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

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 18F-FDG and the proliferation tracer 18F-FLT for treatment response assessment by PET imaging.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 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.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 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).Everolimus 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

[18F]FDG and [18F]FLT positron emission tomography imaging following treatment with belinostat in human ovary cancer xenografts in mice

BACKGROUND: Belinostat is a histone deacetylase inhibitor with anti-tumor effect in several pre-clinical tumor models and clinical trials. The aim of the study was to evaluate changes in cell proliferation and glucose uptake by use of 3’-deoxy-3’-[(18)F]fluorothymidine ([18F]FLT) and 2-deoxy-2-[(18)F]fluoro-D-glucose ([18F]FDG) positron emission tomography (PET) following treatment with belinostat in ovarian cancer in vivo models. METHODS: In vivo uptake of [18F]FLT and [18F]FDG in human ovary cancer xenografts in mice (A2780) were studied after treatment with belinostat. Mice were divided in 2 groups receiving either belinostat (40 mg/kg ip twice daily Day 0–4 and 6–10) or vehicle. Baseline [18F]FLT or [18F]FDG scans were made before treatment (Day 0) and repeated at Day 3, 6 and 10. Tracer uptake was quantified using small animal PET/CT. RESULTS: Tumors in the belinostat group had volumes that were 462 ± 62% (640 mm(3)) at Day 10 relative to baseline which was significantly different (P = 0.011) from the control group 769 ± 74% (926 mm(3)). [18F]FLT SUVmax increased from baseline to Day 10 (+30 ± 9%; P = 0.048) in the control group. No increase was observed in the treatment group. [18F]FDG SUVmean was significantly different in the treatment group compared to the control group (P = 0.0023) at Day 10. Within treatment groups [18F]FDG uptake and to a lesser extent [18F]FLT uptake at Day 3 were significantly correlated with tumor growth at Day 10. CONCLUSIONS: [18F]FDG uptake early following treatment initiation predicted tumor sizes at Day 10, suggesting that [18F]FDG may be a valuable biomarker for non-invasive assessment of anti-tumor activity of belinostat

Semi-automatic tumor delineation for evaluation of 64Cu-DOTATATE PET/CT in patients with neuroendocrine neoplasms:prognostication based on lowest lesion uptake and total tumor volume

Patients with neuroendocrine neoplasms (NENs) have heterogeneous somatostatin receptor expression, with highly differentiated lesions having higher expression. Receptor expression of the total tumor burden may be visualized by somatostatin receptor imaging, such as with (64)Cu-DOTATATE PET/CT. Assessment of maximal lesion uptake is associated with progression-free survival (PFS) but not overall survival (OS). We hypothesized that the lesion with the lowest, rather than the highest, (64)Cu-DOTATATE uptake would be more prognostic, and we developed a semiautomatic method for evaluating this hypothesis. Methods: Patients with NENs underwent (64)Cu-DOTATATE PET/CT. A standardized semiautomatic tumor delineation method was developed and used to identify the lesion with the lowest uptake, that is, with the lowest SUV(mean). Additionally, we assessed total tumor volume derived from the semiautomatic tumor delineation. Kaplan–Meier and Cox regression analyses were used to determine whether there was any association with OS and PFS. Results: In 116 patients with NENs, median PFS (95% CI) was 23 mo (range, 20–31 mo) and median OS was 85 mo (range, 68–113 mo). Minimum SUV(mean) and total tumor volume were significantly associated with PFS and OS in univariate Cox regression analyses, whereas SUV(max) was significant only for PFS. In multivariate Cox analyses, both minimum SUV(mean) and total tumor volume remained statistically significant. Minimum SUV(mean) and total tumor volume were then dichotomized by their median, and patients were categorized into 4 groups: high or low total tumor volume and high or low minimum SUV(mean). Patients with a low total tumor volume and high minimum SUV(mean) had a hazard ratio of 0.32 (95% CI, 0.20–0.51) for PFS and 0.24 (95% CI, 0.13–0.43) for OS, both with P values of less than 0.001 (reference: high total tumor volume and low minimum SUV(mean)). Conclusion: We propose a standardized semiautomatic tumor delineation method to identify the lesion with the lowest (64)Cu-DOTATATE uptake and total tumor volume. Assessment of the lowest, rather than the highest, lesion uptake greatly increases prognostication by (64)Cu-DOTATATE PET/CT. Combining lesion uptake and total tumor volume, we derived a novel prognostic classification system for patients with NENs

¹⁸F-FDG-PET is superior to WHO grading as prognostic tool in neuroendocrine neoplasms and useful in guiding peptide receptor radionuclide therapy:a prospective 10-year follow-up study of 166 patients

Accurate grading of patients with neuroendocrine neoplasms (NENs) is essential for risk stratification and optimal choice of therapy. Currently, grading is based on histologically assessed degree of tumor proliferation. The aim of the present study was to assess the long-term prognostic value of (18)F-FDG PET imaging for risk stratification of NENs and compare it with tumor grading (World Health Organization 2010 classification). Methods: We conducted a prospective cohort study evaluating the prognostic value of (18)F-FDG PET imaging and compared it with histologic grading. Enrolled were 166 patients of all grades and with histologically confirmed NENs of gastroenteropancreatic origin. The primary endpoint was overall survival (OS). Progression-free survival (PFS) was a secondary endpoint. In addition, OS in relation to peptide receptor radionuclide therapy (PRRT) was analyzed as an exploratory endpoint. The median follow-up time was 9.8 y. Results: Analysis of the whole cohort revealed that a positive (18)F-FDG PET scan was associated with a shorter OS than a negative (18)F-FDG PET scan (hazard ratio: 3.8; 95% CI: 2.4–5.9; P < 0.001). In G1 and G2 patients (n = 140), a positive (18)F-FDG PET scan was the only identifier of high risk for death (hazard ratio: 3.6; 95% CI, 2.2–5.9; P < 0.001). In multivariate analysis, (18)F-FDG PET, G3 tumor, ≥2 liver metastases, and ≥2 prior therapies were independent prognostic factors for OS, and (18)F-FDG PET, G3 tumor, and ≥3 liver metastases were independent prognostic factors for PFS. For patients receiving PRRT, (18)F-FDG–negative cases had a significantly longer survival than (18)F-FDG–positive cases, whereas no difference was identified for tumor grading. (18)F-FDG–positive patients receiving PRRT had a significantly longer median survival than patients not receiving PRRT (4.4 vs. 1.4 y, P = 0.001), whereas no difference was seen for (18)F-FDG–negative patients. Conclusion: (18)F-FDG PET is useful for risk stratification of all NEN grades and is superior to histologic grading. (18)F-FDG PET could differentiate G1 and G2 tumors into low- and high-risk groups. In the selection of therapy and for risk stratification of NEN patients, (18)F-FDG PET status should be considered

PET uptake in H727 xenografts.

<p>Uptake of FDG (upper panel) and FLT (lower panel) after treatment of H727 xenografts with everolimus or vehicle. N = 8–10 tumors/group. *) P<0.05 vs. control group on same day, #) P<0.05 and ##) P<0.01 vs. baseline of same group. P-values are Bonferroni corrected.</p