TY - JOUR
T1 - A risk-based treatment strategy for non-rhabdomyosarcoma soft-tissue sarcomas in patients younger than 30 years (ARST0332)
T2 - a Children's Oncology Group prospective study
AU - Spunt, Sheri L.
AU - Million, Lynn
AU - Chi, Yueh Yun
AU - Anderson, James
AU - Tian, Jing
AU - Hibbitts, Emily
AU - Coffin, Cheryl
AU - McCarville, M. Beth
AU - Randall, R. Lor
AU - Parham, David M.
AU - Black, Jennifer O.
AU - Kao, Simon C.
AU - Hayes-Jordan, Andrea
AU - Wolden, Suzanne
AU - Laurie, Fran
AU - Speights, Roseanne
AU - Kawashima, Ellen
AU - Skapek, Stephen X.
AU - Meyer, William
AU - Pappo, Alberto S.
AU - Hawkins, Douglas S.
N1 - Funding Information:
The National Institutes of Health (NIH), through the Cancer Therapy Evaluation Program, reviewed and approved the study design. The Children's Oncology Group approved the study design, oversaw the study conduct including data collection, analysis, and interpretation, and approved the final report for publication. The other funding sources had no role in study design, study conduct, or reporting. SLS, Y-YC, JA, JT, and EH had access to the raw data. None of the sponsors participated in writing of the report. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Funding Information:
This research was supported in part by grants from the National Institutes of Health (NIH) to the Children's Oncology Group (grants U10CA180886, U10CA180899, U10CA098543, U10CA098413; Quality Assurance Review Center grant U10CA29511), and the Imaging and Radiation Oncology Core (grant U10CA180803); and by funding from the St Baldrick's Foundation, the Seattle Children's Foundation (from Kat's Crew Guild through the Sarcoma Research Fund); Solid Tumor Program project grant CA23099 to SLS and ASP; Cancer Center Support CORE grant P30 CA 21765 from the National Cancer Institute to SLS and ASP; and by funding from the American Lebanese Syrian Associated Charities to SLS, RS, and ASP. None of the authors are employed by NIH but SLS, Y-YC, JA, JT, EH, CC, MBM, DMP, SCK, SXS, WM, and DSH are recipients of NIH grants to support this research. No author received an honorarium or other form of financial support related to the development of this manuscript. We gratefully acknowledge all of the patients and their families, care providers, and research personnel who participated in this study.
Funding Information:
De-identified individual patient data from this clinical trial and a data dictionary defining each field in the dataset will be made available on the National Cancer Institute NCTN/NCORP data archive ( https://nctn-data-archive.nci.nih.gov/ ) within 1 year of print publication of this manuscript according to the National Institutes of Health Data Sharing Policy ( https://grants.nih.gov/grants/policy/data_sharing/ ). Data access requires a user account with an official institutional email address and completion of an online Data Request Form that includes a brief research plan and a Data Use Agreement with legally binding signatures by the requestor and an Authorised Representative from his or her institution. Acknowledgments This research was supported in part by grants from the National Institutes of Health (NIH) to the Children's Oncology Group (grants U10CA180886 , U10CA180899 , U10CA098543 , U10CA098413 ; Quality Assurance Review Center grant U10CA29511 ), and the Imaging and Radiation Oncology Core ( grant U10CA180803 ); and by funding from the St Baldrick's Foundation, the Seattle Children's Foundation (from Kat's Crew Guild through the Sarcoma Research Fund); Solid Tumor Program project grant CA23099 to SLS and ASP; Cancer Center Support CORE grant P30 CA 21765 from the National Cancer Institute to SLS and ASP; and by funding from the American Lebanese Syrian Associated Charities to SLS, RS, and ASP. None of the authors are employed by NIH but SLS, Y-YC, JA, JT, EH, CC, MBM, DMP, SCK, SXS, WM, and DSH are recipients of NIH grants to support this research. No author received an honorarium or other form of financial support related to the development of this manuscript. We gratefully acknowledge all of the patients and their families, care providers, and research personnel who participated in this study.
