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Radical radiotherapy for paediatric solid tumour metastases: An overview of current European protocols and outcomes of a SIOPE multicenter survey

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Abstract and Figures

Purpose/objective About 20% of children with solid tumours (ST) present with distant metastases (DM). Evidence regarding the use of radical radiotherapy of these DM is sparse and open for personal interpretation. The aim of this survey was to review European protocols and to map current practice regarding the irradiation of DM across SIOPE-affiliated countries. Materials/methods Radiotherapy guidelines for metastatic sites (bone, brain, distant lymph nodes, lung and liver) in eight European protocols for rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue sarcoma, Ewing sarcoma, neuroblastoma and renal tumours were reviewed. SIOPE centres irradiating ≥50 children annually were invited to participate in an online survey. Results Radiotherapy to at least one metastatic site was recommended in all protocols, except for high-risk neuroblastoma. Per protocol, dose prescription varied per site, and information on delineation and treatment planning/delivery was generally missing. Between July and September 2019, 20/27 centres completed the survey. Around 14% of patients were deemed to have DM from ST at diagnosis, of which half were treated with curative intent. A clear cut-off for a maximum number of DM was not used in half of the centres. Regardless of the tumour type and site, conventional radiotherapy regimens were most commonly used to treat DM. When stereotactic radiotherapy was used, a wide range of fractionation regimens were applied. Conclusion Current radiotherapy guidelines for DM do not allow a consistent approach in a multicentre setting. Prospective (randomised) trials are needed to define the role of radical irradiation of DM from paediatric ST.
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Original Research
Radical radiotherapy for paediatric solid tumour
metastases: An overview of current European protocols
and outcomes of a SIOPE multicenter survey
Sophie C. Huijskens
a
, Petra S. Kroon
a,
*,MarkN.Gaze
b
,
Lorenza Gandola
c
, Stephanie Bolle
d
,StephaneSupiot
e
,
Candan D. Abakay
f
, Aikaterini Alexopoulou
g
, Jelena Bokun
h
,
Marzanna Chojnacka
i
, Alexandre Escande
j
, Jordi Giralt
k
,SemiHarrabi
l
,
John H. Maduro
m,u
, Henry Mandeville
n
, Anna Mussano
o
,
Aleksandra Napieralska
p
, Laetitia Padovani
q
, Giovanni Scarzello
r
,
Beate Timmermann
s
, Line Claude
t
, Enrica Seravalli
a
, Geert O. Janssens
a,u
a
Department of Radiation Oncology, University Medical Center Utrecht, Utrecht, The Netherlands
b
Department of Oncology, University College London Hospitals, London, UK
c
Paediatric Radiotherapy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
d
Department of Radiation Oncology, Gustave Roussy, Villejuif, France
e
Oncologie Radiotherapie, Institut de Cance
´rologie de l’Ouest, Nantes, France
f
Department of Radiation Oncology, Uludag University, Bursa, Turkey
g
Department of Radiation Oncology, Athens General Children’s Hospital, Athens, Greece
h
Institute of Oncology and Radiology of Serbia, Belgrado, Serbia
i
Department of Radiation Oncology, Maria Sklodowska-Curie Memorial Cancer Center-Institute, Warsaw, Poland
j
Department of Radiation Oncology, Oscar Lambret Comprehensive Cancer Center, Lille, France
k
Department of Radiation Oncology, Vall d’Hebron University Hospital, Barcelona, Spain
l
Department of Radiation Oncology and Radiotherapy, Heidelberg University Hospital, Heidelberg, Germany
m
Department of Radiation Oncology, University Medical Center Groningen/Groningen Proton Center, Groningen, The Netherlands
n
Department of Radiotherapy, Royal Marsden Hospital, Sutton, UK
o
Department of Radiation Oncology, Citta della Salute e della Scienza, Torino, Italy
p
Department of Radiation Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology Gliwice
Branch, Gliwice, Poland
q
Department of Radiation Oncology, Centre Hospitalier Universitaire, Marseille, France
r
Department of Radiation Oncology, Veneto Institute of Oncology, Padua, Italy
s
Department of Particle Therapy, University Hospital Essen, West German Proton Therapy Centre Essen (WPE), West
German Cancer Center (WTZ), German Cancer Consortium (DKTK), Essen, Germany
t
Department of Radiation Oncology, Centre Leon Berard, Lyon, France
u
Princess Ma
´xima Center for Paediatric Oncology, Utrecht, The Netherlands
Received 30 June 2020; received in revised form 22 October 2020; accepted 7 December 2020
*Corresponding author: Department of Radiotherapy, University Medical Center Utrecht, Heidelberglaan 100, HP: Q.02.2.314, Utrecht, 3584
CX, The Netherlands.
E-mail address: p.s.kroon-3@umcutrecht.nl (P.S. Kroon).
https://doi.org/10.1016/j.ejca.2020.12.004
0959-8049/ª2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/
licenses/by/4.0/).
