Metastatic NET Research Articles

PWE-160 Interferon Alpha Therapy for Metastatic Neuroendocrine Tumours: A Retrospective Study

IntroductionInterferon alpha has been used in the management of NETs for over 20 years. It has generally not been popular due to perceived lack of efficacy and due to toxicity...

Placebo controlled, double blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors (PROMID): Results on long-term survival.

4030 Background: Octreotide LAR (O) compared to placebo (P) lengthens significantly time to tumor progression (TTP) in patients with metastatic midgut neuroendocrine tumors (Rinke et al. 2009). The antiproliferative response was more pronounced in patients with low (≤ 10%) hepatic tumor load (HL). To investigate whether this beneficial effect also affects overall survival (OS), patients included in the PROMID trial were followed until January 2013 at least once a year. Methods: Between July 2001 and January 2008, 42 and 43 patients were randomly assigned to receive O or P. Post study treatment was at the discretion of the local investigator. Data on cause of death and on post study treatment were documented. OS was analyzed using the Kaplan-Meier method. Treatment groups (O vs. P; HL at study entry ≤ 10% vs. >10%) were compared using the log rank test and hazard ratios were estimated with the use of the Cox proportional hazards model. Results: 41 of 85 patients died until January 2013. 19 in the octreotide and 22 in the placebo arm. Median OS for all 85 patients was 85 months, “not reached” in the O arm and 84 months in the P arm (p=0.59, HR=0.85 [CI 0.46; 1.56]). Cause of death was unrelated to the tumor disease in 8 patients. 26 of 64 patients (10 in the O vs. 16 in the P arm) died in the HL ≤ 10% subgroup and 15 of 21 patients (9 in the O vs. 6 in the P arm) in the HL > 10 % (p=0.002, HR=2.7). Median OS in the HL ≤ 10% subgroup was “not reached” (octreotide) vs 80.5 months (placebo) (p=0.14, HR=0.56 [CI 0.25; 1.23]). In the HL > 10% subgroup the respective numbers were 35 vs. 84 months (p=0.14, HR=2.18 [CI 0.75; 6.33]). Post study treatment in the O and P groups included octreotide LAR (29 vs. 38 patients), hepatic CHE (5 vs. 12 patients), PRRT (13 vs. 13 patients) and CHT (4 vs. 5 patients). Conclusions: Octreotide LAR not only prolongs TTP but also extends OS in the subgroup of patients with metastatic midgut NETs and a low HL (≤ 10% at study entry) but not in the high (HL > 10%) subgroup. Almost all patients who were randomized at study entry in the P group received octreotide LAR after disease progression, but these experienced a less favourable OS in the low HL subgroup. Clinical trial information: NCT00171873.

Surgery for metastatic neuroendocrine tumors with occult primaries

IntroductionNeuroendocrine tumors (NETs) frequently metastasize prior to diagnosis. Although metastases are often identifiable on conventional imaging studies, primary tumors, particularly those in the midgut, are frequently difficult to localize preoperatively. Materials and methodsPatients with metastatic NETs with intact primaries were identified. Clinical and pathologic data were extracted from medical records. Primary tumors were classified as localized or occult based on preoperative imaging. The sensitivities and specificities of preoperative imaging modalities for identifying the primary tumors were calculated. Patient characteristics, tumor features, and survival in localized and occult cases were compared. ResultsSixty-one patients with an intact primary tumor and metastatic disease were identified. In 28 of these patients (46%), the primary tumor could not be localized preoperatively. A median of three different preoperative imaging studies were utilized. Patients with occult primaries were more likely to have a delay (>6 mo) in surgical referral from time of onset of symptoms (57% versus 27%, P = 0.02). Among the 28 patients with occult primary tumors, 18 (64%) were found to have radiographic evidence of mesenteric lymphadenopathy corresponding, in all but one case, to a small bowel primary. In all but three patients (89%), the primary tumor could be identified intraoperatively. ConclusionThe primary tumor can be identified intraoperatively in a majority of patients with metastatic NETs, irrespective of preoperative localization status. Referral for surgical management should not, therefore, be influenced by the inability to localize the primary tumor.

