Acta Ophthalmologica 2020

Second-line therapy in young patients with relapsed

or refractory orbital rhabdomyosarcoma
Ofira Zloto,1,2 Veronique Minard-Colin,3 Helene Boutroux,4 Herve J. Brisse,5 Christine Levy,6
Frederic Kolb,7 Stephanie Bolle,8 Matthieu Carton,9 Sylvie Helfre10 and Daniel Orbach2
1
Goldschleger Eye Institute, Sheba Medical Center, Affiliated with The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv,
Israel
2
SIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), Institut
Curie, PSL University, Paris, France
3
Pediatric Adolescent Young Adult Department, Institut de Cancerologie, Gustave Roussy Cancer Campus (GRCC), Villejuif,
France
4
Department of Pediatric Hematology and Oncology, Trousseau Hospital (AP-HP), Paris, France
5
Imaging Department, Institut Curie, Paris, France
6
Ophthalmology Department, Institut Curie, Paris, France
7
Plastic Surgery Department, Institut de Cancerologie, Gustave Roussy Cancer Campus (GRCC), Villejuif, France
8
Radiation Oncology Department, Institut de Cancerologie, Gustave Roussy Cancer Campus (GRCC), Villejuif, France
9
Department of Biostatistics, Institut Curie, PSL University, Paris, France
10
Radiotherapy Department, Institut Curie, Paris, France

ABSTRACT. Introduction
Objective: Localized orbital rhabdomyosarcoma (oRMS) has an overall
favourable prognosis with more than 90% of survival. Little is known about Rhabdomyosarcoma (RMS) is the
the best strategy in recurrent/refractory (R/R) cases. The purpose is to examine most common soft tissue sarcoma in
the characteristics of patients with R/R-oRMS, focusing on local therapy. children (Doyle, 2014). It accounts for
Methods: This is bicentric retrospective study. Analysis is of young patients 4.5% of all paediatric malignant neo-
(<30 years) with R/R-oRMS who were treated from 1989 to 2018 at the Institut plasms, with an incidence of 4.5/
Curie and Gustave Roussy Cancer Campus, France. 1 000 000 cases (Ray & Huh, 2012).
Results: Twenty-seven out of 162 patients (17%) with oRMS presented with R/R This tumour can be ubiquitous, but the
disease. 6 of these patients had alveolar RMS (22%), 3 of whom had initial main primaries are found in the head
parameningeal extension (11%). During first-line treatment, 18 patients (67%) had and neck, genitourinary tract or
orbital radiotherapy. Median age at R/R was 10 years (ranges: 4–28) after a delay of extremities. Forty per cent of cases
19 months from diagnosis (ranges: 3–40). Tumoral events were local relapses (22 involve the head and neck area (Hicks
cases), local progression (3 cases) or regional relapses (2 cases). Second-line & Flaitz, 2002), while the eye socket is
treatments included chemotherapy (27 cases), radiotherapy (16 cases), surgery the primary site in approximately 10%
(exenteration; 8 cases) and metastasis/ nodal removal (3 cases). After a median follow- of all new cases of RMS (Crist et al.,
up of 99 months (range: 10–306), 4 patients died and 23 arein complete remission(CR) 1995). In two-thirds of all cases, orbital
without treatment. One patient had subsequent relapse treated with exenteration and RMS causes rapidly progressive prop-
brachytherapy until a new tumour remission. Five-year event-free and overall survivals tosis, globe displacement, restriction of
after first tumour event are, respectively, 84.4% (95% confidence interval: 71.5%– eye motility and a palpable mass
98.8%) and 85.8% (95% confidence interval: 72.1%–100.0%) (Shields & Shields, 2003). Rhab-
Conclusion: R/R-oRMS is a rare situation. Second-line therapy is efficient in domyosarcoma (RMS) have been sep-
this location, sometime at the cost of lifesaving mutilating surgery. Second-line arated into 3 different anatomical
local therapy needs therefore to consider local radiotherapy if possible or groups: non-parameningeal orbital
complete wide surgery. tumours, non-orbital cranial para-
meningeal tumours and non-para-
Key words: biostatistics – cancer – oculoplastic – orbit – orbital rhabdomyosarcoma meningeal tumours of the head and
neck. Orbital rhabdomyosarcomas
Acta Ophthalmol.