Available online at www.sciencedirect.com
ScienceDirect
journal homepage: www.ejcancer.com
European Journal of Cancer 145 (2021) 121e131
KEYWORDS
Radiotherapy;
Rhabdomyosarcoma;
Soft-tissue sarcoma;
Ewing sarcoma;
Neuroblastoma;
Renal tumours;
Stage IV;
SIOPE;
Paediatrics;
Metastases
Abstract Purpose
/
objective: About 20% of children with solid tumours (ST) present with
distant metastases (DM). Evidence regarding the use of radical radiotherapy of these DM is
sparse and open for personal interpretation.
The aim of this survey was to review European protocols and to map current practice
regarding the irradiation of DM across SIOPE-affiliated countries.
Materials
/
methods: Radiotherapy guidelines for metastatic sites (bone, brain, distant lymph nodes,
lung and liver) in eight European protocols for rhabdomyosarcoma, non-rhabdomyosarcoma soft-
tissue sarcoma, Ewing sarcoma, neuroblastoma and renal tumours were reviewed. SIOPE centres
irradiating 50 children annually were invited to participate in an online survey.
Results: Radiotherapy to at least one metastatic site was recommended in all protocols, except for
high-risk neuroblastoma. Per protocol, dose prescriptionvariedpersite,andinformationondelin-
eation and treatment planning/delivery was generally missing.
Between July and September 2019, 20/27 centres completed the survey. Around 14% of patients
were deemed to have DM from ST at diagnosis, of which half were treated with curative intent. A
clear cut-off for a maximum number of DM was not used in half of the centres. Regardless of the
tumour type and site, conventional radiotherapy regimens were most commonly used to treat DM.
When stereotactic radiotherapy was used, a wide range of fractionation regimens were applied.
Conclusion: Current radiotherapy guidelines for DM do not allow a consistent approach in a multi-
centre setting. Prospective (randomised) trials are needed to define the role of radical irradiation of
DM from paediatric ST.
ª2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/).
1. Introduction
Advanced treatment strategies for localised paediatric
solid tumours (ST) result in overall survival rates between
60% and 95% [1e5]. However, around 20% of children
present with distant metastases. Improvement in out-
comes for these patients has been limited and achieving
cure remains challenging. Depending on histology, sur-
vival rates are around 35% (range 5e95%) and are mainly
obtained by advances in systemic therapy [4e9].
Whole lung irradiation has been included in pro-
tocols for Ewing sarcoma (ES), rhabdomyosarcoma
(RMS) and unfavourable renal tumours [8,9]. However,
there is little evidence supporting radiotherapy to other
metastatic sites: only a few papers have shown radio-
therapy to be effective for local control [10e15].
Offering patients with oligometastases a potentially
curative treatment, aiming to delay progression and
improve quality of life, is gaining importance in adult
radiation oncology [16e19]. In contrast to common
adult cancers, intensified systemic regimens without
radiotherapy offer some chance of cure for children and
adolescents with distant metastasis due to the increased
sensitivity of paediatric tumours and the plasticity of
normal tissues to recover easily from high-dose therapy
[4,5,8,9].
Stereotactic ablative body radiotherapy is increas-
ingly used in adult patients with oligometastatic disease,
producing good local control with limited toxicity
[16,17]. This technique requires accurate
immobilization, localization imaging and precise treat-
ment planning and delivery systems. It enables hypo-
fractionation with highly conformal dose distributions
and sparing of adjacent normal tissues. This approach
allows smaller margin sizes and larger doses in fewer
fractions compared to conventionally fractionated
radiotherapy [20]. In paediatrics, concomitant irradia-
tion of the primary tumour and all metastatic sites with
a conventional fractionation regimen becomes chal-
lenging with an increasing number of metastatic sites
since a prolonged treatment session demands enormous
compliance of the child, as well as enough machine and
anaesthesia capacity. On the other hand, hypofractio-
nation radiotherapy on metastatic sites allows irradia-
tion of a larger number of metastases within a daily
acceptable time slot while respecting the overall treat-
ment time, making it a more attractive alternative to
conventional radiotherapy.
The literature on the use of a stereotactic approach
with hypofractionation in paediatrics is limited to a
small number of retrospective reports, which demon-
strate feasibility and good local control [21e27]. How-
ever, the radiobiological effect of a higher dose per
fraction and the associated late effects are still unclear.
The purpose of this study is to map the recommended
practice on metastatic site irradiation in ongoing Euro-
pean protocols and to report the outcome of a survey
across SIOPE-affiliated countries of the current practice
of radiotherapy for metastases from paediatric ST.
S.C. Huijskens et al. / European Journal of Cancer 145 (2021) 121e131122
2. Materials and methods
2.1. European protocols applied across SIOPE-affiliated
countries
To evaluate the current radiotherapy guidelines for
children presenting with metastatic disease, European
protocols for RMS and non-rhabdomyosarcoma soft-
tissue sarcoma (STS), ES, neuroblastoma (NBL) and
renal tumours were analyzed. Details regarding the
recommended radiotherapy procedures for metastatic
sites within these protocols were evaluated and stratified
by anatomical site (bone, brain, distant lymph nodes,
lung and liver). The total dose (Gy), dose per fraction,
number of fractions (fx) and the calculated equivalent
dose in 2 Gy fractions (EQD2) using an a/bratio of 3
for late effects and 10 for tumour tissue [28] were eval-
uated. Recommendations on delineation and margins
for the metastatic sites were collected.
