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\begin{document}

\title{Local control of parameningeal rhabdomyosarcoma: An expert consensus
guideline from the International Soft Tissue Sarcoma Consortium
(INSTRuCT)}



\author[1]{Dana Casey}%
\author[2]{Henry Mandeville}%
\author[3]{Julie Bradley}%
\author[4]{Simone ter Horst}%
\author[5]{Anthony Sheyn}%
\author[6]{Beate Timmermann}%
\author[7]{Suzanne Wolden}%
\affil[1]{University of North Carolina at Chapel Hill School of Medicine}%
\affil[2]{The Royal Marsden NHS Foundation Trust}%
\affil[3]{U. Florida Proton Center}%
\affil[4]{University Medical Center Utrecht, Princess Máxima Center for Pediatric Oncology}%
\affil[5]{University of Tennessee Health Science Center}%
\affil[6]{Westdeutsches Protonenthearpiezentrum}%
\affil[7]{Memorial Sloan Kettering Cancer Center}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
The International Soft-Tissue Sarcoma Database Consortium (INSTRuCT)
consists of a collaboration between the Children's Oncology Group (COG)
Soft Tissue Sarcoma Committee, the European pediatric Soft-Tissue
Sarcoma Study Group (EpSSG), and the Cooperative Weichteilsarkom
Studiengruppe (CWS). As part of the larger initiative of INSTRuCT to
provide consensus expert opinions for clinical treatment of pediatric
soft tissue sarcoma, we sought to provide updated, evidenced-based
consensus guidelines for local treatment of parameningeal
rhabdomyosarcoma using both existing literature as well as
recommendations from the relevant cooperative group clinical trials.
Overall, parameningeal rhabdomyosarcoma represents a distinctly
challenging disease to treat given its location near many critical
structures in the head and neck, frequently advanced local presentation,
and predilection for local failure. Definitive chemoradiation remains
the standard treatment approach for parameningeal rhabdomyosarcoma, with
surgery often limited to biopsy or salvage therapy for recurrent
disease. In this consensus paper, we specifically discuss consensus
guidelines and evidence for definitive local management with
radiotherapy, with a focus on imaging for radiotherapy planning, dose
and timing of radiation, approach for nodal irradiation, various
radiation techniques including proton therapy, and the limited role of
surgical resection.%
\end{abstract}%



\sloppy


\textbf{Local control of parameningeal rhabdomyosarcoma: An expert
consensus guideline from the International Soft Tissue Sarcoma
Consortium (INSTRuCT)}

Dana L. Casey, MD\textsuperscript{1,2*}, Henry Mandeville,
MD\textsuperscript{3}, Julie A Bradley, MD\textsuperscript{4}, Simone
A.J. ter Horst, MD PhD\textsuperscript{5}, Anthony Sheyn,
MD\textsuperscript{6}, Beate Timmermann, MD\textsuperscript{7}, Suzanne
L. Wolden, MD\textsuperscript{8}

\textsuperscript{1}Department of Radiation Oncology, University of North
Carolina School of Medicine, Chapel Hill, NC

\textsuperscript{2}Lineberger Comprehensive Cancer Center, University of
North Carolina Hospitals, Chapel Hill, NC

\textsuperscript{3}Royal Marsden NHS Foundation Trust, London, United
Kingdom; Institute of Cancer Research, London, United Kingdom

\textsuperscript{4}Department of Radiation Oncology, University of
Florida, Jacksonville, FL

\textsuperscript{5}Department of Radiology, University Medical Center
Utrecht, Princess M\selectlanguage{ngerman}áxima Center for Pediatric Oncology, Utrecht, the
Netherlands

\textsuperscript{6}Department of Surgery, Division of Otolaryngology,
University of Tennessee Health Science Center, Memphis, Tennessee

\textsuperscript{7} Department of Particle Therapy, University Hospital
Essen, West German Proton Therapy Centre Essen (WPE), West German Cancer
Center (WTZ), German Cancer Consortium (DKTK), Essen, Germany

\textsuperscript{8} Department of Radiation Oncology, Memorial Sloan
Kettering Cancer Center, New York, NY

\emph{Brief Running title:} Parameningeal rhabdomyosarcoma: INSTRuCT
consensus

\emph{*Corresponding Author} : Dana L. Casey, MD University of North
Carolina School of Medicine, Department of Radiation Oncology, 101
Manning Drive CB \#7512; Tel: (984)974-0400; E-mail: dana\emph{\_}
casey@med.unc.edu

\emph{Abstract word count:} 185

\emph{Text word count:} 5806

\emph{Tables:} 1

\emph{Figures:} 1

\emph{Keywords:} rhabdomyosarcoma, radiation therapy, parameningeal,
local control

Abbreviations\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
CBCT & Cone-beam computed tomography\tabularnewline
\midrule
\endhead
CTV & Clinical target volume\tabularnewline
COG & Children's Oncology Group\tabularnewline
CT & Computerized tomography\tabularnewline
CTCAE & Common Toxicities Criteria on Adverse Events\tabularnewline
CWS & Cooperative Weichteilsarkom Studiengruppe\tabularnewline
DW & Diffusion weighted\tabularnewline
EpSSG & European paediatric Soft tissue sarcoma Study
Group\tabularnewline
GTV & Gross tumor volume\tabularnewline
IMPT & Intensity-modulated proton therapy\tabularnewline
IMRT & Intensity-modulated radiotherapy\tabularnewline
INSTRuCT & International Soft Tissue Sarcoma Database
Consortium\tabularnewline
IRSG & International rhabdomyosarcoma study group\tabularnewline
MRI & Magnetic resonance imaging\tabularnewline
OAR & Organs at risk\tabularnewline
PENTEC & Pediatric Normal Tissue Effects in the Clinic\tabularnewline
PET & Positron emission tomography\tabularnewline
PM-RMS & Parameningeal rhabdomyosarcoma\tabularnewline
PT & Proton therapy\tabularnewline
PTV & Planning target volume\tabularnewline
RT & Radiotherapy\tabularnewline
SLN & Sentinel lymph node\tabularnewline
\bottomrule
\end{longtable}

