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\begin{document}

\title{Alveolar rhabdomyosarcoma with regional nodal involvement: results of a
combined analysis from two cooperative groups}



\author[1]{Soledad Gallego}%
\author[2]{Yueh-Yun Chi}%
\author[3]{Gian Luca De Salvo}%
\author[4]{Minjie Li}%
\author[5]{Johannes Merks}%
\author[6]{David A. Rodeberg}%
\author[7]{Sheila Terwisscha van Scheltinga}%
\author[8]{Leo Mascarenhas}%
\author[9]{Daniel Orbach}%
\author[10]{Meriel Jenney}%
\author[11]{Lynn Million}%
\author[12]{Veronique Minard-Colin}%
\author[13]{Suzanne Wolden}%
\author[14]{Ilaria Zanetti}%
\author[2]{David Parham}%
\author[15]{Henry Mandeville}%
\author[16]{Rajkumar Venkatramani}%
\author[17]{Gianni Bisogno}%
\author[18]{Douglas Hawkins}%
\affil[1]{University Hospital Vall d'Hebron}%
\affil[2]{Children’s Hospital Los Angeles}%
\affil[3]{Istituto Oncologico Veneto}%
\affil[4]{University of Florida}%
\affil[5]{Utrecht University}%
\affil[6]{East Carolina University}%
\affil[7]{Princess Maxima Center}%
\affil[8]{Children's Hospital Los Angeles}%
\affil[9]{Institut Curie}%
\affil[10]{University of Wales Cardiff}%
\affil[11]{Stanford Hospital}%
\affil[12]{Gustave Roussy}%
\affil[13]{Memorial Sloan Kettering Cancer Center}%
\affil[14]{University-Hospital of Padova, Division of Hematology/Oncology,}%
\affil[15]{The Royal Marsden NHS Foundation Trust}%
\affil[16]{Baylor College of Medicine}%
\affil[17]{Division of Hematology/Oncology}%
\affil[18]{Seattle Children's Hospital}%


\vspace{-1em}



  
  \date{May 18, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background: Treatment of children and adolescents with alveolar
rhabdomyosarcoma (ARMS) and regional nodal involvement (N1) have been
approached differently by North American and European cooperative
groups. In order to define the better therapeutic strategy, we analyzed
two studies conducted between 2005 and 2016 by the European paediatric
Soft tissue sarcoma Study Group (EpSSG) and Children's Oncology Group
(COG). Methods: We retrospectively identified patients with ARMS N1
enrolled in either EpSSG RMS2005 or in COG ARST0531. Chemotherapy in
RMS2005 comprised IVADo (ifosfamide, vincristine, dactinomycin,
doxorubicin), IVA and maintenance (vinorelbine, cyclophosphamide); in
ARST0531 it consisted on either VAC (vincristine, dactinomycin,
cyclophosphamide) or VAC alternating with VI (vincristine, irinotecan).
Local treatment was similar in both protocols. Results: The analysis of
the clinical characteristics of 239 patients showed some differences
between study groups: in RMS2005, advanced IRS Group and large tumors
predominated. There were no differences in outcomes between the two
groups: 5-year event-free survival (EFS), 49\% (95\%CI=39-59) and 44\%
(95\%CI=30-58), and overall survival (OS), 51\% (95\%CI=41-61) and
53.6\% (95\%CI=40-68), in RMS2005 and ARST0531, respectively. In
RMS2005, EFS of patients with FOXO1-positive tumors was significantly
inferior to those FOXO1-negative (49.3\% vs 73\%, p=0.034). In contrast,
in ARST0531, EFS of patients with FOXO1-positive tumors was 45\%
compared with 43.8\% for those FOXO1-negative. Conclusions: The outcome
of patients with ARMS N1 was similar using different schemas of
chemotherapy. However, patients with FOXO1 fusion-negative tumors
enrolled in RMS2005 showed a significantly better outcome, suggesting
that this subgroup may benefit from the EpSSG strategy which included
maintenance chemotherapy.%
\end{abstract}%



\sloppy


\emph{1. INTRODUCTION}

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in
children and adolescents and comprises two major histologic subtypes:
alveolar RMS (ARMS) and embryonal RMS (ERMS) {[}1-3{]}.