Publisher Copyright:
© 2020 Elsevier Ltd
PY - 2020/1
Y1 - 2020/1
N2 - Background: Tumour grade, tumour size, resection potential, and extent of disease affect outcome in paediatric non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS), but no risk stratification systems exist and the standard of care is poorly defined. We developed a risk stratification system from known prognostic factors and assessed it in the context of risk-adapted therapy for young patients with NRSTS. Methods: In this prospective study, eligible patients enrolled in 159 hospitals in three countries were younger than 30 years, had a Lansky (patients ≤16 years) or Karnofsky (patients >16 years) performance status score of at least 50, and a new diagnosis of a WHO (2002 criteria) intermediate (rarely metastasising) or malignant soft-tissue tumour (apart from tumour types eligible for other Children's Oncology Group studies and tumours for which the therapy in this trial was deemed inappropriate), malignant peripheral nerve sheath tumour, non-metastatic and grossly resected dermatofibrosarcoma protuberans, undifferentiated embryonal sarcoma of the liver, or unclassified malignant soft-tissue sarcoma. Each patient was assigned to one of three risk groups and one of four treatment groups. Risk groups were: low (non-metastatic R0 or R1 low-grade, or ≤5 cm R1 high-grade tumour); intermediate (non-metastatic R0 or R1 >5 cm high-grade, or unresected tumour of any size or grade); or high (metastatic tumour). The treatment groups were surgery alone, radiotherapy (55·8 Gy), chemoradiotherapy (chemotherapy and 55·8 Gy radiotherapy), and neoadjuvant chemoradiotherapy (chemotherapy and 45 Gy radiotherapy, then surgery and radiotherapy boost based on margins with continued chemotherapy). Chemotherapy included six cycles of ifosfamide 3 g/m2 per dose intravenously on days 1–3 and five cycles of doxorubicin 37·5 mg/m2 per dose intravenously on days 1–2 every 3 weeks with sequence adjusted on the basis of timing of surgery or radiotherapy. The primary outcomes were event-free survival, overall survival, and the pattern of treatment failure. Analysis was done per protocol. This study has been completed and is registered with ClinicalTrials.gov, NCT00346164. Findings: Between Feb 5, 2007, and Feb 10, 2012, 550 eligible patients were enrolled, of whom 21 were treated in the incorrect group and excluded from this analysis. 529 evaluable patients were included in the analysis: low-risk (n=222), intermediate-risk (n=227), high-risk (n=80); surgery alone (n=205), radiotherapy (n=17), chemoradiotherapy (n=111), and neoadjuvant chemoradiotherapy (n=196). At a median follow-up of 6·5 years (IQR 4·9–7·9), 5-year event-free survival and overall survival were: 88·9% (95% CI 84·0–93·8) and 96·2% (93·2–99·2) in the low-risk group; 65·0% (58·2–71·8) and 79·2% (73·4–85·0) in the intermediate-risk group; and 21·2% (11·4–31·1) and 35·5% (23·6–47·4) in the high-risk group, respectively. Risk group predicted event-free survival and overall survival (p<0·0001). No deaths from toxic events during treatment were reported. Nine patients had unexpected grade 4 adverse events (chemoradiotherapy group, n=2; neoadjuvant chemoradiotherapy group, n=7), including three wound complications that required surgery (all in the neoadjuvant chemoradiotherapy group). Interpretation: Pre-treatment clinical features can be used to effectively define treatment failure risk and to stratify young patients with NRSTS for risk-adapted therapy. Most low-risk patients can be cured without adjuvant therapy, thereby avoiding known long-term treatment complications. Survival remains suboptimal for intermediate-risk and high-risk patients and novel therapies are needed. Funding: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation, American Lebanese Syrian Associated Charities.