2.2. Survey
To document the current practice of radiotherapy for
metastases from paediatric ST across SIOPE-affiliated
countries (https://www.siope.eu/about-siope/members/),
an online survey with 44 questions was designed with
SurveyMonkey (SurveyMonkey Inc., San Mateo,
California, USA). The survey included multiple-choice,
dichotomous and open-ended questions.
2.2.1. Participants
The European Union Joint Action on Rare Cancer
(JARC) project mapped more than 230 paediatric
radiotherapy centres [29]. Centres irradiating at least 50
children annually were invited to complete the study-
related survey sent by email with a web link.
2.2.2. Population and tumour characteristics
Each department was asked to estimate the number of
children irradiated annually and the number presenting
with metastatic disease from RMS, STS, ES, NBL and
renal tumours. The treatment intent was categorised as
either palliative or curative (aiming to cure the patient
by giving a radical radiotherapy dose at the metastatic
site(s)). Metastatic disease was further stratified by the
treatment site: bone (spine and non-spine), brain, distant
lymph nodes, lung and liver. Numbers and information
on radiotherapy with curative intent for each site were
collected.
2.2.3. Imaging characteristics
For delineation and planning purposes, participants
were asked to indicate the imaging modalities used per
tumour type and site. As computed tomography (CT)
imaging is always needed for planning, the question
focussed on magnetic resonance imaging (MRI) and
positron emission tomography (PET), and specifically
for NBL patients iodine-123-metaiodobenzylguanidine/
single-photon emission computed tomography (mIBG/
SPECT).
2.2.4. RT characteristics
Questions on radiotherapy planning for metastatic sites
paid special attention to the use of a conventional or a
stereotactic technique. A conventional technique was
described according to ICRU 62/83 guidelines [30,31],
using a D
max
<107% and V
95%
>99% for the planning
target volume (PTV) and fraction doses 2.0 Gy. For
stereotactic techniques, D
max
doses up to 140% were
commonly used with fraction doses above 2.0 Gy [32].
No distinction between conventional and stereotactic
techniques was made for the use of clinical target vol-
ume (CTV) margins. Participants indicated whether this
patient cohort was treated within a local, national or
international protocol. Additionally, specific doses and
fractionation schemes were collected and stratified by
the primary tumour site. Questions on immobilization
and position verification were asked.
2.2.5. Future steps
A request was made for future ideas concerning radio-
therapy with curative intent to metastatic sites from ST.
3. Results
3.1. Protocols
Eight European protocols on paediatric ST and their
radiotherapy procedures for primary metastatic disease
are listed in Table 1.
For RMS, the European paediatric Soft-tissue Sar-
coma Study Group (EpSSG) FaR-RMS (Frontline and
Relapsed RhabdoMyoSarcoma) protocol [33] is due to
open in 2020. In this protocol (version 1.0; dd 10-2019),
patients with unfavourable metastatic disease will be
randomised to receive, or not to receive, radiotherapy to
all sites of metastases, where feasible. Site-specific dose
and delineation guidelines for metastatic disease were
described.
For non-rhabdomyosarcoma STS, the EpSSG
NRSTS-2005 protocol (version 1.1; dd 09-2009) was
evaluated [34]. Although primarily for non-metastatic
patients, radiotherapy for bone, brain, lymph nodes,
lung and liver metastases at diagnosis in patients with
extra-renal rhabdoid tumours was included.
For ES, the ‘Radiotherapy Guidelines’ document
(version 2.0; dd 01-2017) from the Euro Ewing-2012
protocol [35] described whole lung irradiation for pul-
monary metastatic disease. In contrast to the Euro-
Ewing-2008 protocol, Euro-Ewing 2012 gave no further
guidelines for brain and other extrapulmonary sites.
For metastatic NBL, the SIOPEN (International So-
ciety of Paediatric Oncology European Neuroblastoma
Group) HR-NBL2 protocol, opened in 2020, did not
S.C. Huijskens et al. / European Journal of Cancer 145 (2021) 121e131 123
Table 1
Recent and current clinical protocols describing radiotherapy procedures for primary metastatic disease from solid tumours with curative intent.
