Preclinical Evaluation of the α-Particle Generator Nuclide 225Ac for Somatostatin Receptor Radiotherapy of Neuroendocrine Tumors

Background & Aims: Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms with unclear etiology that may show functioning or non-functioning features. Primary tumor localization often requires integrated imaging. The European Neuroendocrine Tumors Society (ENETS) guidelines proposed wireless-capsule endoscopy (WCE) as a possible diagnostic tool for NETs, if intestinal origin is suspected. However, its impact on therapeutic management is debated. We aimed to evaluate the yield of WCE in detecting intestinal primary tumor in patients showing liver NET metastases when first-line investigations are inconclusive.Method: Twenty-four patients with histological diagnosis of metastatic NET from liver biopsy and no evidence of primary lesions at first-line investigations were prospectively studied in an ENETS-certified tertiary care center. Wireless-capsule endoscopy was requested before explorative laparotomy and intra-operative ultrasound. The diagnostic yield of WCE was compared to the surgical exploration.Results: Sixteen subjects underwent surgery; 11/16 had positive WCE identifying 16 bulging lesions. Mini-laparotomy found 13 NETs in 11/16 patients (9 small bowel, 3 pancreas, 1 bile ducts). Agreement between WCE and laparotomy was recorded in 9 patients (Sensitivity=75%; Specificity=37.5%; PPV=55%; NPV=60%). Correspondence assessed per-lesions produced similar results (Sensitivity=70%; Specificity=25%; PPV=44%; NPV=50%). No capsule retentions were recorded.Conclusions: Wireless-capsule endoscopy is not indicated as second-line investigation for patients with gastro-entero-pancreatic NETs. In the setting of a referral center, it might provide additional information when conventional investigations are inconclusive about the primary site.Abbreviations: DBE: double balloon enteroscopy; GEP-NET: gastro-entero-pancreatic neuroendocrine tumor; GI: gastrointestinal; ENETS: European Neuroendocrine Tumor Society; NET: neuroendocrine tumor; SSRS: somatostatin receptor scintigraphy; WCE: wireless capsule endoscopy.

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Predictive and Prognostic Impact of Blood-Based Inflammatory Biomarkers in Patients with Gastroenteropancreatic Neuroendocrine Tumors Commencing Peptide Receptor Radionuclide Therapy

Diagnostics ◽

10.3390/diagnostics11030504 ◽

2021 ◽

Vol 11 (3) ◽

pp. 504

Author(s):

Fiona Ohlendorf ◽

Rudolf Werner ◽

Christoph Henkenberens ◽

Tobias Ross ◽

Hans Christiansen ◽

...

Keyword(s):

Treatment Response ◽

Neuroendocrine Tumors ◽

Radionuclide Therapy ◽

Somatostatin Receptor ◽

Peptide Receptor Radionuclide Therapy ◽

Tumor Burden ◽

Inflammatory Biomarkers ◽

Whole Body ◽

Prognostic Impact ◽

Peptide Receptor

Tumor microenvironment inflammation contributes to the proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity, and reduced treatment response. We aimed to evaluate the early predictive and prognostic significance of markers of systemic inflammation in patients receiving somatostatin-receptor targeted peptide receptor radionuclide therapy (PRRT). This retrospective observational cohort study included 33 patients with advanced gastro-entero-pancreatic neuroendocrine tumors (GEP-NETs) treated with PRRT. Pretreatment blood-based inflammatory biomarkers, e.g., Creactive protein levels (CRP), white blood cell count (WBC), and absolute neutrophil count (ANC), were documented and inflammation indexes, e.g., neutrophil-lymphocyte ratio (NLR) and Platelet × CRP multiplier (PCM), were calculated. Tumor burden was determined using [68Ga]GaDOTATATE PET/CT before enrollment and every 2 cycles thereafter until progression. Therapy response was assessed using RECIST 1.1, including its volumetric modification. Inflammatory biomarkers and inflammatory indexes demonstrated marked heterogeneity among patients, and were significantly higher in non-responders (e.g., CRP (P < 0.001), ANC (P = 0.002), and PCM (P < 0.001)). Change in whole-body tumor burden after two cycles of PRRT was significantly associated with CRP (P = 0.0157) and NLR (P = 0.0040) in multivariate regression analysis. A cut-off of 2.5 mg/L for CRP (AUC = 0.84, P = 0.001) revealed a significant outcome difference between patients with adversely high vs. low CRP (median PFS 508 days vs. not yet reached (HR = 4.52; 95% CI, 1.27 to 16.18; P = 0.02)). Tumor-driven systemic inflammatory networks may be associated with treatment response, change in tumor burden, and prognosis in patients with GEPNETs receiving PRRT.

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Assessment of γ-H2AX and 53BP1 Foci in Peripheral Blood Lymphocytes to Predict Subclinical Hematotoxicity and Response in Somatostatin Receptor-Targeted Radionuclide Therapy for Advanced Gastroenteropancreatic Neuroendocrine Tumors

Cancers ◽

10.3390/cancers13071516 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1516

Author(s):

Thorsten Derlin ◽

Natalia Bogdanova ◽

Fiona Ohlendorf ◽

Dhanya Ramachandran ◽

Rudolf A. Werner ◽

...

