Incidence and prognostic value of serotonin secretion in pancreatic neuroendocrine tumours.

BACKGROUND: Serotonin secretion occurs in approximately 1%-4% of patients with a pancreatic neuroendocrine tumour (PNET), but the incidence is not well defined. The aim of this study was to determine the incidence of serotonin secretion with and without carcinoid syndrome and the prognostic value for overall survival (OS). METHODS: Data were collected from 255 patients with a PNET if 24-hours urinary 5-hydroxyindoleacetic acid excretion (5-HIAA) was assessed. Patients were diagnosed with serotonin secretion if 24-hours urinary 5-HIAA excretion was more than 3× the upper limit of normal (ULN) of 50 µmol/24 hours during follow-up. The effect of serotonin secretion on OS was estimated with uni- and multivariate analyses using a Cox regression. RESULTS: Two (0.8%) patients were diagnosed with carcinoid syndrome, and another 20 (7.8%) had a serotonin-secreting PNET without symptoms. These patients mostly had ENETS stage IV disease with high chromogranin A (CgA). Serotonin secretion was a negative prognostic factor in univariate analysis (HR 2.2, 95% CI: 1.27-3.81), but in multivariate analysis, only CgA>10× ULN (HR: 1.81, 95% CI: 1.10-2.98) and neuron-specific enolase (NSE) >ULN (HR: 3.51, 95% CI: 2.26-5.46) were predictors for OS. Immunohistochemical staining for serotonin was positive in 28.6% of serotonin-secreting PNETs (one with carcinoid syndrome) and negative in all controls. CONCLUSION: Carcinoid syndrome is rare in patients with a PNET, but serotonin secretion occurs often. This is a negative prognostic factor for OS, but after correction for CgA and NSE, it is no longer a predictor and probably only a "not-so innocent bystander" in patients with high tumour burden.

Sequential Everolimus and Sunitinib Treatment in Pancreatic Metastatic Well-Differentiated Neuroendocrine Tumours Resistant to Prior Treatments.

OBJECTIVE: Alternating treatment with sunitinib and everolimus has been shown to be efficacious in renal cell carcinoma. However, no data currently exist for the role of alternate sequence administration of these agents in well-differentiated pancreatic neuroendocrine tumours (pNETs). METHODS: Thirty-one patients were administered one compound and upon progression were switched to the other. All patients had grade 1 or 2 tumours and stage IV disease with similar metastatic load. The primary end point included estimation of the median overall progression-free survival (mPFS) along with each drug's mPFS as a first-line (mPFS1) and a second-line treatment (mPFS2); tolerability and serious adverse events were also evaluated. Secondary end points included overall survival (OS), 2-year mortality rate, and incidence of disease progression. RESULTS: Overall, mPFS did not differ between the everolimus to sunitinib group (36.5 months) and the sunitinib to everolimus group (31.6 months) with a hazard ratio of 0.94 ([95% CI, 0.45-1.97], p = 0.7). Although mPFS1 after first-line everolimus was longer (16.3 months) compared to sunitinib (9 months), this was not statistically significant (p = 0.15). Sequential second-line treatment showed no difference in the mPFS2 (p = 0.3). No difference in OS between the 2 groups was observed. Tolerability was better for everolimus compared to sunitinib. CONCLUSIONS: Treatment with sequential molecular target agents was well tolerated and associated with similar overall mPFS in both schemes of administration. Larger prospective studies are required to investigate the long-term efficacy and sequence of administration of alternate therapy with molecular targeting agents in metastatic pNETs and their effect on OS.

Is There an Additional Value of Using Somatostatin Receptor Subtype 2a Immunohistochemistry Compared to Somatostatin Receptor Scintigraphy Uptake in Predicting Gastroenteropancreatic Neuroendocrine Tumor Response?

