Hyperfractionated Treatment with (177)Lu-Octreotate Increases Tumor Response in Human Small-Intestine Neuroendocrine GOT1 Tumor Model

SIMPLE SUMMARY: Neuroendocrine tumors are slow growing and initially associated with vague symptoms and, therefore, often spread in the patient’s body at diagnosis, leading to a poor prognosis without means of curation through surgery. Although tumor-targeting treatments exist and are used in clinics, they are not fully optimized. The aim of this study was to test different dosages and time intervals of the radioactive pharmaceutical (177)Lu-octreotate. We found that dividing a dosage into several portions and administering it at short time intervals resulted in a stronger tumor reduction and/or prolonged time for regrowth in mice than if given as a single dose. The biggest differences were seen in the lower dosage levels of the study. The findings indicate that there is clear room for improvements in the treatment of neuroendocrine tumors with (177)Lu-octreotate. ABSTRACT: Radionuclide treatment of patients with neuroendocrine tumors has advanced in the last decades with favorable results using (177)Lu-octreotate. However, the gap between the high cure rate in animal studies vs. patient studies indicates a potential to increase the curation of patients. The aim of this study was to investigate the tumor response for different fractionation schemes with (177)Lu-octreotate. BALB/c mice bearing a human small-intestine neuroendocrine GOT1 tumor were either mock treated with saline or injected intravenously with a total of 30–120 MBq of (177)Lu-octreotate: 1 × 30, 2 × 15, 1 × 60, 2 × 30, 1 × 120, 2 × 60, or 3 × 40 MBq. The tumor volume was measured twice per week until the end of the experiment. The mean tumor volume for mice that received 2 × 15 = 30 and 1 × 30 MBq (177)Lu-octreotate was reduced by 61% and 52%, respectively. The mean tumor volume was reduced by 91% and 44% for mice that received 2 × 30 = 60 and 1 × 60 MBq (177)Lu-octreotate, respectively. After 120 MBq (177)Lu-octreotate, given as 1–3 fractions, the mean tumor volume was reduced by 91–97%. Multiple fractions resulted in delayed regrowth and prolonged overall survival by 20–25% for the 120 MBq groups and by 45% for lower total activities, relative to one fraction. The results indicate that fractionation and hyperfractionation of (177)Lu-octreotate are beneficial for tumor reduction and prolongs the time to regrowth.