Malignant ectomesenchymoma in children: The European pediatric Soft tissue sarcoma Study Group experience.

Malignant ectomesenchymoma (MEM) is an extremely rare soft tissue tumor typical of young children, currently included in the category of skeletal muscle malignancies and characterized by a neuroblastic component. This study describes a series of 10 patients prospectively registered in the European paediatric Soft tissue sarcoma Study Group (EpSSG) database Of the 10 cases, seven had an initial local diagnosis of rhabdomyosarcoma. All patients received chemotherapy according to rhabdomyosarcoma strategy, four had radiotherapy. Overall, six patients were alive in first remission, two in second remission and one after second tumor. Only the patient with initially metastatic tumor died of disease.

Metastatic rhabdomyosarcoma with exclusive distant lymph node involvement: A European Pediatric Soft tissue sarcoma Study Group (EpSSG) report.

BACKGROUND: The prognosis of patients with metastatic rhabdomyosarcoma (RMS) is not uniformly poor. Tumors with nodal involvement beyond the first lymph node station are currently considered to have distant metastases. The aim of this study is to evaluate the characteristics and outcome of RMS patients with distal nodal involvement as the only site of metastasis. METHODS: This study included all patients with a diagnosis of RMS and distant nodal involvement as the only metastatic site, enrolled in the European Pediatric Soft tissue sarcoma Study Group (EpSSG) protocols. Treatment comprised chemotherapy, surgery, and/or radiotherapy. The main outcome measures were event-free survival (EFS) and overall survival (OS). RESULTS: A total of 22 patients (median age 7.1 years, range 1.4-16.7) fit the inclusion criteria. The extremities were the most common primary tumor site (59%). Twenty-one patients had regional and distant nodal involvement, 12 were PAX3/7-FOXO1 positive. Twenty patients had radiotherapy including 16 to the nodal metastatic area. After a median follow-up of 53.9 months (range 22.8-110.5), 15 patients remain in complete remission, seven had progressive disease or relapse, and six of them died. The 3-year EFS and OS were 67.1% (95% confidence interval [CI]: 42.9-82.9) and 71.9% (95% CI: 47.7-86.3), respectively. Patients with fusion-negative tumors had better outcomes than those with fusion-positive tumors (3-year EFS 100% vs. 46.6%; p = .04). CONCLUSION: In our experience, patients with RMS and distant lymph node involvement as the only site of metastasis present an outcome superior than other metastatic patients and comparable to patients with locoregional nodal involvement. In particular, excellent outcomes were seen in the limited number of patients with fusion-negative tumors.

Intra-abdominal desmoplastic small round cell tumor: The European pediatric Soft tissue sarcoma Study Group (EpSSG) experience.

BACKGROUND: This study describes the clinical findings of a consecutive series of pediatric and adolescent patients with a diagnosis of intra-abdominal desmoplastic small round cell tumor (DSRCT) prospectively enrolled in European pediatric Soft tissue sarcoma Study Group (EpSSG) protocols: the BERNIE study, the EpSSG MTS 2008 study, and the EpSSG NRSTS 2005 study. METHODS: Patients aged less than 21 years with a diagnosis of DSRCT arising in the abdomen were included. All trials recommended a multimodal approach including intensive multidrug chemotherapy and loco-regional treatment with surgery and/or radiotherapy whenever possible. RESULTS: The analysis included 32 cases (median age 13.7 years, male:female ratio 1.5:1). Three patients had localized tumors, seven had regionally disseminated disease, and 22 extraperitoneal metastases. All but one patient received multidrug chemotherapy and 11 had maintenance chemotherapy. Loco-regional treatment consisted of surgery only in seven cases, surgery plus adjuvant radiotherapy in 10, and radiotherapy only in six. Among the 17 cases who had radiotherapy, six had irradiation of the primary site, 10 had whole abdominopelvic radiotherapy plus boost to macroscopic residual disease, and one had irradiation to lung metastases only. With a median follow-up of 76 months (range: 18-124 months), 5-year event-free and overall survivals were 19.7% and 21.0%, respectively. Event-free survival was significantly worse for patients who did not receive loco-regional treatment (p-value .007). CONCLUSIONS: The study confirmed that the outcome of patients with DSRCT remains dismal and did not improve over recent years despite an intensive multimodal treatment approach.