BACKGROUND AND AIMS: It is unknown whether tumoral somatostatin receptor subtype 2a (sst2a) immunohistochemistry (IHC) has additional value compared to somatostatin receptor scintigraphy (SRS) uptake using OctreoScan® in predicting response to peptide receptor radiotherapy using 177Lu-octreotate (PRRT) in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The aims of this study were: (1) to establish the percentage of sst2a immunopositivity in GEP-NET samples of PRRT-treated patients, (2) to determine the relationship between best GEP-NET response using RECIST 1.0 criteria 1 year after PRRT and tumoral sst2a IHC, and (3) to compare characteristics of patients with sst2a IHC-negative and -positive tumors. METHODS: All 73 consecutive patients were selected for PRRT based on a positive SRS. Radiological response was scored according to RECIST 1.0 criteria. sst2a status was detected on tumor samples by IHC. RESULTS: In total, 93% of GEP-NET samples showed sst2a IHC positivity. No statistically significant relationship was observed between in vitro sst2a expression and in vivo best GEP-NET response 1 year after PRRT (p = 0.47). Sex, primary tumor site, disease stage, ENETS TNM classification, Ki-67 index, highest serum chromogranin-A level, and highest neuron-specific enolase level were not significantly different between patients with negative and positive sst2a tumoral IHC with the exception of age at diagnosis (p = 0.007). CONCLUSIONS: sst2a IHC of tumor samples has no additional value compared to SRS uptake using OctreoScan® in predicting tumor response after PRRT.

Effects of Somatostatin Analogs and Dopamine Agonists on Insulin-Like Growth Factor 2-Induced Insulin Receptor Isoform A Activation by Gastroenteropancreatic Neuroendocrine Tumor Cells.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) express insulin-like growth factor (IGF)-related factors [IGF1, IGF2; insulin receptor (IR)-A, IR-B; IGF-binding protein (IGFBP) 1-3] as well as somatostatin (SSTRs) and dopamine D2 receptors (D2Rs). OBJECTIVES: To (1) compare mRNA expression of IGF-related factors in human pancreatic NET (panNET) cell lines with that in human GEP-NETs to evaluate the usefulness of these cells as a model for studying the IGF system in GEP-NETs, (2) determine whether panNET cells produce growth factors that activate IR-A, and (3) investigate whether somatostatin analogs (SSAs) and/or dopamine agonists (DAs) influence the production of these growth factors. METHODS: In panNET cells (BON-1 and QGP-1) and GEP-NETs, mRNA expression of IGF-related factors was measured by quantitative real-time PCR. Effects of the SSAs octreotide and pasireotide (PAS), the DA cabergoline (CAB), and the dopastatin BIM-23A760 (all 100 nM) were evaluated at the IGF2 mRNA and protein level (by ELISA) and regarding IR-A bioactivity (by kinase receptor activation assay) in panNET cells. RESULTS: panNET cells and GEP-NETs had comparable expression profiles of IGF-related factors. Especially in BON-1 cells, IGF2 and IR-A were most highly expressed. PAS + CAB inhibited IGF2 (-29.5 ± 4.9%, p < 0.01) and IGFBP3 (-20.0 ± 4.0%, p < 0.01) mRNA expression in BON-1 cells. In BON-1 cells, IGF2 protein secretion was significantly inhibited with BIM-23A760 (-23.7 ± 3.8%). BON-1- but not QGP-1- conditioned medium stimulated IR-A bioactivity. In BON-1 cells, IR-A bioactivity was inhibited by BIM-23A760 and PAS + CAB (-37.8 ± 2.1% and -30.9 ± 4.1%, respectively, p < 0.0001). CONCLUSIONS: (1) The BON-1 cell line is a representative model for studying the IGF system in GEP-NETs, (2) BON-1 cells produce growth factors (IGF2) activating IR-A, and (3) combined SSTR and D2R targeting with PAS + CAB and BIM-23A760 suppresses IGF2-induced IR-A activation.

The prevalence and relevance of adrenal masses in patients with sporadic gastroenteropancreatic neuroendocrine tumours (GEP-NET).

OBJECTIVE: The widespread application of abdominal computerized tomography (CT) imaging has revealed that 0.98-4.0% of individuals harbour adrenal lesions (incidentalomas). There is, however, paucity of information regarding the prevalence of adrenal lesions in patients with gastroenteropancreatic neuroendocrine tumours (GEP-NETS). Purpose of this study was to estimate the prevalence of adrenal lesions in patients with GEP-NETS and identify their radiological features and clinical significance. DESIGN: The prevalence of adrenal lesions was estimated retrospectively in 438 patients with GEP-NETS who underwent abdominal imaging. Secretory status and changes in size were documented during subsequent follow-up. MEN-1 patients and ectopic ACTH-secreting tumours were excluded. RESULTS: Adrenal lesions were detected in 32 (8.4%) of 383 patients included. The majority (22 patients - 69%) were located at the left adrenal gland and the mean size was 23.6 mm. In two patients, one with a well and another with a poorly differentiated tumour, clinicopathological features suggested adrenal metastases. During a mean follow-up period of 69.5 months, no subsequent growth of any adrenal lesion was observed. Endocrine evaluation documented subclinical glucocorticoid hypersecretion in 4 cases (14%). The presence of adrenal lesions did not correlate to distant metastases, however, they were observed more frequently in patients with G3 tumours. CONCLUSION: The prevalence of adrenal lesions in patients with GEP-NETs was found to be higher than the general population and mostly represent benign adrenal adenomas (except patients with G3 tumours). Nevertheless, individualized assessment of imaging characteristics should be still considered.

