Improving Treatment for Rhabdomyosarcoma: A Collaborative Approach through the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG)

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Pediatric Oncology".

Deadline for manuscript submissions: 31 August 2024 | Viewed by 19877

Special Issue Editors


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Guest Editor
Children and Young People’s Unit, Royal Marsden Hospital, Sutton,London SM2 5PT, UK Institute of Cancer Research, Sutton, London SM2 5NG, UK
Interests: paediatric and adolescent cancer; soft tissue sarcoma; clinical drug development

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Guest Editor
Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, Sutton, London SM2 5NG, UK
Interests: molecular biomarkers; high-risk young onset sarcomas; rhabdomyosarcoma; molecular drivers and therapeutic targets

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Guest Editor
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
Interests: Soft tissue and bone sarcoma; clinical trial development; imaging studies; functional outcome and QoL after local therapy

Special Issue Information

Dear Colleagues,

Rhabdomyosarcoma, the commonest soft tissue sarcoma in children, requires multimodality treatment with chemotherapy, surgery, and/or radiotherapy to effect cure. Although outcomes for localized rhabdomyosarcoma have continued to improve, patients with metastatic or relapsed disease continue to do poorly, and better systemic and local therapy treatments are needed. The European paediatric soft tissue sarcoma study group (https://www.epssgassociation.it/), involving a multidisciplinary collaboration of basic scientists and clinical experts in many countries in Europe and beyond, has recently conducted practice-changing trials in high-risk and relapsed rhabdomyosarcoma and is advancing new treatments for both children and adults with the disease in its new multi-arm, multi-stage Frontline and Relapse Rhabdomyosarcoma Study (FaR-RMS) with associated biomarker and biological studies.

The aim of this Special Issue is to highlight and showcase collaborative research that is shaping our current thinking about how to improve treatment for rhabdomyosarcoma and which new approaches to offer to the highest risk patients. The scope includes original preclinical, translational, or clinical research, review articles, workshop summaries, and perspectives from patients/patient advocates that inform our understanding of how best to treat patients with rhabdomyosarcoma.

Dr. Julia Chisholm
Prof. Dr. Janet Shipley
Dr. Johannes H. M Merks
Guest Editors

Publisher’s notice:

As stated above, the central purpose of this Special Issue is to present research from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG) Project. Given this purpose, the Guest Editors’ contribution to this Special Issue may be greater than outlined in MDPI’s Special Issue guidelines (https://www.mdpi.com/special_issues_guidelines). The Editorial Office and Editor-in-Chief of Cancers has approved this Topic and MDPI’s standard manuscript editorial processing procedure (https://www.mdpi.com/editorial_process) will be applied to all submissions. As per our standard procedure, Guest Editors are excluded from participating in the editorial process for their submission and/or for submissions from persons with whom a potential conflict of interest may exist. More details on MDPI’s Conflict of Interest policy for reviewers and editors can be found here: https://www.mdpi.com/ethics#_bookmark22.

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Keywords

  • rhabdomyosarcoma in children and adolescents
  • rhabdomyosarcoma biology
  • drug targets
  • targeted therapies
  • clinical trials
  • treatment strategies
  • staging approaches
  • biology and imaging biomarkers
  • treatment-related toxicities
  • survivorship care
  • advocacy

Published Papers (10 papers)

