Illustrating repopulation-corrected dose metrics across heterogeneous radiotherapy schedules in nasopharyngeal carcinoma

BACKGROUND: Radiotherapy outcome analyses involve heterogeneous fractionation schemes and treatment times, complicating direct dose comparisons. This is particularly relevant for dose de-escalation in elective lymphatic drainage volumes, where schedules and durations may vary. This study presents the application of repopulation-corrected dose metrics, focusing on the use and limitations of biologically effective dose (BED) and equivalent dose in 2-Gy fractions (EQD2) for heterogeneous radiotherapy schedules in nasopharyngeal carcinoma (NPC). METHODS: A retrospective cohort of NPC patients was analysed. BED values were calculated using a time-inclusive approach accounting for tumor repopulation. Corresponding EQD2 values were derived as proposed by Dale et al. This method systematically accounts for repopulation effects that may occur in the derived schedule. Dose metrics were analysed in relation to overall survival using exploratory statistical analyses, assessing sensitivity to model assumptions and parameter choices. RESULTS: Repopulation-corrected dose metrics (i.e. BEDs and EQD2s calculated by the method of Dale et al.) showed improved internal consistency across heterogeneous treatment schedules compared with cumulative absorbed dose and non-repopulation-adjusted EQD2. Within a limited range of repopulation-corrected doses, an apparent transition in overall survival was observed; however, this effect was sensitive to radiobiological assumptions, treatment time, and cohort size. CONCLUSION: Repopulation-corrected dose metrics provide a practical framework for comparing heterogeneous radiotherapy schedules while highlighting methodological limitations. Transparent reporting of treatment parameters and cautious interpretation of threshold-like effects are essential. Although not establishing definitive dose-outcome relationships, this framework may inform future studies on dose de-escalation of elective lymphatic drainage volumes in NPC.