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Purpose: Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides Y or Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. Methods: In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [Y-DOTA]-TOC or [Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. Results: Overall, 910 patients underwent 1,804 cycles of [Y-DOTA]-TOC and 141 patients underwent 259 cycles of [Lu-DOTA]-TOC. The median survival after [Lu-DOTA]-TOC and after [Y-DOTA]-TOC was comparable (45.5 months versus 35.9 months, hazard ratio 0.91, 95 % confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [Lu-DOTA]-TOC over [Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [Lu-DOTA]-TOC treatment (1.4 vs 10.1 %, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8 %, p = 0.32). Conclusion: The present results revealed no difference in median overall survival after [Lu-DOTA]-TOC and [Y-DOTA]-TOC. Furthermore, [Lu-DOTA]-TOC was less haematotoxic than [Y-DOTA]-TOC. [ABSTRACT FROM AUTHOR] more...

Abstract Background We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. Methods In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. Results Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle), 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle) and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle) [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1–4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1–158) months, 34 (range: 1–118) months and 29 (range: 1–113) months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59) vs. intermediate dose, p = 0.03) and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79) vs. low dose, p = 0.03). Conclusions Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. (ClinicalTrials.gov number NCT00978211). more...

Purpose: Our aim was to assess the prognostic and predictive value of somatostatin receptor 2 (sstr 2 ) in neuroendocrine tumors (NETs)., Methods: We established a tissue microarray and imaging database from NET patients that received sstr 2 -targeted radiopeptide therapy with yttrium-90-DOTATOC, lutetium-177-DOTATOC or alternative treatment. We used univariate and multivariate analyses to identify prognostic and predictive markers for overall survival, including sstr 2 -imaging and sstr 2 -immunohistochemistry., Results: We included a total of 279 patients. In these patients, sstr 2 -immunohistochemistry was an independent prognostic marker for overall survival (HR: 0.82, 95 % CI: 0.67 - 0.99, n = 279, p = 0.037). In DOTATOC patients, sstr 2 -expression on immunohistochemistry correlated with tumor uptake on sstr 2 -imaging (n = 170, p < 0.001); however, sstr 2 -imaging showed a higher prognostic accuracy (positive predictive value: +27 %, 95 % CI: 3 - 56 %, p = 0.025). Sstr 2 -expression did not predict a benefit of DOTATOC over alternative treatment (p = 0.93)., Conclusions: Our results suggest sstr 2 as an independent prognostic marker in NETs. Sstr 2 -immunohistochemistry correlates with sstr 2 -imaging; however, sstr 2 -imaging is more accurate for determining the individual prognosis. more...

We aimed to assess the risk of developing diabetes mellitus and its effects on all-cause mortality after radiopeptide therapy for neuroendocrine tumors (NETs)., Methods: NET patients received somatostatin radiopeptide therapy with 90 Y-DOTATOC or 177 Lu-DOTATOC. The incidence of diabetes mellitus and its mortality were assessed using univariate and multivariate regression., Results: Overall, 1,535 NET patients were enrolled and received 3,807 treatment cycles. After treatment, 72 patients developed diabetes mellitus, including 47 cases after 90 Y-DOTATOC and 25 cases after combined treatment. The diabetes mellitus risk was higher before than after DOTATOC (estimate, 0.0032; P < 0.001), and overall survival was similar in patients with and without diabetes mellitus (hazard ratio, 1.13; 95% confidence interval, 0.91-1.39; n = 1,535; P = 0.27)., Conclusion: Radiopeptide therapy does not appear to increase the risk of developing diabetes mellitus in NET patients, whereas diabetes mellitus does not appear to increase the mortality of NET patients undergoing receptor-targeted radiopeptide therapy., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.) more...

