Publications by authors named "Dieter Hörsch"

36 Publications

Time to Sustained Improvement in Bowel Movement Frequency with Telotristat Ethyl: Analyses of Phase III Studies in Carcinoid Syndrome.

J Gastrointest Cancer 2021 Mar;52(1):212-221

Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin, Berlin, Germany.

Background: Telotristat ethyl is approved to treat carcinoid syndrome diarrhea in combination with somatostatin analogs. In TELESTAR and TELECAST phase III studies, patients with carcinoid syndrome received telotristat ethyl 250 or 500 mg 3 times per day (tid) or placebo tid in addition to somatostatin analogs. The aim of this prespecified analysis was to examine the time to reductions in bowel movements (BMs) in the TELESTAR and TELECAST studies using survival analysis methods.

Methods: First occurrence of sustained response was defined as the time to the first day of 2 consecutive weeks with a mean BM frequency improvement of ≥ 30% from baseline during the 12-week double-blind treatment periods. Time to first ≥ 30% worsening in BM frequency was also measured. Treatments were compared with the log-rank test; Cox regression models provided point and confidence interval estimates of the hazard ratios for each trial.

Results: In TELESTAR and TELECAST, majority of patients (69%) on telotristat ethyl experienced a sustained ≥ 30% improvement in BM frequency. The median time to sustained reduction of at least 30% in BM frequency was significantly faster (fewer days to onset) for telotristat ethyl compared with placebo in both TELESTAR (250 mg, HR = 2.3 [95% CI, 1.3-4.1, P = 0.004]; 500 mg, HR = 2.2 [95% CI, 1.2-3.9, P = 0.009]) and TELECAST (250 mg, HR = 3.9 [95% CI, 1.6-11.1, P = 0.003]; 500 mg, HR = 4.2 [95% CI, 1.7-11.7, P = 0.002]). In TELECAST, 42% of patients on placebo experienced sustained worsening in BM frequency compared with 20% on telotristat ethyl; no significant difference was observed in TELESTAR.

Conclusion: The time of onset of sustained BM frequency improvement mean and range are important when considering use of telotristat ethyl in patients with carcinoid syndrome diarrhea. Telotristat ethyl may also reduce sustained worsening in BM frequency.

Trial Registration: ClinicalTrials.gov Identifiers: NCT01677910, NCT02063659.
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http://dx.doi.org/10.1007/s12029-020-00375-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7714089PMC
March 2021

Prior Resection of the Primary Tumor Prolongs Survival After Peptide Receptor Radionuclide Therapy of Advanced Neuroendocrine Neoplasms.

Ann Surg 2019 Mar 1. Epub 2019 Mar 1.

*Department of General and Visceral Surgery, Zentralklinik Bad Berka, Bad Berka, Germany †Department of Gastroenterology/Endocrinology, Zentralklinik Bad Berka, Bad Berka, Germany ‡Theranostics Center for Molecular Radiotherapy and Precision Oncology, Zentralklinik Bad Berka, Bad Berka, Germany §Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.

MINI: The role of resection of primary tumors in patients with advanced neuroendocrine neoplasms is still unclear. We investigated 2 groups of patients treated using peptide receptor radionuclide therapy (PRRT; mean of 4 cycles PRRT) with and without a prior primary tumors resection. Surgical resection resulted in a significantly prolonged overall- and progression-free survival.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0 OBJECTIVE:: The aim of the study was to compare impact on survival after resection of primary tumors (PTs) after peptide receptor radionuclide therapy (PRRT).

Background: PRRT is a highly effective therapeutic option to treat locally advanced or metastatic neuroendocrine neoplasms (NENs).

Methods: We retrospectively analyzed the data of 889 patients with advanced NEN (G1-G3, stage IV) treated with at least 1 cycle of PRRT. In 486 of 889 patients (55%, group 1), PT had been removed before PRRT. Group 2 constituted 403 patients (45%) with no prior PT resection. Progression-free survival was determined by Ga SSTR-PET/CT in all patients applying RECIST and EORTC.

Results: Most patients had their PT in pancreas (n = 335; 38%) and small intestine (n = 284; 32%). Both groups received a mean of 4 cycles of PRRT (P = 0.835) with a mean cumulative administered radioactivity of 21.6 ± 11.7 versus 22.2 ± 11.2 GBq (P = 0.407). Median OS in group 1 was 134.0 months [confidence interval (CI): 118-147], whereas OS in group 2 was 67.0 months (CI: 60-80; hazard ratio 2.79); P < 0.001. Likewise, the median progression-free survival after first PRRT was longer in group 1 with 18.0 (CI: 15-20) months as compared to group 2 with 14.0 (CI: 15-18; hazard ratio 1.21) months; P = 0.012.

Conclusions: A previous resection of the PT before PRRT provides a significant survival benefit in patients with NENs stage IV.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0.
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http://dx.doi.org/10.1097/SLA.0000000000003237DOI Listing
March 2019

Long-Term Safety Experience with Telotristat Ethyl Across Five Clinical Studies in Patients with Carcinoid Syndrome.

Oncologist 2019 08 16;24(8):e662-e670. Epub 2019 Jan 16.

Lexicon Pharmaceuticals, Inc., The Woodlands, Texas, USA

Background: Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome.

Subjects, Materials, And Methods: Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated.

Results: Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4.

Conclusion: Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome.

Implications For Practice: Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal.
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http://dx.doi.org/10.1634/theoncologist.2018-0236DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693702PMC
August 2019

Octreotide SC depot in patients with acromegaly and functioning neuroendocrine tumors: a phase 2, multicenter study.

Cancer Chemother Pharmacol 2019 02 8;83(2):375-385. Epub 2018 Dec 8.

Endocrinology, DiMI and CEBR, University of Genoa, Genoa, Italy.

Purpose: Octreotide SC depot is a novel, ready-to-use formulation administered via a thin needle. In a phase 1 study in healthy volunteers, this formulation provided higher bioavailability of octreotide with faster onset and stronger suppression of IGF-1 in healthy volunteers versus long-acting intramuscular (IM) octreotide. This phase 2 study evaluated the pharmacokinetics, efficacy, and safety of octreotide SC depot in patients with acromegaly and functioning NETs, previously treated with octreotide IM.