mostly arise from extra-ocular muscles,
ª 2020 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd but also include lesions developed from
eyelids. These tumours can present
doi: 10.1111/aos.14596 local extension to parameningeal

1
Acta Ophthalmologica 2020
structures: roof orbit osteolysis, sphe-
noid, optical nerve and maxillary or
ethmoidal sinuses. In these latter cases,
orbital RMS are classified as ‘para-
meningeal’ primary. The prognosis dif-
fers according to the site of the primary
tumour. Multivariate analyses in the
various clinical trials have demon-
strated that the primary site is a prog-
nostic factor independent of stage and
histology. In addition, the site determi-
nes the quality of local therapy. The
sequelae and functional prognosis are
directly related to the primary site and
the treatment administered to achieve
complete remission (surgery and/or
radiotherapy).
In the 1960s, the 5-year survival
rates for orbital RMS (oRMS) with
exclusive orbital exenteration were
25%–30% (Shields & Shields, 2003).
However, over the last 30 years, with
the development of a multimodal
approach involving a combination of
chemotherapy drugs and local control
mainly with radiotherapy, there was a
significant improvement in the 5-year
survival rate of patients with primary
oRMS of more than 90% (Breneman
et al., 2003; Shields & Shields, 2003;
Clement et al., 2016).
Despite the high rate of survival,
relapse or refractory oRMS (R/R-
oRMS) can occur and seems to bear a
significantly poor prognosis in older
series (Raney et al., 2000; Chisholm
et al., 2011; Raney, Crist, Maurer, &
Foulkes, 1983). There are no estab-
lished standardized treatment guideli-
nes for those patients. Therefore,
patients are treated with various com-
binations of multi-drug chemotherapy,
radiotherapy, brachytherapy and dif-
ferent types of surgery (Chisholm et al.,
2011; Raney et al., 2000). The role of
local therapy, especially orbital exen-
teration after prior radiotherapy, is still
unclear.
Therefore, the purpose of this study
is to examine the clinical, treatment
and prognostic characteristics of
patients with relapsed or refractory
oRMS, focusing on the role of salvage
local therapy in order to define a
strategy adapted to this situation.
Methods
Patients
Medical records of all consecutive
patients diagnosed with oRMS, with
2
or without parameningeal extension,
who were treated at the Institut Curie,
Paris and Gustave Roussy Cancer
Campus, Villejuif, France, from Jan-
uary 1998 to December 2018 were
retrospectively reviewed. These two
centres provide car for all paediatric
patients with solid tumours from 0 to
25 years living in the Ile-de-France
area (12.2 million inhabitants in 2019,
including 3.13 under 20 years old).
Data collection
The following data were retrieved for
all patients with oRMS during their
first and second disease events (Don-
aldson et al., 1986): clinical presenta-
tion, tumour staging (IRS grouping
system), histology, initial and relapse
therapies, as well as outcome. The
ocular examination was performed
with Snellen visual acuity converted
to log of the minimum angle of reso-
lution values at time of diagnosis,
relapse and the end of follow-up.
Histological diagnosis was manda-
tory and the decisive step for diagnosis.
The objective of histological diagnosis
is therefore to establish the malignant
nature of the tumour, document its
striated muscle and mesenchymal ori-
gin (rhabdomyosarcoma), and provide
prognostic criteria, such as the rhab-
domyosarcoma subtype and the differ-
entiated or undifferentiated nature of
the cells. Histological subtypes were
internationally classified as ‘alveolar’
when a zone of alveolar histology was
observed or when a specific fusion
transcript was detected with molecular
biology, otherwise tumours were con-
sidered as ‘embryonal’, ‘botryoid’ or
‘not specified’.
Lymph node involvement was eval-
uated clinically and via imaging, and
confirmed with cytology or histology
when necessary. Distant disease staging
was established with a 99mTechnetium
bone scan, chest computed tomogra-
phy and bone marrow evaluation (bone
marrow aspirations and biopsies).