Site Tumour type Protocol Case Dose in Gy
(þboost)
Fx Dose/Fx EQD2
a/b(3)
EQD2
a/b(10)
Margin Note
Bone RMS RMS-2005 e30 20 1.5e1.8 27e34.6 28.8e35.4 Depending on the site,
age and volume
Far-RMS-2019 Favourable metastatic disease
(Modified Oberlin Prognostic
Score of 1) [46]
41.4 23 1.8 39.7 40.7 GTV-CTV 5
e10 mm þCTV-PTV
local standard of care
Single phase
Exceptional cases of bulky
macroscopic residual metastatic
disease
41.4 (þ9) 23 (þ5) 1.8 48.4 49.6 Two phase or SIB
STS NRSTS-2005 e25.2 14 1.8 24.2 24.8 GTV-CTV
2cmþappropriate
margin for PTV
Entire bone (APPA)
ES Ewing-2008 e45 eee e If available and feasible:
ESRT
Ewing-2012 eeeeee
NBL HR-NBL1 eeeeee
HR-NBL2 eeeeee
Renal Umbrella-2016 e30e30.6 10e17 1.8e3 29.4e36 30.1e32.5
Brain RMS RMS-2005 -eeeee
Far-RMS-2019 Pre-treatment tumour volume
20 cc and diameter <3cm
18e20 1 18e20 75.6 42 Target volume
delineation according to
local standard of care
SRT
24 3 8 52.8 36 SRT
30 5 6 54 40 SRT
Pre-treatment tumour volume
>20 cc and diameter >3cm
30 10 3 36 32.5 Whole brain
STS NRSTS-2005 Boost in patients 3 lesions <
3 years
21.6 (þ10.8) 12 (þ6) 1.8 20.7e31.1 21.2e31.9 Boost margin 0e1 cm Whole brain (boost with
IMRT or SRT)
ES Ewing-2008 Isolated metastases (þboost if 1
or 2 lesions with maximum
diameter 2e3cm)
30 (þ20) 15 (þ10) 2 30e50 30e50 Whole brain (þSRT)
Ewing-2012 eeeeee
NBL HR-NBL1 eeeeee
HR-NBL2 eeeeee
Renal Umbrella-2016 IM (þboost for macroscopic
residual disease)
15 (þ10.8) 10 (þ6) 1.5e1.8 13.5e27.6 14.4e28.3 Whole brain (þSIB)
HI (þboost for macroscopic
residual disease)
25 (þ10.8) 14 (þ6) 1.8 24.2e34.6 24.8e35.4 Whole brain (þSIB)
Distant
lymph nodes
RMS RMS-2005 e30 20 1.5e1.8 27e34.6 28.8e35.4 Depending on the site,
age and volume
Far-RMS-2019 e41.4 23 1.8 39.7 40.7 Target volume
delineation according to
local standard of care
Single phase
STS NRSTS-2005 e19.8 11 1.8 19 19.5 GTV-CTV
1cmþappropriate
margin for PTV
ES Ewing-2008 eeeeee
Ewing-2012 eeeeee
NBL HR-NBL1 eeeeee
S.C. Huijskens et al. / European Journal of Cancer 145 (2021) 121e131124
HR-NBL2 eeeeee
Renal Renal eeeeee
Lung RMS RMS-2005 e15 10 1.5 13.5 14.4 Whole lung
Far-RMS-2019 e15 10 1.5 13.5 14.4 Target volume
delineation according to
local standard of care
Whole lung (APPA)
STS NRSTS-2005 <12 months 10.5 7 1.5 9.5 10.1 CTV-PTV 1e2 mm Whole lung
12 months 15 10 1.5 13.5 14.4 Whole lung
ES Ewing-2008 14 years 15 2 Fx/day 1.25 12.8 14.1 Whole lung (APPA)
>14 years 18 12 1.5 16.2 17.3 Whole lung (APPA)
Ewing-2012 14 years 15 10 1.25 12.8 14.1 CTV-PTV 1 cm Whole lung (APPA)
>14 years 18 12 1.5 16.2 17.3 Respiratory-gated
radiotherapy can be
used
NBL HR-NBL1 eeeeee
HR-NBL2 eeeeee
Renal Renal IM (þboost for macroscopic
residual disease)
12 (þ10-13) 8 1.5 10.8 11.5 Whole lung (þSBRT
boost)
HI (þboost for macroscopic
residual disease)
15 (þ15-20) 10 1.5 13.5 14.4 Whole lung (þSBRT
boost)
Liver RMS RMS-2005 e30 20 1.5e1.8 27e34.6 28.8e35.4 Depending on the site,
age and volume
Far-RMS-2019 eeeeee
STS NRSTS-2005 <12 months 15 10 1.5 13.5 14.4 Whole liver (if diffusely
involved)
12 months 19.8 11 1.8 19 19.5 Whole liver (if diffusely
involved)
ES Ewing-2008 e-----
Ewing-2012 e-----
NBL HR-NBL1 eeeeee
HR-NBL2 eeeeee
Renal Renal IM (þboost for macroscopic
residual disease)
14.4 (þ10.8) 8 (þ6) 1.8 13.8e24.2 14.2e24.8 Whole liver (þSIB/
SBRT)
HI (þboost for macroscopic
residual disease)
20e25.2 (þ16.2) 11 (þ9) 1.8 19.0e34.6 19.5e35.4 Whole liver (þSIB/
SBRT)
Details adapted from recent and current clinical protocols for Rhabdomyosarcoma (RMS, EpSSG-RMS-2005 and Far-RMS-2019), Soft Tissue Sarcoma (STS, EpSSG-NRSTS-2005), Ewing Sarcoma
(ES, EWING-2008 and 2012), Neuroblastoma (NBL, HRNBL-1 and 2 QUARTET), Renal tumours (SIOP-RTSG UMBRELLA 2016).