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Review

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22 pages, 3556 KiB  
Review
The Capacity of Drug-Metabolising Enzymes in Modulating the Therapeutic Efficacy of Drugs to Treat Rhabdomyosarcoma
by Enric Arasanz Picher, Muhammad Wahajuddin, Stefan Barth, Julia Chisholm, Janet Shipley and Klaus Pors
Cancers 2024, 16(5), 1012; https://doi.org/10.3390/cancers16051012 - 29 Feb 2024
Viewed by 1121
Abstract
Rhabdomyosarcoma (RMS) is a rare soft tissue sarcoma (STS) that predominantly affects children and teenagers. It is the most common STS in children (40%) and accounts for 5–8% of total childhood malignancies. Apart from surgery and radiotherapy in eligible patients, standard chemotherapy is [...] Read more.
Rhabdomyosarcoma (RMS) is a rare soft tissue sarcoma (STS) that predominantly affects children and teenagers. It is the most common STS in children (40%) and accounts for 5–8% of total childhood malignancies. Apart from surgery and radiotherapy in eligible patients, standard chemotherapy is the only therapeutic option clinically available for RMS patients. While survival rates for this childhood cancer have considerably improved over the last few decades for low-risk and intermediate-risk cases, the mortality rate remains exceptionally high in high-risk RMS patients with recurrent and/or metastatic disease. The intensification of chemotherapeutic protocols in advanced-stage RMS has historically induced aggravated toxicity with only very modest therapeutic gain. In this review, we critically analyse what has been achieved so far in RMS therapy and provide insight into how a diverse group of drug-metabolising enzymes (DMEs) possess the capacity to modify the clinical efficacy of chemotherapy. We provide suggestions for new therapeutic strategies that exploit the presence of DMEs for prodrug activation, targeted chemotherapy that does not rely on DMEs, and RMS-molecular-subtype-targeted therapies that have the potential to enter clinical evaluation. Full article
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14 pages, 434 KiB  
Review
Maintenance Chemotherapy for Patients with Rhabdomyosarcoma
by Gianni Bisogno, Veronique Minard-Colin, Meriel. Jenney, Andrea Ferrari, Julia Chisholm, Daniela Di Carlo, Lisa Lyngsie Hjalgrim, Daniel Orbach, Johannes Hendrikus Maria Merks and Michela Casanova
Cancers 2023, 15(15), 4012; https://doi.org/10.3390/cancers15154012 - 7 Aug 2023
Cited by 2 | Viewed by 1446
Abstract
Maintenance chemotherapy (MC) defines the administration of prolonged relatively low-intensity chemotherapy with the aim of “maintaining” tumor complete remission. This paper aims to report an update of the RMS2005 trial, which demonstrated better survival for patients with high-risk localized rhabdomyosarcoma (RMS) when MC [...] Read more.
Maintenance chemotherapy (MC) defines the administration of prolonged relatively low-intensity chemotherapy with the aim of “maintaining” tumor complete remission. This paper aims to report an update of the RMS2005 trial, which demonstrated better survival for patients with high-risk localized rhabdomyosarcoma (RMS) when MC with vinorelbine and low-dose cyclophosphamide was added to standard chemotherapy, and to discuss the published experience on MC in RMS. In the RMS2005 study, the outcome for patients receiving MC vs. those who stopped the treatment remains superior, with a 5-year disease-free survival of 78.1% vs. 70.1% (p = 0.056) and overall survival of 85.0% vs. 72.4% (p = 0.008), respectively. We found seven papers describing MC in RMS, but only one randomized trial that did not demonstrate any advantage when MC with eight courses of trofosfamide/idarubicine alternating with trofosfamide/etoposide has been employed in high-risk RMS. The use of MC showed better results in comparison to high-dose chemotherapy in non-randomized studies, including metastatic patients, and demonstrated feasibility and tolerability in relapsed RMS. Many aspects of MC in RMS need to be investigated, including the best drug combination and the optimal duration. The ongoing EpSSG trial will try to answer some of these questions. Full article
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30 pages, 1547 KiB  
Review
Genomic and Epigenetic Changes Drive Aberrant Skeletal Muscle Differentiation in Rhabdomyosarcoma
by Silvia Pomella, Sara G. Danielli, Rita Alaggio, Willemijn B. Breunis, Ebrahem Hamed, Joanna Selfe, Marco Wachtel, Zoe S. Walters, Beat W. Schäfer, Rossella Rota, Janet M. Shipley and Simone Hettmer
Cancers 2023, 15(10), 2823; https://doi.org/10.3390/cancers15102823 - 18 May 2023
Cited by 1 | Viewed by 2739
Abstract
Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children and adolescents, represents an aberrant form of skeletal muscle differentiation. Both skeletal muscle development, as well as regeneration of adult skeletal muscle are governed by members of the myogenic family of regulatory transcription factors [...] Read more.
