TY - JOUR
T1 - Paediatric non-rhabdomyosarcoma soft tissue sarcomas
T2 - the prospective NRSTS 2005 study by the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG)
AU - Ferrari, Andrea
AU - van Noesel, Max M
AU - Brennan, Bernadette
AU - Zanetti, Ilaria
AU - Corradini, Nadege
AU - Casanova, Michela
AU - Berlanga, Pablo
AU - Merks, Johannes H M
AU - Alaggio, Rita
AU - Schifflers, Stefan
AU - Ramirez-Villar, Gema L
AU - Giraudo, Chiara
AU - Burrieza, Gabriela Guillen
AU - Safwat, Akmal
AU - Bisogno, Gianni
AU - De Salvo, Gian Luca
AU - Orbach, Daniel
N1 - Funding Information:
This study was funded by Fondazione Città della Speranza. We dedicate this paper to Prof Modesto Carli, who has recently passed away. He was one of the most outstanding European paediatric oncologists and a passionate physician who was extraordinarily dedicated to his patients. He was one of the founders of EpSSG, which would not exist without his efforts and his vision. We thank Beatrice Coppadoro (Hematology Oncology Division, Department of Women's and Children's Health, University of Padova, Padova, Italy) for her contribution to the statistical analysis. We also thank the patients, caregivers, and medical staff involved in this study in the recruiting countries (Argentina, Belgium, Czech Republic, Denmark, France, Israel, Italy, Netherlands Norway, Slovakia, Slovenia, Spain, UK & Eire). We thank Fondazione Città della Speranza for supporting the EpSSG NRSTS 2005 protocol.
Funding Information:
This study was funded by Fondazione Citt? della Speranza. We dedicate this paper to Prof Modesto Carli, who has recently passed away. He was one of the most outstanding European paediatric oncologists and a passionate physician who was extraordinarily dedicated to his patients. He was one of the founders of EpSSG, which would not exist without his efforts and his vision. We thank Beatrice Coppadoro (Hematology Oncology Division, Department of Women's and Children's Health, University of Padova, Padova, Italy) for her contribution to the statistical analysis. We also thank the patients, caregivers, and medical staff involved in this study in the recruiting countries (Argentina, Belgium, Czech Republic, Denmark, France, Israel, Italy, Netherlands Norway, Slovakia, Slovenia, Spain, UK & Eire). We thank Fondazione Citt? della Speranza for supporting the EpSSG NRSTS 2005 protocol.
Publisher Copyright:
© 2021 Elsevier Ltd
PY - 2021/8
Y1 - 2021/8
N2 - BACKGROUND: A standardised approach to treatment of paediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), which account for about 4% of childhood cancers, is still lacking. We report the results of the NRSTS 2005 protocol developed specifically by the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) to determine a risk-adapted multimodal standard of care for this group of tumours.METHODS: The EpSSG NRSTS 2005 study included two prospective, non-randomised, historically controlled trials (one on localised adult-type NRSTS and the other on localised synovial sarcoma) done at 100 academic centres and hospitals in 14 countries. Patients younger than 21 years with a pathologically proven diagnosis of synovial sarcoma or an adult-type NRSTS, no evidence of metastatic disease, no previous treatment other than primary surgery, and diagnostic specimens available for pathological review were included. Patients were stratified by surgical stage, tumour size, nodal involvement, tumour grade (for adult-type NRSTS), and tumour site (for synovial sarcoma). Patients were then divided into four treatment groups: surgery alone, adjuvant radiotherapy, adjuvant chemotherapy (with or without radiotherapy), or neoadjuvant chemotherapy (with or without radiotherapy). The main chemotherapy regimen was ifosfamide (3·0 g/m2 intravenously per day for 3 days) plus doxorubicin (37·5 mg/m2 intravenously per day for 2 days); only ifosfamide (3·0 g/m2 intravenously per day for 2 days) was given concomitantly with radiotherapy (delivered with three-dimensional conformal external beam technique, using conventional fractionation [1·8 daily fractions, 5 days per week] at a dose of 50·4 Gy or 54·0 Gy, to a maximum of 59·4 Gy). The number of chemotherapy cycles ranged from three to seven depending on the stage of the disease. The primary outcomes were event-free survival and overall survival. This study has been completed, and is registered under EudraCT, 2005-001139-31.FINDINGS: Between May 31, 2005, and Dec 31, 2016, 1321 patients were enrolled, of whom 569 (206 with synovial sarcoma and 363 with adult-type NRSTS), with a median age of 12·6 years (IQR 8·2-14·9), were included in this analysis. With a median follow-up of 80·0 months (IQR 54·3-111·3) for the 467 patients alive, 5-year event-free survival was 73·7% (95% CI 69·7-77·2) and 5-year overall survival was 83·8% (95% CI 80·3-86·7). 5-year event-free survival was 91·4% (95% CI 87·0-94·4) and 5-year overall survival was 98·1% (95% CI 95·0-99·3) in the surgery alone group (n=250); 75·5% (46·9-90·1) and 88·2% (60·6-96·9) in the adjuvant radiotherapy group (n=17); 65·6% (54·8-74·5) and 75·8% (65·3-83·5) in the adjuvant chemotherapy group (n=93); and 56·4% (49·3-63·0) and 70·4% (63·3-76·4) in the neoadjuvant chemotherapy group (n=209). Reported severe adverse events included one case of generalised seizures (probably related to ifosfamide) and six cases of secondary tumours.INTERPRETATION: Findings from the EpSSG NRSTS 2005 study help to define the risk-adapted standard of care for this patient population. Adjuvant treatment can be safely omitted in the low-risk population (classified here as the surgery alone group). Improving the outcome for patients with high-risk, initially resected adult-type NRSTS and those with initially unresectable disease remains a major clinical challenge.FUNDING: Fondazione Città della Speranza.
