Assessing the effect of chemotherapy dose reductions and time delay on event-free survival in Ewing Sarcoma: A retrospective analysis of the Euro Ewing 2012 trial

BACKGROUND: Treatment adjustments are commonly implemented during chemotherapy to mitigate toxicity, but their impact on event-free survival (EFS) remains poorly understood. This study aims to evaluate the causal effect of dose reductions and time delay during the VDC/IE induction regimen (vincristine, doxorubicin, and cyclophosphamide, alternating with ifosfamide and etoposide) on EFS in patients with Ewing Sarcoma. METHODS: Chemotherapy administration data from the Euro Ewing 2012 (EE2012) trial were used to emulate a target trial, where the target exposures were a binary indicator for total dose reduction and a measure of continuous time delay in treatment duration. Propensity score methods were applied to the original EE2012 population to create a target pseudo-population in which treatment adjustments could be regarded as if randomized. A Cox marginal structural model was fitted to the pseudo-population, and EFS benefit compared to the reference strategy (no reduction; no delay) was estimated for different treatment-adjustment profiles, along with bootstrap confidence intervals. RESULTS: Dose reduction was found protective for EFS (HR=0.69; 95%CI: [0.39; 1.24]), whereas time delay showed a slightly detrimental effect (HR=1.02; 95%CI: [0.90; 1.15]), both non-statistically significant. In terms of EFS benefits, dose reduction exhibited a favourable trajectory over time, while a mild trend toward a clinical disadvantage was observed as time delay increased. Results provide no evidence that reductions in dose and delays to administration, when implemented according to protocol, have a significant detrimental effect on EFS outcome. CONCLUSIONS: The findings provide reassurance that treatment adjustments for toxicity management do not substantially compromise patient prognosis.