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Background: The authors report the prospective evaluation of reduced dose alkylator chemotherapy combined with radiotherapy for European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) standard risk nonalveolar rhabdomyosarcoma (NA‐RMS). Patients and Methods: Localized node negative Intergroup Rhabdomyosarcoma Study (IRS) II/III NA‐RMS at favorable sites (subgroup C), <25 years old, received five cycles of ifosfamide, vincristine, and dactinomycin (IVA) chemotherapy (30 g/m2 ifosfamide) and four cycles of vincristine and dactinomycin (if receiving radiotherapy), or nine cycles of IVA (54 g/m2 ifosfamide) ± radiotherapy. Delayed primary tumor excision was considered for IRS III tumors. The primary end points were event‐free survival (EFS) and overall survival (OS). Results: From October 2005 to December 2016, 359 evaluable patients were recruited: orbit, 164 (45.7%); head and neck nonparameningeal, 77 (21.4%); and genitourinary non–bladder/prostate, 118 (32.9%). EFS and OS were 77.4% (95% confidence interval [CI], 72.5–81.6) and 93.5% (95% CI, 90.1–95.8), respectively. Lower dose alkylator chemotherapy and radiotherapy achieved 5‐year OS of 93.7% but the difference with higher dose alkylator chemotherapy +/‐ radiotherapy was not significant (p = 0.8003). Adjuvant radiotherapy improved EFS with 5‐year estimates of 84.7% versus 65.2% for nonirradiated (p <.0001), but not OS (p =.9298). Omitting radiotherapy for orbital tumors reduced OS (5‐year was 87.1% vs. 97.3% for irradiated, p =.0257). Following R0 resection (n = 60), radiotherapy did not significantly improve EFS or OS. Conclusions: Radiotherapy for local tumor control allows for reduction of cumulative dose of alkylators in EpSSG standard risk subgroup C RMS patients. The omission of radiotherapy did not affect OS in all patients except those with orbital RMS and was associated with inferior EFS. Radiotherapy allowed effective reduction in cumulative dose of alkylators for localized Intergroup Rhabdomyosarcoma Study II/III nonalveolar rhabdomyosarcoma (RMS) at favorable sites in the European Pediatric Soft Tissue Sarcoma Study Group RMS 2005 trial. The omission of radiotherapy is associated with inferior event‐free survival but not overall survival (OS), although inferior OS was observed for orbital RMS. [ABSTRACT FROM AUTHOR]

Background: The objective of this study was to investigate the role of clinical factors together with FOXO1 fusion status in patients with nonmetastatic rhabdomyosarcoma (RMS) to develop a predictive model for event‐free survival and provide a rationale for risk stratification in future trials. Methods: The authors used data from patients enrolled in the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) RMS 2005 study (EpSSG RMS 2005; EudraCT number 2005‐000217‐35). The following baseline variables were considered for the multivariable model: age at diagnosis, sex, histology, primary tumor site, Intergroup Rhabdomyosarcoma Studies group, tumor size, nodal status, and FOXO1 fusion status. Main effects and significant second‐order interactions of candidate predictors were included in a multiple Cox proportional hazards regression model. A nomogram was generated for predicting 5‐year event‐free survival (EFS) probabilities. Results: The EFS and overall survival rates at 5 years were 70.9% (95% confidence interval, 68.6%–73.1%) and 81.0% (95% confidence interval, 78.9%–82.8%), respectively. The multivariable model retained five prognostic factors, including age at diagnosis interacting with tumor size, tumor primary site, Intergroup Rhabdomyosarcoma Studies clinical group, and FOXO1 fusion status. Based on each patient's total score in the nomogram, patients were stratified into four groups. The 5‐year EFS rates were 94.1%, 78.4%, 65.2%, and 52.1% in the low‐risk, intermediate‐risk, high‐risk, and very‐high‐risk groups, respectively, and the corresponding 5‐year overall survival rates were 97.2%, 91.5%, 74.3%, and 60.8%, respectively. Conclusions: The results presented here provide the rationale to modify the EpSSG stratification, with the most significant change represented by the replacement of histology with fusion status. This classification was adopted in the new international trial launched by the EpSSG. Traditional clinical factors, together with FOXO1 fusion status, in nonmetastatic rhabdomyosarcoma were investigated to develop a predictive model for event‐free survival and provide a rationale for risk stratification in future trials. The most important result was the replacement of histology with fusion status, and this model was used for patient stratification in the new European Pediatric Soft Tissue Sarcoma Study Group Frontline and Relapse Rhabdomyosarcoma trial (ClinicalTrials.gov identifier NCT04625907). [ABSTRACT FROM AUTHOR]

