in this study met the dose
constraint D
0.1cm
3
< 70 Gy EQD2
a
/b=3
to bony structures to minimise
the risk of fracture as suggested by Hoeben et al. [17].
Stereotactic radiotherapy with hypofractionation can be espe-
cially beneficial for the irradiation of patients with multiple metas-
tases within an acceptable overall treatment time. Compared to a
conventional schedule, using hypofractionation can reduce the
treatment time for metastases from approximately 4 weeks (20
fractions, 5 fractions/week) to 1–2 weeks (3–5 fractions, 3 frac-
tions/week) in neuroblastoma patients and from 6 weeks (30 frac-
tions, 5 fractions/week) to 2–3 weeks (5–10 fractions, 3 fractions/
week) in sarcoma patients. Moreover, with an increasing sensitiv-
ity/specificity of imaging techniques, a larger number of metas-
tases will be detected, making irradiation of the primary tumour
together with the metastatic lesions more challenging regarding
to child compliance and machine capacity. Therefore, combining
a hypofractionation schedule to treat multiple metastases while
simultaneously irradiating the primary tumour in a conventional
manner, could be an attractive alternative to conventional radio-
therapy alone.
In addition, caution regarding the combination of hypofraction-
ated schedules with systemic therapies is needed. Specific
chemotherapy or targeted therapy might increase radiotherapy
side-effects, so timing between treatment modalities as well as rel-
evant constraints for critical OARs in the vicinity of the tumour
during treatment should be carefully considered. In literature, lim-
ited data is available on the effectiveness and toxicity of hypofrac-
tionated treatments, either by radiotherapy alone or by a
combination with chemo/targeted therapy. To find a consensus
on hypofractionation regimens (taking site, histology, number of
lesions and the age group in mind) and to register toxicity from
radiotherapy whether or not combined with systemic agents, a
SIOPE endorsed working group has been established recently.
Given the potential advantages of hypofractionation in daily prac-
tice, this working group will not only focus on paediatric patients
presenting with stage 4 disease treated with a curative intent,
but also on patients referred for radiotherapy with palliative
intent. Performing hypofractionation in children would not only
simplify the treatment logistics for the clinicians and family but
also allow for increased child comfort with patients in a reduced
time under general anaesthesia.
In conclusion, the results from this study show that iso-effective
hypofractionated plans, yielding similar target coverage and
potential dose sparing to the surrounding tissues compared to con-
ventional plans, could be generated for the majority of the patients
with neuroblastoma or sarcoma and metastatic lesions in the bone/
bone marrow. In practice, the most suitable fractionation sched-
ules should be personalised per tumour type and site depending
on the spatial relationship between the target and surrounding
critical structures and the prescription dose.
Funding acknowledgements
KiKa (Children Cancer Free) foundation, grant number no. 343
and title: Towards optimization of radiotherapy techniques for
metastatic lesions in children stage IV disease.
The funding source had no role in the study design, collection,
analysis and interpretation of data, writing of this manuscript, or
the decision to submit the article for publication.
Funding: Stichting Kinderen Kankervrij [project no. 343]
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.radonc.2021.04.020.
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Dosimetric feasibility of hypofractionation for metastatic bone/bone marrow lesions from paediatric solid tumours
174