NRSTS Committee

Tasks
Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) include a large heterogeneus variety of different entities with a clinical behavior varying from relatively benign to highly malignant. While there has historically been a paucity of data on the natural history and treatment of these tumors, in the first decade of the new millennium, pediatric cooperative groups developed multimodal risk-adapted trials tailored specifically to NRSTS. In particular, the EpSSG designed a comprehensive protocol (the EpSSG NRSTS 2005) consisting of two prospective non-randomized studies for patients <21 years old with localized adult-type NRSTS or localized synovial sarcoma, and including also specific clinical recommendations for other NRSTS histotypes found in pediatric patients.
The EpSSG NRSTS 2015 protocol was conducted from 2005 to 2016, and involved 100 academic centers and hospitals in 14 different countries. In terms of rationale, patient stratification and treatment paradigms (based on both pediatric and adult experiences), the EpSSG NRSTS 2005 study was very similar to the ARST0332 study developed by the North-American Soft Tissue Sarcoma Committee of the Children’s Oncology Group (COG), conducted from 2007 to 2012.
The EpSSG has reported on its analyses of various specific histological subgroups, and on the results of treatment in the whole series of patients enrolled in the prospective non-randomized part of the protocol. These analyses, together with the results of the COG ARST0332 study, currently represent the benchmark for NRSTS treatment in pediatric patients, and establish the risk-adapted standard of care.
Overall results, as reported in the main series published on Lancet Child Adol Health. 2021, showed 5-year EFS and OS of 73.7% and 83.8%, respectively, for the whole cohort of 569 patients. Patients were divided into four treatment groups based on surgical stage, tumor size, nodal involvement, and histopathological tumor grade (tumor site was added as a criterion for synovial sarcoma). Outcome was excellent for the group treated with surgery alone (250 cases, resected low grade tumors, or resected and small high grade tumors - 5-uyear OS 98%), demonstrating that adjuvant chemotherapy and radiotherapy can be safely omitted for this low- risk population in an effort to contain short- and long-term treatment-related morbidity. The study showed that, despite a generally favorable prognosis for grossly resected NRSTS, patients with high-grade and large tumors are at high risk of treatment failure: the 5-year EFS and OS were 65.6% and 75.8%, respectively, in adjuvant chemotherapy group. The study struggled to investigate the role of adjuvant chemotherapy in this patient category, however, due to a relatively limited sample size (93 cases). For the neoadjuvant chemotherapy group (i.e. patients with locally advanced and unresectable disease – 209 cases), the NRSTS 2005 study reported an overall response rate of 54%, and 5-year EFS and OS of 56.4% and 70.4%, respectively. The results were better than in historical series; and neoadjuvant ifosfamide–doxorubicin chemotherapy improved the resectability rate for this population.
The new challenge for the EpSSG is developing a systematic multicenter molecular and epigenetic characterization of cases of NRSTS as a standard approach at the time of their diagnosis, i.e. the MYKIDS study (“Molecular Identification and Characterization of non-Rhabdomyosarcoma Soft Tissue Sarcoma in Kids, Adolescents and Young Adults”).
The EpSSG MYKIDS study is the prospective biological investigation recruiting patients in EpSSG countries, open to in 2023. It aims to identify novel translocations and genetic drivers, and to characterize as yet unknown or unclassified sarcomas using whole-exome sequencing (WES), mRNA sequencing (mRNAseq), and DNA methylation profiling. Ultimately, this should lead to an integrated diagnosis, and a comprehensive understanding of the treatment options for a given patient. MYKIDS also aims to identify new, reproducible molecular signatures for predicting outcome and refine risk stratification (i.e. in particular, the study will examine the predictive role of chromosomal instability). Other working packages within the MYKIDS study focus on liquid biopsy, the development of faithful tumor models such as organoids, and post- treatment molecular changes.
In addition, the EpSSG is currently working on the development of a study to investigate whether adding regorafenib to the standard ifosfamide-doxorubicin chemotherapy can improve survival in high-risk NRSTS.