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\begin{document}

\title{The AYA gap for rhabdomyosarcoma.}



\author[1]{Simone Hettmer}%
\author[2]{L. H. Lindner}%
\affil[1]{University of Freiburg}%
\affil[2]{LMU University Hospital}%


\vspace{-1em}



  
  \date{May 18, 2024}


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\textbf{The AYA gap for rhabdomyosarcoma}

Simone Hettmer\textsuperscript{1} and Lars H. Lindner\textsuperscript{2}

Division of Pediatric Hematology and Oncology, Department of Pediatric
and Adolescent Medicine, University Medical Center Freiburg, University
of Freiburg, Freiburg, Germany.

Department of Medicine III, LMU University Hospital, LMU Munich,
Marchioninistr. 15, 81377, Munich, Germany.

To whom correspondence should be addressed. Email:
simone.hettmer@uniklinik-freiburg.de. Phone: +49 761 270-45140; Fax: +49
761 270-4518

Cancer is the leading cause of death among adolescents and young adults
(AYAs). Cancers diagnosed during the AYA period - defined by the
National Cancer Institute as the age from 15 to 39 years - account for
approximately 5\% of all cancers {[}1{]}. As per the national report on
the status of cancer (study period 2015-2019, {[}1{]}), 5-year relative
survival rates for both children and AYAs suffering from cancer are high
(85.1\% for children and 85.8\% for AYAs), and improvements in survival
over time appear to be similar for both age groups {[}1{]}. Yet, the
spectrum of cancer types diagnosed in AYAs varies widely. The most
common malignancies are female breast cancer (15\%), thyroid cancer
(15\%), testicular cancer (8\%) and melanomas (7\%) {[}1{]}, but AYAs
may also suffer from so-called pediatric cancers with peak incidence
during childhood. When compared to their childhood counterparts, worse
outcomes were reported for AYAs diagnosed with pediatric cancers,
including but not limited to leukemias {[}2{]} and sarcomas {[}3{]}.
This ,,AYA gap`` is of concern to both pediatric and adult oncologists.

The accompanying paper by Harrison et al examines a cohort of 2151
patients with rhabdomyosarcomas (RMS) enrolled in consecutive Children's
Oncology Group (COG) trials, including 19\% AYAs aged 15-39 years and
81\% children aged 0-14 years {[}4{]}. Compared to children with RMS,
AYAs experienced significantly lower 5-year event-free survival (EFS;
44\% vs. 67\%) and 5-year overall survival (OS; 52\% vs. 78\%). These
observations are in line with a recent retrospective analysis of nearly
2000 patients treated on European paediatric Soft Tissue Sarcoma Group
(EpSSG) protocols {[}3{]}. Importantly, relative survival of AYAs with
RMS treated on EpSSG and COG protocols appears to be better {[}3, 4{]}
than the survival observed in epidemiological studies such as EUROCARE-5
(39,6\% 5-year relative survival among RMS patients aged 15--19 years,
and 36\selectlanguage{ngerman}·4\% for those aged 20--39 years; study period 2000-2007 {[}5{]}).
Survival benefits for AYA patients treated on pediatric RMS protocols
are consistent with previous observations in AYAs receiving treatment
according to pediatric acute lymphoblastic leukemia (ALL) protocols
{[}2{]} or at pediatric cancer centers/ sites with pediatric oncology
expertise {[}6{]}. AYA cancer patients appear to benefit from
chemotherapy dose intensities higher than what is generally prescribed
to older patients. They may also draw advantages from pediatric
standards with respect to planning of multimodal treatment and cancer
staging. For example, the bone marrow (rarely ever involved in
adult-type soft tissue sarcomas (STS)) is the most frequent site of
metastases in AYAs with RMS treated within the COG cohort reported by
Harrison et al {[}4{]} and should always be considered when planning
pre-treatment examinations of AYAs with RMS. All taken together, adult
oncology providers of AYA patients with RMS are well advised to consult
their pediatric oncology colleagues and/ or consider referral to an
institution with pediatric oncology expertise.

