Combining inter-observer variability, range and setup uncertainty in a variance-based sensitivity analysis for proton therapy

Margin concepts in proton therapy aim to ensure full dose coverage of the clinical target volume (CTV) in presence of setup and range uncertainty. Due to inter-observer variability (IOV), the CTV itself is uncertain. We present a framework to evaluate the combined impact of IOV, setup and range uncertainty in a variance-based sensitivity analysis (SA). For ten patients with skull base meningioma, the mean calculation time to perform the SA including 1.6 x 10(4) dose recalculations was 59 min. For two patients in this dataset, IOV had a relevant impact on the estimated CTV D-95% uncertainty.