Treatment effect heterogeneity of radiotherapy in localized Ewing sarcoma: A secondary analysis of the EURO-E.W.I.N.G. 99 and Ewing 2008 trial

INTRODUCTION: Standard Ewing sarcoma treatment includes chemotherapy and local therapy. Previous studies found no average treatment effect of combined local therapy (radiotherapy and surgery) versus surgery alone, leaving it unclear which patients benefit from combined therapy. METHODS: We analysed patients with localized Ewing sarcoma from the EURO-E.W.I.N.G. 99 and Ewing 2008 trials. Using causal survival forests validated through repeated k-fold cross-validation, we predicted individualized treatment effects (ITEs) for 5-year event-free survival (5y EFS) comparing combined therapy to surgery alone. We developed a personalized treatment rule and evaluated ITE predictors using Shapley additive explanations analysis. RESULTS: Of 1501 patients, 719 received combination therapy and 782 surgery alone. Predicted ITEs showed substantial heterogeneity (range: -0.7-1.0 years). We found that 19.4% of patients derived clinically meaningful benefit (5y EFS increase ≥6 months) from combined therapy. In the quartile predicted to benefit least, hazards of any event were increased by 53% (HR 1.53, 95% CI 1.06-2.20, p = 0.02). Conversely, in the quartile predicted to benefit most, hazards were reduced by 40% (HR 0.60, 95% CI 0.42-0.85, p = 0.004). In patients undergoing combined treatment, surgical margin status was not associated with treatment benefit. A simulation analysis showed that applying our treatment strategy could improve EFS. DISCUSSION: Our predicted ITEs can help identify patients benefiting from combined therapy. The finding that patients with non-wide surgical margins did not benefit from combined therapy challenges current decision-making practices based on traditional subgroup analyses.