Meriel Jenney

Background: The apparent diffusion coefficient (ADC) derived from diffusion-weighted imaging (DWI) is a potential biomarker for treatment response in pediatric rhabdomyosarcoma. Due to its rarity, investigations into this marker require multicenter approaches, which can result in variability in acquisition parameters. Objective: To evaluate the impact of different acquisition parameters on ADC estimates in a multicenter dataset of rhabdomyosarcoma patients. Materials and methods: We included 114 pediatric and adolescent rhabdomyosarcoma patients from 22 treatment centers (195 scans). Median age: 6.0 years (0.3–21.8). We evaluated the impact of voxel size, (number of) b-values, and echo time on tumor ADC values. The effect of the highest b-value was separately investigated on a subset of scans with five or more b-values. Results: We observed a large variability in key acquisition parameters in the overall cohort, and for individual imaging centers. No parameter showed a significant effect on ADC estimates of the whole cohort when corrected for multiple-comparisons. Decreasing the highest b-value within the same acquisition caused ADC to decrease on average by 2.8% per 100 s mm^-2. Differing b-values between scans at diagnosis and treatment response yielded significant changes in the longitudinal ADC for each patient (Pb-value between baseline and follow-up can impact longitudinal ADC estimates. As such, we recommend the highest b-value to remain constant. This retrospective study was reviewed and approved by the Internal Review Board (UMC Utrecht, reference ID: 18-412). Graphical

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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.

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.

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 MYOD1^L122R gene mutation. Here, we review biological information showing that MYOD1^L122R blocks cell differentiation and has a MYC-like activity that enhances tumorigenesis and is linked to an aggressive cellular phenotype. MYOD1^L122R 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. MYOD1^L122R 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. MYOD1^L122R 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 MYOD1^L122R in risk stratification and how to treat these patients most effectively.

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.

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.

Background: Health‐related quality of life (HRQoL) from diagnosis until end of treatment for children with acute lymphoblastic leukaemia was investigated, examining effects of age, gender, risk‐stratified treatment regimen, and therapy intensity (one vs. two ‘delayed intensifications’ [DIs]).Method: In a multi‐centre prospective study, parents reported their child's generic and disease‐specific HRQoL and their own care‐giving burden at five time points. From 1,428 eligible patients, 874 parents completed questionnaires at least once during treatment.Results: At each time point, generic HRQoL was significantly lower than equivalent norm scores for healthy children. HRQoL decreased significantly at the start of treatment, before recovering gradually (but remained below pre‐treatment levels). Parents reported that older children worried more about side effects and their appearance, but showed less procedural anxiety than younger children. Concern for appearance was greater among girls than boys. Compared to Regimen B (i.e. additional doxorubicin during induction and additional cyclophosphamide and cytarabine during consolidation chemotherapy), patients receiving Regimen A had fewer problems with pain and nausea. There were no statistically significant differences in HRQoL by number of DI blocks received.Interpretation: HRQoL is compromised at all stages of treatment, and is partly dependent on age. The findings increase understanding of the impact of therapy on children's HRQoL and parental care‐giving burden, and will contribute to the design of future trials.

Background The three sequential SIOP MMT studies provide the largest dataset available to date, to define the patient and tumour characteristics, treatment modalities and event‐free and overall survival for children with non metastatic rhabdomyosarcoma (RMS) of the bladder and/or prostate (BP). Procedure The combined dataset of 172 patients with BP RMS treated on the SIOP MMT 84, 89 and 95 studies was reviewed to determine tumour characteristics, details of treatment and outcome. Results Median age at diagnosis was 2.5 years (range 2 months–17.8 years) and 138 (79%) were males. Median follow‐up was 11.4 years (range 3 months–22 years). The 5‐year overall survival of the combined cohort was 77% (CI 70–83%). The 5‐year event‐free survival was 63% and included 7 patients (4%) who did not achieve complete remission (CR), and 57 (33%) who relapsed. Age ≥ 10 years (RR 3.7) and alveolar pathology (RR 3.3) were identified as independent prognostic factors on multivariate analysis. Fifty‐nine (50%) of the 119 survivors were cured without significant local therapy, improving from 31% in MMT84 study to 61% in MMT95 study. Conclusion The clinical strategy of the MMT studies aims to minimise the burden of therapy whilst maintaining survival rates. Overall survival is comparable to that of other international groups, despite the lower use of radiotherapy and or radical surgery, although number of events experienced is higher. Further assessment of the late effects of therapy is required to confirm whether this approach results in lower morbidity in the long‐term. Pediatr Blood Cancer 2014;61:217–222.