\textbf{ABSTRACT}

The International Soft-Tissue Sarcoma Database Consortium (INSTRuCT)
consists of a collaboration between the Children's Oncology Group (COG)
Soft Tissue Sarcoma Committee, the European pediatric Soft-Tissue
Sarcoma Study Group (EpSSG), and the Cooperative Weichteilsarkom
Studiengruppe (CWS). As part of the larger initiative of INSTRuCT to
provide consensus expert opinions for clinical treatment of pediatric
soft tissue sarcoma, we sought to provide updated, evidenced-based
consensus guidelines for local treatment of parameningeal
rhabdomyosarcoma using both existing literature as well as
recommendations from the relevant cooperative group clinical trials.
Overall, parameningeal rhabdomyosarcoma represents a distinctly
challenging disease to treat given its location near many critical
structures in the head and neck, frequently advanced local presentation,
and predilection for local failure. Definitive chemoradiation remains
the standard treatment approach for parameningeal rhabdomyosarcoma, with
surgery often limited to biopsy or salvage therapy for recurrent
disease. In this consensus paper, we specifically discuss consensus
guidelines and evidence for definitive local management with
radiotherapy, with a focus on imaging for radiotherapy planning, dose
and timing of radiation, approach for nodal irradiation, various
radiation techniques including proton therapy, and the limited role of
surgical resection.



\textbf{1. INTRODUCTION}

Rhabdomyosarcoma is the most common soft tissue sarcoma in children,
with parameningeal tumors accounting for 15-20\% of all
cases.\textsuperscript{1} Parameningeal rhabdomyosarcoma (PM-RMS)
specifically refers to those tumors arising from the nasopharynx, nasal
cavity, paranasal sinuses, parapharyngeal space, pterygopalantine fossa,
masticator space, mastoid cavity, and middle ear and are distinguished
anatomically and prognostically from the more favorable tumors arising
from the orbit and other head and neck
sites.\textsuperscript{2}Approximately 50\% of patients with PM-RMS will
present with lymph node involvement and 25\% with distant
metastases.\textsuperscript{3}Intracranial extension, skull base
erosion, and cranial nerve palsy all represent poor prognostic factors
related to the local spread of disease. Embryonal histology is the most
common pathologic subtype, representing approximately 70\% of all
parameningeal tumors.\textsuperscript{4,5}

Overall, the prognosis for PM-RMS is unfavorable, with a 10 year event
free survival of \textless{}65\% and overall survival \textless{}70\%
from pooled historical data.\textsuperscript{4} PM-RMS remains a
particularly challenging disease site to treat given its anatomical
location and predilection for local and leptomeningeal failure. Local
relapse results not only in severe loss of form and function in many
patients, but also an unacceptably high rate of mortality, with a 3-year
survival after local failure of \textless{}20\%.\textsuperscript{6}Given
the locally advanced presentation of PM-RMS and the anatomical
constraints of the head and neck, gross total resection is usually not
feasible due to the risks of severe cosmetic and functional morbidity.
As such, definitive chemoradiation remains the preferred initial
treatment modality for PM-RMS, with surgery most commonly limited to an
initial biopsy to establish the diagnosis.

In this consensus review from the International Soft-Tissue Sarcoma
Consortium {[}INSTRuCT, consisting of the Children's Oncology Group
(COG), European Pediatric Soft-Tissue Sarcoma Group (EpSSG), and
Cooperative Weichteilsarkom Studiengruppe (CWS){]}, we provide treatment
recommendations for the local management of PM-RMS.

\textbf{2. CONSENSUS GUIDELINES}

\textbf{2.1 Imaging for radiotherapy planning}

2.1.1 Expert Consensus

Imaging in rhabdomyosarcoma plays a pivotal role for staging, response
assessment, planning of local therapy (radiotherapy and/or surgery),
relapse monitoring, and diagnosis of acute and late complications of
treatment. To guide the optimal radiotherapy plan, it is essential to
image the primary tumor and assess for metastatic sites. For the primary
tumor, magnetic resonance imaging (MRI) is preferred over computerized
tomography (CT) due to superior soft tissue contrast resolution and the
absence of ionizing radiation, although CT is helpful for detection of
bony involvement. PM-RMS is preferably imaged on a 3T MRI scanner
because of its higher resolution in this radiologically challenging
anatomical site, although imaging on a 1.5T MRI scanner is an acceptable
alternative.

For radiotherapy planning, the essential MRI sequences are the
morphological sequences (coronal and axial T1-, T2-weighted sequences
with fat suppressed T2 sequences) and those with the administration of
intravenous contrast such as gadolinium (coronal and axial T1 post-
contrast with and/or without fat suppression). In specific cases, extra
sagittal sequences can aid delineation as can volumetric 3D T1 post
contrast sequences which allow for reformatting of the tumor site from
all different views. Diffusion Weighted (DW) MRI adds to tumor
characterization and differentiation of active residual tumor from
reactive surrounding edema, and DW-MRI allows evaluation of tumor
response, which can also inform radiotherapy planning. Including DW
imaging in the radiotherapy planning protocol represents a key
opportunity to integrate response evaluation with optimization of
imaging to create the most accurate radiotherapy plan. If feasible,
combining and integrating MRI sequences for response assessment and
radiotherapy planning can also save the younger patients an additional
course of anesthesia for separate scans.

