Systemic chemotherapy is indicated in progressive or bulky advanced pancreatic neuroendocrine tumors (NETs) and in grade 3 (G3) neuroendocrine neoplasms (NENs) as per ENETS guidelines. Chemotherapy may be considered in NETs of other sites (lung, thymus, stomach, colon, and rectum) under certain conditions (e.g., when Ki-67 is at a high level [upper G2 range], in rapidly progressive disease and/or after failure of other therapies, or if somatostatin receptor imaging is negative). An ENETS Consensus Conference was held in Antibes (2015) to elaborate guidelines on the standards of care of different diagnostic procedures and therapeutic interventions in NENs. This article provides guidance on chemotherapy including therapeutic indications, dosing schedules, adverse events (including prevention and management), drug interactions, and evaluation of treatment effect for the chemotherapy agents most commonly used in NENs (streptozocin, dacarbazine, fluoropyrimidines, platinum compounds, etoposide, and irinotecan).

68Ga-DOTATOC and 68Ga-DOTATATE are radiolabeled somatostatin analogs used for the diagnosis of somatostatin receptor-expressing neuroendocrine tumors (NETs), and SUV measurements are suggested for treatment monitoring. However, changes in net influx rate (Ki) may better reflect treatment effects than those of the SUV, and accordingly there is a need to compute parametric images showing Ki at the voxel level. The aim of this study was to evaluate parametric methods for computation of parametric Ki images by comparison to volume of interest (VOI)-based methods and to assess image contrast in terms of tumor-to-liver ratio. Methods: Ten patients with metastatic NETs underwent a 45-min dynamic PET examination followed by whole-body PET/CT at 1 h after injection of 68Ga-DOTATOC and 68Ga-DOTATATE on consecutive days. Parametric Ki images were computed using a basis function method (BFM) implementation of the 2-tissue-irreversible-compartment model and the Patlak method using a descending aorta image-derived input function, and mean tumor Ki values were determined for 50% isocontour VOIs and compared with Ki values based on nonlinear regression (NLR) of the whole-VOI time-activity curve. A subsample of healthy liver was delineated in the whole-body and Ki images, and tumor-to-liver ratios were calculated to evaluate image contrast. Correlation (R2) and agreement between VOI-based and parametric Ki values were assessed using regression and Bland-Altman analysis. Results: The R2 between NLR-based and parametric image-based (BFM) tumor Ki values was 0.98 (slope, 0.81) and 0.97 (slope, 0.88) for 68Ga-DOTATOC and 68Ga-DOTATATE, respectively. For Patlak analysis, the R2 between NLR-based and parametric-based (Patlak) tumor Ki was 0.95 (slope, 0.71) and 0.92 (slope, 0.74) for 68Ga-DOTATOC and 68Ga-DOTATATE, respectively. There was no bias between NLR and parametric-based Ki values. Tumor-to-liver contrast was 1.6 and 2.0 times higher in the parametric BFM Ki images and 2.3 and 3.0 times in the Patlak images than in the whole-body images for 68Ga-DOTATOC and 68Ga-DOTATATE, respectively. Conclusion: A high R2 and agreement between NLR- and parametric-based Ki values was found, showing that Ki images are quantitatively accurate. In addition, tumor-to-liver contrast was superior in the parametric Ki images compared with whole-body images for both 68Ga-DOTATOC and 68Ga DOTATATE.

ENETS Consensus Guidelines Update for the Management of Patients with Functional Pancreatic Neuroendocrine Tumors and Non-Functional Pancreatic Neuroendocrine Tumors

miR-196a Is Specifically Regulated in FDG-PET Positive and Negative Small Intestinal Neuroendocrine Tumor Patients at Late Stage of Disease

UNLABELLED:Peptide receptor radionuclide therapy (PRRT) is a promising treatment for patients with neuroendocrine tumors, giving rise to improved survival. Dosimetric calculations in relation to PRRT have been concentrated to normal organ dosimetry in order to limit side effects. However, the relation between the absorbed dose to the tumor and treatment response has so far not been established. Better knowledge in this respect may improve the understanding of treatment effects, allow for improved selection of those patients who are expected to benefit from PRRT, and avoid unnecessary treatments. The aim of the present work was to evaluate the dose-response relationship for pancreatic neuroendocrine tumors treated with PRRT using (177)Lu-DOTATATE. METHODS:Tumor-absorbed dose calculations were performed for 24 lesions in 24 patients with metastasized pancreatic neuroendocrine tumors treated with repeated cycles of (177)Lu-DOTATATE at 8-wk intervals. The absorbed dose calculations relied on sequential SPECT/CT imaging at 24, 96, and 168 h after infusion of (177)Lu-DOTATATE. The unit density sphere model from OLINDA was used for absorbed dose calculations. The absorbed doses were corrected for partial-volume effect based on phantom measurements. On the basis of these results, only tumors larger than 2.2 cm in diameter at any time during the treatment were included for analysis. To further decrease the effect of partial-volume effect, a subgroup of tumors (>4.0 cm) was analyzed separately. Tumor response was evaluated by CT using Response Evaluation Criteria In Solid Tumors. RESULTS:Tumor-absorbed doses until best response ranged approximately from 10 to 340 Gy. A 2-parameter sigmoid fit was fitted to the data, and a significant correlation between the absorbed dose and tumor reduction was found, with a Pearson correlation coefficient (R(2)) of 0.64 for tumors larger than 2.2 cm and 0.91 for the subgroup of tumors larger than 4.0 cm. The largest tumor reduction was 57% after a total absorbed dose of 170 Gy. CONCLUSION:The results imply a significant correlation between absorbed dose and tumor reduction. However, further studies are necessary to address the large variations in response for similar absorbed doses.