Methods: Adult patients with acromegaly or functioning NETs treated for ≥ 2 months with octreotide IM [10/20/30 mg every 4 weeks (q4w)] received the last dose of octreotide IM treatment in study period 0 and were randomized 28 days later to receive octreotide SC depot 10 mg q2w, or 20 mg q4w for 3 months (period 1). The primary objective was to characterize the PK profile of octreotide SC depot after each injection vs PK for octreotide IM (period 0).

Results: Twelve patients were randomized to receive octreotide SC depot 10 mg q2w (acromegaly n = 3; NET n = 1) or 20 mg q4w (acromegaly n = 4; NET n = 4). Plasma levels of octreotide were higher with octreotide SC depot as compared to octreotide IM. Adverse events were reported in 6 and 8 patients during period 0 and period 1, respectively; most common in period 1 were gastrointestinal disorders.

Conclusion: Octreotide SC depot provided higher exposure (AUC) than octreotide IM, maintained biochemical control in patients with acromegaly and symptom control in patients with functioning NETs, and was well tolerated with a safety profile consistent with octreotide IM. CLINICALTRIALS.

Gov Identifier: NCT02299089.
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http://dx.doi.org/10.1007/s00280-018-3734-1DOI Listing
February 2019

Relationship Between Symptoms and Health-related Quality-of-life Benefits in Patients With Carcinoid Syndrome: Post Hoc Analyses From TELESTAR.

Clin Ther 2018 12 24;40(12):2006-2020.e2. Epub 2018 Nov 24.

Dana-Farber Cancer Institute, Boston, MA, USA.

Purpose: Patients with metastatic neuroendocrine tumors and carcinoid syndrome (CS) may experience chronic, recurring symptoms despite somatostatin analogue therapy. Little is known about the relationship between bowel movement (BM) frequency, patient-reported symptoms and health-related quality of life (QoL). Data from the TELESTAR study were used in exploratory, post hoc analyses to understand the relationship between durable reductions in BM frequency, symptom relief, and health-related QoL.

Methods: Patients with metastatic neuroendocrine tumors and CS in the Phase III TELESTAR study were randomized (1:1:1) to receive telotristat ethyl (TE) 250 mg, TE 500 mg, or placebo three times daily (TID) during a 12-week double-blind treatment period (DBTP). All patients received TE 500 mg TID in an open-label extension (OLE) to Week 48. Durable response was predefined. Analyses compared durable responders (DRs) and non-durable responders (NDRs), irrespective of treatment group, at Weeks 12, 24, and 48.

Findings: At the start of the DBTP, 135 patients were randomized, 45 patients each to TE 250 mg, TE 500 mg, and placebo. After the 12-week DBTP, 48 of 135 patients were DRs (TE 250 mg, n = 20; TE 500 mg, n = 19; placebo, n = 9). Of the 115 patients who entered the OLE, 35 were DRs initially randomized to TE 250 mg (n = 18) or 500 mg (n = 17), 29 of whom maintained a durable response throughout the OLE. Of the 71 DBTP-NDRs (inclusive of patients initially randomized to placebo), 28 became OLE-DRs. There were 29 NDRs initially randomized to placebo who entered the OLE, 16 of whom became DRs when switched to TE 500 mg. DRs during the DBTP had greater symptom improvements in the DBTP; these improvements continued over the OLE. DBTP-DRs also maintained more meaningful QoL improvements in EORTC QLQ-C30 global health status, nausea and vomiting, pain, diarrhea, and EORTC QLQ-GINET21 gastrointestinal symptoms over the DBTP and OLE periods than DBTP-NDRs.

Implications: These results suggest that sustained improvements in BM frequency in patients with CS may have multifaceted, long-term effects on a patient's well-being. ClinicalTrials.gov identifiers: NCT01677910.
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http://dx.doi.org/10.1016/j.clinthera.2018.10.008DOI Listing
December 2018

Unmet Needs in Appendiceal Neuroendocrine Neoplasms.

Neuroendocrinology 2019 20;108(1):37-44. Epub 2018 Sep 20.

Department of Pathology, Gustave Roussy Cancer Campus, Villejuif, France.

Appendiceal neuroendocrine neoplasms (ANEN) are mostly discovered coincidentally during appendicectomy and usually have a benign clinical course; thus, appendicectomy alone is considered curative. However, in some cases, a malignant potential is suspected, and therefore additional operations such as completion right hemicolectomy are considered. The existing European Neuroendocrine Tumour Society (ENETS) guidelines provide useful data about epidemiology and prognosis, as well as practical recommendations with regards to the risk factors for a more aggressive disease course and the indications for a secondary operation. However, these guidelines are based on heterogeneous and retrospective studies. Therefore, the evidence does not seem to be robust, and there are still unmet needs in terms of accurate epidemiology and overall prognosis, optimal diagnostic and follow-up strategy, as well as identified risk factors that would indicate a more aggressive surgical approach at the beginning and a more intense follow-up. In this review, we are adopting a critical approach of the ENETS guidelines and published series for ANEN, focusing on the above-noted "grey areas".
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http://dx.doi.org/10.1159/000493894DOI Listing
December 2019

Immunohistochemical Study of Mitosis-regulatory Proteins in Gastroenteropancreatic Neuroendocrine Neoplasms.

Anticancer Res 2018 Jul;38(7):3863-3870

Department of Gastroenterology, Infectious Diseases and Rheumatology, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany.

Background/aim: Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are rare and heterogeneous tumors. Therapeutic targets remain to be identified and apart from the proliferation marker Ki-67, useful prognostic markers are rare. Mitotic proteins, such as forkheadbox protein M1 (FOXM1), survivin and aurora kinases, play a role in GEP-NEN progression. In this study, immunohistochemistry was used to analyze how this protein network is expressed in different subgroups of GEP-NENs and determine potential expression patterns that could be useful as tumor markers.

Materials And Methods: Tumor tissues from 75 patients were studied immunohistochemically with antibodies against aurora B, survivin and FOXM1. The expression pattern was correlated with clinicopathological data such as tumor grading, metastatic state and prognosis.

Results: The immunohistochemical analysis of nuclear aurora kinase B revealed a positive correlation with nuclear survivin and FOXM1 staining patterns. Furthermore, aurora B was positively related to grading and tumor size and negatively to differentiation and functionality.

Conclusion: The expression of aurora kinase B is associated with differentiation, progression and the aggressiveness of GEP-NENs. In the context of tumor progression, aurora B is strongly associated with markers of the mitosis regulatory network, survivin, FOXM1 and Ki-67. A shift of the intracellular localization of aurora B might be useful for the subclassification of intermediate-grade intestinal NET and NEC (20%
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http://dx.doi.org/10.21873/anticanres.12670DOI Listing
July 2018

Changes in Weight Associated With Telotristat Ethyl in the Treatment of Carcinoid Syndrome.