For the detection of locoregional lymph nodes and distant metastases,
{[}F18{]}-2-fluoro-2-deoxygluose (FDG)-positron emission tomography
(PET) or FDG-MRI in combination with chest CT are the recommended
investigations of choice, similar to non-PM-RMS. Histologic evaluation
of any suspicious head and neck nodes seen on PET is recommended to
confirm pathologic involvement.

2.1.2 Evidence

Pediatric deep or extensive soft tissue tumors, such as RMS arising from
the head and neck region, are best depicted with MRI (preferably 3T) due
to excellent spatial resolution, superior soft-tissue contrast, and
multi-planar imaging.\textsuperscript{7,8} These properties allow for
superior delineation of the extent of the tumor and involvement of
adjacent structures compared to CT. This is especially critical in
PM-RMS, where delineation of the extent of intracranial extension (with
increased risk for focal or diffuse leptomeningeal spread), the
different head and neck compartments, the boundaries with vascular
and/or neural structures determining perineural spread, and invasion of
bone, are of utmost importance.\textsuperscript{9,10} Additional CT
imaging is helpful in some cases for detection of the extent of bone
destruction and is usually acquired as part of the radiotherapy planning
process. Raney et al.\textsuperscript{2,11} and Michalsky et
al.\textsuperscript{6} showed that outcome in patients with PM-RMS
significantly improved when high-risk features were clearly identified
with MRI, highlighting the value of the MRI information in contributing
to optimized treatment protocols and radiotherapy planning.~DW series
are standard of care in many centers given their ability to facilitate
the differentiation between active residual disease and reactive
surrounding tissue. However, there is still a need for systematic
prospective evaluation of its role in diagnosis and response evaluation
in PM-RMS, and this is being evaluated in the current EpSSG FaR RMS
study.\textsuperscript{12,13}

Regarding the role FDG-PET, a systemic review reported a sensitivity of
80-100\% and 95-100\% with a specificity of 89-100\% and 80-100\%,
respectively, for locoregional lymph nodes and non-pulmonary distant
metastases.\textsuperscript{14,15} Pathologic confirmation of any
suspicious locoregional nodes seen on FDG-PET is recommended at this
time given the potential for false positives and subsequent impact on
radiation planning and treatment.

\textbf{2.2. Timing of radiation}2.2.1 Expert Consensus For patients
with locoregional PM-RMS, local therapy with definitive radiotherapy, or
in very rare cases, delayed surgical excision of the primary tumor prior
to radiotherapy, should commence at week 13; this approximates to the
5\textsuperscript{th} cycle of induction chemotherapy. Earlier
radiotherapy (beginning at approximately week 4 to 6) may be considered
for certain high risk scenarios, including the presence of intracranial
extension where the risk of leptomeningeal relapse is higher and/or in
the setting of reduced dose cyclophosphamide. In the rare case in which
delayed surgical resection is performed, patients with locoregional
PM-RMS requiring postoperative radiotherapy should commence radiation
within 4- 6 weeks of surgery, usually with the 2\textsuperscript{nd}
cycle of postoperative chemotherapy. For patients with metastatic
PM-RMS, local therapy can be delivered at week 13 as is done in the
patients with localized disease or can be delayed until week 20- 22.

Evidence

The timing of local therapy, including radiotherapy, in the setting of
multimodality treatment for these often highly chemotherapy sensitive
tumors, has become increasingly aligned in recent international
collaborative group protocols where previous significant differences
existed. However, there are still some significant points of debate, and
concerns have been raised that these recommended timings may impact
local control for PM-RMS, particularly for those with high-risk
features.\textsuperscript{16,17}In European studies, the approach used
in both the EpSSG and CWS studies for patients with localized PM-RMS is
to evaluate the response to induction chemotherapy after the
3\textsuperscript{rd} cycle, and then plan for the commencement of
optimal local therapy at week 13, approximating to the
5\textsuperscript{th} cycle of chemotherapy. Outcomes from the first RMS
2005 study randomization of EpSSG high risk rhabdomyosarcoma, where 33\%
of cases were parameningeal, reported the 3-year event free survivals to
be 67.5\% and 63.3\% in the 2 arms, both significantly improved compared
to historical cohorts, although the local failure outcomes are still to
be reported.\textsuperscript{18} In the current EpSSG FaR-RMS study
(NCT04625907), these timings continue to be recommended. By comparison,
the approach for PM-RMS within COG has employed different timings,
previously recommending the delivery of earlier radiotherapy given
concerns about achieving local control for these challenging tumors. In
these earlier protocols through the Intergroup Rhabdomyosarcoma Study
Group (IRSG), there was a recommendation to commence radiotherapy at day
0. A retrospective analysis of patients treated in the IRS-IV and D9803
studies revealed no significant difference in clinical outcomes in those
receiving early radiotherapy compared to patients commencing
radiotherapy at week 12, with 5-year local failure rates of 19\% in both
studies.\textsuperscript{19}Similarly, there was no difference in local
control based on timing of radiation (before 4 weeks or week 12-13) in a
retrospective series from Memorial Sloan Kettering.\textsuperscript{20}
The ARST0531 study, which was open from 2006 until 2012, recommended
radiotherapy at week 4 with the goal of improving local control, yet the
local control in this study was actually inferior to the previous study,
D9803.\textsuperscript{17}However, there are some important confounding
factors that make a direct comparison regarding timing difficult, with
the dose of cyclophosphamide lower in ARST0531, and 47\% of patients
with PM-RMS on D9803 received radiotherapy at week 1. The proximity of
the parameningeal site to the skull base and cranial nerves, and the
infiltrative pattern of growth observed with rhabdomyosarcoma means that
radical delayed surgical resection of the primary tumor is very rarely
undertaken as discussed in more detail below. Although not recommended,
for those rare cases where delayed primary excision is done,
postoperative radiotherapy is indicated. Adjuvant chemotherapy is
usually commenced 2 weeks after surgery, with radiotherapy commencing as
soon as possible after this once the surgical wounds have healed
sufficiently (although delays may be necessary for postoperative
complications). Preoperative radiotherapy has not yet been fully
evaluated in rhabdomyosarcoma, and although it is being investigated in
the FaR-RMS study, it is unlikely to be considered for PM-RMS given the
complexities and potential complications of surgery. For metastatic
PM-RMS, the recommended timings for radiotherapy have historically been
at later time points (week 20-22) in the international collaborative
group studies from both sides of the Atlantic. However, on the now open
high-risk COG study, ARST2031, radiation to the primary site is
delivered at week 12-13 for all tumors including PM-RMS (similar to
patients with localized disease), with this timing representing an
acceptable option for treatment of metastatic PM-RMS. European
recommendations in the now closed BERNIE and MTS-2008 studies were for
local therapy to commence at week 22, approximating to the
8\textsuperscript{th} cycle of chemotherapy, with re-evaluation of cases
after the 6\textsuperscript{th} cycle of chemotherapy. Yet, it is
apparent that these guidelines were not always adhered to, particularly
with the challenges of treating metastatic rhabdomyosarcoma and multiple
disease sites leading to delays in radiotherapy. In the analysis of the
BERNIE study, a cut off of day 221 was used to define radical
radiotherapy to take this issue into account.\textsuperscript{21} Cases
with extensive metastatic disease may require metastatic radiotherapy
delivered in sequential phases, treated in succession to limit the
associated bone marrow and other acute toxicities. Delayed radiotherapy
for metastatic sites is also recommended in COG studies, with metastatic
site radiotherapy to now occur at approximately week 40 after completion
of primary chemotherapy on ARST2031 (previously, on the prior high-risk
study studies, ARST0431 and ARST08P1, there was the option to deliver
metastatic site radiotherapy either with primary site radiation or after
completion of primary chemotherapy).\textbf{2.3 Definitive radiation
dosing and volumes}

