Received: 10 September 2021 Revised: 1 November 2021 Accepted: 20 November 2021

DOI: 10.1002/pbc.29511 Pediatric

Blood &
Cancer The American Society of
Pediatric Hematology/Oncology
REVIEW

An update on rhabdomyosarcoma risk stratification and the

rationale for current and future Children’s Oncology Group
clinical trials

Josephine H. Haduong1 Christine M. Heske2 Wendy Allen-Rhoades3 Wei Xue4

Lisa A. Teot5 David A. Rodeberg6 Sarah S. Donaldson7 Aaron Weiss8
Douglas S. Hawkins9 Rajkumar Venkatramani10
1
Division of Oncology, Hyundai Cancer Institute, Children’s Hospital Orange County, Orange, California, USA
2
Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
3
Division of Pediatric Oncology, Mayo Clinic, Rochester, Minnesota, USA
4
Department of Biostatistics, College of Public Health and Health Professions and College of Medicine, University of Florida, Gainesville, Florida, USA
5
Department of Pathology, Boston Children’s Hospital/Harvard Medical School, Boston, Massachusetts, USA
6
Division of Pediatric Surgery, East Carolina University, Greenville, North Carolina, USA
7
Department of Radiation Oncology, Stanford University, Stanford, California, USA
8
Division of Pediatric Hematology-Oncology, Maine Medical Center, Portland, Maine, USA
9
Division of Hematology/Oncology, Seattle Children’s Hospital, University of Washington, Seattle, Washington, USA
10
Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas, USA

Correspondence
Josephine H. Haduong, Hyundai Cancer Insti- Abstract
tute, Division of Oncology, Children’s Hospi-
tal Orange County, 1201 West La Veta Ave,
Children and adolescents with rhabdomyosarcoma (RMS) comprise a heterogeneous
Orange, CA 92868, USA. population with variable overall survival rates ranging between approximately 6% and
Email: [email protected]
100% depending on defined risk factors. Although the risk stratification of patients has
been refined across five decades of collaborative group studies, molecular prognostic
biomarkers beyond FOXO1 fusion status have yet to be incorporated prospectively in
upfront risk-based therapy assignments. This review describes the evolution of risk-
based therapy and the current risk stratification, defines a new risk stratification incor-
porating novel biomarkers, and provides the rationale for the current and upcoming
Children’s Oncology Group RMS studies.

KEYWORDS
MYOD1, rhabdomyosarcoma, TP53

Abbreviations: ARMS, alveolar rhabdomyosarcoma; CG, clinical group; CI, confidence interval; COG, Children’s Oncology Group; CPMPO , daily oral cyclophosphamide; CR, complete response;
EFS, event-free survival; EpSSG, European Paediatric Soft Tissue Sarcoma Study Group; ERMS, embryonal rhabdomyosarcoma; FFS, failure-free survival; HR, hazard ratio; HR-RMS, high-risk
rhabdomyosarcoma; IR-RMS, intermediate-risk rhabdomyosarcoma; IRS, Intergroup Rhabdomyosarcoma Study; LR-RMS, low-risk rhabdomyosarcoma; ORR, overall response rate; OS, overall
survival; PR, partial response; RMS, rhabdomyosarcoma; VA, vincristine, actinomycin; VAC, vincristine, actinomycin, cyclophosphamide; VI, vincristine irinotecan.

Pediatr Blood Cancer. 2022;69:e29511. wileyonlinelibrary.com/journal/pbc © 2022 Wiley Periodicals LLC 1 of 11

https://doi.org/10.1002/pbc.29511
2 of 11 HADUONG ET AL .