Rhabdomyosarcoma (RMS), the most common soft-tissue sarcoma in children and adolescents, represents an aberrant form of skeletal muscle differentiation. Both skeletal muscle development, as well as regeneration of adult skeletal muscle are governed by members of the myogenic family of regulatory transcription factors (MRFs), which are deployed in a highly controlled, multi-step, bidirectional process. Many aspects of this complex process are deregulated in RMS and contribute to tumorigenesis. Interconnected loops of super-enhancers, called core regulatory circuitries (CRCs), define aberrant muscle differentiation in RMS cells. The transcriptional regulation of MRF expression/activity takes a central role in the CRCs active in skeletal muscle and RMS. In PAX3::FOXO1 fusion-positive (PF+) RMS, CRCs maintain expression of the disease-driving fusion oncogene. Recent single-cell studies have revealed hierarchically organized subsets of cells within the RMS cell pool, which recapitulate developmental myogenesis and appear to drive malignancy. There is a large interest in exploiting the causes of aberrant muscle development in RMS to allow for terminal differentiation as a therapeutic strategy, for example, by interrupting MEK/ERK signaling or by interfering with the epigenetic machinery controlling CRCs. In this review, we provide an overview of the genetic and epigenetic framework of abnormal muscle differentiation in RMS, as it provides insights into fundamental mechanisms of RMS malignancy, its remarkable phenotypic diversity and, ultimately, opportunities for therapeutic intervention. Full article
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14 pages, 1449 KiB  
Review
Biological Role and Clinical Implications of MYOD1L122R Mutation in Rhabdomyosarcoma
by Daniela Di Carlo, Julia Chisholm, Anna Kelsey, Rita Alaggio, Gianni Bisogno, Veronique Minard-Colin, Meriel Jenney, Raquel Dávila Fajardo, Johannes H. M. Merks, Janet M. Shipley and Joanna L. Selfe
Cancers 2023, 15(6), 1644; https://doi.org/10.3390/cancers15061644 - 7 Mar 2023
Cited by 3 | Viewed by 2483
Abstract
Major progress in recent decades has furthered our clinical and biological understanding of rhabdomyosarcoma (RMS) with improved stratification for treatment based on risk factors. Clinical risk factors alone were used to stratify patients for treatment in the European Pediatric Soft Tissue Sarcoma Study [...] Read more.
Major progress in recent decades has furthered our clinical and biological understanding of rhabdomyosarcoma (RMS) with improved stratification for treatment based on risk factors. Clinical risk factors alone were used to stratify patients for treatment in the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS 2005 protocol. The current EpSSG overarching study for children and adults with frontline and relapsed rhabdomyosarcoma (FaR-RMS NCT04625907) includes FOXO1 fusion gene status in place of histology as a risk factor. Additional molecular features of significance have recently been recognized, including the MYOD1L122R gene mutation. Here, we review biological information showing that MYOD1L122R blocks cell differentiation and has a MYC-like activity that enhances tumorigenesis and is linked to an aggressive cellular phenotype. MYOD1L122R mutations can be found together with mutations in other genes, such as PIK3CA, as potentially cooperating events. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, ten publications in the clinical literature involving 72 cases were reviewed. MYOD1L122R mutation in RMS can occur in both adults and children and is frequent in sclerosing/spindle cell histology, although it is also significantly reported in a subset of embryonal RMS. MYOD1L122R mutated tumors most frequently arise in the head and neck and extremities and are associated with poor outcome, raising the issue of how to use MYOD1L122R in risk stratification and how to treat these patients most effectively. Full article
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17 pages, 1119 KiB  
Review
Targeting the Hedgehog Pathway in Rhabdomyosarcoma
by Patricia Zarzosa, Lia Garcia-Gilabert, Raquel Hladun, Gabriela Guillén, Gabriel Gallo-Oller, Guillem Pons, Julia Sansa-Girona, Miguel F. Segura, Josep Sánchez de Toledo, Lucas Moreno, Soledad Gallego and Josep Roma
Cancers 2023, 15(3), 727; https://doi.org/10.3390/cancers15030727 - 24 Jan 2023
Cited by 3 | Viewed by 2236
Abstract
Aberrant activation of the Hedgehog (Hh) signalling pathway is known to play an oncogenic role in a wide range of cancers; in the particular case of rhabdomyosarcoma, this pathway has been demonstrated to be an important player for both oncogenesis and cancer progression. [...] Read more.
Aberrant activation of the Hedgehog (Hh) signalling pathway is known to play an oncogenic role in a wide range of cancers; in the particular case of rhabdomyosarcoma, this pathway has been demonstrated to be an important player for both oncogenesis and cancer progression. In this review, after a brief description of the pathway and the characteristics of its molecular components, we describe, in detail, the main activation mechanisms that have been found in cancer, including ligand-dependent, ligand-independent and non-canonical activation. In this context, the most studied inhibitors, i.e., SMO inhibitors, have shown encouraging results for the treatment of basal cell carcinoma and medulloblastoma, both tumour types often associated with mutations that lead to the activation of the pathway. Conversely, SMO inhibitors have not fulfilled expectations in tumours—among them sarcomas—mostly associated with ligand-dependent Hh pathway activation. Despite the controversy existing regarding the results obtained with SMO inhibitors in these types of tumours, several compounds have been (or are currently being) evaluated in sarcoma patients. Finally, we discuss some of the reasons that could explain why, in some cases, encouraging preclinical data turned into disappointing results in the clinical setting. Full article