Expert Consensus

As surgical resection is typically limited to a biopsy alone at
diagnosis (without upfront gross total resection), the majority of
patients with PM-RMS will have IRS group III disease. The definitive
radiation dose for treatment of the primary site is 50.4 Gy in 28
fractions, similar to the dose delivered for group III tumors at other
sites. A boost to 55.8 Gy or 59.4 Gy total is permitted for treatment of
parameningeal tumors at the discretion of the treating physician, with
unfavorable features such as tumor size [?] 5cm at diagnosis, poor
response to induction chemotherapy, or high-risk meningeal features such
as intracranial extension. Volume reduction is also permitted to account
for the response to initial chemotherapy. In these cases, the
pre-chemotherapy extent of disease should be treated to 36 Gy - 41.4 Gy
in 20-23 fractions, with a boost to the gross residual disease that is
present at the time of radiation planning to the final total dose of
50.4 Gy - 59.4 Gy. The boost may be administered either sequentially as
a cone-down or concurrently as a simultaneous integrated boost with
feasible fraction sizes. The pre-chemotherapy and
post-chemotherapy/pre-radiation imaging including the MRI should be
fused to the CT simulation scan for optimal target delineation as
discussed above. The gross tumor volume at diagnosis as defined by
imaging and physical exam should be transferred to a tumor volume
adapted to the actual geometry at time of radiotherapy planning (taking
into account any anatomical shift due to tumor shrinkage or growth).
This volume should be expanded by approximately 1cm, edited for
anatomical barriers to spread, to account for occult tumor volume and
create the pre-chemotherapy clinical target volume or CTV1 (also known
as CTVp\_pre). Careful attention should be given to including any
initial extent of focal dural involvement in these volumes. The gross
tumor volume at the time of radiation planning as defined by imaging and
physical exam after several weeks of induction chemotherapy should also
be expanded by approximately 0.5-1cm, edited for anatomical barriers to
spread, to create the post-chemotherapy clinical target volume or CTV2
(also known as CTVp\_post). An intermediate volume consisting of the
prechemotherapy extent of tumor without a margin can also be utilized as
is done in the CWS group. The planning target volume then typically
consists of a geometric 3-5mm expansion on each clinical target volume
to account for variability in daily set-up, although this expansion is
uniquely defined for proton therapy. Of note, although radical surgery
is not standard of care, if pursued, adjuvant radiation is often
required due to fusion status, lack of ability to obtain negative
margins, and/or regional nodal involvement. In PM-RMS, inclusion of the
entire surgical scar or even surgical route is not often recommended as
it may mean extensive radiotherapy volumes in some children. See Table 1
for dosing recommendations by clinical group and fusion status,
including those with IRS group I-II disease.

Evidence

Over successive IRS protocols, radiation volumes for parameningeal
tumors drastically decreased with the goal of maximizing the therapeutic
ratio, from craniospinal irradiation in the late 1970s and whole brain
radiation in the 1980s for those with high-risk meningeal features, to
focal radiation for all patients in the 1990s, consisting of a 1-2cm
margin around the gross tumor.\textsuperscript{2} Importantly, omission
of whole brain radiation in lieu of focal radiation volumes did not
compromise outcomes in an analysis of IRS
II-IV,\textsuperscript{2,6}including risk of local failure and risk of
central nervous system recurrence.