1 INTRODUCTION defined risk groups (low, intermediate, and high).15 The current IRS CG
system and the RMS TNM staging system are shown in Tables 1 and 2,
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma respectively.
in children and adolescents, accounting for approximately half of We validated these clinicopathologic factors in 2157 patients
all cases of soft tissue sarcoma in pediatrics in the United States.1,2 enrolled on the IRS V (D9602, D9802, and D9803) and the COG
Patients are assigned a risk group based on clinicopathologic features, ARST studies (ARST0331, ARST0431, ARST0531, and ARST08P1).
which then dictates treatment with multimodal therapy that may Patients ≥10 years old and those with tumors in unfavorable sites
include chemotherapy, surgery, and/or radiation therapy. Despite or with large tumors (>5 cm) had inferior outcomes (Figure 1A–C).
improvements, there continues to be significant variability in sur- Similarly, nodal involvement and CG were prognostic in this large
vival across risk groups, from overall survival (OS) rates of less than cohort of patients (Figure 2A,B), and patients with ARMS had an
20% for patients with high-risk RMS (HR-RMS) to rates greater inferior outcome compared to patients with ERMS (Figure 2C).
than 90% for patients with low-risk RMS (LR-RMS).3 The current As FOXO1 fusion status is a better prognostic classifier,6,7 it has
risk stratification system is based on findings from the Intergroup now replaced histology in the COG risk stratification for RMS
Rhabdomyosarcoma Study (IRS) trials I–IV.4 A key element of risk (Table 3).
stratification has been histology, and the two histologic subtypes that
consistently predict outcomes are embryonal RMS (ERMS) and
alveolar RMS (ARMS).5 Recent studies have demonstrated 2.2 Molecular factors
the importance of molecular features, with FOXO1 fusion sta-
tus a critical prognostic biomarker second only to metastatic Approximately 80% of tumors that are morphologically ARMS carry
status,6–8 providing the rationale for the incorporation of FOXO1 a FOXO1 fusion, whereas more than 95% of tumors that are mor-
fusion status into the current Children’s Oncology Group (COG) phologically ERMS have no FOXO1 fusion,16 and we now understand
intermediate-risk RMS (IR-RMS) study, ARST1431 (NCT02567435). that the presence or absence of the FOXO1 fusion gene drives the
However, additional molecular features that may be prognostic clinical behavior of RMS. Recent molecular diagnostics have uncov-
have yet to be utilized in the risk stratification of patients with ered features beyond FOXO1 fusion status, delineating novel molec-
RMS.9 ular biomarkers that have yet to be incorporated into RMS risk
In this article, we propose an updated risk stratification of RMS that stratification.
incorporates molecular features and provide the rationale for the cur-
rent and planned COG RMS studies for low-, intermediate-, and high-
risk RMS. 2.3 Fusion-positive rhabdomyosarcoma (FP-RMS)

The presence of a FOXO1 fusion refers to one of two chromoso-

2 RISK STRATIFICATION mal translocations—t(2;13) resulting in fusion of PAX3 to FOXO1 or
t(1;13) resulting in fusion of PAX7 to FOXO1. Although infrequent
2.1 Clinicopathologic factors rearrangements of the PAX3 gene (e.g., with NCOA1 or INO80D) have
been described, the rarity of these fusions preclude definitive out-
Since the first IRS trial in 1972, the approach to the treatment of come data. Because the FOXO1 translocation represents the most
patients with RMS has been risk based. IRS I and II employed a post- common translocation observed in patients with rhabdomyosarcoma
surgical clinical group (CG) that classified patients into CG I–IV based with well-defined outcome data, the term “fusion positive” in this
on the extent of surgical resection, lymph node status, and metastatic study refers to those harboring the FOXO1 fusion. Several retro-
disease.10,11 IRS I and II demonstrated that patients with CG I disease spective studies have found that FOXO1 fusion status is an inde-
maintained excellent outcomes with risk-adapted therapy, while those pendent prognostic factor in all risk groups except for patients with
with CG IV disease had poor outcomes despite aggressive treatment.12 metastatic disease.6,8,17,18 In a retrospective analysis that examined
Patients with CG II and III disease had variable outcomes and sub- FOXO1 fusion status in patients with histological ARMS and low-risk
sequent IRS protocols attempted to refine these subsets. IRS III and stage and group, patients with FP-RMS had worse outcomes than those
IV added a pretreatment TNM staging system and included primary with fusion-negative rhabdomyosarcoma (FN-RMS).17 In an analysis
tumor site (favorable/unfavorable) as a prognostic factor.13,14 The clas- of 434 patients treated on D9803, those with FN ARMS had similar
sification of site (favorable vs. unfavorable) has stayed largely consis- outcomes to those with ERMS, suggesting that fusion status rather
tent through the years, with the most recent change being that the bil- than histology is what drives unfavorable outcome.6 Finally, in the
iary tract/liver will again be considered unfavorable in future protocols. largest analysis published to date, 1727 evaluable patients from the
Favorable sites include the orbit, head and neck (non-parameningeal), IRS V and COG ARST studies were analyzed, and only metastatic sta-
and genitourinary (non-bladder/non-prostate), with all other sites con- tus surpassed FOXO1 fusion status as a poor prognostic predictor.8
sidered as unfavorable. The outcomes from IRS III and IV led to further ARST1431 is the first COG study to use FOXO1 fusion status in risk
refinement of risk-adapted therapy assignments with the creation of stratification.
HADUONG ET AL . 3 of 11