Clin Ther 2018 06 1;40(6):952-962.e2. Epub 2018 May 1.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: In the placebo-controlled Phase III TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) trial, the oral tryptophan hydroxylase inhibitor telotristat ethyl significantly reduced bowel movement (BM) frequency during a 12-week, double-blind treatment period in 135 patients with metastatic neuroendocrine tumors with carcinoid syndrome and ≥4 BMs per day. Patients (mean [SD] age, 63.5 [8.9] years; mean [SD] body mass index, 24.9 [4.9] kg/m) received placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day (TID) in addition to somatostatin analogue therapy. Weight loss is associated with uncontrolled carcinoid syndrome and may be associated with reduced survival.

Methods: Assessment of the occurrence of weight change ≥3% at week 12 was prespecified in the statistical analysis plan.

Findings: In 120 patients with weight data available, weight gain ≥3% was observed in 2 of 39 patients (5.1%) taking placebo TID, 7 of 41 (17.1%) taking telotristat ethyl 250 mg TID, and 13 of 40 (32.5%) taking telotristat ethyl 500 mg TID (P = 0.0017) at week 12. Weight loss ≥3% was observed in 5 of 39 patients (12.8%) taking placebo TID, 4 of 41 (9.8%) taking telotristat ethyl 250 mg TID, and 6 of 40 (15.0%) taking telotristat ethyl 500 mg TID (P = 0.77). Biochemical and metabolic parameters of serum albumin and cholesterol significantly increased (P = 0.02 and P = 0.001, respectively) in patients gaining weight and decreased in patients who lost weight, suggesting an improvement in overall nutritional status.

Implications: Up to 32.5% of patients treated with telotristat ethyl experienced significant, dose-dependent weight gain, associated with reduced diarrhea severity and improved biochemical and metabolic parameters. Improved nutritional status could be an additional aspect of telotristat ethyl efficacy among patients with functioning metastatic neuroendocrine tumors. ClinicalTrials.gov identifier: NCT01677910.
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http://dx.doi.org/10.1016/j.clinthera.2018.04.006DOI Listing
June 2018

Results and adverse events of personalized peptide receptor radionuclide therapy with Yttrium and Lutetium in 1048 patients with neuroendocrine neoplasms.

Oncotarget 2018 Mar 15;9(24):16932-16950. Epub 2018 Feb 15.

Department of Gastroenterology/Endocrinology, Center for Neuroendocrine Tumors Bad Berka - ENETS Center of Excellence, Zentralklinik Bad Berka GmbH, Bad Berka, Germany.

Introduction: Peptide receptor radionuclide therapy (PRRT) of patients with somatostatin receptor expressing neuroendocrine neoplasms has shown promising results in clinical trials and a recently published phase III study.

Methods: In our center, 2294 patients were screened between 2004 and 2014 by Ga somatostatin receptor (SSTR) PET/CT. Intention to treat analysis included 1048 patients, who received at least one cycle of Yttrium or Lutetium-based PRRT. Progression free survival was determined by Ga SSTR-PET/CT and EORTC response criteria. Adverse events were determined by CTCAE criteria.

Results: Overall survival (95% confidence interval) of all patients was 51 months (47.0-54.9) and differed significantly according to radionuclide, grading, previous therapies, primary site and functionality. Progression free survival (based on PET/CT) of all patients was 19 months (16.9-21), which was significantly influenced by radionuclide, grading, and origin of neuroendocrine neoplasm. Progression free survival after initial progression and first and second resumption of PRRT after therapy-free intervals of more than 6 months were 11 months (9.4-12.5) and 8 months (6.4-9.5), respectively. Myelodysplastic syndrome or leukemia developed in 22 patients (2.1%) and 5 patients required hemodialysis after treatment, other adverse events were rare.

Conclusion: PRRT is effective and overall survival is favorable in patients with neuroendocrine neoplasms depending on the radionuclide used for therapy, grading and origin of the neuroendocrine neoplasm which is not exactly mirrored in progression free survival as determined by highly sensitive Ga somatostatin receptor PET/CT using EORTC criteria for determining response to therapy.
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http://dx.doi.org/10.18632/oncotarget.24524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908296PMC
March 2018

Telotristat ethyl in carcinoid syndrome: safety and efficacy in the TELECAST phase 3 trial.

Endocr Relat Cancer 2018 03 12;25(3):309-322. Epub 2018 Jan 12.

Oncology DepartmentHospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), UCM, CNIO, CIBERONC, Madrid, Spain.

Telotristat ethyl, a tryptophan hydroxylase inhibitor, was efficacious and well tolerated in the phase 3 TELESTAR study in patients with carcinoid syndrome (CS) experiencing ≥4 bowel movements per day (BMs/day) while on somatostatin analogs (SSAs). TELECAST, a phase 3 companion study, assessed the safety and efficacy of telotristat ethyl in patients with CS (diarrhea, flushing, abdominal pain, nausea or elevated urinary 5-hydroxyindoleacetic acid (u5-HIAA)) with <4 BMs/day on SSAs (or ≥1 symptom or ≥4 BMs/day if not on SSAs) during a 12-week double-blind treatment period followed by a 36-week open-label extension (OLE). The primary safety and efficacy endpoints were incidence of treatment-emergent adverse events (TEAEs) and percent change from baseline in 24-h u5-HIAA at week 12. Patients ( = 76) were randomly assigned (1:1:1) to receive placebo or telotristat ethyl 250 mg or 500 mg 3 times per day (tid); 67 continued receiving telotristat ethyl 500 mg tid during the OLE. Through week 12, TEAEs were generally mild to moderate in severity; 5 (placebo), 1 (telotristat ethyl 250 mg) and 3 (telotristat ethyl 500 mg) patients experienced serious events, and the rate of TEAEs in the OLE was comparable. At week 12, significant reductions in u5-HIAA from baseline were observed, with Hodges-Lehmann estimators of median treatment differences from placebo of -54.0% (95% confidence limits, -85.0%, -25.1%,  < 0.001) and -89.7% (95% confidence limits, -113.1%, -63.9%,  < 0.001) for telotristat ethyl 250 mg and 500 mg. These results support the safety and efficacy of telotristat ethyl when added to SSAs in patients with CS diarrhea (ClinicalTrials.gov identifier: Nbib2063659).
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http://dx.doi.org/10.1530/ERC-17-0455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5811631PMC
March 2018

Understanding the Patient Experience with Carcinoid Syndrome: Exit Interviews from a Randomized, Placebo-controlled Study of Telotristat Ethyl.