Outcome and prognostic factors in pediatric malignant peripheral nerve sheath tumors: An analysis of the European Pediatric Soft Tissue Sarcoma Group (EpSSG) NRSTS-2005 prospective study.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNST) are rare tumors of childhood. The role of standard chemotherapy in unresectable MPNST is still unclear. We report the outcome and prognostic factors in the EpSSG risk-adapted prospective study for localized pediatric MPNST. METHODS: Patients were stratified into four treatment groups defined by surgical resection, tumor size, and tumor grade (G): (a) surgery-only group-resected tumors G1; (b) adjuvant radiotherapy group-R0/R1, G2 tumors; (c) adjuvant chemotherapy group-R0/R1, G3 tumors; and (d) neoadjuvant chemotherapy group-R2 resected tumors and/or nodal involvement. Chemotherapy consisted of four courses of ifosfamide-doxorubicin and two courses of ifosfamide concomitant with radiotherapy (50.4-54 Gy). RESULTS: Overall, the study included 51 patients. The 5-year event-free survival (EFS) and overall survival (OS) were 52.9% (95% confidence interval, 38.1-65.8) and 62.1% (46.7-74.3), respectively. The 5-year EFS was 92% (56.6-98.9) for treatment group 1 (N = 13), 33% (0.9-77.4) for treatment group 2 (N = 4), 29% (4.1-61.2) for treatment group 3 (N = 7), and 42% (23.1-60.1) for treatment group 4 (N = 27). Response rate to chemotherapy (partial response + complete response) in patients with measurable disease was 46%. The presence of neurofibromatosis type 1 (NF1; 51% of patients) was an independent poor prognostic factor for OS and EFS. CONCLUSION: The outcome for patients with resectable MPNST was excellent. Standard ifosfamide-doxorubicin for unresectable MPNST rendered the best reported outcome. Children with NF1 disease seem to have worse prognosis.

Frontline and Relapsed Rhabdomyosarcoma (FAR-RMS) Clinical Trial: A Report from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).

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.

Localised rhabdomyosarcoma in infants (<12 months) and young children (12-36 months of age) treated on the EpSSG RMS 2005 study.

BACKGROUND: Infants (<12 months) with rhabdomyosarcoma have historically had poorer outcome than the older age groups. We present outcomes for infants and young children aged 12-36 months with localised rhabdomyosarcoma with a particular emphasis on infants. PATIENTS AND METHODS: All children less than 36 months of age enrolled on the EpSSG RMS 2005 study for localised disease are included. Treatment comprised chemotherapy, local surgery and/or radiation therapy adapted to risk group and age. Main outcome measures were event free survival (EFS) and overall survival (OS). RESULTS: Outcome data were available for 485/490 patients aged less than 36 months, 110 were infants. Infants received chemotherapy according to the risk group with no toxic deaths. Radiotherapy was delivered to 33.6% of infants and 63.5% of 12-36 months old, with respectively 41.7% and 22.2% receiving brachytherapy. Radical surgery was performed in 62% of infants and 57.1% of 12-36 months old. Median follow up for patients who are alive (n = 393) was 72.7 months (range 6.9-158.2). Five-year OS for infants was 88.4% (95%CI 80.3-93.2), which is significantly better than the OS in 12-36 months old patients of 78.0% (95%CI 73.2-82.0; p = 0.0204). Five-year EFS for infants was 72.5% (95%CI 62.8-80.0) compared with 66.1% (95%CI 61.0-70.7; p = 0.2663) for 12-36 months old. CONCLUSION: Infants treated on RMS 2005 achieved excellent EFS and OS. The EpSSG RMS 2005 chemotherapy regimen, combined with an increase in the application of adequate local therapy, improvements in imaging and supportive care and potentially favourable patients' characteristics may have contributed to these results.

