Treatment of Pediatric, Adolescent, and Young Adult Patients With Fusion-Positive Alveolar Rhabdomyosarcoma Infiltrating Regional Lymph Nodes in the European CWS-2002P and RMS 2005 Studies and the Soft Tissue Sarcoma Registry

Abstract

Pediatric patients; Alveolar rhabdomyosarcoma; Registry

Pacients pediàtrics; Rabdomiosarcoma alveolar; Registre

Pacientes pediátricos; Rabdomiosarcoma alveolar; Registro

Background: Patients with alveolar rhabdomyosarcoma (ARMS) with regional lymph node involvement (N1) are defined as "very-high-risk rhabdomyosarcoma" in Europe. Different chemotherapy regimens were used in European study protocols. Methods: Patients with FOXO1 fusion-positive N1 ARMS registered in the CWS-2002P study, the EpSSG RMS 2005 study, and SoTiSaR were retrospectively investigated. Patients received systemic treatment with chemotherapy (CHT) and local treatment of primary tumor (PT) and involved lymph nodes (LN) with radiotherapy (RT) and/or surgery. Kaplan-Meier estimators and Cox regression were used to examine event-free survival (EFS) and overall survival (OS) according to prognostic factors and treatment. Results: A total of 156 patients registered in RMS 2005 (n = 99), CWS-2002P (n = 20), and SoTiSaR (n = 37) between 2003 and 2020 were eligible for this analysis. Median age at diagnosis was 10.2 years [0.1-21.9]. Treatment comprised CHT with IVADo (ifosfamide, vincristine, actinomycin-D, doxorubicin, n = 93; 60%), VAIA (vincristine, actinomycin-D, ifosfamide, adriamycin/doxorubicin, n = 53; 34%) or other regimens (n = 10; 6%); resection of the PT (n = 89; 57%), LN sampling or dissection (n = 92; 59%), and/or RT (n = 139; 89%). Maintenance treatment (MT) was added in n = 99/135 (73%) patients who achieved complete remission. Five-year EFS and OS of the cohort were 45% and 47%, respectively. Age and tumor size were independent prognostic factors for EFS. Local treatment applied to the LN with surgery, RT or both significantly improved EFS (p = 0.02) and OS (p = 0.04), with no difference between the modalities (p = 0.7). Conclusions: Patients with fusion-positive N1 ARMS carry a poor prognosis. Adequate local treatment of LN improved survival. Keywords: alveolar rhabdomyosarcoma; chemotherapy; fusion‐positive rhabdomyosarcoma; local treatment; lymph node involvement; pediatric/adolescent oncology.

Fondazione Città della Speranza, Italy, has funded the trial management, and Alice's Arc, a children's cancer charity focusing on rhabdomyosarcoma, United Kingdom (alicesarc.org), has funded data management and statistical processing for current analyses. The SoTiSaR registry was supported by the Deutsche Kinderkrebsstiftung, Bonn, Germany, grant nos. A2007/13DKS2009.08, A2012/04DKS2012.05, A2015/16DKS2015.12, A2018/04DKS2018/09 and by the Foerderkreis Krebskranke Kinder Stuttgart, Germany. The CWS-2002P trial was funded by grants from the German Cancer Aid Foundation (Deutsche Krebshilfe), Bonn, Germany, 50-2721-Tr2, and by the Foerderkreis Krebskranke Kinder Stuttgart, Germany. Julia C. Chisholm is supported by the Giant Pledge through the Royal Marsden Cancer Charity. This work represents independent research supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at the Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, London. In France, the RMS 2005 study was supported by the Association Léon Berard Enfant Cancéreux (ALBEC grant 2005). Amadeus T. Heinz was supported by the Stiftung des Foerdervereins für Krebskranke Kinder Tuebingen.