TA B L E 1 Intergroup Rhabdomyosarcoma Study clinical groups

Group Description
I Localized disease, completely resected (no regional lymph node involvement)
II (A–C) Localized disease, gross total resection with microscopic positive margins and/or evidence of regional spread

A. Grossly resected tumor with microscopic residual disease. No evidence of regional node involvement
B. Regional disease with involved nodes, completely resected with no microscopic residual disease, including
most distal node is histologically negative
C. Regional disease with involved nodes, grossly resected, but with evidence of microscopic residual disease
and/or histologic involvement of the most distal regional node (from the primary site) in the dissection

III Localized disease, incomplete resection with gross residual disease or biopsy only
IV Distant metastatic disease present at onset

TA B L E 2 Rhabdomyosarcoma TNM staging

Stage Site T Size N M

1 Orbit, head, and neck (excluding parameningeal), GU – T1 or T2 a or b N0 or N1 or M0
non-bladder/non-prostate Nx
2 Bladder/prostate, extremity, cranial parameningeal, othera T1 or T2 a N0 or Nx M0
(includes trunk, retroperitoneum, etc.)
3 Bladder/prostate, extremity, cranial parameningeal, othera T1 or T2 a N1 M0
(includes trunk, retroperitoneum, etc.)
b N0 or N1 or M0
Nx
4 Any T1 or T2 a or b N0 or N1 M1

Note: Tumor (T): T(site)1 (confined to anatomic site of origin) - a: ≤5 cm in diameter; b: >5 cm in diameter. T(site)2 (confined to anatomic site of origin) - a:
≤5 cm in diameter; b: >5 cm in diameter.
Regional nodes (N): N0 : regional nodes not clinically involved; N1 : regional nodes clinically involved by neoplasm defined as >1 cm by CT or MRI; Nx : clinical
status of regional nodes unknown (especially sites that preclude lymph node evaluation).
Metastasis (M): M0 : no distant metastasis; M1 : distant metastasis present.
a
Biliary tract/liver will be considered unfavorable site in future COG clinical trials.

TA B L E 3 Current Children’s Oncology Group rhabdomyosarcoma 5-year OS for patients with PAX3 fusions was significantly worse than
risk stratification for those with PAX7 fusions (39% vs. 74%, p = .001).7,19 However, this
Clinical finding may be confounded by the association of the PAX fusion partner
Risk group Stage group Age Fusion status with tumor age (≥10 years) and size (>5 cm).20 The prognostic signifi-
Low 1 I, II, III Any FOXO1− cance of the FOXO1 fusion partner will be prospectively evaluated on
(orbit only) ARST1431. Additionally, in the recently activated HR-RMS COG study
2 I, II (ARST2031), tumor tissue will be banked at diagnosis, end of therapy,
Intermediate 1 III Any FOXO1− and relapse, allowing for potential future studies, including those exam-
(non-orbit) ining the effects of alternative fusions seen in patients with ARMS.
1, 2, 3 I, II, III FOXO1+ FP-RMS tumors generally have a low mutational burden, but certain
2, 3 III FOXO1− gene amplifications may carry prognostic significance. Specifically, the
12q13-14 amplification results in overexpression of CDK4 and is asso-
3 I, II FOXO1−
ciated with worse survival (hazard ratio [HR] 2.25, p = .023 for failure-
4 IV <10 years FOXO1−
free survival [FFS] and HR 2.26, p = .04 for OS).21 Additionally, MYCN
High 4 IV ≥10 years FOXO1−
amplification has been associated with decreased survival in patients
Any FOXO1+
with ARMS, with a difference in FFS between those with high and low
MYCN expression (log-rank statistic = 5.82, p = .0158).22 The prog-
Some studies have suggested that the FOXO1 fusion partner (PAX3 nostic significance of CDK4 and MYCN amplification will be examined
or PAX7) may be prognostic. In a series of 287 patients with RMS, the prospectively in the current HR-RMS COG study, ARST2031.
4 of 11 HADUONG ET AL .