AYA cancer patients treated on pediatric protocols -- including those
suffering from RMS - still experience worse outcomes than their
pediatric counterparts {[}2{]}. There is ample evidence to support
higher risk biology, more aggressive clinical phenotypes and higher
rates of early treatment failures in AYAs diagnosed with pediatric
cancers -- including leukemias andsarcomas- compared to children
diagnosed with the same malignancies {[}2-4{]}. For RMS tumors, higher
rates of alveolar histology tumors and metastatic disease in AYAs were
observed in the COG cohort reported here {[}4{]}, as well as in the
EpSSG and other retrospective studies {[}3, 7{]}. In addition to
higher-risk disease manifestation, more frequent treatment-related
toxicities and higher rates of withdrawal from treatment contribute to
worse outcomes of AYAs compared to children with cancer {[}2{]}. There
is a direct association between age and treatment-related deaths for
patients undergoing ALL treatment on pediatric protocols {[}2{]}.
Harrison et al do not comment on differences in treatment-related
toxicities between children and AYAs with RMS, but higher rates of
vincristine neurotoxicity, nausea and pain were previously reported in
older adolescents undergoing RMS treatment on pediatric protocols. Even
in the absence of higher-grade toxicities, a high burden of low-grade
adverse events can have a major impact on the ability to function in
daily life, continue education, maintain employment or participate in
social activities. Many AYAs with cancer need to rely more on their
parents/ support persons, which threatens their age-appropriate strive
for autonomy and may result in them rebelling against treatment
recommendations or failing to self- manage complex medication plans
{[}8{]}. Active involvement of AYAs in the development of a care plan,
which considers dignity, normalcy and family/ social relationships may
improve compliance and, ultimately, treatment success.

RMS is the most common STS in children and adolescents and often
referred to as a pediatric cancer. Nevertheless, it occurs at any age,
and up to 40\% of all cases are diagnosed in adults (including seniors)
{[}9{]}. The molecular and histological heterogeneity of pediatric RMS
was studied intensively in recent years {[}10{]}. However, the insights
provided by Harrison et al {[}4{]} and Ferrrai et al {[}3{]} emphasize
that the remarkable diversity apparent across the RMS spectrum is
multidimensional. Distinct clinical and biological characteristics of
RMS diagnosed in different age groups deserve further attention. The two
main pediatric RMS subtypes are embryonal and alveolar RMS, whereas
pleomorphic RMS and RMS not otherwise specified are predominant in older
adults and considered fundamentally different cancers {[}9{]}. To obtain
a better understanding of RMS diagnosed in AYAs, future study efforts
should aim at investigating the full spectrum of the disease and
differentially consider the molecular underpinnings and therapeutic
requirements of RMS diagnosed at opposite ends of the AYA age range.

\emph{(917 words, max 1000 words)}

\textbf{References}

1. Cronin, K.A., et al., \emph{Annual report to the nation on the status
of cancer, part 1: National cancer statistics.} Cancer, 2022.
\textbf{128} (24): p. 4251-4284.

2. Janardan, S.K. and T.P. Miller,\emph{Adolescents and young adults
(AYAs) vs pediatric patients: survival, risks, and barriers to
enrollment.} Hematology Am Soc Hematol Educ Program, 2023. \textbf{2023}
(1): p. 581-586.

3. Ferrari, A., et al.,\emph{Adolescents and young adults with
rhabdomyosarcoma treated in the European paediatric Soft tissue sarcoma
Study Group (EpSSG) protocols: a cohort study.} Lancet Child Adolesc
Health, 2022. \textbf{6} (8): p. 545-554.

4. Harrison, D., et al.,\emph{Adolescents and Young Adults with
Rhabdomyosarcoma: A Report from the Soft Tissue Sarcoma Committee of the
Children's Oncology Group Short Running Title: Rhabdomyosarcoma in the
AYA Population.} Pediatr Blood Cancer, 2024. \textbf{in press} .

5. Trama, A., et al., \emph{Survival of European adolescents and young
adults diagnosed with cancer in 2000-07: population-based data from
EUROCARE-5.} Lancet Oncol, 2016.\textbf{17} (7): p. 896-906.

6. Kirchhoff, A.C., et al.,\emph{Access to Care for Adolescent and Young
Adults With Cancer in the United States: State of the Literature.} J
Clin Oncol, 2023: p. JCO2301027.

7. Ferrari, A., et al., \emph{Shedding a Light on the Challenges of
Adolescents and Young Adults with Rhabdomyosarcoma.} Cancers (Basel),
2022. \textbf{14} (24).

8. Valtis, Y.K., et al.,\emph{Treatment completion, asparaginase
completion, and oncologic outcomes among children, adolescents and young
adults with acute lymphoblastic leukemia treated with DFCI Consortium
Protocols.}Leukemia, 2024.

9. Sultan, I., et al., \emph{Comparing adult and pediatric
rhabdomyosarcoma in the surveillance, epidemiology and end results
program, 1973 to 2005: an analysis of 2,600 patients.} J Clin Oncol,
2009. \textbf{27} (20): p. 3391-7.

10. Shern, J.F., et al.,\emph{Genomic Classification and Clinical
Outcome in Rhabdomyosarcoma: A Report From an International Consortium.}
J Clin Oncol, 2021.\textbf{39} (26): p. 2859-2871.

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