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

Figures & data

Table 1 Different Published Series and Main Results from the EpSSG NRSTS 2005 Study

Tumor Type and Publication	Main Features
Localized synovial sarcoma Ferrari et al 2015	● EpSSG series: 138 patients (2005–2012) ● median follow-up 52 months; 3-year EFS 81.9%, 3-year OS 97.2% ● Risk groups were the only significant prognostic variable: 3-year EFS was 91.7% for low-risk, 91.2% for intermediate-risk, and 74.4% for high-risk cases ● Higher survival rates than previous series ● Response to chemotherapy = 55.2%
Infantile fibrosarcoma Orbach et al 2016	● EpSSG series: 50 patients, age 0–24 months (2005–2012) ● ETV6-NTRK3 transcript present in 87.2% of the patients investigated ● 3-year EFS 84%, 3-year OS 94% ● VA chemotherapy was the first-line treatment, with a 70% response rate; alkylating or anthracycline chemotherapy was avoided in 71% of the patients needing chemotherapy; mutilating surgery only in 3 cases
Rhabdoid tumors Brennan et al 2016	● EpSSG series: 100 patients (2005–2014), 77 localized, 23 metastatic ● 3-year EFS 32.3% and OS 38.4% ● Unfavorable prognostic factor: age <1 year, metastatic tumor
Low-risk synovial sarcoma Ferrari et al 2017	● Joint EpSSG and COG series: 60 low-risk cases (initial complete resection with histologically free margins, with grade 2 tumors of any size or grade 3 tumors <5 cm), treated with surgery alone ● 3-year EFS 90%, 3-year OS 100% ● All 8 tumor-related events were local recurrences; all patients with recurrences were effectively salvaged ● adjuvant chemotherapy and radiotherapy can be avoided in low-risk synovial sarcoma without jeopardizing outcome
Desmoid-type fibromatosis Orbach et al 2017	● EpSSG series: 173 patients (2005–2016) ● 35% wait-and-see strategy, 31% immediate surgery, 34% immediate chemotherapy ● 5-year PFS 36.5%, with no differences by treatment group ● 172/173 alive (one patient died of a secondary tumor) ● Response to chemotherapy = 35% complete or partial response (57% to VBL-MTX), 45% stable disease ● Prognostic factor: large tumor size (>5 cm)
Alveolar soft part sarcoma Brennan et al 2018	● EpSSG series: 22 patients (2005–2015) ● 20 patients with localized disease (mostly small and resected), 5-year EFS 94.7%, OS 100% ● Response to conventional chemotherapy = 0%
Genomic index in synovial sarcoma Orbach et al 2018	● SYNOBIO study - EpSSG series: 61 tumor samples ● genomic index 1 (no copy number alterations, flat profile): 55.7% of cases – 5-year EFS 93.8% ● genomic index 2 (one or more copy number alterations, rearranged profile): 44.3% of cases – 5-year EFS 64.9% ● Genomic index is an independent prognostic factor on multivariate analysis
Epithelioid sarcoma Spunt et al 2019	● Joint EpSSG and COG series: 63 cases ● 5-year EFS 60.7%, OS 63.6% ● Response to chemotherapy = 50% ● Prognostic factors: tumor size, histological grade, tumor invasiveness, inadequate tumor resection and metastatic disease
Localized malignant peripheral nerve sheath tumors van Noesel et al 2019	● EpSSG series: 51 patients (2005–2016) ● 5-year EFS 52.9%, OS 62.1% ● Response to chemotherapy = 46% ● Unfavorable prognostic factors: neurofibromatosis type 1 (51% of patients)
Inflammatory myofibroblastic tumor Casanova et al 2020	● EpSSG series: 60 patients (2005–2016) ● 59 had localized disease, 1 had multifocal/metastatic disease ● 40 ALK-positive, and 20 ALK-negative ● 5-year EFS 82.9% and OS 98.1% ● Response to chemotherapy = 55% (80% to VBL-MTX) ● Response to ALK-inhibitors = 5/5 ● No clinical variables correlated statistically with outcome
Dermatofibrosarcoma protuberans Brennan et al 2020	● EpSSG series: 46 patients (2005–2016) ● most cases had small (<5 cm) and IRS I tumors; all patients had up-front surgery ● 5-EFS 92.6%, OS 100%
Metastatic NRSTS Ferrari et al 2020	● Part of the EpSSG BERNIE protocol, ie, open-label, multicenter, randomized phase II study on the role of bevacizumab when added to rhabdomyosarcoma-tailored multi-drug chemotherapy ● 49 patients (2008–2013) ● 2-year EFS 27.3%, 3-year OS 35.2% ● Adding the anti-angiogenic agent did not cause any statistically significant improvement ● Patients not receiving any local treatment on primary disease had a worse outcome ● Treatment results were better for patients undergoing surgical resection on metastases.
Whole series Ferrari et al 2021	● EpSSG NRSTS 2005 series: 569 patients <21 years old with localized synovial sarcoma and adult-type NRSTS* (2005–2016, 100 centers in 14 countries) ● 5-year EFS 73.7%, OS 83.8% ● 5-year OS was 98.1% in the group treated with surgery alone (n= 250), 88.2% in the adjuvant radiotherapy group (n= 17), 75.8% in the adjuvant chemotherapy group (n= 93), and 70.4% in the neoadjuvant chemotherapy group (n=209) ● Excellent outcome for the “surgery-alone” group: adjuvant chemotherapy and radiotherapy can be safely omitted in low-risk NRSTS ● Limited sample sizes available to investigate adjuvant chemotherapy. ● Better results than in historical series for unresected cases; neoadjuvant ifosfamide–doxorubicin Chemotherapy improved resectability