Clin Ther 2017 Nov 23;39(11):2158-2168. Epub 2017 Oct 23.

RTI Health Solutions, Research Triangle Park, North Carolina.

Purpose: Telotristat ethyl, an oral tryptophan hydroxylase inhibitor, is intended to treat carcinoid syndrome by reducing serotonin production. Telotristat ethyl was evaluated in TELESTAR, a Phase III study for patients who had carcinoid syndrome with at least 4 bowel movements (BMs) per day and who were receiving somatostatin analogue therapy. This interview substudy was conducted to provide insight into the patient experience in TELESTAR and to help understand whether reductions in BM frequency (the primary end point) and other symptoms were clinically meaningful.

Methods: Participating sites were asked to invite (before randomization) all eligible patients to telephone interviews scheduled at the end of the double-blind treatment period. Patients and interviewers were blinded to treatment.

Findings: All 35 interviewed participants reported diarrhea and/or excessive BMs at baseline. Patients reported that these symptoms negatively affected emotional, social, physical, and occupational well-being. Prespecified criteria for treatment response (achieving ≥30% reduction in BM frequency for at least 50% of the days) were met by 8 of 26 patients taking telotristat ethyl and 1 of 9 patients taking placebo. All 8 patients taking telotristat ethyl described clinically meaningful reductions in BM frequency and were very satisfied with the ability of the study drug to control their carcinoid syndrome symptoms. Overall, reports of being very satisfied were observed in 12 patients taking telotristat ethyl and 0 taking placebo.

Implications: Patient interviews revealed that TELESTAR patients, at baseline, were significantly affected by their high BM frequency. Patient reports of their clinical trial experience supported the significance of the primary end point and clinical responder analysis in TELESTAR, helping identify and understand clinically meaningful change produced by telotristat ethyl.
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http://dx.doi.org/10.1016/j.clinthera.2017.09.013DOI Listing
November 2017

Patient-Reported Outcomes and Quality of Life with Sunitinib Versus Placebo for Pancreatic Neuroendocrine Tumors: Results From an International Phase III Trial.

Target Oncol 2016 12;11(6):815-824

Hôpital Beaujon, Clichy, France.

Objective: The objective of this analysis was to compare patient-reported outcomes and health-related quality of life (HRQoL) in a pivotal phase III trial of sunitinib versus placebo in patients with progressive, well-differentiated pancreatic neuroendocrine tumors (NCT00428597).

Patients And Methods: Patients received sunitinib 37.5 mg (n = 86) or placebo (n = 85) on a continuous daily-dosing schedule until disease progression, unacceptable adverse events (AEs), or death. Patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 at baseline, Day 1 of every 4-week cycle, and end of treatment or withdrawal. Changes ≥10 points on each scale or item were deemed clinically meaningful.

Results: Sunitinib had anti-tumor effects and improved progression-free survival (PFS) compared with placebo. The study was terminated early for this reason and because of more serious AEs and deaths with placebo. Baseline HRQoL scores were well balanced between study arms, and were generally maintained over time in both groups. In the first 10 cycles, there were no significant differences between groups in global HRQoL, cognitive, emotional, physical, role, and social functioning domains, or symptom scales, except for worsening diarrhea with sunitinib (p < 0.0001 vs. placebo). Insomnia also worsened with sunitinib (p = 0.0372 vs. placebo), but the difference was not clinically meaningful.

Conclusion: With the exception of diarrhea (a recognized side effect), sunitinib had no impact on global HRQoL, functional domains, or symptom scales during the progression-free period. Hence, in patients with pancreatic neuroendocrine tumors, sunitinib provided a benefit in PFS without adversely affecting HRQoL.
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http://dx.doi.org/10.1007/s11523-016-0462-5DOI Listing
December 2016

Telotristat Ethyl, a Tryptophan Hydroxylase Inhibitor for the Treatment of Carcinoid Syndrome.

J Clin Oncol 2017 Jan 28;35(1):14-23. Epub 2016 Oct 28.

Matthew H. Kulke, Dana-Farber Cancer Institute, Boston; Douglas Fleming, Ipsen Bioscience, Cambridge, MA; Dieter Hörsch, Zentralklinik Bad Berka, Bad Berka; Marianne Pavel, Charité-Universitätsmedizin, Berlin, Germany; Martyn E. Caplin, Royal Free Hospital, London; Juan W. Valle, The University of Manchester-The Christie National Health Service Foundation Trust, Manchester, United Kingdom; Lowell B. Anthony, University of Kentucky, Lexington, KY; Emily Bergsland, University of California at San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco; Pamela L. Kunz, Stanford University, Palo Alto, CA; Kjell Öberg and Staffan Welin, Uppsala University, Uppsala, Sweden; Richard R.P. Warner, Icahn School of Medicine at Mount Sinai, New York, NY; Catherine Lombard-Bohas, Hôpital Edouard Herriot, Hospices Civils de Lyon, Lyon, France; Pablo Lapuerta, Phillip Banks, Shanna Jackson, Brian Zambrowicz, and Arthur T. Sands, Lexicon Pharmaceuticals, The Woodlands, TX; and Enrique Grande, Hospital Universitario Ramón y Cajal, Madrid, Spain.

Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.
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http://dx.doi.org/10.1200/JCO.2016.69.2780DOI Listing
January 2017

Effectiveness and side-effects of peptide receptor radionuclide therapy for neuroendocrine neoplasms in Germany: A multi-institutional registry study with prospective follow-up.

Eur J Cancer 2016 May 2;58:41-51. Epub 2016 Mar 2.

Clinic of Molecular Radiotherapy, Center for Neuroendocrine Tumors Bad Berka - ENETS Center of Excellence, Zentralklinik Bad Berka GmbH, Bad Berka, Germany.

Background: Monocentric and retrospective studies indicate effectiveness of peptide receptor radionuclide therapy targeting somatostatin receptors of neuroendocrine neoplasms. We assessed overall and progression-free survival and adverse events of peptide receptor radionuclide therapy by a multi-institutional, board certified registry with prospective follow-up in five centres in Germany.