Post-surgical staging was classified
according to the IRS grouping system,
a post-surgical staging system known to
be an independent prognostic factor for
RMS in general. In short, IRS-I corre-
sponds to a complete tumour resection
with histologically clear margins, IRS-II
corresponds to a macroscopic resection
with invaded histological margins and
IRS-III corresponds to a macroscopic
residual tumour. Biopsy alone with no
surgical resection was also classified as
IRS-III (Crist et al., 1995).
Initial treatment
Chemotherapy regimens
All patients followed Malignant Mes-
enchymal Tumor of the International
Pediatric Oncology Society (SIOP-
MMT-95) and European Pediatric Soft
Tissue Sarcoma Group’s (EpSSG-RMS
05) protocols as first-line chemotherapy
(Stevens, 2005; Odile Oberlin et al.,
2012; Bisogno et al., 2018).
Local therapy
Initial surgery was only recommended
for small orbital tumours when a com-
plete resection was expected, especially
for eyelid primaries. For all other
situations, only a biopsy was manda-
tory at diagnosis. Baseline strategy
consisted of first-line neoadjuvant
chemotherapy to reduce and evaluate
tumour response. According to the
SIOP-MMT95 protocol, in some
patients with favourable tumour char-
acteristics, like a non-parameningeal
primary, with complete radiological
remission (CR) after 3 cycles, under
10 years old, with small tumours
(<5 cm) and non-alveolar histology,
no further local therapy was possible
and these patients were treated exclu-
sively with chemotherapy in order to
reduce the total burden of local therapy
(Rodary et al., 1991; Flamant et al.,
1998; Boutroux et al., 2014a). On the
contrary, orbital irradiation (range:
45–55 Gy) was systematically planned
for patients with an incomplete
response after primary chemotherapy
or with poor initial prognostic factors,
such as alveolar histology, large
tumours and/or parameningeal exten-
sion. In EpSSG-RMS 2005 protocol,
radiotherapy was more systematic
according to histotype, tumour
response and resection (range: 36–
55.8 Gy).
Complete remission (CR) was
defined as no imaging or clinical signs
of the disease after first-line therapy
were finished. However, in case of low
orbital residue after first-line therapy,
according to the international defini-
tion, CR was defined as no image
modifications occurring at least
6 months after the end of the last
treatment (Chisholm et al., 2011; Rod-
ary et al., 1991; Winter, Fasola, Brisse,

Mosseri, & Orbach, 2015). Relapses
were defined as patients who had a new
tumoral event (locally or in a distant
site) after a complete remission.
Refractory disease was defined as
patients with tumoral progression at
any time without any previous remis-
sion. Second CR was defined as a CR
after a second-line therapy.
As no specific treatment guidelines
have been defined for relapsed RMS,
the usual recommendations included a
new complete radiological, clinical and
laboratory assessment, similar to the
one performed at diagnosis. Che-
motherapy regimens for relapse
depended on the drugs previously
received for induction and were left to
the physician’s discretion (Stevens,
2005; Boutroux et al., 2014a; O Oberlin
et al., 2001). As a general concept, after
tumour reduction, local therapy
included orbital irradiation if patients
did not previously have radiotherapy
and/or extensive surgery for a local
relapse after initial radiotherapy. The
purpose of the surgery, mainly orbital
exenteration, was to have a complete
excision with free margins (R0 sur-
gery). ‘Total exenteration’ included
removing all intra-orbital components
including the eye, orbital fat and mus-
cles with eyelids if an initial MRI
showed tumoral extension in this last
site, while a ‘subtotal exenteration’ did
not include the eyelid resection
(Nabavi, 2017).
Follow-up assessment
Long-term side-effects were graded
according to the Common Terminol-
ogy Criteria for Adverse Effects
(Health & Institute, 2017). An oph-
thalmological evaluation was per-
formed regularly during follow-up, at
the cancer centres or by a local oph-
thalmologist, and included the follow-
ing: external palpebral and orbital
examination, best corrected visual acu-
ity, slit-lamp examination, measure-
ment of intraocular pressure and
ophthalmoscopy.
