Abstract
Simple SummaryNeuroendocrine 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 177Lu-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 177Lu-octreotate.Radionuclide treatment of patients with neuroendocrine tumors has advanced in the last decades with favorable results using 177Lu-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 177Lu-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 177Lu-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 177Lu-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 177Lu-octreotate, respectively. After 120 MBq 177Lu-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 177Lu-octreotate are beneficial for tumor reduction and prolongs the time to regrowth.
Highlights
Introduction conditions of the Creative CommonsMany neuroendocrine tumors (NETs) are characterized by the overexpression of somatostatin (SS) receptors (SSTRs) on their cell membrane, allowing treatment with peptide receptor radionuclide therapy (PRRT)
Maximal tumor volume reduction for groups was seen after 2 weeks for single administrations of 177 Lu-octreotate, when the mean tumor volume was reduced by 52% and
The maximal mean tumor reduction was 61% after 6 weeks and 91% after 4 weeks for 2 × 15 = 30 and 2 × 30 = 60 MBq groups, respectively (Figure 1)
Summary
Introduction conditions of the Creative CommonsMany neuroendocrine tumors (NETs) are characterized by the overexpression of somatostatin (SS) receptors (SSTRs) on their cell membrane, allowing treatment with peptide receptor radionuclide therapy (PRRT). (177 Lu-octreotate, 177 Lu-DOTATATE, Lutathera® ) is approved by the FDA and EMA for treatment of patients with somatostatin-receptor-positive gastroenteropancreatic (GEP). The most beneficial clinical effects today for 177 Lu-octreotate treatment, administered in up to 4 cycles, are prolonged survival and improved quality of life; a few percent of patients reported complete remission (CR), up to 30% partial remission (PR), and. The main organs at risk in treatment using 177 Lu-octreotate are the bone marrow and kidneys, with transient deprivation of blood cells as acute effects, and delayed effects as loss of renal function and blood malignancies, e.g., leukemia and myelodysplastic syndrome [3,4]. To handle the acute effects on bone marrow, the treatment is given as several administrations (cycles) with enough time between cycles for bone marrow recovery, 7–9 weeks [1]. The number of cycles is limited and the absorbed dose limit suggested for kidneys is usually 23 or 28 Gy [5,6,7]
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