In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27-1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89-4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 - not reached) with pasireotide versus 6.8 months (5.6 - not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20-0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR.

Published online: December 30, 2013. 2014;55:204-210. J Nucl Med. Lundqvist, Dan Granberg and Barbro Eriksson Irina Velikyan, Anders Sundin, Jens Sörensen, Mark Lubberink, Mattias Sandström, Ulrike Garske-Román, Hans Ga-DOTATATE: Net Uptake Rate for Accurate Quantification 68 Ga-DOTATOC and 68 Quantitative and Qualitative Intrapatient Comparison of http://jnm.snmjournals.org/content/55/2/204 This article and updated information are available at: http://jnm.snmjournals.org/site/subscriptions/online.xhtml Information about subscriptions to JNM can be found at: http://jnm.snmjournals.org/site/misc/permission.xhtml Information about reproducing figures, tables, or other portions of this article can be found online at:

A Multicenter, Randomized, Blinded, Phase 3 Study of Pasireotide LAR vs Octreotide LAR in Patients with Metastatic Neuroendocrine Tumors (NET) with Disease-Related Symptoms Inadequately Controlled by Somatostatin Analogs

Comparison of [68Ga]-DOTA-TOC and [68Ga]-DOTA-TATE : Aspects on quantification in neuroendocrine tumour therapy monitoring

Introduction: Insulinoma is the most common form of pancreatic endocrine tumors responsible for hyperinsulinism in adults. These tumors overexpress glucagon like peptide-1 (GLP-1) receptor, and biologically stable GLP-1 analogs have therefore been proposed as potential imaging agents. Here, we evaluate the potential of a positron emission tomography (PET) tracer, [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4, for imaging and quantification of GLP-1 receptors (GLP-1R) in insulinoma.Methods: [68Ga]Ga-DO3A-VS-Cys40-Exendin-4 was evaluated for binding to GLP-1R by in vitro autoradiography binding studies in INS-1 tumor from xenografts. In vivo biodistribution was investigated in healthy control mice, INS-1 xenografted and PANC1 xenografted immunodeficient mice at two different doses of peptide: 2.5 mu g/kg (baseline) and 100 mu g/kg (block). In vivo imaging of [68Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 in xenografted mice was evaluated by small animal PET/CT using a direct comparison with the clinically established insulinoma marker [C-11]5-hydroxy-tryptophan ([C-11]5-HTP).Results: GLP-1 receptor density could be quantified in INS-1 tumor biopsies. [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4 showed significant uptake (p <= 0.05) in GLP1-R positive tissues such as INS-1 tumor, lungs and pancreas upon comparison between baseline and blocking studies. In vivo imaging showed concordant results with higher tumor-to-muscle ratio in INS-1 xenografted mice compared with [C-11]5-HTP.Conclusion: [Ga-68]Ga-DO3A-VS-Cys(40)-Exendin-4 has high affinity and specificity for GLP-1R expressed on insulinoma in vitro and in vivo. (C) 2014 Elsevier Inc. All rights reserved.

Quantitative imaging and dosimetry are crucial for individualized treatment during peptide receptor radionuclide therapy (PRRT). 177Lu-DOTATATE and 68Ga-DOTATOC/68Ga-DOTATATE are used, respectively, for PRRT and PET examinations targeting somatostatin receptors (SSTRs) in patients affected by neuroendocrine tumors. The aim of the study was to quantitatively and qualitatively compare the performance of 68Ga-DOTATOC and 68Ga-DOTATATE in the context of subsequent PRRT with 177Lu-DOTATATE under standardized conditions in the same patient as well as to investigate the sufficiency of standardized uptake value (SUV) for estimation of SSTR expression. Methods: Ten patients with metastatic neuroendocrine tumors underwent one 45-min dynamic and 3 whole-body PET/CT examinations at 1, 2, and 3 h after injection with both tracers. The number of detected lesions, SUVs in lesions and normal tissue, total functional tumor volume, and SSTR volume (functional tumor volume multiplied by mean SUV) were investigated for each time point. Net uptake rate (Ki) was calculated according to the Patlak method for 3 tumors per patient. Results: There were no significant differences in lesion count, lesion SUV, Ki, functional tumor volume, or SSTR volume between 68Ga-DOTATOC and 68Ga-DOTATATE at any time point. The detection rate was similar, although with differences for single lesions in occasional patients. For healthy organs, marginally higher uptake of 68Ga-DOTATATE was observed in kidneys, bone marrow, and liver at 1 h. 68Ga-DOTATOC uptake was higher in mediastinal blood pool at the 1-h time point (P = 0.018). The tumor-to-liver ratio was marginally higher for 68Ga-DOTATOC at the 3-h time point (P = 0.037). Blood clearance was fast and similar for both tracers. SUV did not correlate with Ki linearly and achieved saturation for a Ki of greater than 0.2 mL/cm3/min, corresponding to an SUV of more than 25. Conclusion: 68Ga-DOTATOC and 68Ga-DOTATATE are suited equally well for staging and patient selection for PRRT with 177Lu-DOTATATE. However, the slight difference in the healthy organ distribution and excretion may render 68Ga-DOTATATE preferable. SUV did not correlate linearly with Ki and thus may not reflect the SSTR density accurately at its higher values, whereas Ki might be the outcome measure of choice for quantification of SSTR density and assessment of treatment outcome.

Ga-68-labelling of Exendin-4, preclinical evaluation of the resultant tracer for the imaging and quantification of insulinomas, and case patient examination