Association of treatment delays with an unfavorable outcome in patients with localized Ewing sarcoma: A retrospective analysis of data from the GPOH Euro-E.W.I.N.G.99 trial.
Authors: Dirksen Uta , Ranft Andreas , Baumhoer Daniel , van den Berg Henk , Brichard Bénédicte , Eich Hans-Theodor , Gelderblom Hans , Hardes Jendrik , Hartmann Wolfgang , Juergens Heribert , Kollar Attila , Kruseova Jarmila , Kuehne Thomas , Ladenstein Ruth Lydia , Leithner Andreas , Streitbuerger Arne , Timmermann Beate , Tunn Per-Ulf , Andreou Dimosthenis 
Published: June 2021

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Background: Outcome in EwS has improved by the implementation of dose or time intense systemic treatment. Aim of the study was evaluate whether treatment delays have impact on outcome of patients with localized Ewing sarcoma (EWS). Methods: Data from 692 patients with a tumor of the extremities, the pelvis, the chest wall and the trunk registered in the international database of the German Society for Pediatric Oncology and Hematology (GPOH) and treated in the Euro-E.W.I.N.G. 99 trial (NCT00020566) were analyzed. All patients underwent surgical treatment after induction chemotherapy. The optimal interval cut-off values for survival analyses were calculated with receiver operating characteristics curves. Hazard ratios (HR) were estimated with respective 95% confidence intervals (CI) in multivariate Cox regression models. Results: As per protocol, patients were to receive six cycles of VIDE induction chemotherapy in 21-day intervals. The duration between induction cycles as per protocol was fulfilled in only 5% of patients. In 72% of patients, the average interval duration between induction chemotherapy cycles was 25 days. Median interval between day 1 of the first induction chemotherapy cycle and definitive tumor surgery was 141 (IQR, 133 – 153) days in patients receiving six VIDE cycles prior to surgery. The optimal cut-off value for survival analyses in these patients amounted to 150 days. Patients with a duration of induction chemotherapy > 150 days were at higher risk to develop an event (HR, 1.546; 95% CI, 1.103 – 2.166) and had a higher risk of death (HR, 1.574; 95% CI, 1.095 – 2.262), compared to patients with a duration of induction chemotherapy < 150 days. Patients with delays during the induction chemotherapy also experienced a significant delay between VIDE 6 and surgery (36 vs. 27 days, p < 0.001) and were treated significantly more often at smaller low-volume centers (63% vs. 48%, p = 0.005). Patients with a prolonged interval > 21 days between surgery and day one of postoperative chemotherapy were at a higher risk to develop an event (HR, 1.406; 95% CI, 1.011 – 1.955), and also had a significantly higher rate of postoperative complications (26% vs. 11%, p < 0.001), compared to patients with a shorter interval. Conclusions: Delays between induction chemotherapy and surgery and between surgery and consolidation chemotherapy are independently associated with a poor outcome in patients with localized EWS. Our results also underscore the need to treat EWS patients in larger and experienced sarcoma centers. The implementation of new and standardized methods in the operative strategy and optimized supportive care during systemic therapy are required to reduce perioperative morbidity and treatment delays.