F I G U R E 1 Outcomes of 2157 patients enrolled on Intergroup Rhabdomyosarcoma Study (IRS) V (D9602, D9803, and D9802) and Children’s
Oncology Group (COG) ARST (ARST0331, ARST0531, ARST0431, and ARST08P1) studies based on clinical factors. (A) Event-free survival (EFS)
and overall survival (OS) by age at diagnosis; (B) EFS and OS by tumor site; (C) EFS and OS by tumor size

2.4 Fusion-negative rhabdomyosarcoma and spindle cell tumors that carry VGLL or NCOA translocations.
Although the presence of the translocations is pathognomonic for
FN-RMS has classically referred to tumors that do not harbor the congenital sclerosing/spindle cell RMS, the prognostic significance
FOXO1 fusion protein. However, these tumors may carry other rare of the fusion protein is not clear. FOXO1 FN-RMS tumors are
translocations. One example is very young patients with sclerosing more likely to carry single nucleotide point mutations, particularly
HADUONG ET AL . 5 of 11

F I G U R E 2 Outcomes of 2157 patients enrolled on Intergroup Rhabdomyosarcoma Study (IRS) V (D9602, D9803, and D9602) and Children’s
Oncology Group (COG) ARST (ARST0331, ARST0531, ARST0431, and ARST08P1) studies based on clinical factors. (A) Event-free survival (EFS)
and overall survival (OS) by nodal status; (B) EFS and OS by clinical group; (C) EFS and OS by histology

in the RAS pathway (NRAS, KRAS, HRAS) but also in other genes Mutations in MYOD1 (L122R) are associated with a sclerosing or
(FGFR4, PIK3CA, TP53, MYOD1).23 The prognostic significance of RAS spindle cell phenotype (without the VGLL or NCOA fusions described
mutations remains unclear. However, mutations in MYOD1 (L122R) above), typically seen in older children, and confer a dismal prognosis,
and TP53 are predictors of poor prognosis in patients with FN- with small case series describing survival rates of 0%–30%.26–28 A ret-
RMS.9,24,25 rospective analysis of pediatric RMS in the United States and United
6 of 11 HADUONG ET AL .

TA B L E 4 Current and planned Children’s Oncology Group rhabdomyosarcoma studies

Risk group Stage Clinical group Age Fusion status COG study Therapy
Very low 1 I Any FOXO1 ARST2032a VA × 24 weeks
Low 1 II, III (orbit only) Any FOXO1− (anticipated activation VAC/VA × 24 weeks
spring 2022)a
Low 2 I, II VAC/VA x 24 weeks

Intermediate 1 III (non-orbit) Any FOXO1− ARST1431 Randomization to:

1, 2, 3 I, II, III FOXO1+ VAC/VI x 42 weeks vs.
2, 3 III FOXO1− VAC/VI/Temsirolimus × 42 weeks
3 I, II FOXO1− +
4 IV <10 years FOXO1− Maintenance (CPMPO Vino) ×
24 weeks (all patients)

High 4 IV >10 years FOXO1− ARST2031 Randomization to:

Any FOXO1+ VAC x 42 weeks vs.
VinoAC × 42 weeks
+
Maintenance (CPMPO Vino) × 24
weeks (all patients)

Abbreviations: CPMPO , daily oral cyclophosphamide; VAC, vincristine, dactinomycin, cyclophosphamide regimen using cyclophosphamide dose of
1.2 g/m2 /cycle; Vino, vinorelbine; VinoAC, vinorelbine, dactinomycin, cyclophosphamide regimen using cyclophosphamide dose of 1.2 g/m2 /cycle.
a
Patients treated on VLR or LR arms of ARST2032 must have MYOD1/TP53 wildtype tumors.

