Cycle-dependent variation of tumor absorbed dose rates in 177Lu-DOTATATE therapies

We aimed to evaluate the variability of tumor absorbed dose rate at 24 hours post-injection across multiple cycles of ¹⁷⁷Lu-DOTATATE therapy. Using patient-specific Monte Carlo simulations, we quantified cycle-dependent variations in tumor absorbed dose rate and explicitly separated self- and cross-irradiation contributions. Five patients, with neuroendocrine tumor metastases, who received 3 to 4 cycles of 177Lu-DOTATATE therapy with a fixed activity of 7.4 GBq per cycle, were studied. All patients underwent single-photon emission computed tomography (SPECT) imaging 24 hours after each injection cycle. The GATE Monte Carlo framework (version 8.1) was used for voxel-level tumor dosimetry. Dosimetry was performed for 25 individual lesions, giving a total of 92 individual absorbed dose assessments across all cycles. We focused on relative, cycle-to-cycle comparison of tumor self- and cross-absorbed dose rate. The cross-absorbed dose from surrounding tissues comprised a substantial fraction of total tumor absorbed dose rate, up to 32.64% across individual tumors and cycles. Linear mixed-effects analysis across all five patients revealed statistically significant differences in cross-absorbed dose contribution across treatment cycles (F-values: 4.433-24.607; p-values: 0.002-<0.001). Descriptive statistics revealed that all 25 tumor self-absorbed dose changes ranged from 26.0% to 114.4% (mean: 63.4% ± 27.4%, median: 63.2%) during 3 to 4 cycles, while cross-absorbed dose changes ranged from 4.6% to 330.5% (mean: 98.8% ± 89.4%, median: 76.5%). A key finding of our study is that the cross-absorbed dose originating from organs containing or surrounding the tumor can substantially contribute to the absorbed dose rate, a factor that must be considered for accurate estimations at each cycle of treatment. Despite identical injected activities, tumor self- and cross-dose substantially changed over cycles. These results demonstrate the necessity for patient-specific activity administration protocols and cycle-specific dosimetry assessments in 177Lu-DOTATATE therapy, supporting a paradigm shift from fixed-activity regimens toward individualized, image-based dosimetry-guided treatment strategies.