Other abbreviations: IM: intermediate risk histology, HI: High risk histology, (E)SRT: (extracranial) stereotactic radiotherapy, SIB: simultaneous integrated boost, SBRT: stereotactic body
radiotherapy.
S.C. Huijskens et al. / European Journal of Cancer 145 (2021) 121e131 125
recommend systematic radiotherapy of distant metastatic
sites [36], in line with the earlier HR-NBL1 protocol.
Since June 2019, paediatric renal tumour patients are
registered in the SIOP-Renal Tumour Study Group
UMBRELLA protocol (SIOP-RTSG-UMRELLA-
2016) [37]. For both intermediate- and high-risk histology
subgroups, radiotherapy is advocated for bone, brain,
lung and liver metastases. Unresected residual metastases
or the area of macroscopic incomplete resection of me-
tastases may be boosted by a stereotactic technique or by
using a simultaneous integrated boost (SIB).
In summary, radiotherapy to at least one metastatic
site was recommended in all protocols, except for HR-
NBL2. Dose prescription varied per site. Recommen-
dations for treatment planning and delivery techniques
were sporadic. Protocols mentioned that metastatic site
radiotherapy can be considered by local multidisci-
plinary teams and treated according to local expertise
and practice. Discussion with the study coordinator is
recommended for complex cases.
3.2. Survey
3.2.1. Participants
Twenty-one of 27 centres (78%) from nine countries
responded. One did not complete the survey and was
excluded (resulting NZ20).
3.2.2. Patient selection
Within the twenty radiotherapy departments, an esti-
mated number of 2524 paediatric patients (median per
centre 90, range 50e450) were treated annually.
Approximately 14% (NZ357) presented with meta-
static disease, of which half (NZ181) were treated with
curative intent (Fig. 1). Regardless of the tumour type,
over 65% of the radiotherapy centres agreed that pri-
mary metastatic disease could be irradiated with cura-
tive intent. Poor prognosis was the major reason not to
offer potentially curative radiotherapy (Fig. 2). Half of
the centres did not define a maximum number of met-
astatic lesions, while 13% of the centres did not irradiate
with curative intent when more than one lesion is pre-
sent. If the number of sites would be a limiting factor at
presentation, reconsideration of radiotherapy after
neoadjuvant chemotherapy was mentioned by 75%.
3.2.3. Imaging characteristics
MRI-guided metastatic target volume delineation was
done nearly exclusively for CNS lesions, and commonly
for bone, distant lymph nodes and liver lesions (Fig. 3).
Lung lesions are defined by a CT-scan often combined
with a PET-scan. For NBL, the mIBG/SPECT is used to
define all kind of metastases. Five centres (25%) re-
ported an MRI-scanner within the radiotherapy
department and scanned patients in the radiotherapy
treatment position. Fifteen centres perform their MRI-
scans within the radiology departments and usually
not (12 out of 15 centres) in the radiotherapy treatment
position.
3.2.4. Treatment planning
As illustrated in Fig. 4, all photon radiotherapy de-
partments (NZ19) use at least a conventional planning
technique. Twelve radiotherapy departments (63%) also
use stereotactic planning techniques and fractionation
schemes, in particular for brain metastases. Deciding
between conventional and stereotactic approaches
depended on reasons including the number of lesions,
volume size and dose constraints for organs at risk. Six
out of 20 departments, four in France, used a stereo-
tactic technique according to an institutional or a na-
tional protocol [38,39], yielding varying dose
prescriptions (16e50 Gy) and fractionation schemes
(1e7 fractions), depending on the primary tumour type,
metastatic site, as well as radiotherapy department.
3.2.5. Treatment delivery
A thermoplastic mask and vacuum mattress were
routinely used by all centres depending on the anatom-
ical location (Fig. 5). Position verification was done
either by correcting for rotation and translation (>70%
for both conventional and stereotactic techniques) or
translation only (approximately 20%). Offline correc-
tions were used in a limited number of departments for
conventional techniques only (Fig. 5).
For photon delivery, rotational intensity-modulated
radiation therapy (IMRT) was most commonly used
(85% of the centres, regardless of the lesion site), fol-
lowed by conventional IMRT (on average 41%). For
proton delivery, a pencil beam scanning technique, with
either a uniform dose beam or intensity-modulated
proton therapy was equally reported by the four proton
centres.
Fig. 1. Overview of the estimated annual numbers of paediatric
patients receiving radiotherapy at the 20 participating centres,
categorized as either non-metastatic (grey) or metastatic (blue/
yellow). From the latter category, around 50% is treated with
palliative (blue) or curative (yellow) intent. (For interpretation of
the references to colour in this figure legend, the reader is referred
to the Web version of this article.)
