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

Giulia Tamborino, Julie Nonnekens, Marijke De Saint-Hubert, Lara Struelens, Danny Feijtel, Marion de Jong, Mark W. Konijnenberg

Research output: Contribution to journalArticleAcademicpeer-review

8 Citations (Scopus)
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Abstract

Our rationale was to build a refined dosimetry model for 177Lu- DOTATATE in vivo experiments enabling the correlation of absorbed dose with double-strand break (DSB) induction and cell death. Methods: Somatostatin receptor type 2 expression of NCI-H69 xenografted mice, injected with 177Lu-DOTATATE, was imaged at 0, 2, 5, and 11 d. This expressionwas 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 themodeled in vivo survival to determine the radiosensitivity parameters α and β for comparison with experimental data (cell death assay, volume response) and external-beamradiotherapy. TheDNA-damage repair half-life Tμ and proliferation doubling time TD were obtained by fitting the DSB and tumor volume data over time. Results: A linear correlation with a slope of 0.0223 DSB/cell mGy-1 between the absorbed dose and the number of DSBs per cell has been established.The heterogeneousdosedistributionsdifferedsignificantly from the homogeneous dose distributions, with their corresponding average S values diverging at 11 d by up to 58%. No significant differencebetweenmodeledin vivosurvivalwasobservedin thefirst5d when using heterogeneous and uniform dose distributions. The radiosensitivity parameter analysis for the in vivo survival correlation indicated that theminimal effective dose rates for cell killwas 13.72 and 7.40mGy/h,with an a of 0.14 and 0.264Gy-1, respectively, and an α/β of 100Gy; decreasing the α/β led to a decrease in theminimal effective dose rate for cell kill. Within the linear quadratic model, the best matching in vivo survival correlation (a=0.1Gy-1, α/β=100Gy, Tμ = 60 h, TD = 14.5 d) indicated a relative biological effectiveness of 0.4 in comparison to external-beam radiotherapy. Conclusion: Our results demonstrated that accurate dosimetricmodeling is crucial to establishing dose-response correlations enabling optimization of treatment protocols.

Original languageEnglish
Pages (from-to)100-107
Number of pages8
JournalJournal of nuclear medicine : official publication, Society of Nuclear Medicine
Volume63
Issue number1
DOIs
Publication statusPublished - 1 Jan 2022

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© 2022 by the Society of Nuclear Medicine and Molecular Imaging.

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