AB - BACKGROUND: A standardised approach to treatment of paediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS), which account for about 4% of childhood cancers, is still lacking. We report the results of the NRSTS 2005 protocol developed specifically by the European Pediatric Soft Tissue Sarcoma Study Group (EpSSG) to determine a risk-adapted multimodal standard of care for this group of tumours.METHODS: The EpSSG NRSTS 2005 study included two prospective, non-randomised, historically controlled trials (one on localised adult-type NRSTS and the other on localised synovial sarcoma) done at 100 academic centres and hospitals in 14 countries. Patients younger than 21 years with a pathologically proven diagnosis of synovial sarcoma or an adult-type NRSTS, no evidence of metastatic disease, no previous treatment other than primary surgery, and diagnostic specimens available for pathological review were included. Patients were stratified by surgical stage, tumour size, nodal involvement, tumour grade (for adult-type NRSTS), and tumour site (for synovial sarcoma). Patients were then divided into four treatment groups: surgery alone, adjuvant radiotherapy, adjuvant chemotherapy (with or without radiotherapy), or neoadjuvant chemotherapy (with or without radiotherapy). The main chemotherapy regimen was ifosfamide (3·0 g/m2 intravenously per day for 3 days) plus doxorubicin (37·5 mg/m2 intravenously per day for 2 days); only ifosfamide (3·0 g/m2 intravenously per day for 2 days) was given concomitantly with radiotherapy (delivered with three-dimensional conformal external beam technique, using conventional fractionation [1·8 daily fractions, 5 days per week] at a dose of 50·4 Gy or 54·0 Gy, to a maximum of 59·4 Gy). The number of chemotherapy cycles ranged from three to seven depending on the stage of the disease. The primary outcomes were event-free survival and overall survival. This study has been completed, and is registered under EudraCT, 2005-001139-31.FINDINGS: Between May 31, 2005, and Dec 31, 2016, 1321 patients were enrolled, of whom 569 (206 with synovial sarcoma and 363 with adult-type NRSTS), with a median age of 12·6 years (IQR 8·2-14·9), were included in this analysis. With a median follow-up of 80·0 months (IQR 54·3-111·3) for the 467 patients alive, 5-year event-free survival was 73·7% (95% CI 69·7-77·2) and 5-year overall survival was 83·8% (95% CI 80·3-86·7). 5-year event-free survival was 91·4% (95% CI 87·0-94·4) and 5-year overall survival was 98·1% (95% CI 95·0-99·3) in the surgery alone group (n=250); 75·5% (46·9-90·1) and 88·2% (60·6-96·9) in the adjuvant radiotherapy group (n=17); 65·6% (54·8-74·5) and 75·8% (65·3-83·5) in the adjuvant chemotherapy group (n=93); and 56·4% (49·3-63·0) and 70·4% (63·3-76·4) in the neoadjuvant chemotherapy group (n=209). Reported severe adverse events included one case of generalised seizures (probably related to ifosfamide) and six cases of secondary tumours.INTERPRETATION: Findings from the EpSSG NRSTS 2005 study help to define the risk-adapted standard of care for this patient population. Adjuvant treatment can be safely omitted in the low-risk population (classified here as the surgery alone group). Improving the outcome for patients with high-risk, initially resected adult-type NRSTS and those with initially unresectable disease remains a major clinical challenge.FUNDING: Fondazione Città della Speranza.
KW - Adolescent
KW - Antineoplastic Combined Chemotherapy Protocols/therapeutic use
KW - Chemoradiotherapy, Adjuvant
KW - Child
KW - Disease-Free Survival
KW - Doxorubicin/administration & dosage
KW - Europe
KW - Female
KW - Humans
KW - Ifosfamide/administration & dosage
KW - Male
KW - Neoplasm Staging
KW - Practice Guidelines as Topic/standards
KW - Prospective Studies
KW - Sarcoma, Synovial/drug therapy
KW - Sarcoma/drug therapy
KW - Soft Tissue Neoplasms/drug therapy
UR - http://www.scopus.com/inward/record.url?scp=85110597122&partnerID=8YFLogxK
U2 - 10.1016/S2352-4642(21)00159-0
DO - 10.1016/S2352-4642(21)00159-0
M3 - Article
C2 - 34214481
SN - 2352-4642
VL - 5
SP - 546
EP - 558
JO - The Lancet. Child & adolescent health
JF - The Lancet. Child & adolescent health
IS - 8
ER -