Kingdom showed MYOD1 mutations in 3% (n = 17) of FN-RMS tumors 3.1 Low risk
(n = 515).9 In this cohort, the presence of the MYOD1 (L122R) mutation
resulted in uniformly dismal outcomes irrespective of clinical risk strat- Patients with LR-RMS comprise over a quarter of all patients with
ification, with an associated HR of 6.839 (3.468–13.507, p < .0001) in RMS and carry an excellent prognosis with a 4-year EFS of approx-
the 11 COG patients and an HR of 3.320 (1.212–9.099, p = .0133) in imately 90% following treatment with 48 weeks of vincristine and
the six UK patients. dactinomycin (VA, as in D9602) or 12 weeks of vincristine, dactino-
In a small series, TP53 mutations were seen in 20% of FN-RMS, and mycin, and cyclophosphamide (VAC) followed by 12 weeks of VA (as
the presence of a somatic TP53 mutation was associated with worse OS in ARST0331).29,30 In D9602, patients with ERMS were divided into
(HR 2.3 [1.0–4.9], p = .04).24 In the larger US and UK cohort (n = 515), subgroups A and B. Subgroup A included patients with Stage 1, CG
TP53 mutations were identified in 13% (n = 69) of FOXO1 FN tumors, I/IIA or CG III (orbit only), or Stage 2, CG I disease, and these patients
with uniform distribution across risk groups. Both cohorts demon- were treated with 48 weeks of VA chemotherapy. The 5-year FFS
strated a significantly worse prognosis for those with tumors harbor- and OS for subgroup A patients were 89% (95% confidence interval
ing TP53 mutations (US cohort: event-free survival [EFS] p = .0146; [CI]: 84%–92%) and 97% (95% CI: 90%–99%), respectively. Subset B
HR 1.973 [1.132–3.438], UK cohort: EFS p = .0055; HR 2.105 [1.230– patients included those with Stage 1/CG IIB/C, Stage 1/CG III (non-
3.604]).9 Patients with TP53 or MYOD1 mutated tumors may there- orbital), Stage 2/CG II, and Stage 3/CG I or II patients. These patients
fore benefit from a risk reassignment and potential intensification of also achieved good outcomes (5-year FFS 85% and OS 93%), albeit with
therapy. substantially more alkylator exposure (cumulative cyclophosphamide
dose 26.4 g/m2 over 44 weeks). In ARST0331, patients with ERMS
were divided into subsets 1 and 2, with definitions refined based on the
3 RATIONALE FOR CURRENT AND PLANNED outcomes from D9602. Subset 1 included patients with Stage 1/2, CG
COG RMS STUDIES I/II, or CG III (orbit only) disease who were treated with 12 weeks of
VAC followed by 12 weeks of VA in an attempt to decrease the duration
Based on the data presented above, we propose a revised risk strat- of therapy compared to D9602 while adding minimal alkylator therapy.
ification schema for future COG trials that incorporates molecular The 3-year FFS was 89% (95% CI: 85%–92%) and OS was 98% (95%
biomarkers (specifically MYOD1 and TP53 mutations) in treatment CI: 95%–99%).30 Subset 2 patients had suboptimal outcomes when
assignments. Below we describe the rationale for the current and the cumulative cyclophosphamide dose was decreased from 26.4 to
planned COG RMS studies across all three risk groups, summarized in 4.8 g/m2 and are now treated on the intermediate-risk trial, whereas
Table 4. subset 1 defines the current COG LR-RMS cohort. Recent literature
HADUONG ET AL . 7 of 11

