The AYA gap for rhabdomyosarcoma
Simone Hettmer1 and Lars H. Lindner2
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 36·4% 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.