S.C. Huijskens et al. / European Journal of Cancer 145 (2021) 121e131126
3.2.6. Future steps
All participants expressed concerns about the current lack
of well-defined guidelines in protocols for metastatic
disease, in particular selection criteria for hypofractio-
nation, and dose prescription per tumour type, margin
size and metastatic site. Furthermore, all participants are
in favour of cooperative research groups conducting
(randomised) trials for irradiation of metastatic sites.
4. Discussion
This study describes a subset of European protocols and
clinical practice of radical radiotherapy for metastatic
sites in childhood ST across twenty major European
departments. It shows significant variation in protocol
recommendations and reported practice.
The overall survival of metastatic paediatric ST can
range between 5% and 95%, mainly depending on his-
tology, site and number of metastases [40,41]. In contrast
to adults with stage IV disease, no randomised trials have
been completed to demonstrate the role of radiotherapy
to metastases in children [16e18]. However, the current
FaR-RMS trial includes a randomisation to evaluate
this. Patients with unfavourable metastatic disease will
be randomised to receive loco-regional radiotherapy
only versus radiotherapy to all metastatic sites where
feasible. However, further details or criteria for this
feasibility are lacking in the protocol. So far, evidence for
radiotherapy is limited to a small number of retrospec-
tive analyses [10e14]. Nevertheless, most survey re-
spondents are in favour of potentially curative metastatic
radiotherapy, with some disagreement on the maximum
number of metastatic sites, taking into account that with
an increasing number of metastases, prognosis worsens
[40e42]. The exact number of lesions does not play a key
role in current European protocols [33e37]. Whether the
number should be used as a cut-off for curative radio-
therapy is uncertain, as high-resolution imaging tech-
niques are of higher possibility to demonstrate more
smaller lesions. With an increasing number of visible
metastases, the feasibility of conventional radiotherapy
will become more challenging. On the other hand, a
stereotactic technique with a limited number of fractions
may facilitate full treatment respecting the overall
treatment time.
In adults, the current radiotherapy approach for
multifocal metastatic disease has a strong focus on ste-
reotactic techniques with hypofractionation [16e18]. In
general, carcinomas require a much higher biological
dose than paediatric embryonal tumours to achieve local
control. Given the higher incidence and the longer
experience of biologically effective dose calculations,
dose and fractionation schemes are well developed for
the vast majority of adult tumours [43]. Similar radio-
biological data for children, balancing the lower doses
needed to obtain disease control and the higher age-
dependent risk of normal tissue toxicity by the use of
hypofractionation regimens, are lacking. The latter be-
comes even more important when thinking of hypo-
fractionation with protons [44].
This survey shows that conventionally fractionated
rotational IMRT is currently the main technique for the
radical irradiation of metastatic disease in children
regardless of any tumour type. Also in the literature,
evidence for hypofractionated stereotactic radiotherapy
in children is limited. Some studies showed the feasi-
bility of a stereotactic technique, with varying dose and
fractionation schemes [26,39,45]. Local control rates
ranged from 50 to 85% at a median follow-up of 2 years,
with no acute or severe late toxicities observed
[26,39,44]. Casey et al. retrospectively evaluated the in-
dications for a radiotherapy dose and fractionation
schedule with curative intent of 49 bone metastases in
RMS and ES patients [12]. Hypofractionation with
3.0e8.0 Gy per fraction was utilized in 10/49 bone le-
sions only, conventional normofractionation in 34/49
bones and hyperfractionation with 1.5 Gy twice per day
in 5/49 bones. The use of mild hypofractionation resul-
ted in a similar local control.
All respondents mentioned that large prospective
registration studies are needed to understand tumour
Fig. 2. Potential limiting factors for radiotherapy with curative intent on metastatic sites (x-axis) (left). Focussing on the number of
metastatic sites, centres indicated whether they use a maximum number of candidate lesions or not (right).
S.C. Huijskens et al. / European Journal of Cancer 145 (2021) 121e131 127
control and side-effects on different tissues after non-
conventional fractionation regimens. In France, a na-
tional prospective study considering a stereotactic
approach in children was started in 2013 and included
48 patients so far [38]. Fifteen patients underwent
hypofractionation radiotherapy for brain, lung or spinal
lesions during first-line treatment. The stereotactic
approach was feasible and safe for all patients, but more
follow-up is needed to evaluate middle-term and long-
term toxicity [38]. Without any further results from
these prospective trials, prescribed doses to metastases
in the biologic range of the primary tumour dose are
recommended [12]. In addition to registration studies,
dosimetric studies investigating a range of dose and
fractionation schedules for different metastatic sites and
related constraints could lead to a better understanding
of the feasibility of hypofractionation and the dose
distribution in healthy surrounding tissues in children.