Regarding the evolution of radiation dose for parameningeal tumors, on
IRS-II and III, radiation dose depended on both the size of the tumor
and age of the patient, with a median dose of approximately 45 Gy and
50.4 Gy delivered for those \textless{}6 years of age
and\emph{\textgreater{}} 6 years of age, respectively. On IRS-IV,
patients were randomized to receive either 50.4 Gy in 1.8 Gy fractions
delivered daily or 59.4 Gy in 1.1 Gy fractions delivered twice daily,
with similar local relapse rates observed in both
arms.\textsuperscript{22} Overall, doses less than 47.5 Gy have been
associated with worse local control for parameningeal
tumors,\textsuperscript{6} in part supporting the radiation doses
currently utilized on the ongoing protocols through the COG, EpSSG, and
CWS. Previous smaller studies had also identified a similar relationship
between improved local control and higher radiation doses for
PM-RMS.\textsuperscript{23,24}

Even with these doses, local relapse remains the dominant form of
failure for PM-RMS, with localized failure seen in approximately 70\% of
those who relapse on both European and North American cooperative group
trials. The majority of local failures occur in the high dose
region,\textsuperscript{25-27} suggesting that marginal misses or
volumetric coverage are not the issue. Furthermore, the utilization of a
post-chemotherapy cone-down volume (to reduce the high-dose treatment
volume) does not appear to compromise local
control.\textsuperscript{28,29} Unfortunately, local failure for
parameningeal tumors has actually worsened over time on the most recent
COG studies from 16\% on IRS-IV,\textsuperscript{22} to 19\% on
D9803,\textsuperscript{30} to 28\% on ARST0531\textsuperscript{17} with
similarly high rates of local failure seen in recent single institution
studies,\textsuperscript{16,20,27} thought in part to be due to the
lower doses of cyclophosphamide utilized on recent trials. In addition,
leptomeningeal failure is a common and devastating pattern of relapse
among patients with PM-RMS, especially among those with intracranial
extension at diagnosis.\textsuperscript{31-33}

Ongoing strategies to overcome the possibly radioresistant phenotype of
parameningeal tumors include radiation dose escalation.
Hyperfractionation to 59.4 Gy on IRS-IV did not result in increased
local control compared to 50.4 Gy with daily fractionation, although
59.4 Gy delivered in 54 fractions twice a day may not deliver a more
biologically effective dose than 50.4 Gy in 28 daily fractions. Thus,
current efforts to mitigate the worsening local control include
radiation dose escalation to 59.4 Gy with daily fractionation in
tumors\emph{\textgreater{}} 5cm, as larger tumor size has consistently
been associated with increased local failure
rates.\textsuperscript{4,17,30,34} Given the infiltrative nature,
location near many critical structures, and utilization of concurrent
chemotherapy, escalation beyond 59.4 Gy may not be feasible, and doses
\textgreater{}57 Gy did not show a benefit on the CWS
studies.\textsuperscript{35} In the FaR-RMS study, all patients with
PM-RMS are eligible to be randomized between 50.4 Gy and 59.4 Gy, which
will provide future guidance regarding the true benefit of dose
escalation for these tumors. Improvements in systemic therapy such as
with higher doses of alkylating agents and/or introduction of concurrent
radiosensitizers are promising for reducing the incidence of local
failure. In addition, given the key role of radiotherapy in the
definitive treatment of PM-RMS, efforts to identify molecular
determinants of radiation response are critical to enhance local control
and outcomes for patients with parameningeal disease.

\textbf{2.4 Nodal irradiation}

2.4.1 Expert Consensus:

For node negative PM-RMS, prophylactic nodal irradiation is not
recommended. For node positive PM-RMS (clinical or pathologic
involvement), 36-41.4 Gy at 1.8 Gy per fraction is recommended to the
involved nodal chain or site. For nodal volumes, the GTV consists of the
gross nodal disease, with a 1cm expansion edited for normal tissue
barriers to disease extension to create the CTV. The CTV should also
encompass the entire lymph node drainage chain or, as per EpSSG
practice, a 2-3 cm expansion superiorly and inferiorly in the direction
of nodal drainage, using a involved site approach as an acceptable
alternative. The CTV is then expanded by 3-5mm for PTV. The recommended
dose to grossly involved nodes at the time of radiation planning is 50.4
Gy at 1.8 Gy per fraction, while 36-41.4 Gy is sufficient for nodes that
have had a complete response to chemotherapy at the time of radiation.

2.4.2 Evidence:

Nodal involvement at diagnosis and regional recurrence after definitive
therapy are known patterns of spread in PM-RMS. In a series of 94
patients with RMS (no elective nodal irradiation), 21\% developed
regional recurrence and two-thirds of these relapses occurred in
patients with a head and neck primary site.\textsuperscript{36} A larger
percent of patients developed nodal metastases in a smaller series of
head and neck RMS that included only patients with alveolar
histology.\textsuperscript{37} After a median follow-up of 4.3 years,
with regional radiation targeted only to involved nodes, 75\% of
patients with N0 disease developed isolated nodal relapse in the
ipsilateral first-echelon nodal basin, and 33\% of patients with N1
disease developed nodal relapse, one isolated and one concomitantly with
local progression.

Given the concern for nodal progression particularly in alveolar RMS,
prophylactic nodal irradiation has been investigated. In a retrospective
series consisting of 47 patients with PM-RMS treated with definitive
IMRT to 50.4 Gy in 28 fractions and chemotherapy, patients [?] 14 years of
age with alveolar histology (n=13) were treated to 36 Gy at 1.3 Gy per
fraction the bilateral cervical nodal chains.\textsuperscript{33} Ten of
these patients had N1 disease, and gross nodal disease was boosted to
50.4 Gy. Of patients with embryonal histology, none experienced regional
failure (though the number with N1 disease was not reported), nor did
any with alveolar histology who received bilateral cervical nodal
radiation. Of those with alveolar histology who did not receive
bilateral cervical nodal radiation, the 5 year regional failure rate was
37\%. However, distant disease (including CNS dissemination) remained
the dominant pattern of failure in these patients. Another series of 46
patients with head and neck rhabdomyosarcoma yielded similar results. In
this cohort, 5-year regional control rate was
73\%.\textsuperscript{31}Those with alveolar histology experienced
higher rates of nodal recurrence or progression compared to embryonal
histology, with 5 year regional control rate of 37\% vs 88\%,
respectively.

