Robustness of proliferation‐based constrained spatiotemporal fractionation under setup and radiobiological uncertainties in liver radiotherapy
Min Ma, Ke Zhang, Xuesong Chen, Kuo Men, Jianrong DaiAbstract
Background
Spatiotemporal fractionation redistributes dose between fractions and may reduce normal‐tissue exposure. Its sensitivity to setup uncertainty and radiobiological assumptions requires evaluation before clinical use.
Purpose
To evaluate proliferation‐based constrained spatiotemporal fractionation (p‐cSTF) under geometric and radiobiological perturbations in conventionally fractionated liver radiotherapy. The focus was normal‐liver dose.
Methods
Thirty‐five patients with hepatocellular carcinoma were included. Uniform fractionation, proliferation‐based spatiotemporal fractionation (p‐STF), and p‐cSTF were evaluated over 25 fractions. The primary comparison matched nominal mean gross tumor volume (GTV) biologically effective dose (BED); a supplementary comparison matched nominal model‐derived tumor control probability (TCP). Setup tests comprised 18 single‐axis offsets (± 1, ± 2, and ± 3 mm) and 24 transverse voxel offsets, each held constant over treatment. Thirty scenarios varied biological‐model parameters; precision checks used two 480‐scenario sequences. Nominal dose grids were evaluated under perturbations without reoptimization. Endpoints included physical dose, BED, equivalent dose in 2 Gy fractions (EQD2), coverage, and response‐model scores.
Results
Under biological‐parameter variation, normal‐liver (liver excluding GTV) BED was 26.22 ± 7.00 Gy for p‐cSTF, 28.18 ± 7.57 Gy for Uniform, and 28.05 ± 7.76 Gy for p‐STF. Corresponding EQD2 values were 14.92 ± 3.96, 16.05 ± 4.29, and 15.96 ± 4.39 Gy. Values are cohort means and between‐patient standard deviations of patient‐specific scenario means. Normal‐liver BED remained lower with p‐cSTF after nominal TCP matching, although fixed transverse offsets produced lower GTV TCP than with Uniform. Expanded sampling retained the direction of the liver‐dose difference; the original 30 scenarios did not meet the specified precision criteria for scenario variability.
Conclusions
P‐cSTF retained a simulated normal‐liver dose advantage under the tested perturbations, including after nominal TCP matching. This advantage must be considered alongside target‐response trade‐offs and uncertainty in scenario‐variability estimates. Clinical toxicity and treatment deliverability were not evaluated.