has also shed light on the impact of the biliary tract, previously con- VAC followed by 12 weeks of VA. Patients who have MYOD1 or TP53
sidered a favorable site in D9602 and ARST0331. An analysis of 17 pathogenic mutations will be treated on study with 42 weeks of VAC
patients with localized biliary RMS treated on D9602 and ARST0331 therapy using a cumulative cyclophosphamide dose of approximately
revealed a 5-year EFS and OS of 70.6% and 76.5%, respectively.31 The 16.8 g/m2 .
biliary tract/liver site will be considered unfavorable in future studies. ARST2032 will be the first study to incorporate real-time molecu-
Most patients with Stage 1, CG I tumors in D9602 and ARST0331 lar risk stratification into a prospective cooperative group RMS clinical
had paratesticular disease. These patients achieved excellent out- trial and will simultaneously attempt to decrease therapy for the nearly
comes without alkylator therapy on D9602 (5-year EFS 96% and OS 15% of patients with RMS who have Stage 1, CG I disease.
100%),29 comparable to the outcomes seen on ARST0331 (3-year FFS
93% and OS 99%).30 IRS-IV also produced excellent outcomes among
the paratesticular patients <10 years (3-year FFS 90%) with the omis- 3.2 Intermediate risk
sion of cyclophosphamide and a shorter duration of therapy (36 weeks)
with VA. Finally, the recently concluded European Paediatric Soft Tis- Patients with IR-RMS represent the most heterogeneous risk group
sue Sarcoma Study Group (EpSSG) RMS 2005 trial showed excellent with 5-year EFS rates between 50%–75% and comprise more than
outcomes in their low-risk patients (non-alveolar histology, CG I, age half of newly diagnosed patients with RMS.8,35 The definition of what
<10 years, and tumor size ≤5 cm) with 24 weeks of VA (5-year EFS constitutes IR-RMS has evolved and as such, the eligibility criteria
of 95.5% [95% CI: 86.8–98.5] and OS of 100%).32 An analysis of 240 for the current IR-RMS study (ARST1431) differs from prior studies.
patients treated on D9602 and ARST0331 with Stage 1, CG I FN-RMS, While D9803 enrolled patients younger than 10 years with ERMS and
has defined a subset of patients with LR-RMS who experience exceed- metastatic disease, they were not eligible for ARST0531 and were
ingly good outcomes, achieving 5-year EFS of 91% (95% CI: 87%– treated on HR-RMS trials (ARST0431 and ARST08P1).36,37 ARST0431
95%), suggesting that this subset of patients may benefit from therapy and ARST08P1, the two most recent studies for patients with upfront
reduction.8 These patients will be classified as very low-risk (VLR) RMS metastatic RMS, both demonstrated that patients <10 years of age
in the future LR-RMS study ARST2032. with metastatic ERMS had superior outcomes compared to other
Patients with CG III orbital disease have very good outcomes but patients with HR-RMS, with 3-year EFS between 60% and 64%,
have suffered from incremental increases in local failure rate (while while patients ≥10 years of age with metastatic ERMS had 3-year
retaining a very high OS) with sequential reductions in alkylator and EFS between 32% and 48%.38,39 These patient are therefore now
radiation doses. Although patients with CG III orbital disease had low reclassified as intermediate risk.36,38,39 In addition, patients previ-
local failure rates (2%) and higher 5-year FFS (94%) in IRS IV, it was ously considered LR on subset 2 of ARST0331 (ERMS Stage 1, CG
achieved with a significant burden of therapy, using a high cumulative III with non-orbit primary or Stage 3, CG I/II disease) had inferior
dose (26.4 g/m2 ) of cyclophosphamide and higher doses of radiation outcomes when treated with a de-intensified regimen consisting of
(50.4–59.4 Gy).33 In ARST0331, patients with orbital RMS had 3-year 48 weeks of therapy using a cumulative cyclophosphamide dose of
FFS and OS of 87% (95% CI: 77%–92%) and 97% (95% CI: 90%–99%), only 4.8 g/m2 , compared to those treated on D9602, which used
respectively, and all relapses in patients with CG III orbital tumors were a higher cyclophosphamide dose.29,40 These patients are also now
local.30 ARST0331 treated these patients with a cumulative cyclophos- considered IR. In an additional refinement to the risk stratification,
phamide dose of 4.8 g/m2 and 45 Gy of radiotherapy, resulting in a 21% ARST1431 uses FOXO1 fusion status instead of histology for study eli-
local failure rate in those achieving partial response (PR) at 12 weeks gibility based on analyses demonstrating that it is more predictive of
versus 0% in those achieving complete response (CR) at 12 weeks.34 outcome.6,7,19,41–43
Patients with orbital disease may therefore benefit from intensifica- ARST1431 is the first IR-RMS study to test a molecularly tar-
tion of local control treatment while continuing minimal alkylator expo- geted agent in upfront treatment for RMS. Patients are randomized
sure. ARST2032 will increase radiation dose to 50.4 Gy (from 45 Gy in to receive VAC alternating with vincristine and irinotecan (VAC/VI)
ARST0331) for patients with Stage 1, CG III orbital RMS who do not or VAC/VI plus temsirolimus, an mTOR inhibitor. There is substan-
achieve radiological CR at week 12. tial preclinical data demonstrating that the mTOR pathway is fre-
Based on the adverse prognostic effect of MYOD1 or TP53 quently activated in RMS.44–54 Furthermore, clinical data from a prior
pathogenic mutations, patients whose tumors have these mutations randomized COG study for patients with relapsed RMS (ARST0921)
will no longer be considered LR and will be treated in a separate arm in demonstrated superior 6-month EFS and response rates for the
ARST2032. By reclassifying patients with adverse molecular features temsirolimus-containing regimen versus the bevacizumab-containing
(MYOD1 or TP53 mutations), ARST2032 will be enriched with patients regimen.55
with a more favorable prognosis. This molecularly defined LR cohort Following the initial 42 weeks of VAC/VI therapy, patients treated
will then be subdivided into two newly defined risk groups: (a) patients on ARST1431 receive 24 weeks of maintenance therapy consisting
with VLR-RMS (FN, Stage 1, CG I, MYOD1 and TP53 wild type [WT]) of continuous daily low-dose oral cyclophosphamide (CPMPO ) plus
who will receive a reduction in therapy with 24 weeks of VA; and (b) weekly IV vinorelbine on 3 out of every 4 weeks. The inclusion of main-
patients with LR-RMS (FN, Stage 1 CG II, or Stage 2 CG I/II or CG tenance is based on results from EpSSG RMS 2005, designed to test
III (orbit only), MYOD1 and TP53 WT) who will receive 12 weeks of the addition of maintenance to the standard 27 weeks of induction with
8 of 11 HADUONG ET AL .

