# Childhood, Adolescent and Young Adult Poor-Prognosis Rhabdomyosarcoma

## TL;DR

This review discusses poor-prognosis rhabdomyosarcoma in children and young adults, highlighting the need for better treatments and summarizing current and emerging approaches.

## Contribution

The paper focuses on the most challenging subgroups of RMS patients and summarizes novel therapeutic strategies being explored.

## Key findings

- Patients with PAX3(7)::FOXO1 gene fusions and other adverse features have the worst outcomes.
- Adolescents and young adults with RMS face poorer prognoses compared to younger children.
- Metastatic and relapsed RMS cases remain difficult to treat despite multimodal therapies.

## Abstract

Rhabdomyosarcoma (RMS) is an aggressive soft tissue sarcoma which primarily affects children, adolescents and young adults. Multimodality approaches to treatment include chemotherapy, surgery and radiotherapy. Despite attempts to improve outcomes over recent decades, survival rates remain poor for patients with advanced and relapsed/progressive disease and those who have tumours with aggressive biologic features. This review article focuses on patient groups with the poorest outcomes which include those with (1) PAX3(7)::FOXO1 gene fusions and other adverse biological features; (2) RMS in adolescents and young adults; (3) RMS that has already spread to distant organs at the time of first presentation (metastatic disease); (4) RMS that progresses or recurs following first-line treatment. This review highlights the ongoing urgent unmet need for improved treatments in these patients and discusses novel therapeutic approaches currently being investigated.

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and young people. Despite the advances in multimodality treatment over recent decades through successive prospective clinical trials, improved rates of survival for patients are mainly limited to those with localised RMS without adverse biologic features. Current clinicopathologic prognostic factors include PAX3(7)::FOXO1 fusion status, the site of primary disease, the pre-chemotherapy extent of disease (including microscopic vs. macroscopic residual disease, locoregional nodal involvement and metastatic status), tumour size and patient age. These factors are used to stratify patients into prognostic risk groups that guide treatment intensity and duration. Risk stratification algorithms are evolving, supported by advances in molecular biology and cancer genomics. In this review we focus on the poorest prognostic groups of paediatric-type RMS (i.e., Very High Risk or relapsed/progressive disease). These include patients whose tumours harbour poor biological characteristics such as PAX3(7)::FOXO1 fusion-positive tumours with locoregional nodal involvement and tumours harbouring other poor-risk genetic variants (particularly MYOD1 and TP53 variants); adolescent and young adult patients; newly diagnosed patients with metastatic RMS; and patients with relapsed and refractory disease. Here we aim to describe the clinical characteristics of these patients, outline current standard multimodality treatments in the context of sequential international clinical trials across the major cooperative groups and summarise emerging novel diagnostic and therapeutic approaches.