Abstract
IntroductionThe 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 18F-FDG and the proliferation tracer 18F-FLT for treatment response assessment by PET imaging.MethodsThe 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 18F-FDG or 18F-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.ResultsEverolimus 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 18F-FDG and 18F-FLT showed little differences between control and treatment groups, but individual mean uptake of 18F-FDG at day 3 correlated with tumor growth day 10 (r2 = 0.45; P = 0.034), 18F-FLT mean uptake at day 1 correlated with tumor growth day 7 (r2 = 0.63; P = 0.019) and at day 3 18F-FLT correlated with tumor growth day 7 (r2 = 0.87; P<0.001) and day 10 (r2 = 0.58; P = 0.027).ConclusionEverolimus was effective in vitro and in vivo in human xenografts lung carcinoid NETs and especially early 18F-FLT uptake predicted subsequent tumor growth. We suggest that 18F-FLT PET can be used for tailoring therapy for neuroendocrine tumor patients through early identification of responders and non-responders.
Highlights
The mammalian target of rapamycin (mTOR) inhibitor everolimus has shown promising results in some but not all neuroendocrine tumors
Neuroendocrine tumors (NETs) are a heterogeneous group of tumors derived from neuroendocrine cells mainly from the gastrointestinal tract and the bronchopulmonary system
Treatment of H727 xenografts with everolimus 5 mg/kg daily for 10 days resulted in decreases in tumor sizes compared to the vehicle treated control group
Summary
The mTOR inhibitor everolimus has shown promising results in some but not all neuroendocrine tumors. Early assessment of treatment response would be beneficial. We investigated the in vivo and in vitro treatment effect of everolimus in neuroendocrine tumors and evaluated the performance of 18F-FDG and the proliferation tracer 18F-FLT for treatment response assessment by PET imaging. NETs have been considered a rare type of cancer but according to epidemiological data, the incidence has increased five-fold from 1.09 to 5.25/100.000 from 1973 to 2004. Since the survival has increased as well, gastrointestinal NET is the second most prevalent cancer in the gastrointestinal tract [1]. The treatment of NETs has for many years been multifaceted including surgery, somatostatin analogs, interferon alfa, chemotherapy, and peptide receptor radionuclide therapy [2,3]. Targeted therapies with everolimus and sunitinib have recently been approved for subgroups of NETs [4]
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