AB - Background: Tumour grade, tumour size, resection potential, and extent of disease affect outcome in paediatric non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS), but no risk stratification systems exist and the standard of care is poorly defined. We developed a risk stratification system from known prognostic factors and assessed it in the context of risk-adapted therapy for young patients with NRSTS. Methods: In this prospective study, eligible patients enrolled in 159 hospitals in three countries were younger than 30 years, had a Lansky (patients ≤16 years) or Karnofsky (patients >16 years) performance status score of at least 50, and a new diagnosis of a WHO (2002 criteria) intermediate (rarely metastasising) or malignant soft-tissue tumour (apart from tumour types eligible for other Children's Oncology Group studies and tumours for which the therapy in this trial was deemed inappropriate), malignant peripheral nerve sheath tumour, non-metastatic and grossly resected dermatofibrosarcoma protuberans, undifferentiated embryonal sarcoma of the liver, or unclassified malignant soft-tissue sarcoma. Each patient was assigned to one of three risk groups and one of four treatment groups. Risk groups were: low (non-metastatic R0 or R1 low-grade, or ≤5 cm R1 high-grade tumour); intermediate (non-metastatic R0 or R1 >5 cm high-grade, or unresected tumour of any size or grade); or high (metastatic tumour). The treatment groups were surgery alone, radiotherapy (55·8 Gy), chemoradiotherapy (chemotherapy and 55·8 Gy radiotherapy), and neoadjuvant chemoradiotherapy (chemotherapy and 45 Gy radiotherapy, then surgery and radiotherapy boost based on margins with continued chemotherapy). Chemotherapy included six cycles of ifosfamide 3 g/m2 per dose intravenously on days 1–3 and five cycles of doxorubicin 37·5 mg/m2 per dose intravenously on days 1–2 every 3 weeks with sequence adjusted on the basis of timing of surgery or radiotherapy. The primary outcomes were event-free survival, overall survival, and the pattern of treatment failure. Analysis was done per protocol. This study has been completed and is registered with ClinicalTrials.gov, NCT00346164. Findings: Between Feb 5, 2007, and Feb 10, 2012, 550 eligible patients were enrolled, of whom 21 were treated in the incorrect group and excluded from this analysis. 529 evaluable patients were included in the analysis: low-risk (n=222), intermediate-risk (n=227), high-risk (n=80); surgery alone (n=205), radiotherapy (n=17), chemoradiotherapy (n=111), and neoadjuvant chemoradiotherapy (n=196). At a median follow-up of 6·5 years (IQR 4·9–7·9), 5-year event-free survival and overall survival were: 88·9% (95% CI 84·0–93·8) and 96·2% (93·2–99·2) in the low-risk group; 65·0% (58·2–71·8) and 79·2% (73·4–85·0) in the intermediate-risk group; and 21·2% (11·4–31·1) and 35·5% (23·6–47·4) in the high-risk group, respectively. Risk group predicted event-free survival and overall survival (p<0·0001). No deaths from toxic events during treatment were reported. Nine patients had unexpected grade 4 adverse events (chemoradiotherapy group, n=2; neoadjuvant chemoradiotherapy group, n=7), including three wound complications that required surgery (all in the neoadjuvant chemoradiotherapy group). Interpretation: Pre-treatment clinical features can be used to effectively define treatment failure risk and to stratify young patients with NRSTS for risk-adapted therapy. Most low-risk patients can be cured without adjuvant therapy, thereby avoiding known long-term treatment complications. Survival remains suboptimal for intermediate-risk and high-risk patients and novel therapies are needed. Funding: National Institutes of Health, St Baldrick's Foundation, Seattle Children's Foundation, American Lebanese Syrian Associated Charities.
UR - http://www.scopus.com/inward/record.url?scp=85077144150&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85077144150&partnerID=8YFLogxK
U2 - 10.1016/S1470-2045(19)30672-2
DO - 10.1016/S1470-2045(19)30672-2
M3 - Article
C2 - 31786124
AN - SCOPUS:85077144150
SN - 1470-2045
VL - 21
SP - 145
EP - 161
JO - The Lancet Oncology
JF - The Lancet Oncology
IS - 1
ER -