Methods: A total of 450 patients were included and followed for a mean of 24.4 months. Most patients had progressive low- or intermediate grade neuroendocrine neoplasms and 73% were pretreated with at least one therapy. Primary neuroendocrine neoplasms were mainly derived of pancreas (38%), small bowel (30%), unknown primary (19%) or bronchial system (4%). Patients were treated with Lutetium-177 in 54%, with Yttrium-90 in 17% and with both radionuclides in 29%. Overall and progression-free survival was determined with Kaplan-Meier curves and uni-variate log rank test Cox models.

Findings: Median overall survival of all patients was 59 (95% confidence interval [CI] 49-68.9) months. Overall survival was significantly inferior in the patients treated with Yttrium-90 solely (hazard ratio, 3.22; 95% CI, 1.83-5.64) compared to any peptide receptor radionuclide therapy with Lutetium-177. Grade II (hazard ratio, 2.06; 95% CI, 0.79-5.32) and grade III (hazard ratio, 4.22; 95% CI, 1.41-12.06) neuroendocrine neoplasms had significantly worse overall survival than grade I neuroendocrine neoplasms. Patients with small neuroendocrine neoplasms of small bowel had significantly increased survival (hazard ratio, 0.39; 95% CI, 0.18-0.87) compared to neuroendocrine neoplasms of other locations. Median progression-free survival was 41 (35.9-46.1) months and significantly inferior in patients treated with Yttrium solely (hazard ratio, 2.7; 95% CI, 1.71-4.55). Complete remission was observed in 5.6% of patients, 22.4% had a partial remission, 47.3% were stable and 4% were progressive as best response. Adverse events of bone marrow and kidney function higher than grade III occurred in 0.2-1.5% of patients.

Interpretation: These results indicate that peptide receptor radionuclide therapy is a highly effective therapy for patients with low to intermediate grade neuroendocrine neoplasms with minor adverse events.
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http://dx.doi.org/10.1016/j.ejca.2016.01.009DOI Listing
May 2016

Impact of Previous Somatostatin Analogue Use on the Activity of Everolimus in Patients with Advanced Neuroendocrine Tumors: Analysis from the Phase III RADIANT-2 Trial.

Neuroendocrinology 2015 21;102(1-2):18-25. Epub 2015 Mar 21.

Markey Cancer Center, University of Kentucky, Lexington, Ky., USA.

Background/aims: The phase III placebo-controlled RADIANT-2 trial investigated the efficacy of everolimus plus octreotide long-acting repeatable (LAR) in patients with advanced neuroendocrine tumors (NET) associated with carcinoid syndrome. Here we report a secondary analysis based on the previous somatostatin analogue (SSA) exposure status of patients enrolled in RADIANT-2.

Methods: Patients were randomly assigned to receive oral everolimus 10 mg/day plus octreotide LAR 30 mg intramuscularly (i.m.) or to receive matching placebo plus octreotide LAR 30 mg i.m. every 28 days. SSA treatment before study enrollment was permitted. Patient characteristics and progression-free survival (PFS) were analyzed by treatment arm and previous SSA exposure status.

Results: Of the 429 patients enrolled in RADIANT-2, 339 were previously exposed to SSA (95% received octreotide); 173 of 339 patients were in the everolimus plus octreotide LAR arm. All patients had a protocol-specified history of secretory symptoms, but analysis by type showed that more patients who previously received SSA therapy had a history of flushing symptoms (77%), diarrhea (86%), or both (63%) compared with SSA-naive patients (62, 62, and 24%, respectively). Patients who received everolimus plus octreotide LAR had longer median PFS regardless of previous SSA exposure (with: PFS 14.3 months, 95% confidence interval, CI, 12.0-20.1; without: 25.2 months, 95% CI, 12.0-not reached) compared with patients who received placebo plus octreotide LAR (with: 11.1 months, 95% CI, 8.4-14.6; without: 13.6 months, 95% CI, 8.2-22.7).

Conclusion: Everolimus in combination with octreotide improves PFS in patients with advanced NET associated with carcinoid syndrome, regardless of previous SSA exposure.
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http://dx.doi.org/10.1159/000381715DOI Listing
June 2016

Telotristat etiprate for carcinoid syndrome: a single-arm, multicenter trial.

J Clin Endocrinol Metab 2015 Apr 30;100(4):1511-9. Epub 2015 Jan 30.

Charité - Universitätsmedizin (M.P., B.W.), Department of Gastroenterology and Hepatology, 13353 Berlin Germany; Zentralklinik Bad Berka GmbH (D.H.), Department of Gastroenterology and Endocrinology, 99437 Bad Berka, Germany; Royal Free London National Health Service (NHS) Foundation Trust (M.C.), Department of Gastroenterology and Hepatobiliary Medicine, London NW3 2QG, United Kingdom; Basingstoke and North Hampshire NHS Foundation Trust (J.R.), Department of Gastroenterology, Hampshire RG24 9NA, United Kingdom; Ulm University (T.S.), Department of Internal Medicine I, 89070 Ulm, Germany; The University of Manchester/The Christie NHS Foundation Trust (J.V.), Department of Medical Oncology, Manchester M20 4BX, United Kingdom; and Lexicon Pharmaceuticals, Inc (P.B., P.L., A.S., B.Z., D.F.), Department of Clinical Development, The Woodlands, Texas 77381.

Context: Carcinoid syndrome (CS) is associated with elevated serotonin, diarrhea, flushing, and increased risk of valvular heart disease. Many patients respond to somatostatin analogs initially, but response diminishes in most patients. Additional options are needed.

Objective: To assess whether telotristat etiprate (TE) can reduce gastrointestinal symptoms in CS and reduce urinary 5-hydroxyindoleacetic acid (u5-HIAA; a biomarker of serotonin).

Design: A prospective, exploratory, dose-escalating 12-week, open-label, multicenter study of TE with efficacy and safety analyses.

Setting: A multicenter study.

Patients: Eligible patients had metastatic, well-differentiated, neuroendocrine tumors and CS with ≥ four bowel movements (BMs) per day. Somatostatin analog use was allowed.

Interventions: TE, a novel oral inhibitor of peripheral serotonin synthesis.

Main Outcome Measures: Primary: safety. Secondary: daily BMs, stool form, and u5-HIAA.

