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.