However, other studies have found lower rates of regional recurrence
with irradiation of only the involved nodal basin for patients with node
positive disease, without prophylactic nodal irradiation. In a
retrospective review of a prospective database, patterns of failure were
reported on 66 children with RMS across diverse primary
sites.\textsuperscript{38} Overall, 7 patients developed local
recurrence (n=6 with embryonal histology), achieving 88\% 2-year local
control for the cohort. No patients with parameningeal disease developed
regional failure. Another series that used proton therapy for the
treatment of RMS across primary sites reported no regional failures,
with radiotherapy directed only to involved nodal
levels.\textsuperscript{25} In a retrospective review of 24 patients
with alveolar PM-RMS in which radiation was directed only to the
involved nodal level(s) with a boost to the involved nodes, 3 year
regional control was 94\%.\textsuperscript{32} One patient with a node
negative nasal cavity primary developed a submental nodal recurrence.
None of the node-positive patients treated with nodal irradiation
developed regional progression, though node positive disease was
associated with inferior overall survival due to distant disease
progression. An interim report on RMS13 described concerning rates of
disease progression in patients with PM-RMS receiving reduced dose
cyclophosphamide, prompting a change in the timing of
radiotherapy.\textsuperscript{16} Local and CNS progression
predominated, with no patients developing nodal relapse.

Gallego et al. reported on a combined analysis of patients with node
positive alveolar RMS treated on EpSSG RMS 2005 and COG ARST0531, with
parameningeal primaries in 34\% and 25\%,
respectively.\textsuperscript{39} Metastatic progression comprised the
dominant pattern of relapse in both trials. Nodal recurrence alone
occurred in 12\% of patients in EpSSG RMS 2005 and 9\% on ARST0531,
while nodal recurrence with local and/or metastatic progression occurred
in an additional 10\% and 8\%, respectively. Of note, of those who had
regional nodes evaluated pathologically, positive nodes were identified
in 92\% on EpSSG RMS 2005 and 74\% in ARST0531, highlighting a
discrepancy between clinically positive and pathologically positive
nodes in rhabdomyosarcoma. Sentinel lymph node (SLN) biopsy has been
evaluated as a possible tool for accurate nodal staging in patients with
head and neck rhabdomyosarcoma. In a small series of 6 patients, 2 of 3
patients with radiographically suspicious nodes by PET and/or MRI had a
positive SLN, while 1 of 3 with negative imaging had a positive
SLN.\textsuperscript{40} Mapping of SLN yielded an unanticipated
location of the SLN in 2 patients, with the nodes mapping in the
contralateral neck. The use of SLN resulted in a change in the
recommended treatment in 2 of the 6 patients. Overall, the use of SLN in
PM-RMS remains investigational at the present time.

\textbf{Radiotherapy techniques}

2.5.1 Expert Consensus

Due to the proximity to relevant structures like the optic chiasm,
brainstem, salivary and lacrimal glands, and pituitary, PM-RMS is a
particularly challenging site when tailoring local therapy. Typical
radiation doses, especially when combined with intensive chemotherapy,
may exceed organ tolerance of the head and neck structures, particularly
with regard to the young patient age. In order to maximize form and
function and minimize toxicity, RT should be done with careful planning
and attention to organs at risk (OAR), and dose constraints should be
applied as per the Pediatric Normal Tissue Effects in the Clinic
(PENTEC) report\textsuperscript{41} and according to current study
guidelines in these young, curable patients. In addition, functional
assessments (ex. hearing, vision, neuroendocrine) are encouraged prior
to starting radiation to serve as a baseline.

Several highly conformal radiation techniques are available that enable
protection of healthy tissue while maximizing tumor control. For PM-RMS,
predominantly techniques such as proton therapy (PT) or
intensity-modulated RT (IMRT) should be used. In addition,
immobilization with a face mask and careful image guidance with
cone-beam computed tomography (CBCT) to ensure reliable daily set up are
recommended. As many of the patients with PM-RMS may be too young to
consciously cooperate, sedation with anesthesia may be required to
safely perform daily radiotherapy.

For younger patients and for treatment of tumors located near critical
structures such as those in the head and neck or near the brainstem,
modern treatment concepts encourage the use of highly conformal
techniques such as PT to minimize dose to normal tissue secondary to the
steep dose gradient of PT. In general, intensity modulation in PT (IMPT)
can offer additional benefits when compared to single field optimization
PT techniques, especially if lymph nodes of the neck are involved.
However, the use of PT is restricted to radiation oncologists
experienced in this field with access to a proton center, and randomized
studies comparing PT versus IMRT are scarce, with ethical concerns often
hampering the conduction of such studies. Given the limitations in
access to proton therapy, IMRT can be used in order to achieve highly
conformal treatment as well. However, due to the high integral dose and
low dose bath associated with IMRT, it is typically applied in older
patients or whenever PT is not available or technically restricted (e.g.
lack of gantries, lack of high energies). Additionally, as social,
logistical, and financial issues may make PT prohibitive, IMRT may be
preferred in those scenarios. In specialized programs, brachytherapy can
also be explored, particularly in the locally recurrent setting or as
part of clinical protocols like AMORE, a local treatment regimen
consisting of Ablative surgery, Moulage technique brachytherapy and
surgical Reconstruction.\textsuperscript{42-44}