Results: Fifteen patients were enrolled, and 14 completed the treatment period. All patients experienced reductions in BMs per day (mean decrease, 43.5%). A 74.2% mean reduction in u5-HIAA, the main metabolite of serotonin, was observed, with generally greater reductions in patients with greater reductions in BMs per day. Nine patients (75%) reported "adequate relief" of gastrointestinal symptoms at 12 weeks, compared with two (17%) at baseline. Stool form and flushing also improved. Adverse events were mostly gastrointestinal (n = 10; 67%), consistent with underlying illness; three adverse events were serious (abdominal pain, diarrhea, and gastroenteritis) but were judged unrelated.

Conclusion: TE was generally safe and well tolerated. Patients experienced substantial improvement in CS and reductions in u5-HIAA, consistent with the mechanism of action of TE. These results support further evaluation in phase 3 studies.
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http://dx.doi.org/10.1210/jc.2014-2247DOI Listing
April 2015

THERANOSTICS-clinical aimshots in surgical warfare against well-differentiated neuroendocrine neoplasms.

Ann Transl Med 2014 Jan;2(1)

1 Internal Medicine/Gastroenterology and Endocrinology, Center for Neuroendocrine Tumors Bad Berka-ENETS Center of Excellence, Zentralklinik Bad Berka GmbH, Robert-Koch-Allee 9, 99437 Bad Berka, Germany ; 2 THERANOSTICS Center for Molecular Radiotherapy and Molecular Imaging, Center for Neuroendocrine Tumors Bad Berka-ENETS Center of Excellence, Zentralklinik Bad Berka GmbH, Robert-Koch-Allee 9, 99437 Bad Berka, BRD, Germany.

Targeted, personalized or molecular medicine all imply maximal treatment with minimal side effects and requires definition and detection of molecular targets prior to therapy. THERANOSTICS in nuclear medicine utilizes the same vector with distinct radionuclides for diagnosis and treatment and has become innovative standard for the treatment of somatostatin receptor expressing neuroendocrine neoplasms.
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http://dx.doi.org/10.3978/j.issn.2305-5839.2013.07.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4200649PMC
January 2014

Neuroendocrine tumors of the bronchopulmonary system (typical and atypical carcinoid tumors): current strategies in diagnosis and treatment. Conclusions of an expert meeting February 2011 in Weimar, Germany.

Oncol Res Treat 2014 14;37(5):266-76. Epub 2014 Apr 14.

Klinik für Innere Medizin, Gastroenterologie und Endokrinologie, Zentralklinik Bad Berka, Bad Berka, Germany.

Neuroendocrine tumors (NETs; syn. carcinoid tumors) are highly or moderately differentiated neoplasms. They comprise a large variety of rare and heterogeneous tumors with an estimated incidence of 3-5/100,000/year. They can arise in virtually every internal organ, but mainly occur in the gastroenteropancreatic and bronchopulmonary systems. Around 25% of the NETs are localized in the bronchopulmonary system. Approximately 2% of all lung tumors are NETs. According to the World Health Organization (WHO) classification of lung tumors, bronchopulmonary NETs are subdivided into typical carcinoids (TCs) and atypical carcinoids (ACs). The parameter with the highest impact on NET behavior and prognosis is the histological classification and staging according to the tumor/node/metastasis (TNM) system. The diagnosis of NETs is established by histological examination and the immunohistochemical detection of general neuroendocrine markers, such as chromogranin A (CgA) and synaptophysin. Serum markers and the use of functional imaging techniques are important additive tools to establish the diagnosis of a NET. The only curative option for lung NETs is complete surgical resection. Beyond that, the currently available interdisciplinary therapeutic options are local ablation, biotherapy (somatostatin analogues), or chemotherapy. New therapeutic options such as peptide receptor radionuclide therapy (PRRT) and molecularly targeted therapies achieve promising results and are under further evaluation. This report is a consensus summary of the interdisciplinary symposium 'Neuroendocrine Tumors of the Lung and of the Gastroenteropancreatic System (GEP NET) - Expert Dialogue' held on February 25-26, 2011 in Weimar, Germany. At this conference, a panel of 23 German experts shared their knowledge and exchanged their thoughts about research, diagnosis, and clinical management of NETs, whereby special attention was paid to NETs of the respiratory tract.
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http://dx.doi.org/10.1159/000362430DOI Listing
January 2015

Practical management of everolimus-related toxicities in patients with advanced solid tumors.

Onkologie 2013 5;36(5):295-302. Epub 2013 Apr 5.

Klinik für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Medizinische Hochschule Hannover, Germany.

Everolimus is an orally administered inhibitor of the mammalian target of rapamycin (mTOR), an intracellular protein kinase downstream of the phosphatidylinositol 3-kinase/AKT pathway involved in key components of tumorigenesis, including cell growth, proliferation, and angiogenesis. In the advanced cancer setting, based on favorable results from phase III trials, everolimus is indicated for the treatment of advanced renal cell carcinoma, advanced neuroendocrine tumors of pancreatic origin, and advanced hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer. Additional oncology indications for everolimus include renal angiomyolipoma with tuberous sclerosis complex and subependymal giant-cell astrocytoma. Although it is generally well tolerated, with most adverse events of mild to moderate severity and manageable, everolimus exhibits a distinct adverse event profile that warrants guidance for proper diagnostic and medical management. This guidance is particularly important given the potential for widespread long-term use of everolimus. This review will focus on the most relevant toxicities associated with mTOR inhibitors and on their management. Practical treatment recommendations are presented for stomatitis, noninfectious pneumonitis, rash, selected metabolic abnormalities, and infections. Provided these events are rapidly identified and treated, the vast majority should resolve with minimal effect on treatment outcomes and patients' quality of life.
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http://dx.doi.org/10.1159/000350625DOI Listing
January 2014

Peptide receptor radionuclide therapy for neuroendocrine tumors in Germany: first results of a multi-institutional cancer registry.

Recent Results Cancer Res 2013 ;194:457-65

Department of Gastroenterology and Endocrinology, Center of Neuroendocrine Tumors Bad Berka-ENETS Center of Excellence, Bad Berka, Germany.