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15 pages, 626 KiB  
Review
Developments in the Surgical Approach to Staging and Resection of Rhabdomyosarcoma
by Sheila Terwisscha van Scheltinga, Timothy Rogers, Naima Smeulders, Federica deCorti, Florent Guerin, Ross Craigie, Gabriela Guillén Burrieza, Ludi Smeele, Marinka Hol, Rick van Rijn, Joerg Fuchs, Guido Seitz, Andreas Schmidt, Beate Timmermann, Per-Ulf Tunn, Cyrus Chargari, Raquel Dávila Fajardo, Olga Slater, Jenny Gains and Hans Merks
Cancers 2023, 15(2), 449; https://doi.org/10.3390/cancers15020449 - 10 Jan 2023
Cited by 4 | Viewed by 1959
Abstract
Although survival after rhabdosarcoma treatment has improved over the years, one third of patients still develop locoregional relapse. This review aims to highlight developments pertaining to staging and local treatment of specific RMS tumor sites, including head and neck, chest/trunk, bladder-prostate, female genito-urinary, [...] Read more.
Although survival after rhabdosarcoma treatment has improved over the years, one third of patients still develop locoregional relapse. This review aims to highlight developments pertaining to staging and local treatment of specific RMS tumor sites, including head and neck, chest/trunk, bladder-prostate, female genito-urinary, perianal, and extremity sites. Full article
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9 pages, 548 KiB  
Review
Using Evidence-Based Medicine to Support Clinical Decision-Making in RMS
by Robert S. Phillips, Bas Vaarwerk and Jessica E. Morgan
Cancers 2023, 15(1), 66; https://doi.org/10.3390/cancers15010066 - 22 Dec 2022
Cited by 2 | Viewed by 1539
Abstract
The foundations of evidence-based practice are the triad of patient values and preferences, healthcare professional experience, and best available evidence, used together to inform clinical decision-making. Within the field of rhabdomyosarcoma, collaborative groups such as the European Paediatric Soft Tissue Sarcoma Group (EpSSG) [...] Read more.
The foundations of evidence-based practice are the triad of patient values and preferences, healthcare professional experience, and best available evidence, used together to inform clinical decision-making. Within the field of rhabdomyosarcoma, collaborative groups such as the European Paediatric Soft Tissue Sarcoma Group (EpSSG) have worked to develop evidence to support this process. We have explored many of the key research developments within this review, including patient and public involvement, decision-making research, research into areas other than drug development, core outcome sets, reporting and dissemination of research, evidence synthesis, guideline development and clinical decision rules, research of research methodologies, and supporting research in RMS. Full article
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16 pages, 310 KiB  
Review
Shedding a Light on the Challenges of Adolescents and Young Adults with Rhabdomyosarcoma
by Andrea Ferrari, Susanne Andrea Gatz, Veronique Minard-Colin, Rita Alaggio, Shushan Hovsepyan, Daniel Orbach, Patrizia Gasparini, Anne-Sophie Defachelles, Michela Casanova, Giuseppe Maria Milano, Julia C. Chisholm, Meriel Jenney, Gianni Bisogno, Timothy Rogers, Henry C. Mandeville, Janet Shipley, Aisha B. Miah, Johannes H. M. Merks and Winette T. A. van der Graaf
Cancers 2022, 14(24), 6060; https://doi.org/10.3390/cancers14246060 - 9 Dec 2022
Cited by 3 | Viewed by 1610
Abstract
Rhabdomyosarcoma (RMS) is a typical tumour of childhood but can occur at any age. Several studies have reported that adolescent and young adult (AYA) patients with RMS have poorer survival than do younger patients. This review discusses the specific challenges in AYA patients [...] Read more.
Rhabdomyosarcoma (RMS) is a typical tumour of childhood but can occur at any age. Several studies have reported that adolescent and young adult (AYA) patients with RMS have poorer survival than do younger patients. This review discusses the specific challenges in AYA patients with pediatric-type RMS, exploring possible underlying factors which may influence different outcomes. Reasons for AYA survival gap are likely multifactorial, and might be related to differences in tumor biology and intrinsic aggressiveness, or differences in clinical management (that could include patient referral patterns, time to diagnosis, enrolment into clinical trials, the adequacy and intensity of treatment), as well as patient factors (including physiology and comorbidity that may influence treatment tolerability, drug pharmacokinetics and efficacy). However, improved survival has been reported in the most recent studies for AYA patients treated on pediatric RMS protocols. Different strategies may help to further improve outcome, such as supporting trans-age academic societies and national/international collaborations; developing specific clinical trials without upper age limit; defining integrated and comprehensive approach to AYA patients, including the genomic aspects; establishing multidisciplinary tumor boards with involvement of both pediatric and adult oncologists to discuss all pediatric-type RMS patients; developing dedicated projects with specific treatment recommendations and registry/database. Full article