1157O - Pazonet: A Phase II Trial of Pazopanib as a Sequencing Treatment in Progressive Metastatic Neuroendocrine Tumors (NETS) Patients (PTS), On Behalf of The Spanish Task Force for Nets (GETNE)

ABSTRACT Background Pazopanib is an oral tyrosine kinase inhibitor of the VEGFR, PDGFR and KIT with demonstrated clinical activity in NETs. The aims of our study were to assess efficacy, safety and potential predictive biomarkers of pazopanib in pts with NETs who may have received previous antiangiogenic or mTOR inhibitor treatment. Methods All pts had pancreatic or extra-pancreatic metastatic NET disease documented as progressive. Pazopanib 800 mg was given daily until disease progression (DP) or unacceptable toxicity. Primary endpoint was Clinical Benefit Rate (CBR) at 6 months (m) defined as Complete Response (CR) plus Partial Response (PR) plus Stable Disease (SD) by RECIST-V-1.0. Optimal two-stage Simon design was utilized with H1 and H0 set at 70 % and 50 % respectively, Kaplan-Meier estimates were used for the analysis of time-to-event variables: 95% CI. Results 41 evaluable pts for response per protocol. 53.7% males, mean age 59.2 ± 10.3 years. At 6 months, 3 pts had PR (7.36%), 32 SD (78.0%), and 6 DP (14.6%), thus the CBR was 85.4%. Global median PFS 48,3 (13.9-82.7) weeks (w). By subgroups, CBR at 6 m and median PFS were 100% and 25.7 w in pts with no previous targeted therapy (9 pts), 88.9% and 48.3 w in pts with previous mTOR inhibitors (9 pts), 83.3% and 50.3 w in pts with previous antiangiogenics (16 pts) and 71.4% and 20.6 w in pts with previous antiangiogenics and mTOR inhibitors (7 pts) respectively. The sum of the longest diameter of target lesions had a decrease > 10% in 32.5 % of pts (37.5% without previous biological treatment, 22.2 % with previous mTOR inhibitor, 31.3% with prior multitarget inhibitor, and 42.9% with previous multitarget and mTOR, p = 0.506). Most frequent toxicities at of any grade were: asthenia (75%), diarrhoea (63%), nausea (42%). Translational studies on angiogenesis and inmunohistochemistry biomarkers and CTCs are ongoing. Conclusions Pazopanib 800 mg daily has promising activity in advanced NET regardless of previous treatment with other targeted therapies. This trial suggests the role that treatment sequencing with novel targeted agents may have in NETs. Disclosure All authors have declared no conflicts of interest.

A multi-institutional phase II open-label study of AMG 479 in advanced carcinoid and pancreatic neuroendocrine tumors.

4125 Background: The IGF pathway is thought play an important role in neuroendocrine tumor progression. We therefore investigated AMG 479, a human monocolonal antibody against IGF1-R, in patients with metastatic progressive carcinoid and pancreatic neuroendocrine tumors (NETS). Methods: This open-label phase II study enrolled patients (≥18 yrs) with metastatic low and intermediate-grade carcinoid and pancreatic NETs. Key inclusion criteria included evidence of progressive disease (by RECIST) within 12 months of enrollment, ECOG PS 0-2, and fasting blood sugar <160mg/dL. Prior treatments were allowed, and concurrent somatostatin analog therapy was permitted as long as patients remained on a stable dose. The primary endpoint was objective response rate. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Results: 60 patients (30 carcinoid, 30 pancreatic NET) were treated with AMG 479 18mg/kg every 3 weeks and 54 patients were evaluable for response. There were no objective responders by RECIST. When best response to therapy was evaluated, 10/27 (37%) evaluable carcinoid patients and 8/26 (31%) evaluable pancreatic NET patients experienced 1-29% tumor shrinkage, while 17/27 (63%) of the carcinoid patients and 15/26 (58%) of the pancreatic NET patients appeared to experience continued tumor growth. Median PFS was 6.3 months (95% CI 4.2-12.6) for the entire cohort; 10.5 months for carcinoid patients and 4.2 months for pancreatic NET patients. The OS rate at 12 months was 70% (55%-81%) for the entire cohort. Median OS has not been reached. Treatment related grade 3/4 AEs were rare and consisted of hyperglycemia (4%), neutropenia (4%), thrombocytopenia (4%) and infusion reaction (1%). Conclusions: While well-tolerated, single-agent AMG 479 was not found to result in major tumor responses among patients with metastatic low-intermediate grade carcinoid or pancreatic NET. Subgroup analysis to identify characteristics of patients who may have benefited from therapy with AMG 479 is ongoing.

