Dosimetric Evaluation of the Effect of Receptor Heterogeneity on the Therapeutic Efficacy of Peptide Receptor Radionuclide Therapy: Correlation with DNA Damage Induction and In Vivo Survival.

Our rationale was to build a refined dosimetry model for Lu-DOTATATE in vivo experiments enabling the correlation of absorbed dose with double-strand break (DSB) induction and cell death. Somatostatin receptor type 2 expression of NCI-H69 xenografted mice, injected with Lu-DOTATATE, was imaged at 0, 2, 5, and 11 d. This expression was used as input to reconstruct realistic 3-dimensional heterogeneous activity distributions and tissue geometries of both cancer and heathy cells. The resulting volumetric absorbed dose rate distributions were calculated using the GATE (Geant4 Application for Tomographic Emission) Monte Carlo code and compared with homogeneous dose rate distributions. The absorbed dose (0-2 d) on micrometer-scale sections was correlated with DSB induction, measured by γH2AX foci. Moreover, the absorbed dose on larger millimeter-scale sections delivered over the whole treatment (0-14 d) was correlated to the modeled in vivo survival to determine the radiosensitivity parameters α and β for comparison with experimental data (cell death assay, volume response) and external-beam radiotherapy. The DNA-damage repair half-life T and proliferation doubling time T were obtained by fitting the DSB and tumor volume data over time. A linear correlation with a slope of 0.0223 DSB/cell mGy between the absorbed dose and the number of DSBs per cell has been established. The heterogeneous dose distributions differed significantly from the homogeneous dose distributions, with their corresponding average S values diverging at 11 d by up to 58%. No significant difference between modeled in vivo survival was observed in the first 5 d when using heterogeneous and uniform dose distributions. The radiosensitivity parameter analysis for the in vivo survival correlation indicated that the minimal effective dose rates for cell kill was 13.72 and 7.40 mGy/h, with an α of 0.14 and 0.264 Gy, respectively, and an α/β of 100 Gy; decreasing the α/β led to a decrease in the minimal effective dose rate for cell kill. Within the linear quadratic model, the best matching in vivo survival correlation (α = 0.1 Gy, α/β = 100 Gy, T = 60 h, T = 14.5 d) indicated a relative biological effectiveness of 0.4 in comparison to external-beam radiotherapy. Our results demonstrated that accurate dosimetric modeling is crucial to establishing dose-response correlations enabling optimization of treatment protocols.