Extracranial rhabdoid tumours: Results of a SFCE series of patients treated with a dose compression strategy according to European Paediatric Soft tisue sarcoma Study Group recommendations.

BACKGROUND AND AIMS: Extracranial malignant rhabdoid tumours are tumours that mainly affect young children and have a poor prognosis. In 2014, the European Paediatric Soft-tissue sarcoma Study Group developed treatment recommendations consisting in intensive dose chemotherapy every 2 weeks using vincristine-doxorubicin-cyclophosphamide (VDCy) and ifosfamide-etoposide (IE) associated with early surgery and irradiation of tumour sites. METHODS: A retrospective study was conducted on children treated in France by these new recommendations up to January 2019. RESULTS: Thirty-five patients were identified. The primary tumour was in miscellaneous soft parts for 18 patients, in the kidney for 11 and in the liver for six. The median age at diagnosis was 17.5 months (range 1.2-198.2). Distant locations (metastatic or synchronous tumours) were present in 37.1% at diagnosis. SMARCB1 germline pathogenic variant was detected in 17.1% of patients. Overall tolerance was good, with 87-97% of theoretical chemotherapy cumulative doses actually delivered. The median interval between two courses was 18 days. Surgical resection was performed in 83% (19 R0, 7 R1 and 3 R2) and local radiotherapy in 49% of patients. After a median follow-up of 50.4 months (range 16.5-134.1), the 2-year overall and event-free survivals were 47.6% (95% confidence interval [CI] 30.2-63.1) and 42.9% (95% [CI] 26.5-58.3), respectively. On univariate analyses, localised disease and gross total resection were significantly associated with favourable outcomes. CONCLUSIONS: Intensive dose chemotherapy with VDCy/IE can be administrated with no remarkable short-term toxicity, including in infants. However, the outcome remains poor for patients without gross total resection and with metastatic or multifocal disease. These patients could be stratified into a high-risk group that requires a new immediate therapeutic approach such as targeted agents combined with multimodal therapy.

Pediatric Non-Rhabdomyosarcoma Soft Tissue Sarcomas: Standard of Care and Treatment Recommendations from the European Paediatric Soft Tissue Sarcoma Study Group (EpSSG).

This paper describes the standard of care for patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) and the therapeutic recommendations developed by the European paediatric Soft tissue sarcoma Study Group (EpSSG). NRSTS form a very mixed group of mesenchymal extraskeletal malignancies. Their rarity, heterogeneity, and aggressiveness make the management of children and adolescents with these tumors complex and challenging. The overall cure rate for patients with NRSTS is around 70%, but survival depends on several prognostic variables, such as histotype and tumor grade, extent of disease and stage, tumor size, and tumor site. While surgery remains the mainstay of treatment for most of these tumors, a multimodal therapeutic approach including radiotherapy and chemotherapy is required in many cases. The EpSSG NRSTS 2005 study was the first prospective protocol tailored specifically to NRSTS. Together with the ARST0332 study developed by the North-American Soft Tissue Sarcoma Committee of the Children's Oncology Group (COG), the EpSSG NRSTS 2005 study currently represents the benchmark for these tumors, establishing risk-adapted standards of care. The EpSSG has developed common treatment recommendations for the large group of adult-type NRSTS (including synovial sarcoma), and specific treatment recommendations for other particular adult-type histologies (ie, alveolar soft-part sarcoma, clear cell sarcoma and dermatofibrosarcoma protuberans); other highly malignant tumors with a biology and clinical behavior differing from those of adult-type NRSTS (ie, rhabdoid tumors and desmoplastic small round cell tumor); and soft tissue tumors of intermediate malignancy (ie desmoid-type fibromatosis, inflammatory myofibroblastic tumors, and infantile fibrosarcoma). New effective drugs are needed for patients whose NRSTS carries the worst prognosis, ie, those with unresectable tumors, metastases at diagnosis, or relapsing disease. Progress in this area relies on our ability to develop international integrated prospective collaborations, both within existing pediatric oncology networks and, importantly, between the communities of specialists treating pediatric and adult sarcoma.

