Before performing ¹⁷⁷Lu-DOTATATE therapy for neuroendocrine tumors, somatostatin receptor (SSTR) PET imaging is currently used to confirm sufficient tumor SSTR expression, but it also has potential to be used to personalize treatment by predicting absorbed doses to critical organs. This study aims to validate the predictive capability of SSTR PET in anticipating renal absorbed dose in the first cycle of ¹⁷⁷Lu-DOTATATE using a multicenter dataset to analyze and derive insights from a broader patient population. Methods: Retrospective data from 5 centers were included in this study: 1 in Canada (n = 25), 1 in Norway (n = 75), 1 in Sweden (n = 18), and 2 in the United States (n = 36 and n = 26). At each center, pretherapy SSTR PET/CT imaging and postcycle 1 ¹⁷⁷Lu imaging–based dosimetry were performed according to site-specific protocols. The mixed-effects model treating centers as random effects was developed using baseline SSTR PET renal uptake values to predict renal absorbed dose from ¹⁷⁷Lu-DOTATATE. Additionally, leave-one-center-out cross-validation and leave-one-sample-out cross-validation were implemented for external and internal validation, respectively, measuring mean absolute error and mean relative absolute error. Results: Across all participating centers, the median cycle 1 renal absorbed dose was 0.56 Gy/GBq (range, 0.14–1.27 Gy/GBq), whereas the median pretherapy SSTR PET renal uptake was 110.7 Bq/mL/MBq (range, 28.6–287.7 Bq/mL/MBq). The differences among center means were statistically significant for both absorbed dose and PET uptake (P < 0.0001 from 1-way ANOVA). A significant (P < 0.05) correlation was observed between kidney SSTR PET uptake and ¹⁷⁷Lu-DOTATATE absorbed dose for each center (center-specific coefficient of determination ranged from 0.14 to 0.53). When data across all centers were aggregated, the mixed-effects model achieved a coefficient of determination of 0.25 (P < 0.01), resulting in an mean absolute error of 0.15 Gy/GBq (SD, 0.11 Gy/GBq) and an mean relative absolute error of 28% (SD, 24%) for external validation and 0.12 Gy/GBq (SD, 0.10 Gy/GBq) and 22% (SD, 20%) for internal validation. Conclusion: The correlations observed between SSTR PET renal uptake and ¹⁷⁷Lu-DOTATATE absorbed dose to kidneys across a multicenter population are statistically significant yet modest. The prediction model achieved a mean relative absolute error 28% or less for both external and internal validation of PET-predicted absorbed doses. The intercenter differences suggest the need for standardized imaging protocols and dosimetry workflows. Visual Abstract

Approval of ¹⁷⁷ Lu-DOTATATE for the treatment of neuroendocrine tumors (NETs) requires monitoring for therapeutic efficacy and safety. A retrospective review was conducted on 173 patients who received ¹⁷⁷ Lu-DOTATATE at the University of Michigan to identify if posology changes would improve therapy tolerance and completion. Patients were followed up to 3 years following their last cycle of treatment to determine long-term adverse events. Dose reduction (from 7.4 GBq to 3.7 GBq) was used in 13 patients, and cycle delay (8±1 wk to >16-week gap) was used in 36 patients, leading to 82% completion of 4 cycles of therapy. Dose reduction led to higher rates for completing all 4 cycles of therapy, whereas cycle delay led to worsened outcomes. Amino acid infusions led to limited adverse events with nausea, vomiting, and fatigue, even with antiemetic prophylaxis. Carcinoid crisis was observed in 1.2% of patients, which was similar to the findings in the NETTER-1 trial. Acute decline in neutrophils and platelets was observed; however, these blood values rebounded. A decline in renal function (4.3 mL/min/1.73 m ² over 4 years compared with untreated patients) suggests a potential long-term risk for renal toxicity; however, it could also be associated with changes in therapy. When adverse events were severe due to underlying disease, dose reduction, or cycle delay did not adequately impact therapy completion, and required further therapy monitoring. Long-term occurrence of myelodysplasia syndrome was 1.8%, comparable to reported occurrences requiring further monitoring. Our analysis reinforces that ¹⁷⁷ Lu-DOTATATE is an effective, well-tolerated treatment for NETs with low incidences of long-term adverse events.