Establishing In Vitro Dosimetric Models and Dose-Effect Relationships for Lu-DOTATATE in Neuroendocrine Tumors.

This study investigates the radiobiology of peptide receptor radionuclide therapy (PRRT) using clinically relevant cancer cell lines by developing a framework for realistic cellular dosimetry in 2- and 3-dimensional cluster-forming configurations. The radiobiologic responses of GOT1 and NCI-H69 tumor cell lines to PRRT and external beam radiotherapy (EBRT) were compared. Viability at 7 d and cell death at multiple time points were assessed. Image-based multicellular dosimetry models were developed to reflect in vitro exposure complexity and were compared with traditional approaches. The PRRT absorbed dose in suspension was dominated by medium during incubation and by a cross-dose within small clusters after incubation. Our findings reveal that traditional dosimetry can underestimate absorbed doses by up to 90% in plated setups and overlooks dose heterogeneity, with initial dose rates varying by up to 2.3-fold based on cluster size and cell arrangement. The maximum relative biologic effectiveness of PRRT compared with EBRT for loss of viability at 7 d was 0.43 ± 0.07 for NCI-H69 cells and 0.22 ± 0.02 for GOT1 cells. NCI-H69 cells showed greater resistance to PRRT-induced cell death than to EBRT, whereas GOT1 cells exhibited similar cell death levels for both treatments, albeit with different dose-response dynamics. PRRT requires on average an absorbed dose 3 times higher than EBRT to achieve equivalent effects in vitro. Traditional dosimetry overestimates the relative biologic effectiveness by underestimating the absorbed dose.