Keyword(s):

Treatment Response ◽

Neuroendocrine Tumors ◽

Peripheral Blood ◽

Somatostatin Receptor ◽

Therapy Response ◽

Strand Break ◽

Peripheral Blood Lymphocytes ◽

Radioligand Therapy ◽

Gastroenteropancreatic Neuroendocrine Tumors ◽

Blood Lymphocytes

Background: We aimed to characterize γ-H2AX and 53BP1 foci formation in patients receiving somatostatin receptor-targeted radioligand therapy, and explored its role for predicting treatment-related hematotoxicity, and treatment response. Methods: A prospective analysis of double-strand break (DSB) markers was performed in 21 patients with advanced gastroenteropancreatic neuroendocrine tumors. γ-H2AX and 53BP1 foci formation were evaluated in peripheral blood lymphocytes (PBLs) at baseline, +1 h and +24 h after administration of 7.4 GBq (177Lu)Lu-DOTA-TATE. Hematotoxicity was evaluated using standard hematology. Therapy response was assessed using (68Ga)Ga-DOTA-TATE PET/CT before enrollment and after 2 cycles of PRRT according to the volumetric modification of RECIST 1.1. Results: DSB marker kinetics were heterogeneous among patients. Subclinical hematotoxicity was associated with γ-H2AX and 53BP1 foci formation (e.g., change in platelet count vs change in γ-H2AX+ cells between baseline and +1 h (r = −0.6080; p = 0.0045). Patients showing early development of new metastases had less γ-H2AX (p = 0.0125) and less 53BP1 foci per cell at +1 h (p = 0.0289), and demonstrated a distinct kinetic pattern with an absence of DSB marker decrease at +24 h (γ-H2AX: p = 0.0025; 53BP1: p = 0.0008). Conclusions: Assessment of γ-H2AX and 53BP1 foci formation in PBLs of patients receiving radioligand therapy may hold promise for predicting subclinical hematotoxicity and early treatment response.

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Peptide Receptor Radionuclide Therapy With 177Lu-DOTATATE for Patients With Somatostatin Receptor–Expressing Neuroendocrine Tumors

Pancreas ◽

10.1097/mpa.0000000000000113 ◽

2014 ◽

Vol 43 (4) ◽

pp. 518-525 ◽

Cited By ~ 70

Author(s):

Ebrahim S. Delpassand ◽

Amin Samarghandi ◽

Sara Zamanian ◽

Edward M. Wolin ◽

Mohammadali Hamiditabar ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Radionuclide Therapy ◽

Somatostatin Receptor ◽

Peptide Receptor Radionuclide Therapy ◽

Peptide Receptor

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Optimizing Somatostatin Receptor Imaging in Patients With Neuroendocrine Tumors

Clinical Nuclear Medicine ◽

10.1097/rlu.0000000000001877 ◽

2017 ◽

Vol 42 (12) ◽

pp. 905-911 ◽

Cited By ~ 7

Author(s):

Jolanta Kunikowska ◽

Valerie Lewington ◽

Leszek Krolicki

Keyword(s):

Neuroendocrine Tumors ◽

Somatostatin Receptor ◽

Receptor Imaging ◽

Somatostatin Receptor Imaging

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Prognostic Value of Somatostatin Receptor Subtypes in Pancreatic Neuroendocrine Tumors

Pancreas ◽

10.1097/mpa.0000000000000493 ◽

2016 ◽

Vol 45 (2) ◽

pp. 187-192 ◽

Cited By ~ 14

Author(s):

Ki Byung Song ◽

Song Cheol Kim ◽

Ji Hun Kim ◽

Dong-Wan Seo ◽

Seung-Mo Hong ◽

...

Keyword(s):

Neuroendocrine Tumors ◽

Prognostic Value ◽

Somatostatin Receptor ◽

Receptor Subtypes ◽

Pancreatic Neuroendocrine Tumors ◽

Somatostatin Receptor Subtypes

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Effect of Peptide Receptor Radionuclide Therapy on Somatostatin Receptor Status and Glucose Metabolism in Neuroendocrine Tumors: Intraindividual Comparison of Ga-68 DOTANOC PET/CT and F-18 FDG PET/CT

International Journal of Molecular Imaging ◽

10.1155/2011/524130 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 18

Author(s):

Sowon Oh ◽

Vikas Prasad ◽

Dong Soo Lee ◽

R. P. Baum

Keyword(s):

