Dosing ${}^{225}$Ac-DOTATOC in patients with somatostatin-receptor-positive solid tumors. 5-year follow-up of hematological and renal toxicity

The aim of this retrospective analysis is to estimate the most appropriate single cycle and cumulative doses of ${}^{225}$Ac-DOTATOC in patients treated for somatostatin-receptor-expressing cancers. ${}^{225}$Ac-DOTATOC was administered to thirty-nine patients with various somatostatin-receptor-positive tumors. Baseline and follow-up ${}^{68}$Ga-DOTATOC PET/CT, lab tests, and renal scintigraphy were obtained. Patients received long-term follow-up either at the local cancer center or in close collaboration with external oncologists. Acute and chronic hematological toxicity was evaluated quantitatively over time. Long-term follow-up of creatinine was used to approximate the annual loss of estimated GFR (eGFR). Dose-dependent acute hematological toxicity was seen at single doses above 40 MBq or repeated doses greater than approximately 20 MBq ${}^{225}$Ac-DOTATOC at 4 month intervals. Treatment-related kidney failure occurred in 2 patients after a delay of >4 years but was independent of administered radioactivity, and other clinical risk factors were important contributors to renal decline. In general, the annual decline of eGFR among patients did not follow a clear dose-effect relationship even in patients with previous $\beta$-therapy. An average eGFR-loss of 8.4ml/min (9.9%) per year was observed which is similar to the experience with $\beta$-therapy studies. Treatment activities of approx. 20 MBq per cycle (4 monthly repetition) and cumulative doses up to 60-80 MBq generally avoided both acute and chronic grade 3/4 hematotoxicity in patients with advanced stage malignancies. Chronic renal toxicity was observed at these doses, but pre-existing renal risk factors were important co-factors. These data represent a starting point for additional research to more precisely define safety thresholds of ${}^{225}$Ac-DOTATOC.