ifosfamide, dactinomycin, and vincristine ± doxorubicin (IVA or IVADo) Vinorelbine, a second-generation vinca alkaloid has been tested as
in patients with nonmetastatic ARMS and locally advanced ERMS who a single agent and in combination with cyclophosphamide in patients
had achieved complete remission post induction. Patients were ran- with heavily pretreated RMS. In two phase 2 trials, the ORR observed
domized to receive an additional 24 weeks of maintenance therapy with single-agent vinorelbine (30 mg/m2 ) was 36% and 50%, includ-
on the same schedule as ARST1431 versus no maintenance therapy. ing one CR and nine PRs.59,60 A lower dose of vinorelbine (25 mg/m2 )
Patients who received maintenance had improved 5-year OS of 86.5% was evaluated in combination with CPMPO in a larger cohort of heav-
versus 73.7% (p = .0097), although improvement in 5-year disease- ily pretreated patients with relapsed/refractory RMS. Four CRs and 14
free survival did not reach statistical significance (77.6% vs. 69.8%, PRs were observed, with an ORR of 36%.61 These response rates are
p= .061]).56 Despite the differences between the EpSSG and COG superior to those seen in other phase 2 trials for patients with relapsed
approaches to RMS, including the use of different agents and dura- RMS, and comparable to response rates with other agents tested in
tions of induction in distinct patient populations, the overall conclu- upfront phase 2 windows in treatment-naïve patients,62–71 suggesting
sions of the study may be relevant for all patients with IR or HR-RMS. that vinorelbine is a highly active agent in RMS that warrants further
Maintenance has therefore been incorporated into ARST1431 for all investigation. Additionally, a recent meta-analysis of five studies for
patients on both study arms. As all patients will be receiving mainte- patients with relapsed or refractory RMS demonstrated that patients
nance on ARST1431, the effect of adding maintenance to a 42-week with ARMS have a 41% improved response rate compared to those
VAC/VI chemotherapy regimen will be assessed by comparing the out- with ERMS when treated with vinorelbine alone or in combination with
come of patients treated on the non-temsirolimus arm of ARST1431 lower dose or oral cyclophosphamide.72
to the outcome of historical control patients who were treated with Because neither the cyclophosphamide dose intensity on D9802,
VAC/VI on ARST0531. This will help to contextualize the results of nor the intensified backbones utilized on ARST0431 and ARST08P1
the RMS2005 study for COG patients and provide greater insight improved outcomes for patients with HR-RMS, ARST2031 employs
into the role of maintenance therapy added to a COG backbone in a VAC backbone with an intermediate cyclophosphamide dose
IR-RMS. (1.2 g/m2 /cycle) and utilize vinorelbine in the experimental arm. Addi-
tionally, the role of maintenance as published in the EpSGG RMS 2005
study is unknown in patients with COG-defined HR-RMS. ARST2031
3.3 High risk will compare induction using VAC versus vinorelbine-AC (VINO-AC) in
a randomized manner for patients with HR-RMS, while adding main-
Patients with HR-RMS comprise approximately 15% of all patients with tenance with vinorelbine-CPMPO to both arms to improve outcomes
RMS but represent the most challenging to treat, with dismal out- of patients with HR-RMS. Finally, ARST2031 will prospectively exam-
comes. While successive IRS trials (IRS I–IV) have improved EFS and ine the potential association of CDK4 and MYCN amplification with EFS
OS for localized RMS patients using VAC as the primary chemotherapy and OS in patients with newly diagnosed HR-RMS, given data suggest-
regimen, variations on VAC have failed to improve outcomes for HR- ing that amplification of CDK4 and MYCN are associated with a poorer
RMS patients.4,14,35,36,39,57 prognosis.21,22
Results from the two most recent HR-RMS COG trials, ARST0431
and ARST08P1, have defined HR-RMS to include patients with Stage
4 ERMS aged 10 years or greater and patients with Stage 4 ARMS 4 FUTURE DIRECTIONS
or FP-RMS. These studies, in an attempt to maximize dose inten-
sity, incorporated all known active agents (vincristine, doxorubicin, Through collaborative, large-scale next-generation sequencing efforts,
cyclophosphamide, ifosfamide/etoposide, and VAC) into an interval significant progress has been made in understanding the genomic land-
compressed, intensified backbone and also evaluated promising novel scape of RMS and the potential effects of these alterations on the
agents (irinotecan, temozolomide or cixutumumab).38,39 Both studies clinical behavior of RMS tumors. More nuanced risk stratification that
demonstrated that patients younger than 10 years of age with Stage incorporates molecular prognostic factors may allow for the reduction
4 ERMS had superior outcomes when compared to other HR-RMS of therapy in patients with excellent prognoses while also identifying
patients, with 3-year EFS ranging from 60% to 64%, an outcome simi- those who may benefit from therapy intensification and/or the use of
lar to that observed on D9803, the IRS-V IR-RMS study. In contrast, the novel agents.
3-year EFS for Stage 4 ERMS patients older than 10 years was 32%– Although knowledge of the molecular mechanisms driving RMS has
48%. Patients with ARMS continue to have the worst outcomes with 3- advanced quickly, the availability of agents that target these molecu-
year EFS ranging from 6% to 16%.38,39 In D9802, window therapy with lar drivers has lagged. Current investigational therapies for patients
VI was added to a VAC backbone utilizing 2.2 g/m2 /cycle of cyclophos- with relapsed or refractory RMS include the use of kinase inhibitors,
phamide. Although response rates to VI window therapy were promis- insulin-like growth factor antibodies, histone deacetylase inhibitors,
ing (overall response rate [ORR] 42% [95% CI: 38%–80%]), the FFS and poly ADP ribose polymerase (PARP) inhibitors among other agents
in patients with HR-RMS with and without window therapy remained and are used alone or in combination with various salvage chemother-
equally dismal at under 20%.58 Further, patients with FP-RMS enrolled apy backbones.73,74 As the data utilizing molecular biomarkers for risk
on D9802 and ARST0431 had a 6% 5-year EFS (95% CI: 0%–11%).8 stratification mature, thus identifying smaller cohorts of patients with
HADUONG ET AL . 9 of 11

