Treatment Of Carcinoid Syndrome Research Articles

The role of serotonin inhibition within the treatment of carcinoid syndrome.

Carcinoid syndrome is the most frequent hormonal complication associated with neuroendocrine neoplasms. It was first reported in 1954, and the classical symptoms are diarrhoea, flushing and abdominal pain. It is caused by the secretion of several vasoactive substances, the most prominent being serotonin, which play a pathophysiological role in the clinical symptoms which characterise carcinoid syndrome. Therefore, the focus of carcinoid syndrome treatment is to reduce serotonin production and hence improve the patient's quality of life. There are a variety of management options for carcinoid syndrome including medical, surgical and loco-regional interventional radiological procedures. The most widely used are somatostatin analogues with three clinically approved drugs: lanreotide and octreotide (first-generation) and pasireotide (second-generation). Both everolimus and interferon used in combination with octreotide have shown significant reduction in urinary 5-hydroxyindoleacetic acid compared to octreotide alone. Telotristat ethyl has been increasingly utilised for patients with symptoms despite taking somatostatin analogues. It has also been shown to have a significant improvement in bowel movement frequency which was associated with a significant improvement in quality of life. Peptide receptor radionuclide therapy has proven symptomatic improvement in patients with uncontrolled symptoms. Chemotherapy is primarily reserved for patients with high proliferation tumours, with limited research on the efficacy in reducing symptoms. Surgical resection remains the optimal treatment due to being the only one that can achieve a cure. Liver-directed therapies are considered in patients where curative resection is not possible. There are therefore numerous different therapies. This paper describes the pathophysiology and therapy of carcinoid syndrome.

Telotristat Etiprate alleviates rheumatoid arthritis by targeting LGALS3 and affecting MAPK signaling.

Rheumatoid arthritis (RA) is one of the most widespread chronic immune-mediated inflammatory diseases characterized by continuous erosion of bone and cartilage by synovial hyperplasia. Telotristat Etiprate is an inhibitor of tryptophan hydroxylase, a rate-limiting enzyme in the biosynthesis of serotonin. Telotristat Etiprate can be used in the treatment of carcinoid syndrome. The purpose of this study was to explore the effect of Telotristat Etiprate on RA and its mechanism. We investigated Telotristat Etiprate in collagen-induced arthritis (CIA) model mice and in rheumatoid arthritis synovial fibroblasts (RASFs). Results showed that Telotristat Etiprate had anti-inflammatory effects both in vitro and in vivo, can inhibit the invasion and migration of cells, inhibit the formation of pannus, and induce cell apoptosis. Transcriptome sequencing (RNA-seq) and mass spectrometry analysis showed that Galectins-3 (LGALS3) could be a newly identified target of Telotristat Etiprate, affecting the phosphorylation of the MAPK signaling pathway through UBE2L6, thereby improving RA.

Carcinoid Syndrome: Preclinical Models and Future Therapeutic Strategies

Carcinoid syndrome represents a debilitating paraneoplastic disease, caused by the secretion of several substances, occurring in about 10-40% of patients with well-differentiated neuroendocrine tumors (NETs). The main signs and symptoms associated with carcinoid syndrome are flushing, diarrhea, hypotension, tachycardia, bronchoconstriction, venous telangiectasia, dyspnea and fibrotic complications (mesenteric and retroperitoneal fibrosis, and carcinoid heart disease). Although there are several drugs available for the treatment of carcinoid syndrome, the lack of therapeutic response, poor tolerance or resistance to drugs are often reported. Preclinical models are indispensable tools for investigating the pathogenesis, mechanisms for tumor progression and new therapeutic approaches for cancer. This paper provides a state-of-the-art overview of in vitro and in vivo models in NETs with carcinoid syndrome, highlighting the future developments and therapeutic approaches in this field.