2.5.2 Evidence

Evolving techniques have improved the application of radiotherapy in the
last decades for PM-RMS. IMRT has enabled better target dose coverage
than three-dimensional conformal radiotherapy,\textsuperscript{45} and
PT has further promised the reduction of unnecessary dose to critical
structures in the head and neck such as the optic apparatus,
hypothalamic-pituitary axis, brainstem, musculoskeletal structures, as
well as salivary glands. Thus far, several studies have examined the
application of PT for PM-RMS, resulting in similar oncologic outcomes as
photon therapy, with overall survival rates ranging between 58\% and
88.9\% and local control rates between 66\% and
84\%.\textsuperscript{25,26,32,46} Unfortunately, local failure in the
high-dose region remains problematic after both IMRT and
PT.\textsuperscript{20,25}

Although local control is deemed the main focus of radiotherapy for
pediatric rhabdomyosarcoma, late effects such as endocrine dysfunction,
secondary cancers, and cosmetic outcomes like facial hypoplasia are a
significant relevant issue, with the latter affecting up to 97\% of
treated patients.\textsuperscript{26,43,46} For PM-RMS specifically,
dosimetric comparisons have shown that PT, as compared to IMRT, achieves
improved sparing of relevant structures for a variety of organs like
brainstem, pituitary, and ipsilateral and contralateral lacrimal and
parotid glands.\textsuperscript{47} Regarding acute toxicity, a study
examining PT versus IMRT for PM-RMS reported no overall difference in
acute toxicity grade \textless{} 3. However, the risk of experiencing
grade 3 dermatitis was higher after PT, while the risk of experiencing
grade 3 mucositis was higher after IMRT.\textsuperscript{20} Regarding
long-term toxicity after IMRT for RMS of the head and neck, among the
Memorial Sloan Kettering series, after a median follow up of 7.7 years,
the most common long-term toxicity was facial disfigurement (observed in
77\% of patients), with other common toxicities including growth hormone
deficiency, dental problems, and cataracts (all seen in 30-40\% of
patients).\textsuperscript{48} Overall, clinical reports on toxicity for
PM-RMS have shown a low probability of adverse events after PT, although
the number of patients in available studies and length of follow-up are
limited. In an analysis of 46 children treated with PT, the mean maximal
acute and late toxicity score according to Common Toxicities Criteria on
Adverse Events (CTCAE) were 2.1 and 1.1, respectively and no acute or
late toxicity exceeding grade 3 was
reported.\textsuperscript{25}Importantly, within this study, the risk
for a field-border or marginal recurrence was low. This is in accordance
with other studies reporting low rates of acute or late toxicity after
PT with a toxicity [?]grade 3 free survival of 95\% at five
years.\textsuperscript{26} A study from Massachusetts General Hospital
looking at late toxicity after PT for rhabdomyosarcoma showed overall
low rates of low toxicity (35\% late toxicity of any grade with median
follow up of 47 months), with specific late toxicities in those with
head and neck disease including facial hypoplasia (9\%), dry eye (9\%)
and cataracts (3\%).\textsuperscript{49}With regard to second cancer
risk, PT has also shown reduced risk when compared to IMRT across
different cancer types, although prospective long-term comparison of the
second cancer risk after PT versus IMRT is lacking.\textsuperscript{50}

Brachytherapy only plays a minor role in current treatment of PM-RMS. As
such, evidence for brachytherapy is limited. However, brachytherapy was
used as part of upfront and salvage treatment after prior external beam
RT in the AMORE protocol, and results seem to be
promising.\textsuperscript{44}

\textbf{2.6 Surgical resection}

2.6.1 Expert Consensus

Pediatric parameningeal tumors typically present with locally advanced
disease secondary to the non-specific nature of the symptoms that they
cause. Due to the anatomical constraints and infiltrative nature of
parameningeal tumors, it is very difficult to obtain oncologically
negative margins without compromise of form and function (for example,
cranial nerve deficits, disfigurement of the facial bones). Surgical
resection thus holds a minimal role in the upfront management of PM-RMS
and should, for the most part, only be considered for non-parameningeal
head and neck sites where resection can be done with minimal morbidity
and little cosmetic/functional deficits. For PM-RMS specifically,
surgical approaches have typically been limited to biopsy and salvage
for recurrent disease. If resection is performed, a multidisciplinary
team at a specialized center should be involved, including
otolaryngology, neurosurgery, plastic surgery, and oral maxillofacial
surgery.

2.6.2 Evidence

The large majority of patients with parameningal tumors
(\textasciitilde{}95\%) will have IRS group III disease secondary to the
anatomical difficulties and morbidity of performing a gross total
resection at diagnosis.\textsuperscript{6,35} Surgery for parameningeal
sites has been considered to be unfavorable, due to risk of
disfigurement, injury to neurovascular structures, and difficulty in
achieving complete resection.\textsuperscript{51,52} Common toxicities
of surgical resection for parameningeal tumors can include cranial nerve
palsy, CSF leaks, trismus, and poor cosmesis.\textsuperscript{1}

With advances in endoscopic approaches and the quality of imaging,
certain tumors within the nasopharynx, sinonasal cavities, and skull
base without dural involvement may be amenable to endoscopic approaches
at specialized treatment centers.\textsuperscript{53} If surgical
resection is considered, smaller tumors (\textless{}5 cm, those without
dural involvement) appear to be more amenable to resection relative to
larger ones.\textsuperscript{51} Primary resection in smaller tumors may
have advantages such as avoidance of short and long term morbidities
associated with radiation to the pediatric skull base and sinonasal
cavities as described in small series.\textsuperscript{51,53} However,
there is often difficulty in obtaining negative margins, necessitating
postoperative radiation therapy.\textsuperscript{52,54} The advancement
of microsurgical techniques has also rendered surgery a treatment option
in select cases. When amenable to resection, these tumors are usually
approached through a transfacial or cranio-orbito-zygomatic approach,
which requires reconstruction after tumor resection is completed. Use of
free tissue transfer has enabled the ability to reconstruct areas once
thought to be unreachable by pedicled vascular
flaps.\textsuperscript{55}