Statistical analysis
Quantitative variables were described
as median and range. Categorical vari-
ables were described with absolute and
relative frequencies. A chi-squared test
was performed in order to compare
categorical variables between patients
that underwent irradiation with those
who did not. t-Test analyses were
carried out in order to compare quan-
titative variables between patients who
underwent irradiation with those who
did not. The overall significance level
was set at a = 0.05. The statistical
analysis was carried out using Micro-
soft Excel 2017 (Microsoft Corpora-
tion, Redmond, WA) and IBM SPSS
software version 24.0 (SPSS, Inc.,
Chicago, IL, USA). Event-free and
overall survivals were calculated with
the Kaplan–Meier analysis.
This study complied with the refer-
ence methodology MR-004 from the
Commission Nationale de
l’Informatique et des Libertes (CNIL).
Institutional review board approval
was obtained.
Results
Demographics
Among the 162 patients with orbital
RMS treated during this period, 27 (22
male and 5 female, median age 6 years,
range 1.8–26.5 years) were diagnosed
with relapsed or refractory orbital
RMS (R/R-oRMS), which represents
17% of the population. None of these
patients had a family history of cancer
or other personal history of cancer.
Initial tumoral characteristics
At diagnosis, 22 patients (81%) had
exclusive orbital involvement while 5
patients (19%) had eyelid involvement.
Overall, one lesion (4%) was IRS-I,
three lesions (11%) were IRS-II and 23
lesions (85%) were IRS-III. Three
patients (11%) had initial para-
meningeal involvement. No metastasis
was found in patients upon presenta-
tion.
Twenty RMS (74%) were embry-
onal subtype, 6 cases (22%) were his-
tologically alveolar RMS and one
Table 1. Clinical presentation at first event (27 patients).
Clinical presentation and examination
Presenting initial symptoms
Swelling
Pain
Diplopia
Decreased visual acuity
Eye involvement
Right eye
Left eye
Median Visual Acuity (range) of the affected eye
Acta Ophthalmologica 2020
lesion (4%) unspecified histological
type. Among the 6 alveolar RMS, only
one had FOXO1-positive fusion, a
tumour molecular translocation asso-
ciated with an aggressive behaviour in
alveolar rhabdomyosarcomas (Arnold
et al., 2016). The clinical presentation is
summarized in Table 1.
All patients were initially treated
with systemic chemotherapy except
one initially treated in Africa. Five of
them (19%) reached a complete radio-
logical remission (CR) after 3 cycles of
chemotherapy. Therefore, they did not
receive any radiotherapy. Three other
patients with IRS-I, and IRS-II tumour
were not assessable for tumour
response and did not receive radiother-
apy. One additional patient (4%) had a
germline P53 mutation and was not
treated with irradiation. All others 18
patients (67%) received orbital irradi-
ation according to protocols. No
patient had delayed surgery. Details
of initial therapy are summarized in
Table 2.
At the end of the first-line therapy,
24 patients (89%) were in CR after a
median time of 6.5 months from diag-
nosis (range: 2.3–14.1).
Second tumoral event
A relapse occurred in 24 patients after a
median delay of 17 months (range, 6–
41). Among them, 22 patients (92%)
had isolated local orbital relapse and 2
patient (8%) developed regional relapse
to the parotid and mandibula nodes.
Median age at diagnosis of the
second tumoral event was 7.7 years
old (4–28). During the tumoral event,
21 patients (96%) had orbital involve-
ment and 1 patient (4%) an eyelid
involvement. New biopsies were per-
formed for 5 patients (18.5%) and
confirmed the tumour relapse.
Three additional patients (11%) had
progressive disease during first-line
Number of cases Per cent of cases
23 85
2 7
1 4
1 4
14 52
13 48
0.22 (0–1.3) -
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Acta Ophthalmologica 2020

Table 2. Characteristics of treatment delivered during first-line therapy (27 patients). embryonal disease. One of them (13%)
had parameningeal involvement. None
Characteristics of the treatment Number of cases Per cent of cases
of them had lymph node involvement or
Type of chemotherapy: metastasis at the time of the second
IVA 18 67 tumoral event. Seven of these patients
Other regimens 4 14 (87%) were initially treated with a first-
6-drug regimen 3 11 line therapy including chemotherapy
VAC 1 4 and orbital irradiation.