Targeted diagnosis and therapy enable precise tumor detection and treatment. Successful examples for precise tumor targeting are diagnostic and therapeutic radioligands. However, patients with tumors expressing low levels of the relevant molecular targets are deemed ineligible for such targeted approaches., Methods: We performed a screen for drugs that upregulate the somatostatin receptor subtype 2 (sstr 2 ). Then, we characterized the effects of these drugs on transcriptional, translational, and functional levels in vitro and in vivo., Results: We identified 9 drugs that act as epigenetic modifiers, including the inhibitor of DNA methyltransferase decitabine as well as the inhibitors of histone deacetylase tacedinaline and romidepsin. In vitro, these drugs upregulated sstr 2 on transcriptional, translational, and functional levels in a time- and dose-dependent manner. Thereby, their combinations revealed synergistic effects. In vivo, drug-based sstr 2 upregulation improved the tumor-to-background and tumor-to-kidney ratios, which are the key determinants of successful sstr 2 -targeted imaging and radiopeptide therapy., Conclusion: We present an approach that uses epigenetic modifiers to improve sstr 2 targeting in vitro and in vivo. Translation of this method into the clinic may potentially convert patients ineligible for targeted imaging and therapy to eligible candidates., (© 2016 by the Society of Nuclear Medicine and Molecular Imaging, Inc.) more...

Purpose: Somatostatin receptor-targeted radiopeptide therapy is commonly performed using single radioisotopes. We evaluated the benefits and harms of combining radioisotopes in radiopeptide therapy in patients with neuroendocrine tumor., Methods: Using multivariable-adjusted survival analyses and competing risk analyses we evaluated outcomes in patients with neuroendocrine tumor receiving (90)Y-DOTATOC, (177)Lu-DOTATOC or their combination., Results: (90)Y-DOTATOC plus (177)Lu-DOTATOC treatment was associated with longer survival than (90)Y-DOTATOC (66.1 vs. 47.5 months; n = 1,358; p < 0.001) or (177)Lu-DOTATOC alone (66.1 vs. 45.5 months; n = 390; p < 0.001). (177)Lu-DOTATOC was associated with longer survival than (90)Y-DOTATOC in patients with solitary lesions (HR 0.3, range 0.1 - 0.7; n = 153; p = 0.005), extrahepatic metastases (HR 0.5, range 0.3 - 0.9; n = 256; p = 0.029) and metastases with low uptake (HR 0.1, range 0.05 - 0.4; n = 113; p = 0.001). (90)Y-DOTATOC induced higher hematotoxicity rates than combined treatment (9.5% vs. 4.0%, p = 0.005) or (177)Lu-DOTATOC (9.5 vs. 1.4%, p = 0.002). Renal toxicity was similar among the treatments., Conclusions: Using (90)Y and (177)Lu might facilitate tailoring radiopeptide therapy and improve survival in patients with neuroendocrine tumors. more...

Unlabelled: Meningiomas express members of the somatostatin receptor family. The present study assessed the long-term benefits and harm of somatostatin-based radiopeptide therapy in meningioma patients., Methods: Patients with progressive unresectable meningioma were treated with (90)Y-DOTATOC and (177)Lu-DOTATOC until tumor progression or permanent toxicity occurred. Multivariable Cox regression analyses were used to study predictors of survival., Results: Overall, 74 treatment cycles were performed on 34 patients. Stable disease was achieved in 23 patients. Severe hematotoxicity occurred in 3 patients, and severe renal toxicity in 1 patient. Mean survival was 8.6 y from the time of recruitment. Stable disease after treatment (hazard ratio, 0.017 vs. progressive disease; 95% confidence interval, 0.001-0.35; n = 34; P = 0.01) and high tumor uptake (hazard ratio, 0.046 vs. intermediate or low tumor uptake; 95% confidence interval, 0.004-0.63; n = 34; P = 0.019) were associated with longer survival., Conclusion: (90)Y-DOTATOC and (177)Lu-DOTATOC are promising tools for treating progressive unresectable meningioma, especially in cases of high tracer uptake in the tumor., (© 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.) more...

The present report describes the synthesis and biological evaluation of a molecular imaging platform based on gold nanoparticles directly labeled with indium-111. The direct labeling approach facilitated radiolabeling with high activities while maintaining excellent stability within the biological environment. The resulting imaging platform exhibited low interference of the radiolabel with targeting molecules, which is highly desirable for in-vivo probe tracking and molecular targeted tumor imaging. The indium-111 labeled gold nanoparticles were synthesized using a simple procedure that allowed stable labeling of the nanoparticle core with various indium-111 activities. Subsequent surface modification of the particle cores with RGD-based ligands at various densities allowed for molecular targeting of the αvß3 integrin in-vitro and for molecular targeted imaging in human melanoma and glioblastoma models in-vivo. The results demonstrate the vast potential of direct labeling with radioisotopes for tracking gold nanoparticles within biological systems., (Copyright © 2014 Elsevier Ltd. All rights reserved.) more...