The Role of Somatostatin Analogues in the Control of Diarrhea and Flushing as Markers of Carcinoid Syndrome: A Systematic Review and Meta-Analysis

Somatostatin analogues (SSAs) are the cornerstone of treatment for carcinoid syndrome (CS)-related symptoms. The aim of this systematic review and meta-analysis is to evaluate the percentage of patients achieving partial (PR) or complete response (CR) with the use of long-acting SSAs in patients with CS. A systematic electronic literature search was conducted in PubMed, Cochrane, and Scopus to identify eligible studies. Any clinical trials reporting data on the efficacy of SSAs to alleviate symptoms in adult patients were considered as potentially eligible. A total of 17 studies reported extractable outcomes (PR/CR) for quantitative synthesis. The pooled percentage of patients with PR/CR for diarrhea was estimated to be 0.67 (95% confidence interval (CI): 0.52-0.79, I2 = 83%). Subgroup analyses of specific drugs provided no evidence of a differential response. With regards to flushing, the pooled percentage of patients with PR/CR was estimated to be 0.68 (95% CI: 0.52-0.81, I2 = 86%). Similarly, no evidence of a significant differential response in flushing control was documented. We estimate there is a 67-68% overall reduction in symptoms of CS associated with SSA treatment. However, significant heterogeneity was detected, possibly revealing differences in the disease course, in management and in outcome definition.

Lung transplantation in patients with pulmonary arterial hypertension: The opinion of the Polish Cardiac Society Working Group on Pulmonary Circulation.

Pulmonary arterial hypertension is a rare but progressive disease that leads to death. Modern drug treatment slows the progression of the disease and prolongs patients' lives, but often, even maximal treatment with parenteral prostacyclin does not prevent deterioration. In the case of inadequate clinical response to drug treatment, lung transplantation (LTx) should be considered. This article aims to analyze thoroughly indications to refer a patient for consultation with a transplant center, the optimal timing of listing for LTx, contraindications for the procedure, bridging techniques, as well as tests needed before and after transplantation. We outline the technique of the procedurę and evaluate psychological aspects of LTx.

S3514 A Case of Symptomatic Ileal Non-Secretory Neuroendocrine Tumor Successfully Treated With Octreotide

Introduction: Neuroendocrine tumor incidence is steadily increasing, likely from detection due to better imaging, routine colonoscopies, and endoscopies. Most NETs, 55%, are found in the GI tract and only 0.1-1% found on routine colonoscopy. About 40% of NETs are hormone producing leading to the clinical diagnosis of carcinoid syndrome. One of the most common symptoms of carcinoid syndrome is diarrhea occuring in 80% percent of cases, however diarrhea can be present in non-secretory NETs. Here we report a case of GNET presenting as diarrhea that responded to octreotide injections despite having normal 5-HIAA and chromogranin A levels. Case Description/Methods: Our patient is an 80 year old female with past medical history of hypertension, renal stones, and IBS with baseline diarrhea of about 2-4 pasty stools a day. In November she developed two days of severe diarrhea with 10 watery stools a day and multiple episodes of incontinence which prompted patient to go to the ED. The inpatient workup was negative for acute causes, CT showed diverticulosis, and stools returned to baseline. The patient was discharged with outpatient GI follow up. At home the severe diarrhea retuned so outpatient GI planned for colonoscopy. Results of the procedure included a 2cm submucosal non-obstructing mass in the terminal ileum. Pathology showed a G1 well differentiated neuroendocrine tumor. Patient was referred to oncology and workup revealed no metastasis on PET/CT and negative 5-HIAA and chromogranin A levels. During initial oncology visit patient was started on octreotide injections which greatly improved the diarrhea. Even with negative carcinoid workup the decision was made to continue octreotide injections and not to pursue surgical options. (Figure) Discussion: The terminal ileum is the most common GI location for NETs. Terminal ileum intubation on coloscopy is attempted 30-80% and greatly aids in diagnosis, as with our patient. Once diagnosed, there is limited guidance on treatment of diarrhea in patients with NETs and negative carcinoid workup. There are no abstracts or research on treatment of diarrhea with negative carcinoid syndrome. One treatment for carcinoid syndrome is somatostatin analogues but no guidelines with non-carcinoid NETs and therapeutic value in octreotide. However, with our patient, treatment with monthly octreotide injections resolved their symptoms. Our case emphasizes importance of ileal intubation in coloscopy and that somatostatin analogue treatment should be considered in non carcinoid NETs.Figure 1.: Small bowel (terminal ileum): well-differentiated neuroendocrine tumor (G1).

