(18)F-FDG and (18)F-FLT-PET Imaging for Monitoring Everolimus Effect on Tumor-Growth in Neuroendocrine Tumors: Studies in Human Tumor Xenografts in Mice

INTRODUCTION: The mTOR inhibitor everolimus has shown promising results in some but not all neuroendocrine tumors. Therefore, early assessment of treatment response would be beneficial. In this study, we investigated the in vivo and in vitro treatment effect of everolimus in neuroendocrine tumors and evaluated the performance of (18)F-FDG and the proliferation tracer (18)F-FLT for treatment response assessment by PET imaging. METHODS: The effect of everolimus on the human carcinoid cell line H727 was examined in vitro with the MTT assay and in vivo on H727 xenograft tumors. The mice were scanned at baseline with (18)F-FDG or (18)F-FLT and then treated with either placebo or everolimus (5 mg/kg daily) for 10 days. PET/CT scans were repeated at day 1,3 and 10. RESULTS: Everolimus showed significant inhibition of H727 cell proliferation in vitro at concentrations above 1 nM. In vivo tumor volumes measured relative to baseline were significantly lower in the everolimus group compared to the control group at day 3 (126±6% vs. 152±6%; p = 0.016), day 7 (164±7% vs. 226±13%; p<0.001) and at day 10 (194±10% vs. 281±18%; p<0.001). Uptake of (18)F-FDG and (18)F-FLT showed little differences between control and treatment groups, but individual mean uptake of (18)F-FDG at day 3 correlated with tumor growth day 10 (r(2) = 0.45; P = 0.034), (18)F-FLT mean uptake at day 1 correlated with tumor growth day 7 (r(2) = 0.63; P = 0.019) and at day 3 (18)F-FLT correlated with tumor growth day 7 (r(2) = 0.87; P<0.001) and day 10 (r(2) = 0.58; P = 0.027). CONCLUSION: Everolimus was effective in vitro and in vivo in human xenografts lung carcinoid NETs and especially early (18)F-FLT uptake predicted subsequent tumor growth. We suggest that (18)F-FLT PET can be used for tailoring therapy for neuroendocrine tumor patients through early identification of responders and non-responders.