Simple Summary: The updated results of the RMS2005 randomized study confirm that patients with non-metastatic high risk rhabdomyosarcoma have an improved survival when maintenance chemotherapy (MC) with vinorelbine and low dose cyclophosphamide is added to the standard multidisciplinary treatment. A more recent randomized study adopted the same strategy, but different drugs were used in the MC phase (trofosfamide, idarubicin and etoposide). No survival improvement was evident in the MC group, suggesting that not all types of MC are equally effective. A revision of the literature demonstrates that the role of MC in patients with metastatic or relapsed RMS may be a promising approach but need more investigations. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: The myogenic differentiation 1 gene (MYOD1) p.L122R mutation was first discovered in a subset of clinically aggressive rhabdomyosarcomas in both adults and children. It occurs most frequently in spindle cell (Sp) or sclerosing (Sc) RMS, but also occasionally in ERMS, including 3% of all PAX fusion-negative RMS. The presence of the MYOD1L122R mutation seems to be associated with a very poor prognosis, especially when it occurs concomitantly with other mutations such as PIK3CA. In this review, we consider the known biological effects of MYOD1 mutations and present a review of published cases of RMS with MYOD1 mutations. Together, the reviewed biological characteristics and the clinical features focus attention on this specific subgroup of patients with poor outcome and highlight the need to identify an optimal therapeutic strategy. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Children with rhabdomyosarcoma often experience difficulties as a result of their disease and treatment, such as pain or low mood. This can have a significant impact on their overall quality of life. It is important to evaluate these outcomes independently and prospectively, to improve the care provided for this population. One approach is to use questionnaires (or patient-reported outcome measures, PROMs) completed by patients. This commentary aims to encourage the use of PROMs by informing professionals in the field. The few available studies suggest that the quality of life of children with rhabdomyosarcoma is impaired. Additionally, children with rhabdomyosarcoma may have problems specifically related to their disease, for example due to their appearance after having surgery and/or radiotherapy. It is therefore important to develop questionnaires that include disease-specific issues. These can be used in addition to the generic quality of life questionnaires which are now more often used for children with cancer. 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. [ABSTRACT FROM AUTHOR]

Simple Summary: Rhabdomyosarcoma is the most frequent soft tissue sarcoma of childhood, but can occur at any age. Adolescent and young adult patients with rhabdomyosarcoma often have poorer outcomes than do children. This survival gap may be related to differences in clinical management or differences in tumor biology and intrinsic aggressiveness. Various studies have suggested that young adults may have better outcomes when treated with multidisciplinary treatment in line with the pediatric approach. However, treatment results seem to remain worse in young adults when compared with children, even when they were treated in the same way, and this suggest that part of the prognostic gap between children and adults may be attributable to biological differences in rhabdomyosarcoma arising in different age groups. A multifaced strategy is needed to further improve outcome of adults with rhabdomyosarcoma, including a trans-age academic societies and national/international cooperation, the definition of integrated biologic and genomic approach, and the development of collaborative rhabdomyosarcoma clinical trials without upper age limit. 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. [ABSTRACT FROM AUTHOR]

Objective. To assess the health-related quality of life (HRQL) of 8- to 12-year-old children undergoing therapy for cancer or childhood-cancer survivors by using the Minneapolis-Manchester Quality of Life-Youth Form (MMQL-YF), a comprehensive, multidimensional self-report instrument with demonstrable reliability and validity. Design, Setting, and Patients. The MMQL-YF consists of 32 items comprising 4 scales: physical functioning, psychologic functioning, physical symptoms, and outlook on life. Scoring on the MMQL ranges from 1 to 5; 5 indicates maximal HRQL. An overall quality-of-life (QOL) score is also computed. By using a cross-sectional study design, the MMQL-YF was administered to 90 off-therapy cancer survivors, 72 children with cancer undergoing active therapy, and 481 healthy children without a history of cancer or other chronic disease. Results. Compared with healthy controls, children actively undergoing cancer treatment report low overall QOL, physical functioning, and outlook-on-life scores. However, off-therapy survivors report a superior overall QOL, compared with age-matched healthy controls. Conclusions. Young survivors of childhood cancer report a favorable HRQL relative to healthy controls. These results are reassuring, suggesting that this group of survivors may have been too young to encounter some of the negative psychosocial impacts of cancer and its treatment, health-related quality of life, childhood-cancer survivors., ABBREVIATIONS. HRQL, health-related quality of life; QOL, quality of life; MMQL, Minneapolis-Manchester Quality of Life; YF, Youth Form; RR, relative risk; CI, confidence interval. Treatment advances over the past decades [...]