The prognosis of RMS has improved considerably over time due to numerous
clinical trials conducted by collaborative groups working in North
America: Intergroup Rhabdomyosarcoma Study Group (IRS) and Children's
Oncology Group (COG), and in Europe: International Society of Paediatric
Oncology-Malignant Mesenchymal Tumour Group (SIOP-MMT), Italian Soft
Tissue Sarcoma Committee-STSC, Gesellschaft Cooperative Soft Tissue
Sarcoma Study Group-CWS and more recently, EpSSG (European paediatric
Soft tissue sarcoma Study Group). Despite this successful history, the
improvement in the prognosis of patients with RMS has not been uniform.
While the probability of cure in pediatric patients with localized
disease is over 70\%, the prognosis of those with distant metastatic
disease remains poor {[}4-8{]}, and the presence of disseminated disease
at diagnosis continues to be the most powerful prognostic factor in this
neoplasm.

For patients with localized RMS, clinical and tumor characteristics are
used to classify RMS in different risk categories and to determine
treatment intensity. These characteristics include histology, tumor
invasiveness, tumor location, nodal involvement, tumor size and patient
age {[}9-11{]} and they constitute the basis for the risk stratification
system used in North America by COG and in Europe by EpSSG. Patients
with ARMS and regional lymph node involvement represent approximately
5-10\% of all cases of RMS in children and adolescents. Previous
experience suggested that these patients represent a group with
particularly poor prognosis {[}9{]}.

In the EpSSG RMS2005 study, we stratified these patients into a very
high risk (VHR) category and treated them with an intensified regimen of
chemotherapy that included doxorubicin added to the standard schema of
IVA (ifosfamide, vincristine, and dactinomycin) in the first 4 cycles,
followed by 5 cycles of IVA and six cycles of intravenous vinorelbine
and daily oral cyclophosphamide {[}12{]}. During the same period, COG
conducted the ARST0531 study for intermediate risk RMS patients that
included those with non-metastatic ARMS at any primary site without
distant metastases; these patients were randomly assigned to receive the
standard schema VAC (vincristine, dactinomycin, and cyclophosphamide) or
VAC alternating with VI (vincristine, irinotecan) for 42 weeks {[}13{]}.

Herein we report the results of a combined analysis of patients with
ARMS and regional nodal involvement enrolled in the aforementioned
studies, and we compare these results to determine which therapy
optimizes survival.

\emph{2. PATIENTS AND METHODS}

\emph{2.1. Patients}

For the purpose of this analysis eligible patients were those with:

a. Alveolar rhabdomyosarcoma confirmed by histology \textbf{and}

b. Regional nodal involvement defined by clinical
\textbf{or}radiological \textbf{or} pathologic criteria, without distant
metastases, \textbf{and}

c. Enrolled in protocol EpSSG RMS2005, between November 1, 2005 and
December 31, 2016 \textbf{or}

d. Enrolled in protocol COG ARST0531, between December 1, 2006 and
December 31, 2012.

Date of data cutoff for the analysis were: Dec 31, 2019 for RMS2005 and
Dec 31, 2018 for ARST0531.

\emph{2.2. Treatment}

2.2.1\textbf{.} \emph{EpSSG RMS2005}

Patients received intensified induction chemotherapy and additional
maintenance chemotherapy with systematic local treatment to primary and
nodal sites. Induction chemotherapy comprised four 21-day cycles of
IVADo (ifosfamide 3 g/m\textsuperscript{2} on days 1-2 with MESNA,
vincristine 1.5 mg/m\textsuperscript{2} {[}max dose 2 mg{]} on days 1, 8
and 15 in the first 2 cycles and on day 1 in cycles 3 and 4,
dactinomycin 1.5 mg/m\textsuperscript{2} {[}max dose 2 mg{]} on day 1,
and doxorubicin 30 mg/m\textsuperscript{2} on days 1-2) followed by five
21-day cycles of IVA and six 28-day cycles of maintenance chemotherapy
comprising continuous daily oral cyclophosphamide 25 mg/m\selectlanguage{ngerman}² and
intravenous vinorelbine 25 mg/m² on days 1, 8 and 15 of each cycle. The
total duration of chemotherapy was 50 weeks.