In the hands of experienced surgical teams, there appears to be a low
risk of severe postoperative morbidity, although this is very dependent
on experience. The morbidity of surgical resection combined with the
potential need for adjuvant radiation must be carefully evaluated for
each patient.\textsuperscript{53,56} In the minority of patients who
were able to undergo initial resection with microscopic residual disease
on COG protocols, the addition of surgery with resulting lower IRS group
was not associated with an improvement in
outcomes,\textsuperscript{4}and radiation continued to be delivered in
the setting of microscopic residual disease and/or positive margins (IRS
group II). In addition, when performed as a delayed primary excision or
second look surgery, although radiation doses can be reduced to 36-41.4
Gy, radiation is still necessary, and there is no clear oncologic
benefit from delayed primary excision in this setting for
PM-RMS.\textsuperscript{57} In general, the tradeoff in morbidity
between the reduction in radiation dose with the addition of surgery in
the setting of delayed primary excision must be further explored with
quality of life and late effect assessments on future rhabdomyosarcoma
protocols.\textsuperscript{58}Overall though, without an oncologic
benefit with the addition of surgery to radiation, the acute and
long-term toxicity of trimodality therapy must be carefully considered
and selectively applied.

\textbf{GUIDELINE SUMMARY (Fig. 1)}

PM-RMS represents a very challenging site to treat with local failure
remaining the dominant form of failure. Definitive chemoradiation is the
preferred treatment approach for PM-RMS, with the goal of maximizing
cure while minimizing loss of form and function. Radiation timing,
volumes, and techniques have evolved greatly over the last 50 years with
this goal in mind.

Imaging with MRI of the head neck is critical in PM-RMS to assess the
extent of disease (including any possible intracranial extension),
evaluate response, and fuse for accurate radiation planning. Although
radiotherapy was previously delivered earlier for those with high-risk
parameningeal features, the timing of primary site radiotherapy for
localized PM-RMS is now similar to other sites at week 13 (and up to
week 20-22 in the metastatic setting). The recommended radiation dose
for PM-RMS is 50.4 Gy in 28 fractions, with a boost to 55.8 - 59.4 Gy
allowed for unfavorable features. To account for the response to
chemotherapy prior to radiation, the pre-chemotherapy extent of disease
can be treated to 36 Gy - 41.4 Gy, with a boost to the macroscopic
residual disease present at the time of radiation planning to the final
dose. Radiation target volumes have reduced drastically over time, with
the goal of enhancing the therapeutic ratio, from prior craniospinal
irradiation to now conformal treatment of the tumor with a 1-1.5cm
margin. Although prophylactic nodal irradiation is not recommended, for
patients with clinical or pathologic involvement of nodes, a dose of
36-41.4 Gy over 20-23 fractions (with gross disease to 50.4 Gy) is
recommended to the involved nodal chain or site. To minimize toxicity
and dose to the many critical organs at risk in the head and neck,
highly conformal techniques like IMRT or proton therapy must be
utilized, with proton therapy specifically encouraged whenever feasible
to minimize normal tissue toxicity. Despite advancements in volumes and
technology, morbidity of local therapy with radiation to the head and
neck remains significant, including cosmetic defects, endocrinopathies,
impaired vision and hearing, dental complications, and second cancers.

Given the locally infiltrative nature and difficulty with obtaining
negative margins, the role of surgical resection is often limited to
initial biopsy and for local therapy in the relapsed setting. However,
constant re-evaluation of the optimal treatment approach for patients
with PM-RMS is necessary. Overall, we recommend a multi-disciplinary
approach for treatment of PM-RMS, with the primary goal of maximizing
cure while maintaining form and function.

ACKNOWLEDGMENTS

We would like to thank Suzi Birz for her organizational and
administrative expertise. The International Soft Tissue Sarcoma
Consortium and the Pediatric Cancer Data Commons are supported in part
by Cancer Research Foundation, Children's Research Foundation, Comer
Development Board, Kick Cancer, King Baudouin Foundation, Rally
Foundation for Childhood Cancer Research, Seattle Children's Foundation
from Kat's Crew Guild through the Sarcoma Research Fund, St. Baldrick's
Foundation, and The Andrew McDonough B+ Foundation. This work is made
possible through the efforts of Children's Oncology Group, Cooperative
Weichteilsarkom Studiengruppe der GPOH, The European paediatric Soft
tissue sarcoma Study Group, MMT Malignant Mesenchymal Tumour Committee,
and STSC AIEOP Italian Soft Tissue Sarcoma Committee.

CONFLICT OF INTEREST STATEMENT:

DC, SH, AS, BT, SW have no relevant conflicts to disclose. HM
acknowledges the support of the NIHR Biomedical Research Centre at The
Royal Marsden NHS Foundation Trust and The Institute of Cancer Research.
JB acknowledges a research grant from Asco/Pfizer.

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\textbf{FIGURE 1} INSTRuCT consensus guideline summary for local
management of parameningeal rhabdomyosarcoma

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\verb`table 1 pm-rms pbc.docx`  available at \url{https://authorea.com/users/452579/articles/558643-local-control-of-parameningeal-rhabdomyosarcoma-an-expert-consensus-guideline-from-the-international-soft-tissue-sarcoma-consortium-instruct}\selectlanguage{english}
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