Our survey has certain limitations. It relied on re-
spondents’ knowledge and experience, and questions
were answered on how participating radiation oncolo-
gists (would) act in specific situations. Since some of the
cases described in this survey are relatively rare, to
ensure a minimum of clinical experience, only centres
irradiating at least 50 children annually were invited to
participate [29]. All participants irradiated at least one
Fig. 3. Percentages of centres indicating which imaging modalities were used to define (and delineate) the target volume for a metastatic
site, such as bone, brain, lymph nodes, lung and liver. Abbreviations: PET,Positron Emission Tomography;MRI,Magnetic Resonance
Imaging and MIBG/SPECT:iodine-123-metaiodobenzylguanidine/single-photon emission computed tomography.
Fig. 4. Percentages of departments using conventional only (in blue), stereotactic only (in yellow) or both techniques (in green) for
metastatic disease categorised by site and per primary tumour (between brackets (N)Znumber of centres that indicated to irradiate with
curative intent) Abbreviations: RMS,rhabdomyosarcoma; STS,soft-tissue sarcoma; ES,Ewing sarcoma; NBL,neuroblastoma and R,renal
tumours. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
S.C. Huijskens et al. / European Journal of Cancer 145 (2021) 121e131128
patient of the type being surveyed (median 6, range
1e37), annually. Although smaller centres were not
invited for the survey, this study reflects on current
radiotherapy practices applicable to the whole paediat-
ric radiotherapy community.
In addition, our protocol review and survey focussed
on radiotherapy procedures with curative intent for
metastatic disease at primary diagnosis and makes no
recommendations for radiotherapy on metastatic sites in
the context of salvage or palliation. The role of radio-
therapy to metastatic sites as part of a salvage approach
at the time of disease relapse is best discussed on an
individual basis within a multidisciplinary team or by
contacting experts in the field. In the context of pallia-
tion, hypofractionation radiotherapy with a variety of
fractions and doses can easily be applied mainly
depending on the tumour type, site and life expectancy.
The next step towards further consensus is to set up a
radiotherapy working group for ST with primary met-
astatic disease to discuss the total- and fraction dose-
related issues per site, age group and per disease cate-
gory, and tackling issues like normal tissue tolerance
and biologically effective dose calculations. To
understand tumour control and side-effects, taking into
account the potential variables, large registries are
needed.
In conclusion, the present study reviewed the radio-
therapeutic approach for metastatic sites in current
European paediatric ST study protocols. A survey
across SIOPE-affiliated centres unveiled consistencies
and differences regarding patient selection and treat-
ment characteristics. A collaboration of experts from
leading paediatric radiotherapy departments is needed
to reach consensus on the local approach of metastatic
sites. This is essential to set up prospective (randomised)
trials to generate more evidence on the first-line radio-
therapy to metastatic sites in stage IV disease.
Authors contributions
Study concepts: P.S. Kroon, E. Seravalli, G.O. Janssens.
Study design: P.S. Kroon, E. Seravalli, G.O.
Janssens.
Data acquisition: All co-authors.
Quality control of data and algorithms: S.C.
Huijskens, P.S. Kroon, G.O. Janssens.
Fig. 5. Details regarding immobilization devices (upper panel) and position verification methods (lower panel) used for conventional (left
bar) and stereotactic (right bar) planning techniques indicated per metastatic site. The number between the brackets indicates the number
of centres reporting the use of conventional and/or stereotactic planning techniques.
S.C. Huijskens et al. / European Journal of Cancer 145 (2021) 121e131 129
Data analysis and interpretation: S.C. Huijskens, P.S.
Kroon, G.O. Janssens.
Statistical analysis: NA.
Manuscript preparation: S.C. Huijskens, P.S. Kroon,
E. Seravalli, G.O. Janssens.
Manuscript editing: All co-authors.
Manuscript review: All co-authors.
Funding and role of the funding source
Stichting Kinderen Kankervrij [project no. 343].
KiKa (Children Cancer Free) foundation, grant
number 343 and title: Towards optimization of radio-
therapy 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.
Conflict of interest statement
None declared.
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S.C. Huijskens et al. / European Journal of Cancer 145 (2021) 121e131 131
... In patients with residual tumors, the availability of on-board functional imaging (DWI, ADC) may help to individualize the treatment fractions [17][18][19][20]. Although rarely integrated in current pediatric protocols, a comprehensive local approach including adiotherapy to metastatic sites in children, in line with tackling oligometastatic disease in adults, is an interesting option for upcoming study protocols [25]. Therefore, in our opinion assessing the added value of MRgRT is essential to understand for which indications this technology should be introduced/used. ...