Peptide receptor radionuclide therapy is an effective treatment option for patients with well-differentiated somatostatin receptor-expressing neuroendocrine tumors. However, published data result mainly from retrospective monocentric studies. We initiated a multi-institutional, prospective, board-reviewed registry for patients treated with peptide receptor radionuclide therapy in Germany in 2009. In five centers, 297 patients were registered. Primary tumors were mainly derived from pancreas (117/297) and small intestine (80/297), whereas 56 were of unknown primary. Most tumors were well differentiated with median Ki67 proliferation rate of 5% (range 0.9-70%). Peptide receptor radionuclide therapy was performed using mainly yttrium-90 and/or lutetium-177 as radionuclides in 1-8 cycles. Mean overall survival was estimated at 213 months with follow-up between 1 and 230 months after initial diagnosis, and 87 months with follow-up between 1 and 92 months after start of peptide receptor radionuclide therapy. Median overall survival was not yet reached. Subgroup analysis demonstrated that best results were obtained in neuroendocrine tumors with proliferation rate below 20%. Our results indicate that peptide receptor radionuclide therapy is an effective treatment for well- and moderately differentiated neuroendocrine tumors irrespective of previous therapies and should be regarded as one of the primary treatment options for patients with somatostatin receptor-expressing neuroendocrine tumors.
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http://dx.doi.org/10.1007/978-3-642-27994-2_25DOI Listing
June 2013

Targeting aurora kinases with danusertib (PHA-739358) inhibits growth of liver metastases from gastroenteropancreatic neuroendocrine tumors in an orthotopic xenograft model.

Clin Cancer Res 2012 Sep 2;18(17):4621-32. Epub 2012 Jul 2.

I. Medizinische Klinik, Diagnostische und Interventionelle Radiologie, II. Medizinische Klinik, Onkologisches Zentrum, Universitätsklinikum Hamburg-Eppendorf; Labor Lademannbogen, Hamburg, Germany.

Purpose: Aurora kinases play a crucial role in cell-cycle control. Uncontrolled expression of aurora kinases causes aneuploidy and tumor growth. As conservative treatment options for advanced gastroenteropancreatic neuroendocrine tumors (GEP-NET) are disappointing, aurora kinases may be an interesting target for novel therapeutic strategies.

Experimental Design: Human GEP-NETs were tested for aurora kinase expression. The efficacy of the new aurora kinase inhibitor danusertib was evaluated in two human GEP-NET cell lines (BON1 and QGP) in vitro and in vivo.

Results: The majority of ten insulinomas and all 33 nonfunctional pancreatic or midgut GEP-NETs expressed aurora A despite a mostly high degree of cell differentiation. Both human GEP-NET cell lines expressed aurora kinase A and B, and high Ser10 phosphorylation of histone H3 revealed increased aurora B activity. Remarkably, danusertib led to cell-cycle arrest and completely inhibited cell proliferation of the GEP-NET cells in vitro. Decreased phosphorylation of histone H3 indicated effective aurora B inhibition. In a subcutaneous murine xenograft model, danusertib significantly reduced tumor growth in vivo compared with controls or mice treated with streptozotocine/5-fluorouracil. As a consequence, decreased levels of tumor marker chromogranin A were found in mouse serum samples. In a newly developed orthotopic model for GEP-NET liver metastases by intrasplenic tumor cell transplantation, dynamic MRI proved significant growth inhibition of BON1- and QGP-derived liver metastases.

Conclusions: These results show that danusertib may impose a new therapeutic strategy for aurora kinase expressing metastasized GEP-NETs.
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http://dx.doi.org/10.1158/1078-0432.CCR-11-2968DOI Listing
September 2012

Role of PET/CT in the functional imaging of endocrine pancreatic tumors.

Abdom Imaging 2012 Dec;37(6):1004-20

Department of Bioimaging and Radiological Sciences, Institute of Nuclear Medicine, Agostino Gemelli Hospital, Università Cattolica del Sacro Cuore, Roma, Italy.

Endocrine pancreatic tumors (EPTs) are a heterogeneous group of neoplasms with variable clinical and biological features and prognosis, ranging from very slow-growing tumors to highly aggressive and very malignant ones. As other neuroendocrine tumors, EPTs are characterized by the presence of neuroamine uptake mechanisms and/or peptide receptors at the cell membrane and these features constitute the basis of the clinical use of specific radiolabeled ligands, both for imaging and therapy. The more widespread use of hybrid machines, i.e., positron emission tomography/computed tomography (PET/CT), allows to perform imaging with high resolution and high diagnostic accuracy especially for small lesions, and to correlate anatomic location with function. The recent WHO recommendations for classification and prognostic factors help the selection of tracers likely to show a positive image on PET; therefore, tracers exploiting specific metabolic patterns ((18)F-DOPA and (11)C-5-HTP) or specific receptor expression ((68)Ga-DOTA-peptides) are suited to well-differentiated tumors, while the use of (18)F-FDG is preferred for poorly-differentiated neoplasms with high proliferative activity and loss of neuroendocrine features. In differentiated EPTs, (11)C-5-HTP performs better than (18)F-DOPA even though its use is hampered by its complex production and limited availability and experience; (68)Ga-peptides are indicated for all type of gastroenteropancreatic (GEP) neuroendocrine tumors, regardless of their functional activity. In addition, (68)Ga-DOTA-peptides play a distinctive role in planning peptide receptor radionuclide therapy.
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http://dx.doi.org/10.1007/s00261-012-9871-9DOI Listing
December 2012

Concomitant lung and gastroenteropancreatic neuroendocrine tumors and the value of gallium-68 PET/CT.

Cancer Imaging 2011 Nov 26;11:179-83. Epub 2011 Nov 26.

Department of General and Visceral Surgery, Zentralklinik Bad Berka, Germany.

Well-differentiated neuroendocrine tumors (NETs) of the lung occur as typical and atypical carcinoids. Little is known about the biology of these tumors in respect of their ability to metastasize or the probability of development of concomitant neuroendocrine tumors. Here we report a patient diagnosed with a second neuroendocrine tumor of the ileum 4 years after curative resection of a typical carcinoid of the left lung. The intestinal neuroendocrine tumor was successfully detected by gallium-68 based somatostatin receptor positron emission tomography (PET)/computed tomography (CT) and surgically removed using gamma probe detection based on the same labeling. This case report underlines the utility of somatostatin receptor PET/CT based detection and follow-up of NETs.
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http://dx.doi.org/10.1102/1470-7330.2011.0035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266592PMC
November 2011

Everolimus plus octreotide long-acting repeatable for the treatment of advanced neuroendocrine tumours associated with carcinoid syndrome (RADIANT-2): a randomised, placebo-controlled, phase 3 study.

Lancet 2011 Dec 25;378(9808):2005-2012. Epub 2011 Nov 25.