different prognoses, our ability to offer appropriate risk-based therapy 11. Maurer HM, Gehan EA, Beltangady M, et al. The Intergroup Rhab-
for all patients should improve, including for those with the most dismal domyosarcoma Study-II. Cancer. 1993;71(5):1904-1922.
12. Crist WM, Garnsey L, Beltangady MS, et al. Prognosis in children
prognoses.
with rhabdomyosarcoma: a report of the intergroup rhabdomyosar-
coma studies I and II. Intergroup Rhabdomyosarcoma Committee. J
ACKNOWLEDGMENTS Clin Oncol. 1990;8(3):443-452.
This work was supported by grants from the National Cancer Insti- 13. Crist W, Gehan EA, Ragab AH, et al. The Third Intergroup Rhab-
tute, National Institutes of Health to the Children’s Oncology Group domyosarcoma Study. J Clin Oncol. 1995;13(3):610-630.
14. Crist WM, Anderson JR, Meza JL, et al. Intergroup Rhabdomyosar-
(U10CA180899, U10CA180886). We would like to acknowledge
coma Study-IV: results for patients with nonmetastatic disease. J Clin
Amira Qumseya for her assistance in creating Figures 1 and 2. We also Oncol. 2001;19(12):3091-3102.
acknowledge the contributions of our patients with RMS and their fam- 15. Meza JL, Anderson J, Pappo AS, Meyer WH, Children’s Oncol-
ilies who provided decades of experience and data through their enroll- ogy Group. Analysis of prognostic factors in patients with non-
metastatic rhabdomyosarcoma treated on intergroup rhabdomyosar-
ment on clinical trials.
coma studies III and IV: the Children’s Oncology Group. J Clin Oncol.
2006;24(24):3844-3851.
CONFLICT OF INTEREST 16. Parham DM, Barr FG. Classification of rhabdomyosarcoma and its
The authors declare that there is no conflict of interest. molecular basis. Adv Anat Pathol. 2013;20(6):387-397.
17. Arnold MA, Anderson JR, Gastier-Foster JM, et al. Histology, fusion
status, and outcome in alveolar rhabdomyosarcoma with low-risk clin-
ORCID
ical features: a report from the Children’s Oncology Group. Pediatr
Josephine H. Haduong https://orcid.org/0000-0002-9135-7739 Blood Cancer. 2016;63(4):634-639.
David A. Rodeberg https://orcid.org/0000-0003-3594-7547 18. Rudzinski ER, Anderson JR, Chi YY, et al. Histology, fusion sta-
Sarah S. Donaldson https://orcid.org/0000-0001-7125-3118 tus, and outcome in metastatic rhabdomyosarcoma: a report from
the Children’s Oncology Group. Pediatr Blood Cancer. 2017;64(12):
Douglas S. Hawkins https://orcid.org/0000-0003-3602-1375
e26645.
19. Duan F, Smith LM, Gustafson DM, et al. Genomic and clinical anal-
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