Whole body diffusion for metastatic disease assessment in neuroendocrine carcinomas: comparison with OctreoScan® in two cases

Neuroendocrine tumor (NET) patients must be adequately staged in order to improve a multidisciplinary approach and optimal management for metastatic disease. Currently available imaging studies include somatostatin receptor scintigraphy, like OctreoScan®, computed tomography (CT), scans and magnetic resonance imaging (MRI), which analyze vascular concentration and intravenous contrast enhancement for anatomic tumor localization. However, these techniques require high degree of expertise for interpretation and are limited by their availability, cost, reproducibility, and follow-up imaging comparisons. NETs significantly reduce water diffusion as compared to normal tissue. Diffusion-weighted imaging (DWI) in MRI has an advantageous contrast difference: the tumor is represented with high signal over a black normal surrounding background. The whole-body diffusion (WBD) technique has been suggested to be a useful test for detecting metastasis from various anatomic sites. In this article we report the use of DWI in MRI and WBD in two cases of metastatic pulmonary NET staging in comparison with OctreoScan® in order to illustrate the potential advantage of DWI and WBD in staging NETs.

Metastasis of neuroendocrine tumors are characterized by increased cell proliferation and reduced expression of the ATM gene.

PurposeGastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare group of tumors with a wide spectrum of clinical behavior. However, there are no known clinically relevant biomarkers to predict metastasis.Experimental DesignTo investigate differential gene expression signatures of metastatic vs non-metastatic NETs, we studied cell cycle regulatory genes in 19 metastatic and 22 non-metastatic colorectal NETs by PCR arrays. Immunohistochemistry (IHC) and quantitative real-time RT-PCR were performed to verify the results and another set of 38 GEP-NETs were further studied for validation.ResultsWe first delineated six candidate genes for metastasis including ATM, CCND2, RBL2, CDKN3, CCNB1, and GTSE1. ATM was negatively correlated with metastatic NETs (p<0.001) with more than 2-fold change compared to non-metastatic NETs. Overexpression of ATM protein by IHC was strongly correlated with high ATM mRNA levels and low Ki-67 labeling index. Patients with ATM-negativity by IHC showed significantly decreased overall survival than patients with ATM-positivity (median OS, metastatic vs non-metastatic NETs; 2.7 years vs not reached; p = 0.003) and 85.7% of metastatic NETs were ATM-negative. In another validation set of GEP-NETs, decreased mRNA of ATM gene was associated with metastasis and remained significant (p = 0.023).ConclusionsATM down-regulation was strongly associated with metastatic NETs when compared with non-metastatic NETs and ATM may be a potential predictive marker for metastasis as well as a novel target in metastatic GEP-NETs.

The efficacy of capecitabine and temozolomide for the treatment of metastatic neuroendocrine tumors: Memorial Sloan-Kettering Cancer Center experience.

363 Background: Emerging literature has suggested the benefit of capecitabine/temozolomide (C/T) therapy in metastatic pancreatic NETs (pNETs) as first line therapy. We conducted a retrospective analysis of the efficacy of (C/T) therapy in all patients with metastatic NETs treated at MSKCC. Methods: Using the electronic pharmacy database, we included all patients’ ≥ 18 years of age who received C/T combination therapy for pNETs between 1/2003-10/2010. Primary endpoint was the overall response rate (ORR). Secondary endpoints included progression-free survival (PFS) and overall survival (OS). Response rates were evaluated by a radiologist using CT scans and per RECIST 1.1. MGMT tumor expression was conducted to correlate with response. Results: Twenty patients (mean age 64, 35% female) were identified. There were 16 (80%) pNETs (1 functional, 15 nonfunctional), 2 (10%) carcinoid, 1 high grade biliary (5%) and 1 (5%) gastric neuroendocrine carcinoma. Eight tumors were low grade (1 carcinoid, 7 pNET), 8 intermediate grade (7 pNET, 1 carcinoid), and 4 high grade (2 pNET, 1 stomach, 1 biliary). Twelve (60%) received C/T in the first-line setting and 8 in the relapsed setting. Six (30%) had a partial response and 7 (35%) had stable disease. There were no complete responses ( Table 1 ). With a median follow-up of approximately 3 years, the PFS was 16.4 months. Four pNET patients had unresectable disease at presentation and 2/4 were resected and rendered free of disease after C/T therapy. There were no high grade responders. Liver tumor burden (0%, &lt;10%, 10-50%, &gt;50%), number of prior treatments, and tumor grade did not predict response. Grade 3-4 events potentially related to C/T included neutropenia (1/20, 5%), nausea (3/20 15%), diarrhea (1/20, 5%), and fatigue (3/20, 15%). Conclusions: Combination C/T for the treatment of pNETs is an effective regimen for well differentiated NETs irrespective of tumor burden and prior treatment. No responses were seen in our carcinoid patients. MGMT expression will be presented at the meeting. [Table: see text]

