May bone-targeted radionuclide therapy overcome PRRT-refractory osseous disease in NET? A pilot report on (188)Re-HEDP treatment in progressive bone metastases after (177)Lu-octreotate.

Bone metastases (BM) of gastroenteropancreatic neuroendocrine tumours (GEP-NET) can be effectively controlled by peptide receptor radionuclide therapy (PRRT). Eventually, however, BM may become refractory and determine survival. We aimed to assess the clinical benefit of bone-targeted radionuclide therapy (BTRT) in this subgroup of patients failing PRRT. A small cohort of n=6 patients with progressive BM failing PRRT with (177)Lu-octreotate (mean cumulative activity, 46.7 GBq) were treated with a total of 11 cycles BTRT using 2.6-3.3 GBq (188)Re-HEDP per cycle and a median cumulative activity of 5.9 GBq. Pain palliation was quantified applying the visual analogue scale (VAS). The mean VAS decreased from 6.6 (range 5-8) to 3.7 (range 2-7). Five patients experienced partial resolution of bone pain (≥ 2 steps reduction on the VAS for at least 2 weeks) and one patient had no significant improvement. Flare phenomena occurred in 2 patients and lasted for 2-3 days. Tumor response consisted of stable disease in 2 and progressive disease in 4 patients. No regression of bone metastases has been observed. The median overall survival was 5 months (range 2-9). Relevant myelosuppression (grade 3-4; self-limited with no interventions or hospitalization), occurred 4-6 weeks post-treatment, and after 2 (18.1%) administrations or in 1 (16.7%) patient. No other relevant toxicities or treatment-related death was observed. (188)Re-HEDP may be safely applied in patients with bone metastatic GEP-NET previously treated with (177)Lu-octreotate. While acceptable pain relief may be expected, no tumor-regression or long-term disease stabilization with apparent survival benefit has been observed. This disputes the use of BTRT as salvage anti-tumor therapy in PRRT-refractory neuroendocrine bone metastases.