Response was evaluated at weeks 9, 27 and at the end of treatment. If
free margins were achievable without organ or functional impairment,
local treatment after the initial 4 cycles of IVADo (week 13) included
delayed surgical resection. External beam radiotherapy was administered
to the primary tumor area and the affected lymph node region, delivered
using a daily dose per fraction of 1.8 Gy. Doses varied according to
chemotherapy response and surgical results. The total dose to the
primary tumor following delayed surgery with complete resection was 41.4
Gy. For IRS Group III with incomplete resection, or when delayed surgery
was not feasible, total dose was 50.4 Gy with an optional additional
boost of 5.4 Gy in 3 fractions for large tumors with poor response to
chemotherapy. Radiotherapy (RT) was recommended for involved lymph nodes
at a dose of 41.4 Gy regardless of the extent of surgical resection.

2.2.2\emph{. COG ARST531}

Patients were randomly assigned to receive either VAC (vincristine 1.5
mg/m\textsuperscript{2} {[}max dose 2 mg{]}, dactinomycin 0.045 mg/kg
{[}max dose 2.5 mg{]}, cyclophosphamide 1.2 g/m\textsuperscript{2} with
MESNA) or VAC alternating with VI (vincristine 1.5
mg/m\textsuperscript{2}, irinotecan 50 mg/m\textsuperscript{2} on 5
consecutive days) intravenously. During the first 12 weeks, the two
treatment arms were identical in duration and schedule, with the
exception of substituting irinotecan for dactinomycin and
cyclophosphamide at week 4 and for cyclophosphamide at week 7 in VAC/VI.
During the subsequent 30 weeks of therapy, irinotecan replaced
dactinomycin and cyclophosphamide at weeks 16, 19, 25, 31, and 37 in
VAC/VI. The schedule of vincristine differed slightly between the two
treatment regimens, allowing for its administration during the weeks
that followed all courses of irinotecan, but the total number of
vincristine doses was the same in both regimens. The total duration of
chemotherapy was 42 weeks.

Patients were evaluated for response at weeks 15 and 30 and at the end
of therapy. For patients older than 24 months, definitive RT was the
planned local control modality. Delayed primary resection was allowed
but not encouraged. For patients younger than 24 months, individualized
local control approaches, including delayed primary excision and
response-adapted RT, were permitted. RT started at week 4, and the dose
was determined by clinical group and histology at study entry: IRS Group
II ARMS with regional lymph node involvement, 41.4 Gy; IRS Group III
ARMS with orbital primary site, 45 Gy; and non-orbital primary sites,
50.4 Gy. RT was delivered using megavoltage photon, proton, and/or
electron beams. For tumors with a rapid substantial decrease in tumor
size, a volume reduction by cone down after 36 Gy was permitted,
particularly for tumors with pushing rather than infiltrating margins.

\emph{}

\emph{2.3. Statistical analysis}

Survival time was calculated from the date of diagnosis to the time of
event or last follow-up. Tumor progression, relapse, occurrence of
second malignancy, or death due to any cause were considered for event
free survival (EFS). Overall survival (OS) was measured from the date of
diagnosis to death from any cause. Patients still alive at the end of
the study were censored at the date of the last observation. Survival
probability was calculated by the Kaplan-Meier method and heterogeneity
in survival among strata of selected variables was assessed with the
Log-Rank test {[}14{]}. Five-year EFS and OS were reported along with
their 95\% confidence intervals (CI) as computed using the Peto-Peto
method {[}15{]}. The Cox proportional hazards models were fit to compare
EFS and OS while adjusting for potential confounders. Categorical
variables were reported as counts and percentages and compared using
Fisher's Exact test. All data analyses were performed using the SAS
statistical package (SAS, release 9.4; SAS Institute Inc., Cary, NC,
USA).

\emph{}

\emph{3. RESULTS}

\emph{3.1. Patient characteristics}

The clinical characteristics of 154 patients enrolled in EpSSG RMS2005
and 85 patients enrolled in COG ARST0531 are presented in \textbf{Table
1.}

Adverse prognostic factors including tumor size \textgreater{} 5 cm,
advanced IRS Group and tumor location at unfavorable sites, predominated
in both cohorts. Large tumors (\textgreater{}5 cm) were more frequent in
EpSSG than in COG patients: 71\% \emph{vs} 53\%, respectively, (p-value
0.0029). IRS Group III tumors were also more frequent in the EpSSG than
in the COG cohort: 93\% \emph{vs} 80\%, respectively, (p-value 0.0027).
Tumor location at unfavorable sites (parameningeal, limbs,
bladder-prostate, other sites) (79\% in EpSSG and 84\% in COG) and
invasiveness (T-stage 2, 60\% in EpSSG and 65\% in COG), were similar in
both cohorts.