Treatment upon Metastatic Pancreatic Nets: Does Chemotherapy Still Play a Role in the Area of Targeting Treatment?

Treatment upon metastatic pancreatic Nets : Does cheomotherapy still paly a role in the area of targeted treatment?

Clinical Significance of Protein Expression of Cyclooxygenase-2 and Somatostatin Receptors in Gastroenteropancreatic Neuroendocrine Tumors

PurposeThis study was undertaken to evaluate the significance of cyclooxygenase-2 (COX2) overexpression and the expression of somatostatin receptor (SSTR) subtypes in gastroenteropancreatic neuroendocrine tumors (GEP-NETs).Materials and MethodsTwo hundred and forty-seven cases of GEP-NET, comprising 86 foregut and 156 hindgut primary NETs, and 5 metastatic NETs in the liver, were studied retrospectively with immunohistochemistry for COX2, chromogranin A, Ki-67, SSTR1, SSTR2, and SSTR5.ResultsCOX2 overexpression was observed in 54%(126 of 234), and SSTR1, SSTR2, and SSTR5 positivity in 84%(196 of 233), 72%(168 of 233), and 55%(128 of 232), respectively. COX2 overexpression was found to be positively correlated with Ki-67 labeling index and inversely correlated with the expression of SSTR subtypes. In addition, the expression of SSTR subtypes was tightly correlated in any comparative pairs. A significant inverse correlation was found between COX2 and SSTR2 expression in the foregut, but not hindgut NETs. Kaplan-Meier analyses showed that COX2 overexpression (p=0.003) and high Ki-67 labeling index (p<0.001) were associated with poor overall survival (OS), whereas expression of SSTR2 (p<0.001) was associated with better OS of GEP-NET patients. Multivariate analysis revealed negative SSTR2 expression as an independent prognostic marker in GEP-NET patients (p<0.001).ConclusionOur results suggest that expression of SSTR subtypes is associated with favorable prognosis, whereas COX2 overexpression is associated with poor prognosis in GEP-NETs. Taken together, COX2 could be a possible therapeutic target in some subsets of GEP-NETs.

Time to tumor progession (TTP) of patients with octreotide-positive metastatic low-grade well-differentiated gastrointestinal neuroendocrine tumors (GEPNETs).

e14516 Background: Defining prognosis in our patients with metastatic well-differentiated NETs poses a significant challenge because of tumor heterogeneity and varying degree of aggressiveness. Somatostatin scintigraphy (herein Octreoscan) positive disease and histologic grade (defined by Ki-67 or mitotic rate) are 2 predictors that could be used to determine prognosis. We sought to measure TTP of newly diagnosed well differentiated low grade Octreoscan positive GEPNETs at the time of diagnosis with liver metastases. Methods: Computerized medical records identified patients who underwent an Octreoscan SPECT-CT (2007-2010). Octreoscans and CT or MRI were reviewed by a radiologist at the time of diagnosis. TTP was defined by RECIST version 1.1. Pathology slides (11 metastatic sites,1 terminal ileum) were reviewed by a pathologist. Well differentiated intermediate grade and high grade NEC were excluded. Clinical records were reviewed as indicated. Patients without liver metastases, with insufficient follow-up, who underwent surgery or embolization prior to disease progression, or had insufficient pathology were excluded. All enrolled patients were started on octreotide therapy alone at the time of diagnosis. Results: Twelve eligible patients were identified: 8 pNET, 4 small bowel. With a median follow-up of approximately 3 years, median TTP was 16.8 months with 95% CI 5.9 to infinity. The wide TTP range was irrespective of organ of origin or clinical features (i.e. tumor burden, functional tumor). Four patients had a TTP < 6 months and 2/4 died within 3 years of their diagnosis. 5/12 had a TTP ≥ 1 year, 1 of which died 5 years after diagnosis. 3/12 patients have not yet reached TTP. Conclusions: Generally, low grade well differentiated octreotide positive NETs follow an indolent course, however, clinical behavior can be heterogeneous irrespective of treatment. Undersampling of the tumor may be one reason to explain the discrepancy. Reliable genomic clinical or other radiographic predictors could provide significant advancements in prognosis and, possibly, treatment.

Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE)

BackgroundNeuroendocrine tumors (NETs) are an unusual family of neoplasms with a wide and complex spectrum of clinical behavior. Here, we present the first report of a National Cancer Registry of gastroenteropancreatic neuroendocrine tumors from a Southern European country. Patients and methodsData was provided online at www.retegep.net by participating centers and assessed for internal consistency by external independent reviewers. ResultsThe study cohort comprised 907 tumors. The most common tumor types were carcinoids (55%), pancreatic nonfunctional tumors (20%), metastatic NETs of unknown primary (9%), insulinomas (8%) and gastrinomas (4%). Forty-four percent presented with distant disease at diagnosis, most often those from small intestine (65%), colon (48%), rectum (40%) and pancreas (38%), being most unusual in appendix primaries (1.3%). Stage at diagnosis varied significantly according to sex, localization of primary tumor, tumor type and grade. Overall 5-year survival was 75.4% (95% confidence interval 71.3% to 79.5%) and was significantly greater in women, younger patients and patients with hormonal syndrome and early stage or lower grade tumors. Prognosis also differed according to tumor type and primary tumor site. However, stage and Ki-67 index were the only independent predictors for survival. ConclusionThis national database reveals relevant information regarding epidemiology, current clinical practices and prognosis of NETs in Spain, providing valuable insights that may contribute to understand regional disparities in the incidence, patterns of care and survival of this heterogeneous disease across different continents and countries.

A Case of Ectopic Adrenocorticotropic Hormone-producing Pancreatic Neuroendocrine Tumor with Multiple Liver Metastases

Ectopic adrenocorticotropic hormone (ACTH) production by the pancreatic neuroendocrine tumor (p-NET) is relatively rare, and patients with this tumor show poor prognosis. In this study, we present the case of a 64-year-old woman who presented with ectopic ACTH syndrome due to p-NET with multiple liver metastases. Computed tomography revealed that she had multiple masses in the liver and a solid mass in the head of the pancreas. Endocrinological examinations revealed markedly elevated plasma ACTH (735.0 pg/mL) and cortisol (34.7 microg/dL) levels associated with hypokalemia (2.7 mEq/L), diabetes and typical Cushingoid features. Histological examinations by needle biopsy of liver tumors in S5 and S8 indicated metastatic ACTH-producing NET, which was also confirmed by venous sampling. The metastatic live tumor was somatostatin receptor (SSTR)-2a- and SSTR-5-positive as revealed by immunohistochemical staining, and reverse transcription polymerase chain reaction revealed divergent expression patterns of SSTRs, pro-opiomelanocortin, and gastrin mRNA. To avoid complications of hypercortisolemia, metyrapone was first administered to reduce the cortisol levels. After near-normalization of cortisol levels, transarterial chemoembolization and somatostatin analogue treatment were performed. The combination of these treatments effectively decreased ACTH and cortisol levels and also ameliorated hyperglycemia. We have achieved controlled hormone secretion and prevented tumor growth in this patient for more than 20 months, suggesting that highly individualized treatment for NET should be undertaken because of its divergent and heterogeneous characteristics.