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Importance Complete metastatic ablation of oligometastatic prostate cancer may provide an alternative to early initiation of androgen deprivation therapy (ADT). Objective To determine if stereotactic ablative radiotherapy (SABR) improves oncologic outcomes in men with oligometastatic prostate cancer. Design, Setting, and Participants The Observation vs Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) phase 2 randomized study accrued participants from 3 US radiation treatment facilities affiliated with a university hospital from May 2016 to March 2018 with a data cutoff date of May 20, 2019, for analysis. Of 80 men screened, 54 men with recurrent hormone-sensitive prostate cancer and 1 to 3 metastases detectable by conventional imaging who had not received ADT within 6 months of enrollment or 3 or more years total were randomized. Interventions Patients were randomized in a 2:1 ratio to receive SABR or observation. Main Outcomes and Measures The primary outcome was progression at 6 months by prostate-specific antigen level increase, progression detected by conventional imaging, symptomatic progression, ADT initiation for any reason, or death. Predefined secondary outcomes were toxic effects of SABR, local control at 6 months with SABR, progression-free survival, Brief Pain Inventory (Short Form)–measured quality of life, and concordance between conventional imaging and prostate-specific membrane antigen (PSMA)–targeted positron emission tomography in the identification of metastatic disease. Results In the 54 men randomized, the median (range) age was 68 (61-70) years for patients allocated to SABR and 68 (64-76) years for those allocated to observation. Progression at 6 months occurred in 7 of 36 patients (19%) receiving SABR and 11 of 18 patients (61%) undergoing observation (P = .005). Treatment with SABR improved median progression-free survival (not reached vs 5.8 months; hazard ratio, 0.30; 95% CI, 0.11-0.81; P = .002). Total consolidation of PSMA radiotracer-avid disease decreased the risk of new lesions at 6 months (16% vs 63%; P = .006). No toxic effects of grade 3 or greater were observed. T-cell receptor sequencing identified significant increased clonotypic expansion following SABR and correlation between baseline clonality and progression with SABR only (0.082085 vs 0.026051; P = .03). Conclusions and Relevance Treatment with SABR for oligometastatic prostate cancer improved outcomes and was enhanced by total consolidation of disease identified by PSMA-targeted positron emission tomography. SABR induced a systemic immune response, and baseline immune phenotype and tumor mutation status may predict the benefit from SABR. These results underline the importance of prospective randomized investigation of the oligometastatic state with integrated imaging and biological correlates. Trial Registration ClinicalTrials.gov Identifier: NCT02680587
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Hypofractionated radiotherapy is attractive concerning patient burden and therapy costs, but many aspects play a role when it comes to assess its safety. While exploited for conventional photon therapy and carbon ion therapy, hypofractionation with protons is only rarely applied. One reason for this is uncertainty in the described dose, mainly due to the relative biological effectiveness (RBE), which is small for protons, but not negligible. RBE is generally dose-dependent, and for higher doses as used in hypofractionation, a thorough RBE evaluation is needed. This review article focuses on the RBE variability in protons and associated issues or implications for hypofractionation.
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Background: The oligometastatic paradigm suggests that some patients with a limited number of metastases might be cured if all lesions are eradicated. Evidence from randomised controlled trials to support this paradigm is scarce. We aimed to assess the effect of stereotactic ablative radiotherapy (SABR) on survival, oncological outcomes, toxicity, and quality of life in patients with a controlled primary tumour and one to five oligometastatic lesions. Methods: This randomised, open-label phase 2 study was done at 10 hospitals in Canada, the Netherlands, Scotland, and Australia. Patients aged 18 or older with a controlled primary tumour and one to five metastatic lesions, Eastern Cooperative Oncology Group score of 0-1, and a life expectancy of at least 6 months were eligible. After stratifying by the number of metastases (1-3 vs 4-5), we randomly assigned patients (1:2) to receive either palliative standard of care treatments alone (control group), or standard of care plus SABR to all metastatic lesions (SABR group), using a computer-generated randomisation list with permuted blocks of nine. Neither patients nor physicians were masked to treatment allocation. The primary endpoint was overall survival. We used a randomised phase 2 screening design with a two-sided α of 0·20 (wherein p<0·20 designates a positive trial). All analyses were intention to treat. This study is registered with ClinicalTrials.gov, number NCT01446744. Findings: 99 patients were randomised between Feb 10, 2012, and Aug 30, 2016. Of 99 patients, 33 (33%) were assigned to the control group and 66 (67%) to the SABR group. Two (3%) patients in the SABR group did not receive allocated treatment and withdrew from the trial; two (6%) patients in the control group also withdrew from the trial. Median follow-up was 25 months (IQR 19-54) in the control group versus 26 months (23-37) in the SABR group. Median overall survival was 28 months (95% CI 19-33) in the control group versus 41 months (26-not reached) in the SABR group (hazard ratio 0·57, 95% CI 0·30-1·10; p=0·090). Adverse events of grade 2 or worse occurred in three (9%) of 33 controls and 19 (29%) of 66 patients in the SABR group (p=0·026), an absolute increase of 20% (95% CI 5-34). Treatment-related deaths occurred in three (4·5%) of 66 patients after SABR, compared with none in the control group. Interpretation: SABR was associated with an improvement in overall survival, meeting the primary endpoint of this trial, but three (4·5%) of 66 patients in the SABR group had treatment-related death. Phase 3 trials are needed to conclusively show an overall survival benefit, and to determine the maximum number of metastatic lesions wherein SABR provides a benefit. Funding: Ontario Institute for Cancer Research and London Regional Cancer Program Catalyst Grant.