Glucose Metabolism ◽

Neuroendocrine Tumors ◽

Fdg Pet ◽

Radionuclide Therapy ◽

Somatostatin Receptor ◽

Peptide Receptor Radionuclide Therapy ◽

Receptor Expression ◽

Peptide Receptor ◽

Pet Ct ◽

Fdg Pet Ct

The heterogeneous nature of the neuroendocrine tumors (NET) makes it challenging to find one uniformly applicable management protocol which is especially true for diagnosis. The discovery of the overexpression of somatostatin receptors (SMS-R) on neuroendocrine tumor cells lead to the generalized and rapid acceptance of radiolabeled somatostatin receptor analogs for staging and restaging of NET as well as for Peptide Receptor Radionuclide Therapy (PRRNT) using Y-90 and Lu-177 DOTATATE/DOTATOC. In this present work we tried to look in to the effect of PRRNT on the glucose metabolism assessed by F-18 FDG PET/CT and SMS-R density assessed by Ga-68 DOTANOC PET/CT. We observed a complex relationship between the somatostatin receptor expression and glucose metabolism with only 56% (77/138) of the lesions showing match, while the others show mismatch between the receptor status and metabolism. The match between receptor expression and glucose metabolism increases with the grade of NET. In grade 3 NET, there is a concurrence between the changes in glucose metabolism and somatostatin receptor expression. PRRNT was found to be more effective in lesions with higher receptor expression.

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SSTR1 and SSTR5 subtypes are the dominant forms of somatostatin receptor in neuroendocrine tumors.

Folia Histochemica et Cytobiologica ◽

10.2478/v10042-008-0103-7 ◽

2010 ◽

Vol 48 (1) ◽

Cited By ~ 8

Author(s):

Hanna Pisarek ◽

Marek Pawlikowski ◽

Jolanta Kunert-Radek ◽

Robert Kubiak ◽

Katarzyna Winczyk

Keyword(s):

Neuroendocrine Tumors ◽

Somatostatin Receptor

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Making Sense of a Complex Disease: A Practical Approach to Managing Neuroendocrine Tumors

JCO Oncology Practice ◽

10.1200/op.21.00240 ◽

2021 ◽

Author(s):

Janie Y. Zhang ◽

Pamela L. Kunz

Keyword(s):

Functional Status ◽

Neuroendocrine Tumors ◽

Complex Disease ◽

Treatment Plan ◽

Performance Status ◽

Somatostatin Receptor ◽

The United States ◽

Making Sense ◽

Pathologic Classification ◽

Therapeutic Decision Making

Neuroendocrine tumors (NETs) are a heterogeneous clinical entity with a broad range of grade, pace of disease, functional status, and primary sites. Pathologic classification, diagnostic modalities, and therapeutic options for NETs have evolved considerably in the past decade. In part driven by these advances, incidence and prevalence of NETs are rising in the United States and the practicing oncologist is likely to encounter these in the clinic. However, there are no clear lines of therapy for unresectable or metastatic NETs, and sequencing of systemic therapies depends on consideration of patient and tumor characteristics including extent of disease, grade, pace of growth, functional status, primary site, somatostatin receptor status, performance status, and comorbidities. Familiarity with ongoing clinical trials will guide therapeutic decision making as well. In this review, we seek to provide a framework to formulate and tailor an individualized treatment plan for each patient with a NET.

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Prognostic Value of Volume-Based Parameters Measured by SSTR PET/CT in Neuroendocrine Tumors: A Systematic Review and Meta-Analysis

Frontiers in Medicine ◽

10.3389/fmed.2021.771912 ◽

2021 ◽

Vol 8 ◽

Author(s):

Jiale Hou ◽

Yi Yang ◽

Na Chen ◽

Dengming Chen ◽

Shuo Hu

Keyword(s):

Positron Emission Tomography ◽

Neuroendocrine Tumors ◽

Prognostic Value ◽

Meta Analysis ◽

Somatostatin Receptor ◽

Progression Free Survival ◽

Emission Tomography ◽

Cochrane Library ◽

Positron Emission ◽

Pet Ct

Purpose: A meta-analysis was conducted to investigate the value of the volume parameters based on somatostatin receptor (SSTR)-positron emission tomography (PET) in predicting the prognosis in patients with neuroendocrine tumors (NETs).Material: PUBMED, EMBASE, Cochrane library, and Web of Knowledge were searched from January 1990 to May 2021 for studies evaluating prognostic value of volume-based parameters of SSTR PET/CT in NETs. The terms used were “volume,” “positron emission tomography,” “neuroendocrine tumors,” and “somatostatin receptor.” Pooled hazard ratio (HR) values were calculated to assess the correlations between volumetric parameters, including total tumor volume (TTV) and total-lesion SSTR expression (TL-SSTR), with progression-free survival (PFS) and overall survival (OS). Heterogeneity and subgroup analysis were performed. Funnel plots, Begg's and Egger's test were used to assess possible underlying publication bias.Results: Eight eligible studies involving 593 patients were included in the meta-analysis. In TTV, the pooled HRs of its prognostic value of PFS and OS were 2.24 (95% CI: 1.73–2.89; P < 0.00001) and 3.54 (95% CI, 1.77–7.09; P = 0.0004), respectively. In TL-SSTR, the pooled HR of the predictive value was 1.61 (95% CI, 0.48–5.44, P = 0.44) for PFS.Conclusion: High TTV was associated with a worse prognosis for PFS and OS in with patients NETs. The TTV of SSTR PET is a potential objective prognosis predictor.

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