Notes: *Histotypes included: alveolar soft part, angiosarcoma, clear-cell sarcoma, dermatofibrosarcoma protuberans, epithelioid sarcoma, adult-type fibrosarcoma, leiomyosarcoma, liposarcoma, low-grade fibromyxoid sarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, sarcoma not otherwise specified, synovial sarcoma.

Abbreviations: EpSSG, European paediatric Soft tissue sarcoma Study Group; COG, Children Oncology Group; EFS, event-free survival; PFS, progression-free survival; OS, overall survival; VA, vincristine, actinomycin-D; VBL-MTX, vinblastine–methotrexate; IRS, Intergroup Rhabdomyosarcoma Study.

Table 2 A Practical Classification of the Main Pediatric NRSTS Histotypes

Adult-type NRSTS requiring the same therapeutic approach Synovial sarcoma Malignant peripheral nerve sheath tumor Adult-type fibrosarcoma Epithelioid sarcoma Leiomyosarcoma Liposarcoma Angiosarcoma Undifferentiated high-grade pleomorphic sarcoma

Adult-type NRSTS requiring a specific therapeutic approach Alveolar soft part sarcoma Clear cell sarcoma Dermatofibrosarcoma protuberans

Malignant soft tissue tumors requiring a specific therapeutic approach Rhabdoid tumor Desmoplastic small round cell tumor Undifferentiated soft part sarcoma Undifferentiated sarcoma of the liver BCOR family/CIC-rearranged undifferentiated sarcomas

Soft tissue tumors of intermediate malignancy requiring specific therapeutic approaches Desmoid-type fibromatosis Infantile fibrosarcoma Inflammatory myofibroblastic tumors Epithelioid hemangioendothelioma

Figure 1 EpSSG standard-risk stratification and treatment recommendations for local/locoregional adult-type NRSTS (including synovial sarcoma).