Fusion status of tumors, determined by the presence of
\emph{FOXO1}translocation (regardless of the \emph{PAX} fusion partner),
was analyzed in 81\% of patients in EpSSG and in 93\% in COG.
\emph{FOXO1}translocation, when \emph{FOXO1} fusion status was known
(76\% in EpSSG and 79\% in COG), was similar in both series.

Histological analysis of nodal involvement was performed less frequently
(50\%) in patients enrolled in EpSSG (nodal biopsy was not mandatory in
RMS2005, except for tumors arising in extremities), as compared to COG
(81\%) (p-value 0.0035).

\emph{3.2. Treatment}

Systemic and local treatment given to patients in both protocols are
detailed in \textbf{Table 2} . One hundred and forty-five (145) patients
who were enrolled in RMS2005 (94\%) received chemotherapy according to
protocol, 8 patients received IVA without doxorubicin, and 1 patient
received IVA followed by VA. All patients included in ARST0531 received
chemotherapy according to protocol: 44 received VAC and 41 VAC/VI.

Radiotherapy to the site of primary tumor and nodes was administered in
132 (86\%) and 82 (97\%) patients enrolled in RMS2005 and ARST0531,
respectively (Table 2). A significantly higher proportion of patients in
EpSSG did not receive RT for the following reasons: parent refusal (2),
early progression (6), amputation (2), very young age (1) and treatment
center decision (7). Four patients received nodal RT only. The most
common type of radiotherapy in both series was photon external beam, and
a minority of patients in both protocols received proton beam
radiotherapy.

In the EpSSG cohort, 75 out of 154 patients (49\%) underwent surgical
resection of the primary tumor: up-front primary resection in 10/75
(13\%) and delayed primary resection in 65/75 (87\%). Results of surgery
included complete local resection (R0) in 55 (73\%), microscopic
residual disease (R1) in 14 (19\%), and macroscopic residual (R2) in 6
(8\%). In the COG cohort, 22 out of 85 patients (26\%) underwent
surgical resection of the primary tumor: up-front primary resection in
17/22 (77\%) and delayed primary resection in 5/22 (23\%). R0 was
achieved in 20 (91\%) and R1 in 2 (9\%).

\emph{3.3. Outcome and prognostic factors}

The median follow-up of patients was 5.2 years in COG study and 5.4
years in EpSSG. At the time of the analysis, 45 patients in the COG
cohort had relapsed, of whom, 38 died (37 by disease progression and 1
by an unrelated disease). Seventy-eight patients in the EpSSG cohort had
relapsed, 69 of whom died (66 by disease progression, 2 by toxic deaths
and 1 by a second neoplasm). Outcomes of patients (EFS and OS) included
in the study are detailed in \textbf{Table 3} . The 5-year EFS of the
COG cohort was 44\% (95\% CI: 30.0-58.1) compared with 49\% (95\% CI
38.8-59.3) of the EpSSG. The 5-year OS was 53.6\% in COG (95\% CI
39.6-67.7) and 51\% in EpSSG (95\% CI 40.9-60.9) (\textbf{Figure 1} ).
There were no differences in EFS or OS between the analytic cohort of
RMS2005 and ARST0531. These results held when EFS (p=0.2) and OS
(p=0.28) were compared while adjusting for tumor size, nodal status and
IRS Group (I/II \emph{vs} III). In the combined analysis of both
cohorts, outcomes by \emph{FOXO1} fusion status showed 5-year EFS of
63\% for patients with fusion-negative tumors (95\% CI
44.6-81.0)\emph{vs} 47.6\% for fusion-positive (95\% CI 37.2-58.1). The
5-year OS for patients with fusion-negative tumors was 69\% (95\% CI
51.7-86.3) compared with 52.7\% (95\% CI 42.6-62.9), for
fusion-positive.

However, results from each cohort showed striking differences on the
impact of the presence of \emph{FOXO1} fusion on prognosis. In EpSSG,
the 5-year EFS of patients with \emph{FOXO1} fusion-positive tumors
(49.3\%, 95\% CI 35.8-62.8) was significantly inferior to those
with\emph{FOXO1} fusion-negative ones (73\%, 95\% CI 53.0-92.8)
(p=0.034). In contrast, COG patients showed no differences between these
two groups: The EFS of COG patients with \emph{FOXO1} fusion-positive
tumors was 45.1\% (95\% CI 28.8-61.5) compared with 43.8\% (95\% CI
6.6-80.9\%) of \emph{FOXO1} fusion-negative (\textbf{Figure 2} ).