Staged treatment of carcinoid syndrome complicated with severe tricuspid regurgitation.

Staged treatment of carcinoid syndrome complicated with severe tricuspid regurgitation.

Efficacy, safety and unmet needs of evolving medical treatments for carcinoid syndrome

This review reports on the currently available medical treatment options for the control of symptoms due to carcinoid syndrome in patients with neuroendocrine tumors. The efficacy and adverse events (AEs) of approved drugs such as somatostatin analogues (SSA), telotristat ethyl (TE) and interferon-alpha, are reviewed. Somatostatin analogues remain the standard treatment of carcinoid syndrome based on the high expression of somatostatin receptors and the resulting inhibition of secretion of bioactive compounds; their use is associated with relatively mild AEs, involving mainly the gastrointestinal system, and being usually transient. Although dose escalation of SSA remains an unapproved option, it is clinically implemented to alleviate symptoms in refractory carcinoid syndrome and supported by the most recent guidelines. The side effects associated with the increased dose are in general mild and consistent with standard dose of SSA. Telotristat ethyl, an oral inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis, represents a rather novel innovative treatment option in patients with carcinoid syndrome suffering from diarrhea and complements the standard therapy of SSA. Given the low toxicity profile, TE may be considered an early add-on treatment to SSA in patients with uncontrolled carcinoid syndrome. However, further prolonged follow-up of patients treated with TE may be needed to exclude potential AEs, such as liver toxicity or depressed mood, in patients with long-term treatment. Interferon alpha is a cytokine with direct inhibitory effect on hormone secretion and tumor cell proliferation and an approved therapy in carcinoid syndrome but is associated with significant AEs in the majority of the patients requiring frequently dose reduction. The finding of a more favorable tolerability of pegylated interferon needs to be confirmed in a prospective study.

European Neuroendocrine Tumor Society (ENETS) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease

European Neuroendocrine Tumor Society (<scp>ENETS</scp>) 2022 Guidance Paper for Carcinoid Syndrome and Carcinoid Heart Disease

Peptide Receptor Radionuclide Therapy With 177Lu-DOTATATE for Symptomatic Control of Refractory Carcinoid Syndrome.

ContextPeptide receptor radionuclide therapy (PRRT) with [Lutetium-177-DOTA0-Tyr3]octreotate (177Lu-DOTATATE) results in an increase of progression-free survival and quality of life in patients with progressive, well-differentiated neuroendocrine neoplasms (NENs).ObjectiveTo study the effect of 177Lu-DOTATATE in patients with carcinoid syndrome and radiologically stable or newly diagnosed disease treated solely for the purpose of symptom reduction.DesignRetrospective cohort study.SettingTertiary care hospital.PatientsTwenty-two patients with a metastatic midgut NEN, elevated urinary 5-hydroxyindolacetic acid excretion, and flushing and/or diarrhea despite treatment with a somatostatin analog, without documented disease progression.InterventionPRRT with 177Lu-DOTATATE (intended cumulative dose: 29.6 GBq) with a primary aim to reduce symptoms.ResultsAfter PRRT, mean bowel movement frequency (BMF) decreased from 6.1 ± 3.4 to 4.6 ± 3.6 per day (P = 0.009). Flushes decreased from 4.3 ± 2.9 to 2.4 ± 2.7 flushes per day (P = 0.002). A decrease of BMF of more than 30% occurred in 47% of patients with baseline BMF of 4 or more (n = 17). In patients with ≥2 episodes of flushing a day (n = 15), 67% of patients had more than 50% decrease of daily flushing. A decrease in urinary 5-hydroxyindolacetic acid excretion of more than 30% was seen in 56% of patients. The European Organization for Research and Treatment of Cancer–Core Module diarrhea subscale score showed a trend toward improvement by an average of 16.7 ± 33.3 points (P = 0.11).ConclusionPRRT with 177Lu-DOTATATE effectively reduced diarrhea and flushing in patients with carcinoid syndrome and can be considered for symptomatic treatment of carcinoid syndrome insufficiently controlled with somatostatin analogs.