Non-parameningeal head and neck rhabdomyosarcoma in children, adolescents, and young adults: Experience of the European paediatric Soft tissue sarcoma Study Group (EpSSG) - RMS2005 study.

BACKGROUND/OBJECTIVES: The primary aim of this study was to analyse and evaluate the impact of different local treatments on the pattern of relapse in children with primary head and neck non-parameningeal (HNnPM) rhabdomyosarcoma (RMS), treated in the European paediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 study. The secondary aim was to assess whether current risk stratification is valid for this specific site. DESIGN/METHODS: This study includes all patients with localised HNnPM RMS enrolled in the RMS2005 study between 2005 and 2016. Treatment comprised chemotherapy adapted to risk group, with local surgery and/or radiation therapy. The main outcome measures were event-free survival (EFS) and overall survival (OS). RESULTS: A total of 165 patients were identified; the median age was 6.4 years (range, 0.1-25). The most common tumour sites were cheek/chin (22%) and nasal ala/nasolabial fold (20%). Histology was unfavourable for 40%, and regional nodal involvement present in 26%. Local therapy included surgery (58%) and/or radiotherapy (72%) to primary tumour and/or regional lymph nodes. After a median follow-up of 66 months (range, 6-158), 42 patients experienced an event, and 17 are still alive. Tumour events were frequent in oral primary (36%), parotid site (26%), cheek/chin (24%), and nasal ala/nasolabial fold (24%) and included locoregional failure in 84% of cases. The 5-year EFS and OS were 75% (95% confidence interval [CI]: 67.3-81.2) and 84.9% (95% CI: 77.5-89.7), respectively. Favourable histology was associated with a better EFS (82.3% versus 64.6%; p = 0.02) and nodal spread with a worse OS (88.6% versus 76.1%; p = 0.04). Different sublocations within the HNnPM primary did not have significant impact on outcome. CONCLUSION: Locoregional relapse/progression is the main tumour failure event in this site. Despite frequent unfavourable risk factors, HNnPM RMS remains a favourable location in the context of a risk-adapted strategy.

Genomic complexity in pediatric synovial sarcomas (Synobio study): the European pediatric soft tissue sarcoma group (EpSSG) experience.

A genomic index (GI) tool using array comparative genomic hybridization (aCGH) on tumor cells has emerged as independent prognostic factor associated with the risk of metastatic relapse in synovial sarcoma (SS). The aim was to assess GI in pediatric patients with SS, to determine its value as a prognostic factor. All pediatric/adolescent/young adults' (<25 years) with localized SS prospectively included in the European EpSSG-NRSTS05 protocol with a contributive aCGH were selected. Definition of GI was A2 /C, where A is the total number of alterations (segmental gains and losses) and C is the number of involved chromosomes on aCGH results. GI1 group corresponds to cases with no copy number alterations (flat profile, GI = 0) and GI2 group cases with at least one or more copy number alterations (rearranged profile; GI ≥ 1). Samples were available from 61 patients. The median age of the cohort was 13 years (range: 4-24). Overall, 55.7% were GI1 group, and 44.3% GI2 . After a median follow-up of 62 months (range: 0.1-112), 10 tumor events occurred and five patients died. Respectively, for GI1 versus GI2 groups, five-year event-free survival (EFS) was 93.8 ± 4.2% versus 64.9 ± 10.1% (P < 0.006) and five-year Metastatic-Free Survival (MFS) 93.8 ± 4.2% versus 72.9 ± 9.5% (P < 0.04). In multivariate analysis, GI status as adjusted for IRS group, patient age, site, and tumor size remain independent prognostic for EFS with a relative risk (RR) of 6.4 [1.3-31.9] (P < 0.01) and RR for MFS is 4.8 [0.9-25.7] (P < 0.05). Genomic complexity evaluated through GI may explain the metastatic behavior of pediatric SS.