Five-year OS of patients with \emph{FOXO1} fusion-positive tumors in the
EpSSG cohort was 51.6\%, compared with 76\% of
\emph{FOXO1}fusion-negative and approached significance (p=0.069). In
contrast, there were no differences in the outcomes between COG patients
with fusion-positive or fusion-negative tumors (53.7\% and 56.2\%,
respectively) (\textbf{Figure 3} ).

The pooled COG and EpSSG 5-year EFS and OS did not show statistically
significant differences by location of primary tumor.

The site of the first relapse was also similar in both cohorts
(\emph{Supplementary Table S4} ). Metastatic relapses with or without
local recurrence represented half of the relapses in both protocols.
Loco-regional relapses represented 35\% and 29\% of all recurrences in
COG and EpSSG cohorts, respectively. Tumor progression during treatment
occurred in 13\% of the patients in COG and 18\% in EpSSG.

\emph{4. DISCUSSION}

The combined analysis of the results of these two cooperative studies
suggests that different strategies of chemotherapy may have an impact in
the outcome of a subgroup of patients with ARMS and regional nodal
involvement.

The prognosis of patients with ARMS N1 has been reported to be poor in
the historical series of European co-operative studies. In the CWS-86
study, 3-year EFS was 25\% and OS 29\% {[}11{]}. In the SIOP MMT84
study, 5-year EFS was 31\% comparable to that of stage IV disease
{[}16{]}.

The experience of similar patients in North American cooperative groups
has been better than that of the European studies. Of 125 patients with
localized RMS and nodal involvement enrolled in the IRS-IV study,
Rodeberg et al {[}17{]} reported 43\% five-year failure-free survival of
patients with ARMS and nodal involvement. The overall outcome of
patients with alveolar histology and N1 disease reported in that study
was similar to that of patients with metastatic disease at a single
site.

We recently reported the experience of EpSSG RMS2005 {[}12{]} in
patients with ARMS N1 and showed results similar to the IRS-IV study.
The reasons for this apparent improvement in the outcome of these
patients, compared to those treated within previous European studies,
could be due in part to better risk stratification, more adequate
treatment with intensified chemotherapy, systematic local treatment
and/or improvement in supportive care.

Failures among patients reported in the present study were predominantly
with metastatic disease and was similar in both cohorts. Their tumors
frequently presented with advanced IRS Group and unfavorable location,
characteristics related to an increased risk of distant metastatic
disease {[}18-20{]}. Local recurrences represented one-third of all
relapses in both protocols and local treatment in RMS2005 and in
ARST0531 was identical. However, Casey et al {[}21{]} reported more
loco-regional relapses in patients enrolled in ARST0531 compared with
the previous COG intermediate-risk RMS study, D9803. The reasons for
this increase in local relapses were not clear but may have been related
to changes in cyclophosphamide dosing, changes in RT administration and
fewer surgical procedures.

The most important difference between EpSSG and COG protocols was the
type of chemotherapy. Patients received three different regimens based
on the use of the standard combination (IVA in EpSSG and VAC in COG) to
which was added doxorubicin and 6 months of maintenance chemotherapy
with vinorelbine and cyclophosphamide in the European study or
irinotecan in the North American study. In RMS2005, doses of alkylating
agents included 54 g/m\textsuperscript{2} of ifosfamide plus 4.5
g/m\textsuperscript{2} of cyclophosphamide. In contrast, COG patients
received 16.8 g/m\textsuperscript{2} (VAC) or 8.4
g/m\textsuperscript{2}of cyclophosphamide (VAC/VI). Moreover, patients
in EpSSG received doxorubicin at a total dose of 240
mg/m\textsuperscript{2}. One-half of the patients in COG received
irinotecan. Total duration of chemotherapy was 42 weeks in COG protocol
\emph{vs} 50 weeks in EpSSG.