Update on Pathophysiology, Treatment, and Complications of Carcinoid Syndrome.

Carcinoid syndrome (CS) develops in patients with hormone-producing neuroendocrine neoplasms (NENs) when hormones reach a significant level in the systemic circulation. The classical symptoms of carcinoid syndrome are flushing, diarrhoea, abdominal pain, and wheezing. Neuroendocrine neoplasms can produce multiple hormones: 5-hydroxytryptamine (serotonin) is the most well-known one, but histamine, catecholamines, and brady/tachykinins are also released. Serotonin overproduction can lead to symptoms and also stimulates fibrosis formation which can result in development of carcinoid syndrome-associated complications such as carcinoid heart disease (CaHD) and mesenteric fibrosis. Transforming growth factor beta (TGF-β) is one of the main factors in developing fibrosis, but platelet-derived growth factor (PDGF), basic fibroblast growth factor (FGF2), and connective tissue growth factor (CTGF or CCN2) are also related to fibrosis development. Treatment of CS focuses on reducing serotonin levels with somatostatin analogues (SSA's). Telotristat ethyl and peptide receptor radionuclide therapy (PRRT) have recently become available for patients with symptoms despite being established on SSA's. Screening for CaHD is advised, and early intervention prolongs survival. Mesenteric fibrosis is often present and associated with poorer survival, but the role for prophylactic surgery of this is unclear. Depression, anxiety, and cognitive impairment are frequently present symptoms in patients with CS but not always part of their care plan. The role of antidepressants, mainly SSRIs, is debatable, but recent retrospective studies show evidence for safe use in patients with CS. Carcinoid crisis is a life-threatening complication of CS which can appear spontaneously but mostly described during surgery, anaesthesia, chemotherapy, PRRT, and radiological procedures and may be prevented by octreotide administration.

Inhibition of serotonin synthesis: A novel therapeutic paradigm.

The rate-limiting enzyme in serotonin synthesis is tryptophan hydroxylase (TPH). There are two independent serotonin systems in the body characterized by two isoforms of TPH, TPH1 and TPH2. While TPH2 synthesizes serotonin in the brain, TPH1 is expressed in the gut and in other peripheral tissues and supplies platelets in the circulation with serotonin. This duality of the serotonin system is enforced by the blood-brain barrier which is impermeable for serotonin. In the brain serotonin acts as neurotransmitter and is a main target for the treatment of psychiatric disorders. In the periphery it is released by platelets at the site of activation and elicits numerous physiological effects. TPH1 deficient mice were shown to be protected from diverse diseases including hemostatic, inflammatory, fibrotic, gastrointestinal, and metabolic disorders and therefore serotonin synthesis inhibition emerged as a reasonable therapeutic paradigm. Recently the first TPH inhibitor, telotristat ethyl, came on the market for the treatment of carcinoid syndrome. This review summarizes the state of development and the therapeutic opportunities of such compounds.

A Patient-Reported Outcomes Analysis Of Lanreotide In The Treatment Of NETs Patients With Carcinoid Syndrome: Evidence From The ELECT Trial.

PurposeThe purpose of this analysis of patient-reported outcomes from the ELECT (Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment) trial (NCT00774930) was to explore the effect of lanreotide on symptoms of carcinoid syndrome. Specifically, this post hoc analysis was designed to identify the most important patient-reported outcomes for patients in ELECT.MethodsThe post hoc analysis of ELECT, a placebo-controlled study of lanreotide in patients with neuroendocrine tumors, evaluated patient-reported outcomes during the double-blind phase of the trial, specifically daily diarrhea and flushing symptoms, octreotide rescue use, and the EORTC QLQ-C30 and QLQ-GINET21 questionnaires at baseline and week 12. Principal component (PC) analysis was applied on baseline data to identify independent variable clusters and clinically meaningful summary measures that highly correlated to these PCs. From those, the minimum clinical important differences were derived so to perform a responder analysis.ResultsThe three largest PCs captured 42.9% of the variation among baseline variables. The C30 summary score (C30-SS), diarrhea burden, and flushing burden were highly correlated with PC1, PC2, and PC3, respectively. Lanreotide patients were more likely to experience an improvement on the C30-SS (risk ratio [RR] 2.42; P=0.023), diarrhea burden (RR 2.85; P=0.005), and flushing burden (RR 1.39; P=0.31) compared to placebo patients. Lanreotide-treated patients have a higher probability of being a responder on at least one of the three domains of C30-SS, diarrhea burden, or flushing burden compared to placebo patients (RR 1.48; P=0.06).ConclusionThe higher response rates in the diarrhea burden are consistent with the previously reported effects of lanreotide on octreotide rescue medication use, while the findings of a greater efficacy of lanreotide vs placebo in the quality-of-life domains represent a novel aspect in the benefits of lanreotide.Trial registrationClinicalTrials.gov identifier: NCT00774930.