Effect of hormone secretory syndromes on neuroendocrine tumor prognosis.

The treatment of hormone hypersecretory syndromes caused by neuroendocrine tumors (NETs) can be a major challenge. NETs originating from the small intestine often secrete serotonin causing flushing, diarrhea and valve fibrosis, leading to dehydration or heart failure in severe cases. NETs from the pancreas can secrete a wider variety of hormones, like insulin, glucagon and gastrin leading to distinct clinical syndromes. Historically mortality in patients with functioning NETs was high due to the complications caused by the hypersecretion of hormones. This has been reduced with several drugs: proton-pump inhibitors decrease acid secretion caused by gastrinomas. Somatostatin analogs can inhibit the secretion of multiple hormones and these are now the cornerstone for treating patients with a gastroenteropancreatic NET. However, peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogs and everolimus can also decrease symptoms of hypersecretion and increase progression-free survival. Several factors affect the survival in patients with a functioning NET. Complications of hypersecretion negatively impact survival; however, secretion of hormones is also often a sign of a well-differentiated NET and due to the symptoms, functioning NETs can be detected in an earlier stage suggesting a positive effect on prognosis. The effect on survival is also dependent on the type of hormone being secreted. This review aims to study the effect of hormone secretion on the prognosis of NETs with the contemporary treatments options available today.

Limited value for urinary 5-HIAA excretion as prognostic marker in gastrointestinal neuroendocrine tumours.

OBJECTIVE: To determine if urinary 5-hydroxyindoleacetic acid (5-HIAA) excretion is of prognostic value for overall survival (OS) in patients with a gastrointestinal neuroendocrine tumour (NET) and to compare the prognostic value with patient characteristics, ENETS/WHO grading, ENETS TNM staging and biomarkers. DESIGN AND METHODS: Data was collected from patients with a gastrointestinal NET or a NET with gastrointestinal metastases and available 5-HIAA excretion in 24-h urine samples. Laboratory results were stratified for urinary 5-HIAA and chromogranin A (CgA): <2× upper limit of normal (ULN), 2-10× ULN, or >10× ULN. For neuron-specific enolase (NSE), this was the reference range or >1× ULN. OS was compared using Kaplan-Meier and log-rank tests, and hazard ratios were calculated using Cox regression for univariate and multivariate analyses. RESULTS: A total of 371 patients were included, 46.6% female with a mean age of 59.9 years. OS was shortest in patients with urinary 5-HIAA excretion >10× ULN vs reference range (median 83 months vs 141 months, P = 0.002). In univariate analysis, urinary 5-HIAA excretion >10× ULN was a negative predictor (HR 1.62, 95% CI: 1.09-2.39). However, in multivariate analysis, only age (HR 1.04, 95% CI: 1.01-1.08), grade 3 disease (HR 5.09, 95% CI: 2.20-11.79), NSE >1× ULN (HR 2.36, 95% CI: 1.34-4.14) and CgA >10× ULN (HR 3.61, 95% CI: 1.56-8.34) remained as the predictors. CONCLUSION: Urinary 5-HIAA excretion >10× ULN is a negative predictor for OS. However, when added to other biomarkers and grading, it is no longer a predictor for OS. Therefore, it should only be determined to assess carcinoid syndrome and not for prognostic value.

Parathyroid hormone-related peptide (PTHrP) secretion by gastroenteropancreatic neuroendocrine tumors (GEP-NETs): clinical features, diagnosis, management, and follow-up.