No chemotherapy 1 4 One patient reached CR after induc-
Median number of chemotherapy courses (range) 9 (4–9)
tion chemotherapy. He did not get
Type of irradiation:
No radiotherapy 9 33 radiotherapy because he had ataxia–
Photon therapy 9 33 telangiectasia. His second-line therapy
Proton therapy 8 30 after tumour relapse included
Proton therapy + Photon therapy 1 4 chemotherapy. Due to the absence of
Median irradiation dosage Gy (range) 50.4 (30–55) response in tumoral volume after this
therapy, he underwent orbital exenter-
6 drugs = IVA, carboplatin, etoposide, epirubicin; Gy = Gray; IVA = Ifosfamide, Actinomycin-
D, Vincristine; VAC = Vincristine, Actinomycin-D, Cyclophosphamide.
ation.
Two patients underwent total orbital
exenteration (25%), while 6 patients
(75%) had subtotal orbital exentera-
Table 3. Characteristics of second-line therapy after tumoral event.
tion with free flap, local flap and
Characteristics of the treatment Number of patients Per cent of patients median forehead flap. Complete free
margins (R0) were found in 7 cases,
Chemotherapy: and one patient underwent comple-
Yes 27 100 mentary lower eyelid resection to
No 0 0
reach complete resection. All of them
Type of chemotherapy:
Various regimens*,+ 12 44
received perioperative chemotherapy
6-drug regimen+ 8 30 (Table 3), and one patient (13%) had
VIT 4 15 additional irradiation of 54 Gy. At the
VAC 2 7 end of follow-up, all of them are alive
VA 1 4 in CR out of treatment.
Median number of chemotherapy courses (range) 6 (1-11)
Radiotherapy:
Yes 16 59 Characteristics of patients according to
No 10 37 first-line treatment with or without orbital
Unknown 1 4 irradiation
Type of irradiation:
Proton therapy 12 75 Eight patients (89%) who did not
Photon therapy 4 25 receive irradiation during their first line
Median irradiation dosage (range) 50.4 (20-57) of therapy underwent irradiation as
Exenteration: local therapy after the second tumoral
Yes 8 30 event. One patient (11%) underwent
No 19 70
orbital exenteration without irradiation
Metastasis/Nodal removal
Yes 3 11
due to ataxia–telangiectasia.
No 0 89 Orbital radiotherapy was used in 18
patients as first-line therapy at a
VA = Actinomycin-D, Vincristine, VAC = Vincristine, Actinomycin-D, Cyclophosphamide, median dose of 50.4 Gy. Among those
VIT = Vincristine, Irinotecan, Temozolomide. 18 patients, 3 patients (17%) had
* Various regimens with IVA = Ifosfamide, Vincristine, Actinomycin-D, CEV = Carboplatin, progressive disease, 2 patients (11%)
Etoposide, Vincristine, VCyDE = Bortezomib, Cyclophosphamide, Dexamethasone, ICE = Ifos-
had regional relapse, and 13 patients
famide, Carboplatin, Etoposide. Other regimens include a combination of doxorubicin,
carboplatin, ifosfamide, epirubicin, etoposide, vincristine, irinotecan, vinorelbine and cisplatin. (72%) had a relapse in the previous
+
CEV/IVA/IVE. orbital irradiated area.
Eight (44%) out of the 18 patients
who were irradiated in the first-line
therapy were re-irradiated: six of them
therapy. Two of the patients with tumoral event, which allowed 24 (75%) to the entire orbital area and 2
progressive disease (67%) developed patients (89%) to go into a second of them (25%) to the regional nodes
metastasis during the follow-up period. CR after a median of 7 months (3–14). area. The re-irradiation was after a
Metastasis involved the breast, lungs median delay of 581 days following
and bones. They underwent metastatic first irradiation (365–4674 days). The
Orbital exenteration group
lesion removal. median cumulative orbital dose after
Table 3 summarizes the second-line Eight patients were treated with orbital re-irradiation was 98.6 Gray (range:
therapy delivered after a second exenteration. All of them had an 70.4–112).

4

Table 4. Comparative analysis of patients according to delivered radiotherapy during first-line
therapy.
