PT - JOURNAL ARTICLE AU - Giulia Tamborino AU - Julie Nonnekens AU - Marijke De Saint-Hubert AU - Lara Struelens AU - Danny Feijtel AU - Marion de Jong AU - Mark W Konijnenberg TI - Dosimetric evaluation of receptor-heterogeneity on the therapeutic efficacy of peptide receptor radionuclide therapy: correlation with DNA damage induction and <em>in vivo</em> survival AID - 10.2967/jnumed.121.262122 DP - 2021 Apr 01 TA - Journal of Nuclear Medicine PG - jnumed.121.262122 4099 - http://jnm.snmjournals.org/content/early/2021/04/09/jnumed.121.262122.short 4100 - http://jnm.snmjournals.org/content/early/2021/04/09/jnumed.121.262122.full AB - Rationale: To build a refined dosimetry model for [177Lu]Lu-DOTA-[Tyr3]octreotate (177Lu-DOTATATE) in vivo experiments enabling the correlation of absorbed dose with double strand breaks (DSBs) induction and cell death. Methods: Somatostatin receptor type-2 (SSTR2) expression of NCI-H69 xenografted mice, injected with 177Lu-DOTATATE, was imaged at 0, 2, 5, 11 days. This 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 GATE Monte Carlo code and compared to homogenous dose rate distributions. The absorbed dose (0-2 days) on µm-scale sections was correlated with DSBs induction, measured by γH2AX foci. Moreover, the absorbed dose on larger mm-scale sections delivered over the whole treatment (0-14 days) was correlated to the modelled 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 (EBRT). The DNA-damage repair half-life Tμ and proliferation doubling time TD were obtained by fitting the DSBs and tumor volume data over time. Results: A linear correlation with a slope of 0.0223 DSBs/cell mGy-1 between the absorbed dose and the number of DSBs/cell has been established. The heterogeneous dose distributions differ significantly from the homogenous dose distributions, with their corresponding average S-values diverging at 11 days up to +58%. No significant difference between modelled in vivo survival is observed in the first 5 days when using heterogeneous and uniform dose distributions, respectively. The radiosensitivity parameter analysis for the in vivo survival correlation indicates that the minimal effective dose rates for cell kill are 13.72 mGy/h and 7.40 mGy/h, with α=0.14 Gy-1 and 0.264 Gy-1, respectively and α/β=100 Gy; decreasing the α/β leads to a decrease in the minimal effective dose rate for cell kill. Within the linear quadratic (LQ) model, the best matching in vivo survival correlation (α=0.1 Gy-1, α/β=100 Gy, Tµ=60 h, TD=14.5 d) indicates a relative biological effectiveness value of 0.4 in comparison to EBRT. Conclusion: Our results demonstrate that accurate dosimetric modelling is crucial to establish dose-response correlations enabling optimization of treatment protocols.