University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Background: Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumour activity in patients with advanced pancreatic neuroendocrine tumours. We aimed to assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid).

Methods: We did a randomised, double-blind, placebo-controlled, phase 3 study comparing 10 mg per day oral everolimus with placebo, both in conjunction with 30 mg intramuscular octreotide LAR every 28 days. Randomisation was by interactive voice response systems. Participants were aged 18 years or older, with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological assessment within the past 12 months. Our primary endpoint was progression-free survival. Adjusted for two interim analyses, the prespecified boundary at final analysis was p≤0·0246. This study is registered at ClinicalTrials.gov, number NCT00412061.

Findings: 429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16·4 (95% CI 13·7-21·2) months in the everolimus plus octreotide LAR group and 11·3 (8·4-14·6) months in the placebo plus octreotide LAR group (hazard ratio 0·77, 95% CI 0·59-1·00; one-sided log-rank test p=0·026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62%vs 14%), rash (37%vs 12%), fatigue (31%vs 23%), and diarrhoea (27%vs 16%).

Interpretation: Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome.

Funding: Novartis Pharmaceuticals.
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http://dx.doi.org/10.1016/S0140-6736(11)61742-XDOI Listing
December 2011

Sunitinib malate for the treatment of pancreatic neuroendocrine tumors.

N Engl J Med 2011 Feb;364(6):501-13

Service Inter-Hospitalier de Cancérologie et Service de Gastroenteropancréatologie, Hôpital Beaujon, Clichy, France.

Background: The multitargeted tyrosine kinase inhibitor sunitinib has shown activity against pancreatic neuroendocrine tumors in preclinical models and phase 1 and 2 trials.

Methods: We conducted a multinational, randomized, double-blind, placebo-controlled phase 3 trial of sunitinib in patients with advanced, well-differentiated pancreatic neuroendocrine tumors. All patients had Response Evaluation Criteria in Solid Tumors-defined disease progression documented within 12 months before baseline. A total of 171 patients were randomly assigned (in a 1:1 ratio) to receive best supportive care with either sunitinib at a dose of 37.5 mg per day or placebo. The primary end point was progression-free survival; secondary end points included the objective response rate, overall survival, and safety.

Results: The study was discontinued early, after the independent data and safety monitoring committee observed more serious adverse events and deaths in the placebo group as well as a difference in progression-free survival favoring sunitinib. Median progression-free survival was 11.4 months in the sunitinib group as compared with 5.5 months in the placebo group (hazard ratio for progression or death, 0.42; 95% confidence interval [CI], 0.26 to 0.66; P<0.001). A Cox proportional-hazards analysis of progression-free survival according to baseline characteristics favored sunitinib in all subgroups studied. The objective response rate was 9.3% in the sunitinib group versus 0% in the placebo group. At the data cutoff point, 9 deaths were reported in the sunitinib group (10%) versus 21 deaths in the placebo group (25%) (hazard ratio for death, 0.41; 95% CI, 0.19 to 0.89; P=0.02). The most frequent adverse events in the sunitinib group were diarrhea, nausea, vomiting, asthenia, and fatigue.

Conclusions: Continuous daily administration of sunitinib at a dose of 37.5 mg improved progression-free survival, overall survival, and the objective response rate as compared with placebo among patients with advanced pancreatic neuroendocrine tumors. (Funded by Pfizer; ClinicalTrials.gov number, NCT00428597.).
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http://dx.doi.org/10.1056/NEJMoa1003825DOI Listing
February 2011

Neoadjuvant peptide receptor radionuclide therapy for an inoperable neuroendocrine pancreatic tumor.

World J Gastroenterol 2009 Dec;15(46):5867-70

Department of General and Visceral Surgery, Zentralklinik Bad Berka, 99437 Bad Berka, Germany.

Pancreatic endocrine tumors are rare but are among the most common neuroendocrine neoplasms of the abdomen. At diagnosis many of them are already advanced and difficult to treat. We report on an initially inoperable malignant pancreatic endocrine tumor in a 33-year-old woman, who received neoadjuvant peptide receptor radionuclide therapy (PRRT) as first-line treatment. This resulted in a significant downstaging of the tumor and allowed its subsequent complete surgical removal. Follow-up for eighteen months revealed a complete remission. This is the first report on neoadjuvant PRRT in a neuroendocrine neoplasm with subsequent successful complete resection.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2791284PMC
http://dx.doi.org/10.3748/wjg.15.5867DOI Listing
December 2009

Loss of nuclear p27 expression and its prognostic role in relation to cyclin E and p53 mutation in gastroenteropancreatic neuroendocrine tumors.

Clin Cancer Res 2008 Nov;14(22):7378-84

Medizinische Klinik I, Gastroenterologie/Infektiologie/Rheumatologie, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.

Purpose: Gastroenteropancreatic neuroendocrine tumors (GEP-NET) are classified by the WHO, yet its prognostic value needs to be confirmed. Therefore, we aimed to determine the prognostic role of cell cycle key regulatory genes p53, p27kip1 (p27), and cyclin E in this tumor entity.

Experimental Design: Tumor specimen from 89 patients with a complete follow-up were studied immunohistochemically for p27 and cyclin E expression and for p53 mutations. The functional relevance of p27 was evaluated in the neuroendocrine cell lines BON1 (human) and INS1 (rat) by the use of small interfering RNA.

Results: Twenty-six of 29 benign, well-differentiated endocrine tumors (WHO class 1) showed a high expression (> 50%) of p27, whereas all 10 poorly differentiated endocrine carcinomas (WHO class 3) displayed a low expression of p27. Metastatic well-differentiated endocrine carcinomas (WHO class 2) showed a low p27 expression in 20 of 50 (40%) patients, which conferred a poor prognosis (median survival, 57 versus 140 months; P = 0.037). This prognostic dichotomy was improved by the use of a combination of p27 and cyclin E (high cyclin E/low p27 versus low cyclin E/high p27: median survival 53 months versus not reached; P = 0.0044). p53 mutations were rare (1 of 10 poorly differentiated endocrine carcinomas).

Conclusions: Loss of p27 and overexpression of cyclin E play a critical role in the aggressiveness of gastroenteropancreatic neuroendocrine tumors. This coincides with increased cell cycle progression. We propose a discussion whether to incorporate the immunohistochemical expression of p27 into a revised classification to individualize therapeutic strategies in this tumor entity.
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http://dx.doi.org/10.1158/1078-0432.CCR-08-0698DOI Listing
November 2008