There is no evident advantage of adding doxorubicin or irinotecan to the
standard chemotherapy in these patients. Hawkins et al {[}13{]} have
previously reported a lack of improvement with the addition of
irinotecan to VAC in the same of group of patients as the present
analysis. The European experience demonstrated that the addition of
doxorubicin to IVA in patients with high-risk disease also failed to
improve outcome when compared to standard chemotherapy {[}22{]}.
Moreover, previous experiences in Europe demonstrated that the addition
of carboplatin, etoposide, and epirubicin did not improve the outcome
for patients with high-risk disease enrolled in the SIOP MMT-95 study
{[}8{]}. In RMS2005, two toxic deaths and one secondary neoplasm
occurred, so that when designing future studies, we consequently should
search for a balance between the total burden of chemotherapy and the
risk of toxicity.

The impact of \emph{FOXO1} fusion status in the outcome of patients in
both cohorts showed important differences. In the European study,
fusion-positive tumors had significantly worse EFS as well as a trend
toward inferior OS, while the EFS/OS of patients enrolled in the COG
study was the same whether they had fusion-positive or fusion-negative
tumors. These contradictory results are intriguing. Numerous studies
have reported the impact of fusion status on the outcome of patients
with ARMS {[}23-25{]}. However, this impact could be different in
patients with other adverse prognostic factors. For example, in patients
classified as low or intermediate risk in COG studies, the presence
of\emph{FOXO1} fusion has a strong impact in prognosis {[}25,26{]} while
in patients of high risk with metastatic disease, the clinical
prognostic factors have a stronger impact than the fusion status
{[}27{]}. However, these observations do not explain the differences we
observed between our two homogeneous cohorts. In the European study the
EFS of patients with fusion-negative tumors was 73\%, similar to that of
patients considered as high risk in the same protocol {[}22{]}.

We can hypothesize that those patients with fusion-negative tumors
benefit from a more intense chemotherapy. Patients in ARST0531 received
a lower cumulative dose of cyclophosphamide than in previous COG RMS
studies, with a possible negative impact on outcome {[}13{]}. In
contrast, patients with ARMS N1 in RMS2005 could have had a benefit from
the addition of maintenance chemotherapy, similar to the results of
high-risk patients {[}28{]}.

However, our study presents some limitations, such as the relatively
small number of patients with fusion-negative tumors in both cohorts,
and the higher proportion of patients with fusion status unknown in the
EpSSG cohort, which could reduce the precision of the EFS estimations.

In conclusion, there are some lessons learned from the present combined
analysis that should be further explored in the upcoming studies of both
cooperative groups: First, very different treatment strategies in two
concurrent clinical trials generated similar outcomes for patients with
ARMS and regional lymph node involvement. Second, among patients
with\emph{FOXO1} fusion-negative ARMS and regional lymph node
involvement, the cumulative dose of alkylators and/or maintenance
chemotherapy may influence outcome and, third, a need persists for
innovative therapeutic strategies for those patients with
fusion-positive tumors.

\emph{}

\emph{Potential conflicts of interest:} The author(s) indicated no
potential conflicts of interest.

\emph{Disclaimer:}

The content is solely the responsibility of the authors and does not
necessarily represent the official views of the National Institutes of
Health.

\textbf{Acknowledgements}

We are indebted to all children and families that participated in the
trials.

\emph{Author's contribution:}\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
Conceptualization, formal analysis, investigation, methodology, writing
and editing & Soledad Gallego, Johannes H.M. Merks, David A. Rodeberg,
Sheila Terwisscha van Scheltinga, Leo Mascarenhas, Daniel Orbach, Meriel
Jenney, Lynn Million, Veronique Minard-Colin, Suzanne Wolden, David M.
Parham, Henry Mandeville, Rajkumar Venkatramani, Gianni Bisogno, Douglas
S. Hawkins\tabularnewline
\midrule
\endhead
Collection and assembly of data, data analysis and interpretation &
Yueh-Yun Chi, Gian Luca de Salvo, Minjie Li, Ilaria
Zanetti\tabularnewline
Approval of the final version of the manuscript & All
authors\tabularnewline
\bottomrule
\end{longtable}



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\textbf{FIGURE LEGENDS}

Figure 1 Kaplan-Meier curves representing 5-year EFS (A) and 5-year OS
(B), by protocol.

\textbf{Figure 2} Kaplan-Meier curves representing 5-year \textbf{EFS by
fusion status} in separated cohorts, (A) EpSSG RMS2005 and (B) COG
ARST0531.

\textbf{Figure 3} Kaplan-Meier curves representing 5-year \textbf{OS by
fusion status} in separated cohorts (A) EpSSG RMS2005 and (B) COG
ARST0531.\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/ARMSN1-Figure-3/ARMSN1-Figure-3}

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