Histological subtype:
Embryonal
Alveolar
Unspecified
Initial parameningeal involvement:
Yes
No
CR after initial first 3 chemotherapy cycles:
Yes
No
Not assessable
CR at the end of first-line therapy:
Yes
No
Median time (months) from
CR to second event (range)
Second event – distant metastasis:
Yes
No
Exenteration after tumoral event:
Yes
No
Irradiation after tumoral relapse/progression:
Yes
No
CR at the end of second-line therapy:
Yes
No
Median time (months) from
second event to subsequent CR (range)
Alive at the end of the follow-up
Yes
No
CR = complete remission.
* Statistically significant.
Table 4 summarizes therapeutic
characteristics’ differences between
patients who underwent previous irra-
diation to those who did not, during
their first-line therapy.
Outcome
The median follow-up time of the pop-
ulation was 60 months from the first
tumoral event (10–306 months). Over-
all, 4 patients (15%) died, 3 after
tumoral progression and 1 from a
mucoepidermoid ethmoidal carcinoma
with cerebral and cavernous sinus
involvement. Among the 23 patients
who were in second CR after the treat-
ment, 22 patients remained in second
CR and 1 had subsequent local relapse
treated with subtotal exenteration and
orbital brachytherapy with 55 Gy.
Acta Ophthalmologica 2020
led to an ocular phthisis requiring a
late secondary enucleation. Therefore,
11 of the survivors (48%) underwent
Previous
No irradiation radiotherapy exenteration or enucleation.
Number Number of
of patients (%) patients (%) p Value Discussion
0.09 In accordance with previous studies
9 (43) 11 (57) that demonstrate the rarity of oRMS
0 6 (100)
failure (10% to 30%), in our bicentric
0 1 (100)
0.20
study, the absolute rate of patients with
0 3 (100) R/R-oRMS was 17% (Mannor et al.,
9 (37) 15 (63) 1997; Pappo et al., 1999; Raney et al.,
0.01* 2013). However, our experience shows
5 (100) 0 that second-line therapies are effective
1 (5) 18 (95) in such situations with survival rates up
3 (100) 0 to 85%, but only in such cases with an
0.22
active strategy including mutilating
9 (38) 15 (62)
0 (0) 3 (100)
surgery in up to 48% of the cases,
22 (9–29.1) 14 (3.3–29.5) 0.13 and the need for re-irradiation in 35%
of them. In summary, 11/23 of sur-
0.71 vivors had mutilating surgery with eye
0 3 (100) removal or exenteration.
9 (37) 15 (63) Rhabdomyosarcoma (RMS) is a
0.11 tumour with striated muscle differenti-
1 (12) 7 (88)
ation arising at the expense of non-
8 (42) 11 (58)
0.11
osseous support tissue. It is essentially
8 (50) 6 (50) a paediatric tumour, as the median age
1 (9) 10 (91) of onset of orbital RMS is 6.8 years (1–
0.22 17). Two onset peaks have been
9 (37) 15 (63) described: early childhood, between
0 3 (100) the ages of 2 and 5 years, and adoles-
5.6 (2.6–19.3) 7.6 (3.3–35.5) 0.06 cence, between the ages of 15 and
19 years, with a global male predomi-
0.14
9 (39) 14 (61)
nance (sex ratio: 1.5). Orbital non-
0 4 (100) parameningeal lesions are observed in
10% of all sites. Rhabdomyosarcoma
(RMS) is a relatively rapid-growing
tumour. Orbital RMS remains con-
fined to local or regional tissues for a
long time. 70% of children with forms
Twenty-three (85%) were alive after localized to the orbit are confined to
therapy. Five-year event-free and over- the organ or tissues of origin (stage T1)
all survivals after first tumour event and 30% involve contiguous organs or
are, respectively, 84.4% (95% confi- tissues (stage T2). Lymph node inva-
dence interval: 71.5%–98.8%) and sion is also uncommon, and metastatic
85.8% (95% confidence interval: lesions (stage IV) are rare (2%–2.7%)
72.1%–100.0%) (Figure 1). in primary cases such as these (Bou-
In regard to side-effects, 4 patients troux et al., 2014b). Considering the
(15%) had long-term chronic keratitis excellent prognosis of orbital RMS,
(grade 4 in 2 cases, grade 2 in 1 case reducing these late effects is an impor-
and grade 1 in 1 case), 4 (15%) had tant part of the local treatment strat-
grade II temporal depression, and one egy.