Other

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23 pages, 1282 KiB  
Perspective
Frontline and Relapsed Rhabdomyosarcoma (FAR-RMS) Clinical Trial: A Report from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG)
by Julia Chisholm, Henry Mandeville, Madeleine Adams, Veronique Minard-Collin, Timothy Rogers, Anna Kelsey, Janet Shipley, Rick R. van Rijn, Isabelle de Vries, Roelof van Ewijk, Bart de Keizer, Susanne A. Gatz, Michela Casanova, Lisa Lyngsie Hjalgrim, Charlotte Firth, Keith Wheatley, Pamela Kearns, Wenyu Liu, Amanda Kirkham, Helen Rees, Gianni Bisogno, Ajla Wasti, Sara Wakeling, Delphine Heenen, Deborah A. Tweddle, Johannes H. M. Merks and Meriel Jenneyadd Show full author list remove Hide full author list
Cancers 2024, 16(5), 998; https://doi.org/10.3390/cancers16050998 - 29 Feb 2024
Viewed by 1842
Abstract
The Frontline and Relapsed Rhabdomyosarcoma (FaR-RMS) clinical trial is an overarching, multinational study for children and adults with rhabdomyosarcoma (RMS). The trial, developed by the European Soft Tissue Sarcoma Study Group (EpSSG), incorporates multiple different research questions within a multistage design with a [...] Read more.
The Frontline and Relapsed Rhabdomyosarcoma (FaR-RMS) clinical trial is an overarching, multinational study for children and adults with rhabdomyosarcoma (RMS). The trial, developed by the European Soft Tissue Sarcoma Study Group (EpSSG), incorporates multiple different research questions within a multistage design with a focus on (i) novel regimens for poor prognostic subgroups, (ii) optimal duration of maintenance chemotherapy, and (iii) optimal use of radiotherapy for local control and widespread metastatic disease. Additional sub-studies focusing on biological risk stratification, use of imaging modalities, including [18F]FDG PET-CT and diffusion-weighted MRI imaging (DWI) as prognostic markers, and impact of therapy on quality of life are described. This paper forms part of a Special Issue on rhabdomyosarcoma and outlines the study background, rationale for randomisations and sub-studies, design, and plans for utilisation and dissemination of results. Full article
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12 pages, 288 KiB  
Commentary
Patient Reported Outcomes and Measures in Children with Rhabdomyosarcoma
by Marloes van Gorp, Martha A. Grootenhuis, Anne-Sophie Darlington, Sara Wakeling, Meriel Jenney, Johannes H. M. Merks, Lisa Lyngsie Hjalgrim and Madeleine Adams
Cancers 2023, 15(2), 420; https://doi.org/10.3390/cancers15020420 - 9 Jan 2023
Cited by 1 | Viewed by 1576
Abstract
In addition to optimising survival of children with rhabdomyosarcoma (RMS), more attention is now focused on improving their quality of life (QOL) and reducing symptoms during treatment, palliative care or into long-term survivorship. QOL and ongoing symptoms related to the disease and its [...] Read more.
In addition to optimising survival of children with rhabdomyosarcoma (RMS), more attention is now focused on improving their quality of life (QOL) and reducing symptoms during treatment, palliative care or into long-term survivorship. QOL and ongoing symptoms related to the disease and its treatment are outcomes that should ideally be patient-reported (patient-reported outcomes, PROs) and can be assessed using patient-reported outcome measures (PROMS). This commentary aims to encourage PRO and PROM use in RMS by informing professionals in the field of available PROMs for utilisation in paediatric RMS and provide considerations for future use in research and clinical practice. Despite the importance of using PROMs in research and practice, PROMs have been reported scarcely in paediatric RMS literature so far. Available literature suggests lower QOL of children with RMS compared to general populations and occurrence of disease-specific symptoms, but a lack of an RMS-specific PROM. Ongoing developments in the field include the development of PROMs targeted at children with RMS specifically and expansion of PROM evaluation within clinical trials. Full article
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