CONTEXT: Only a small number of case reports has been published on patients with PTHrP-hypersecreting metastatic gastroenteropancreatic (GEP) neuroendocrine tumors (NETs). OBJECTIVE: The objective of this study was to evaluate the clinical, biochemical, and radiological features, management, and treatment outcome of patients with PTHrP-hypersecreting GEP-NETs. DESIGN: Retrospective case series. SETTING: Tertiary referral hospital. MAIN OUTCOME MEASURES: Clinical, biochemical, and radiological features were measured, as well as response to therapy and survival. PATIENTS: Ten patients with PTHrP-secreting GEP-NETs (nine pancreatic and one unknown primary) with a median age of 50.4 years (range, 38.3-61.1) were studied. Multiple endocrine neoplasia type 1 patients were excluded. RESULTS: The median follow-up was 57.2 months (range, 11.6-204.5 mo). Median overall survival was 86.0 months. In total, 51 different treatment interventions and combinations were applied. In seven of the 10 patients, somatostatin analog (SSA) treatment resulted in a temporary normalization of serum calcium levels with a long-term response observed in two patients (up to 35.2 mo). Peptide receptor radiotherapy (PRRT) with radiolabeled SSAs induced long-term responses ranging from 9.0-49.0 months in four of six patients treated with PRRT. CONCLUSIONS: Hypersecretion of PTHrP by metastatic GEP-NETs is very rare and seems to be exclusively associated with metastatic pancreatic NETs. PTHrP production has major clinical impact because poorly controllable hypercalcemia is associated with increased morbidity and mortality. The most successful treatment options for PTHrP-producing GEP-NETs are SSAs and PRRT using radiolabeled SSAs. Isotonic saline and bisphosphonates can be considered as supportive therapies.

Safety and efficacy of everolimus in gastrointestinal and pancreatic neuroendocrine tumors after (177)Lu-octreotate.

Although (177)Lu-octreotate is an effective treatment for patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs), some patients will fail or develop disease progression necessitating further treatment. We examined whether the safety and efficacy of everolimus after prior treatment with (177)Lu-octreotate is different from the published safety profile of everolimus in GEP-NETs. In this multicenter study, 24 GEP-NET patients were included. Adverse events were assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Tumor response was measured according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.0. Major clinical adverse events (grade 3 or 4) during treatment with everolimus were hyperglycemia (20.8%), fatigue (8.3%), thrombocytopenia (8.3%), and elevated alanine transaminase levels (8.3%). By radiological review, there were four partial responses (16.7%), five patients (62.5%) with stable disease, and three patients (12.5%) with progressive disease. For two patients (8.3%), no data on tumor response were available. Median progression-free survival (PFS) was 13.1 months (95% CI, 11.5-21.2). Median PFS of the current study was longer when compared with the RADIANT-3 trial (13.1 vs 11.4 months) and shorter when compared with the RADIANT-1 trial (13.1 vs 16.7 months). In conclusion, the safety profile of everolimus is not influenced by previous treatment with peptide receptor radiotherapy.

Occurrence of second primary malignancies in patients with neuroendocrine tumors of the digestive tract and pancreas.

An increased association between neuroendocrine tumors of the gastrointestinal tract and pancreas (GEP-NET) and other second primary malignancies has been suggested. We determined whether there is indeed an increased risk for second primary malignancies in GEP-NET patients compared with an age- and sex-matched control group of patients with identical malignancies. The series comprised 243 men and 216 women, diagnosed with a GEP-NET between 2000 and 2009 in a tertiary referral center. The timeline, before-at-after diagnosis, and the type of other malignancies were studied using person-year methodology. Poisson distributions were used for testing statistical significance. All data were cross-checked with the Dutch National Cancer Registry. Out of 459 patients with GEP-NET, 67 (13.7%) had a second primary cancer diagnosis: 25 previous cancers (5.4%), 13 synchronous cancers (2.8%), and 29 metachronous cancers (6.3%). The most common types of second primary cancer were breast cancer (n=10), colorectal cancer (n=8), melanoma (n=6), and prostate cancer (n=5). The number of patients with a cancer history was lower than expected, although not significant (n=25 vs n=34.5). The diagnosis of synchronous cancers, mainly colorectal tumors, was higher than expected (n=13 vs n=6.1, P<0.05). Metachronous tumors occurred as frequent as expected (n=29 vs n=25.2, NS). In conclusion, our results are in contrast to previous studies and demonstrate that only the occurrence of synchronous second primary malignancies, mainly colorectal cancers, is increased in GEP-NET patients compared with the general population.