Molecular imaging of PET/CT with Ga-68 DOTATOC and F-18 FDG in the detection of neuroendocrine gastroenteropancreatic tumors (GEP NETs)

Aim: Functional imaging methods, such as somatostatin-receptor (SSR) scintigraphy in combination with anatomical techniques like CT can be regarded as advanced and elegant molecular imaging procedures enabling mapping of SSRs in GEP NETs. The SSR status of GEP NETs is of great relevance, because receptor-negative lesions may be poorly differentiated and characterised by aggressive growth and poor prognosis – with consequences for the choice of therapy. Ga-68 DOTA-D-Phe(1)-Tyr(3)-octreoide (Ga-68 DOTATOC) is a newly developed PET-radiotracer with a high specific binding to SSR2, a subtype of SSRs, most often expressed in GEP NETs. F-18 FDG is routinely applied in the work-up of malignant tumors and is of particular interest in the assessment of poorly differentiated tumors. This study compares the clinical performance of both PET-tracers in detecting SSR2-positive GEP-NETs. Material and Methods: Forty patients with metastatic GEP NETs were enrolled in this study. Both imaging methods were applied to each patient – in a time distance of less than 2 weecks (GE Discovery LS PET/CT: 360 MBq F-18 FDG, Scan: 1h p.i.; 100 MBq Ga-68 DOTATOC, Scan: 40 Min. p.i.). F-18 FDG and Ga-68 DOTATOC were compared with respect to tumor uptake differences. Results: In 34 patients, the uptake of Ga-68 DOTATOC was significantly higher than that of F-18 FDG (which was weak to zero); only two patients showed higher F-18 FDG accumu-lation compared to Ga-68 DOTATOC. GEP NETs with a high grade of differentiation tend to show high Ga-68 DOTATOC uptake and low F-18 FDG uptake, whereas in poorly differentiated GEP NETS the uptake of Ga-68 DOTATOC was significantly lower than that of F-18 FDG. In 4 patients we could demonstrate a mosaic pattern of tracer uptake: lesions with high Ga-68 DOTATOC and low F-18 FDG uptake neighboured by lesions having a reversed uptake picture, i.e. high F-18 FDG and low Ga-68 DOTATOC uptake. This phenomenon points to the possibility of different grades of differentiation within metastases of the same patient. Conclusion: Ga-68 DOTATOC- and F-18 FDG-PET/CT together could be an ideal tool to characterise the grade of differentiation of GEP NETs and their metastases, thus providing the most adequate choice of therapy for each patient.

Efficacy and safety of use of somatostatin (SS) analogues in metastatic neuroendocrine tumours

15641 Background: Malignant neuroendocrine gastroenteropancreatic tumours (GEP) showed a 5-year survival rate of 20%. It has been described that in about 50% of the patients with metastatic or locally advanced NETs, SS analogues therapy result in disease stabilization. The risk of developing gallstones in patients undergoing SS analogs approaches 50%, nevertheless only <1% of patients require cholecystectomy. We analysed caracteristics, clinical outcome and toxicity, of patients with progressive metastatic NET undergoing SS analogues therapy. Methods: Twenty six evaluable patients, not previously treated, identified between 2004 and 2007, classified as metastatic NETs, were given long-acting SS analogues (octreotide 30 mg: n=27; lanreotide gel: n=2 every 28 days) until evidence of disease progression. Mean age: 69 (51–94), 14 men, 8 NET were identified has hormone producing tumours. The primary tumour was determined in 19 patients: 8-pancreatic, 2-gastric, 1-bronchial and 8-midgut. As concerns to sites of metastases: 17 patients had liver metastases only, 2-lung, 2-liver and lymph node, 1-liver and bone; 1- mesentery, 1-mediastinum, and 1-liver, mesentery and mediastinum. Octreoscan was positive in 17 patients. The treatment activity was evaluated by objective response with CT scans according RECIST criteria. Safety and tolerability were also assessed. Results: The mean time on SS analogues therapy was 19 months (2–61). Three partial objective tumour responses were obtained (5, 12 and 36 month duration); disease stabilization over 3 months (3–61 months) was achieved in 16 patients (64%); progressive disease was observed in 6 patients (one patient died 5 months after diagnosis). Among the patients that achieved partial response all had ki67 index<10%. In all functioning tumours symptomatic and biochemical response was observed. In respect to toxicity, 12% (n=3) of patients had gallbladder stones development, one with cholecystitis. All patients were in SS analogues therapy for > 3 months (6, 59, 61 months respectively). Conclusions: Long-acting SS analogues were seen to be effective in controlling the disease and were well tolerated. The main adverse event was gallblader stones development, that seems to be related with duration of SS analogues therapy. No significant financial relationships to disclose.