(4%) had grade I hypothyroidism. Management of orbital RMS at
The ocular prognosis of the 23 diagnosis is multidisciplinary, compris-
survivors including 9 who had been ing chemotherapy, conservative sur-
exenterated (8 during the treatment of gery and radiotherapy, for which the
the second event and one after the third indications, time of administration and
event) and 2 additional patients who modalities vary from country to coun-
had severe chronic keratitis after orbi- try. Rhabdomyosarcoma is a chemo-
tal irradiation (after a cumulative dose and radiosensitive tumour. Some inter-
of 50.2 and 85.2 Gy, respectively) that national cooperative groups examined
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Acta Ophthalmologica 2020
Fig. 1. Survival and event-free survival curve.
the efficacy and the role of orbital
radiotherapy as first-line therapy in
orbital primaries. The Intergroup
Rhabdomyosarcoma Study Group
and the Children’s Oncology Group’s
philosophies were that radiotherapy
should be given to practically all
patients in order to reach a high local
control rate of the disease (Pappo et al.,
1999). The drawbacks of this approach
resulted from the ocular side-effects of
this treatment, which included severe
dry eyes that can cause perforation,
cataracts, lacrimal system dysfunction,
retinal damage, visual acuity impair-
ment and failed orbital bone growth
causing the face to become disfigured
(Raney et al., 2000; Stevens, 2005).
Therefore, the SIOP-MMT strategy
was quite different and recommended
an initial biopsy followed by immediate
chemotherapy (O Oberlin et al., 2001;
Stevens et al., 2005). In cases of a
complete radiological response after 3
cycles of chemotherapy in patients with
favourable risk factors (age <10 years
old, non-alveolar subtype and non-
parameningeal primary), orbital radio-
therapy could be omitted in order to
reduce long-term side-effects. The pur-
pose of this adapted strategy was to
6
reduce the long-term effects of the
therapy, but the risk of local relapse
(42%) was higher in the SIOP-MMT
group than in the one from the Chil-
dren’s Oncology Group study. How-
ever, they considered that radiotherapy
on tissue in the eye and orbit could be
avoided in approximately 40% of
patients with an orbital tumour, in
contrast to the Intergroup Rhab-
domyosarcoma Study Group study
for which almost all survivors received
radiotherapy (94%). Nevertheless, one
should also consider that second-line
therapy should contain an additional
line of chemotherapy, which mainly
leads to an elevated cumulative dose of
alkylating agents, for all these patients.
The main conclusion after comparing
both strategies (Children’s Oncology
Group versus SIOP-MMT) was that an
adapted overall strategy in orbital
RMS causes a higher risk of local
relapses, but overall survivals were
similar (Odile Oberlin et al., 2012).
In our study, in agreement with this
strategy, 33% of patients were not
initially treated with radiotherapy. In
almost all patients, this was due to CR
after first rounds of chemotherapy and
in one patient because he had a
germline P53 mutation. When compar-
ing the groups that underwent irradia-
tion with the one that did not have
irradiation, we found that all patients
with tumoral events without any pre-
viously irradiation are alive after sec-
ond-line therapy. This confirm again
the overall safety of this adapted
approach. Although not statistically
significantly different, cases of mortal-
ity only occurred in the group of
patients initially irradiated. This is
probably due to the fact that these
cases had initially worse predictive
factors.