Notes: I-D=ifosfamide (3 g/m² per day intravenously, for 3 days) plus doxorubicin (37.5 mg/m² intravenously per day for 2 days). I=ifosfamide (3 g/m² intravenously per day for 2 days). Ifosfamide should be given with hyperhydration and mesna infusion (3 g/m² per day intravenously). Chemotherapy cycles should be administered every 21 days. *Total of 6 courses for synovial sarcoma, 7 courses for the other adult-type NRSTS.

Abbreviations: IRS, Intergroup Rhabdomyosarcoma Study; IRS group I, complete resection at first surgery (initial R0 surgery); IRS group II, microscopic residual disease after initial R1 surgery); IRS group III, biopsy or initial macroscopic residual disease after R2 surgery; IRS group IV, metastatic disease at onset; G, tumor grade (according to the Fédération Nationale des Centres de Lutte Contre le Cancer grading system); N1, nodal involvement.

Table 3 Summary of Treatment Recommendations for Specific Histotypes

Histotype	Clinical Features	EpSSG Treatment Recommendations
Adult-type NRSTS requiring a specific therapeutic approach
Alveolar soft part sarcoma	Highly malignant; conventional chemotherapy is ineffective	Surgery (± radiotherapy) for localized resectable tumors (no adjuvant chemotherapy). Targeted agents in case of unresectable/metastatic disease. Promising data on immune checkpoint inhibitors
Clear cell sarcoma	Highly malignant, no response to chemotherapy	Local therapy (surgery ± radiotherapy). Promising results with immunotherapy
Dermatofibrosarcoma protuberans	Generally low-grade, small, superficial	Wide surgery is the mainstay. Imatinib mesylate in unresectable or metastatic cases (very rare in pediatric age)
Malignant soft tissue tumors requiring a specific therapeutic approach
Undifferentiated soft part sarcoma	Debated if it is really a clinical entity	Treatment according to strategy for rhabdomyosarcoma (9 courses of IVA), or ifosfamide-doxorubicin as for high-risk adult-type NRSTS
Undifferentiated (embryonal) sarcoma of the liver	Generally good response to conventional chemotherapy	Complete surgery is the mainstay. Patients with initial resection: 4–6 courses of IVA ± doxorubicin. Patients with unresectable tumor: 9 courses of IVA ± doxorubicin to shrink the tumor and enable resection
Extra-cranial malignant rhabdoid tumors	Highly aggressive tumors of young children	Dose-intensive multi-drug chemotherapy every 2 weeks (eg VDCy-IE). Local therapy as soon as possible (taking the patient’s age into account)
Desmoplastic small round cell tumors	Abdominal mass widely disseminated at diagnosis; poor prognosis	Intensive chemotherapy (eg VDCy-IE, or IVADo or IrIVA), surgery, whole abdominal radiotherapy, maintenance therapy
Soft tissue tumors of intermediate malignancy requiring specific therapeutic recommendations
Desmoid-type fibromatosis	Intermediate malignancy, local aggressiveness	Wait-and-see for non-evolving disease; low-dose methotrexate plus vinblastine in cases with tumor progression
Inflammatory myofibroblastic tumor	Intermediate malignancy	Surgery remains the mainstay of treatment In cases of advanced disease: vinblastine-methotrexate or targeted therapy (eg ALK inhibitors)
Infantile fibrosarcoma	Low malignant potential; initial rapid growth and huge size at onset	Surgery remains the mainstay of treatment VA chemotherapy and NTRK inhibitors are both options for patients with advanced localized disease.

Abbreviations: IVA, ifosfamide, vincristine, actinomycin-D; IVAd, ifosfamide, vincristine, doxorubicin; VDCy, vincristine–doxorubicin–cyclophosphamide; IE, ifosfamide–etoposide; IVADo, ifosfamide, vincristine, actinomycin-D, doxorubicin; IrIVA, irinotecan, ifosfamide, vincristine, actinomycin-D; VA, vincristine–actinomycin-D.

Figure 2 EpSSG flow chart for desmoid-type fibromatosis.