From uniform to heterogeneous dose models: connecting cellular and tumor absorbed dose-response for [¹⁷⁷Lu]Lu-DOTATATE and [¹⁶¹Tb]Tb-DOTATATE

Abstract: Knowledge of tumor absorbed dose (AD)–response relationships is a critical first step toward personalizing dose regimens. This study investigated these relationships at a preclinical scale and modeled the observed tumor growth by considering both cellular AD-response relationships and tumor AD distributions. Using this framework, we compared the tumor AD-response of [¹⁷⁷Lu]Lu-DOTATATE and [¹⁶¹Tb]Tb-DOTATATE. Methods: CA20948 xenograft-bearing mice were injected with a range of activities of [¹⁷⁷Lu]Lu-DOTATATE (1 nmol, 21.6–115.4 MBq) and [¹⁶¹Tb]Tb-DOTATATE (1 nmol, 17.3–91.7 MBq). The tumor doubling time was measured and correlated with individual tumor AD, determined with micro-SPECT imaging. The tumor-growth was also modeled based on cellular AD-response relationships, while considering subtumor AD distributions that were determined either with digital autoradiography or micro-SPECT. Results: [¹⁶¹Tb]Tb-DOTATATE showed a 30% higher S-value for tumors compared to [¹⁷⁷Lu]Lu-DOTATATE, after a correction for subcellular heterogeneity. Both treatments reached a clinically relevant tumor AD-range of 9–85 Gy and 5–87 Gy, respectively. A positive correlation was observed between the tumor doubling time and the tumor AD (p < 0.0001, R² = 0.58), with no significant difference in AD-response between [¹⁷⁷Lu]Lu-DOTATATE and [¹⁶¹Tb]Tb-DOTATATE (p = 0.24). The performance of the tumor-growth-model improved substantially after considering AD heterogeneity (from R² = -64 up to R² = 0.16). Conclusion: The tumor doubling time showed a positive correlation with the tumor AD which was largely affected by the heterogeneous AD distribution within the tumor. Findings confirm that [¹⁶¹Tb]Tb-DOTATATE does not increase the therapeutic efficacy compared to [¹⁷⁷Lu]Lu-DOTATATE.