Local control of the tumour is cru-
cial in obtaining long-term survivals,
even after tumoral events. Among the
23 patients with orbital R/R disease
alive at the end of follow-up, 13
underwent first-time irradiation, 9
underwent exenteration and 5 re-irra-
diation. Therefore, in order to reach
complete local tumour control, more
than 1/3 of patients needed orbital
exenteration. Orbital exenteration is a
broad, absolute surgical procedure that
involves removing the entire eyeball,
muscles, fat, nerves and in some cases
even the eyelids. It is usually done only
for refractory orbital malignancies. At
the end of the procedure, the area is
packed for haemostasis and a local or
free flap is usually inserted to fill the
cavity’s void and provide a more
favourable aesthetic appearance. Three
to four weeks later, if there are no
complications, an orbital prosthesis
(i.e. epithesis) can be fitted. In this
current series, most of the patients
(71%) that underwent exenteration
underwent subtotal exenteration (with
preservation of the eyelids). In cases
where eyelid involvement is suspected
on the diagnostic MRI showing
relapse, the eyelids must also be
removed to ensure a complete resection
of the tumour. The main purpose of
this surgery is to remove all the tumour
en-bloc to obtain R0 margins. How-
ever, in our series, all patients received
several lines of chemotherapy and
orbital radiotherapy to try to control
the disease in a more conservative way
before receiving this mutilating sur-
gery. In all orbital exenteration cases,
second CR was achieved with surgery
(R0: 8/8 cases) and all patients were
alive at the end of follow-up, confirm-
ing that this strategy is an efficient
curative treatment. Patients who need
to undergo orbital exenteration should

be managed by a multidisciplinary
team that includes paediatric oncolo-
gists, ophthalmologists, plastic sur-
geons, radiation oncologists,
psychologists and social workers in
order to decide the procedure and to
inform the family and patients about
this type of surgery. Good communi-
cation between all of these disciplines
will make it possible to optimize treat-
ment-related decisions and ensure sup-
portive long-term follow-up for those
patients and their family. In order to
try and reduce the aesthetic conse-
quences, magnetic or bone-anchored
epithesis is typically proposed to
patients (Kesting et al., 2017).
In this cohort, almost half of the
previously irradiated patients were re-
irradiated, mostly at the orbital site.
Notably, this re-irradiation – while
generating a high cumulative dose –
has allowed the cure of some patients,
with 63% of them alive at the end of
follow-up. With this high cumulative
dose of irradiation, however, the long-
term risks of ophthalmologic dysfunc-
tion are significant (Boutroux et al.,
2015). Consequently, all paediatric
patients who had orbital irradiation
and especially re-irradiation need to
have close long-term ophthalmologic
follow-up to detect corneal, retinal or
orbital dysfunctions. This strategy of
re-irradiation after a local tumour
relapse is also used in other paediatric
tumours like ependymoma (Regnier
et al., 2019). In our opinion, re-irradi-
ation can be offered to very carefully
selected patients. It can be discussed
after exenteration in cases of positive
margins or unresectable parameningeal
involvement upon recurrence. More-
over, it may be discussed for patients
with limited irradiation fields at diag-
nosis and/or late relapse.
In conclusion, the treatment of the
second tumoral event in children and
young adults with orbital RMS should
be in accordance with the first delivered
therapy. Best strategy should be dis-
cussed by a multidisciplinary team and
take into account the family’s opinion.
However, in all cases, intensive second-
line multi-drug chemotherapy regimens
should be included. Local treatment
should be irradiation for patients who
did not undergo radiation during first-
line therapy or for selected patients
who can undergo second irradiation
(second irradiation can be mainly used
in cases of a long delay between the
first and second tumoral events). For
patients who developed local disease
and underwent previous orbital irradi-
ation and cannot undergo second irra-
diation, orbital exenteration should be
recommended. We believe that
although orbital exenteration has a
strong long-term impact on patient’s
self-esteem and quality of life, it is a
lifesaving salvage treatment.
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Received on February 7th, 2020.
Accepted on July 9th, 2020.
Correspondence:
Ofira Zloto, MD
The Goldschleger Eye Institute
Sheba Medical Center
Tel Hashomer
Israel
Tel 972-03-5302321
Fax: 972-3-5302822
Email: ozloto@gmail.com
This research received no specific grant from any
funding agency in the public, commercial or not-
for-profit sectors. All authors certify that they have
no affiliations with or involvement in any organi-
zation or entity with any financial interest (such as
honoraria; educational grants; participation in
speakers’ bureaus; membership, employment, con-
sultancies, stock ownership, or other equity interest;
and expert testimony or patent-licensing arrange-
ments), or non-financial interest (such as personal
or professional relationships, affiliations, knowledge
or beliefs) in the subject matter or materials
discussed in this manuscript.