Strategies for optimisation of 177Lu-octreotate therapy – exploring local administration and combination therapy regimens

Sammanfattning: Neuroendocrine tumours (NETs) are a group of heterogeneous tumour types that originate in hormone-producing organs. Patients with NETs are often diagnosed after the primary tumour has metastasised. One treatment option for these patients that has shown very promising results is systemic treatment using the radiolabelled somatostatin analogue 177Lu-octreotate. However, the outcome of this treatment is currently restricted by healthy organs at risk. The aim of this work was to optimise 177Lu-octreotate therapy of NETs by investigating strategies based on local administration and on combination therapy regimens. The feasibility of local treatment of liver metastases was evaluated by administering 177Lu-octreotate via isolated hepatic perfusion (IHP) in a pig animal model. During IHP, the liver was completely isolated from the systemic circulation. An intraoperative gamma detector was evaluated for the purpose of determining 177Lu activity concentration in vivo during treatment. This detector was also evaluated by assessment of its technical performance parameters using phantoms. In summary, the results showed that it could be feasible to treat patients with liver metastases from NETs with 177Luoctreotate via IHP. A relatively inhomogeneous uptake was obtained and to accurately quantify 177Lu activity concentration using an intraoperative gamma detector, measurements may need to be performed at several positions over the liver. In the combination therapy experiments, nude mice transplanted with NETs were treated with radiation therapy alone (as 177Lu-octreotate or external beam radiotherapy) and in combination with one of the drugs gemcitabine, vandetanib, cabozantinib, or ganetespib. After treatment, tumour volume was followed and compared with that in control mice. Overall, combination treatment resulted in the largest decrease in tumour volume and the longest time to progression. The results indicated that additive, and sometimes synergistic, effects could be obtained when combining 177Luoctreotate with another drug for treatment of patients with NETs.