Carcinoid Syndrome: Updates and Review of Current Therapy.

Carcinoid syndrome (CS) is a complex disorder caused by functional neuroendocrine tumors (NETs). This debilitating disease is characterized by hyper-secretion of biologically active substances eliciting major hormonal symptoms burden and fibrotic changes that are often challenging for management. There have been a number of insights that have substantially advanced treatments since the introduction of somatostatin analogs (SSAs). Second-line treatments are needed in a substantial proportion of patients with advanced disease that have uncontrolled hormone secretion on the highest labeled doses of SSAs. International guidelines suggest several available options including dose escalation of SSAs, interferon alpha, everolimus, radionuclide therapy, liver-directed therapies, and the novel tryptophan hydroxylase 1 inhibitor, telotristat ethyl. The clear preference of one second-line therapy over the other is not stated since their relative and long-term efficacy are largely unknown, and standardized approach of hormonal response assessment is lacking in the literature. In the clinical setting, the treatment of CS is guided in conjunction with patients' performance status, tumor origin, grade, stage, and growth rate, with regard to both anti-hormonal, as well as anti-proliferative effect. There is an unmet need for further well-designed randomized placebo-controlled and head-to-head studies that systematically assess CS symptom control and biochemical response following a specific intervention.

Video-based patient education on carcinoid syndrome: Positive knowledge and behavior shift for patients.

e15697 Background: Carcinoid syndrome (CS) negatively affects quality of life (QOL), compromising physical, daily, and emotional functioning. Reticence to discuss symptoms, particularly debilitating diarrhea, perpetuates negative QOL, as does confusion of CS symptoms with other conditions and dietary challenges. To address these needs, we created video-based patient education activities with the Carcinoid Cancer Foundation (CCF) to empower patients with information and resources on CS facts, diagnosis, medical management, eating well and self-care. Methods: Two 1-hour patient education activities were broadcast live online and on-demand in 2017 and 2018 at CancerCoachLive.com , carcinoid.org, and Facebook Live for 6+ months. Features included panel discussions, slides, live polling and Q&amp;A, and video vignettes of real patient experiences. Knowledge-focused test questions were administered at 3 time points (pre-activity, immediate post-activity, and 8-week [follow-up] post). Behavioral and communication-focused questions were also asked at follow up. Data from these questions, live poll responses, and learner-submitted questions pre-event and during live Q&amp;A were analyzed to determine engagement, lessons learned and continuing patient needs. Results: In total, 1,893 patients took part in the activities, and attracted 39,821 Facebook engagements (“views”). Respondents (n = 116-119) reported: 57%, improved communication with their healthcare providers (HCPs) regarding CS; 44%, improved feeling of being “in-control” of health care decision; 31%, improved care behaviors for their health. Improved communication with their HCPs were specific to: their disease and symptoms, treatments, and diet. Changes in behaviors included: dietary changes, more “involved” in care decisions, asking questions of HCPs, and proactively learning about CS. Knowledge improvements were observed on 7 of 8 questions on CS facts, diet, and treatment (5 of 7 statistically significant; average effect size = 1.16; n averaged 382 pre and 96 post). Conclusions: Patient education on CS can yield immediate and sustained gains in knowledge and behavior, which may improve diagnosis, treatment, and improve patient QOL.

Predicting human disease mutations and identifying drug targets from mouse gene knockout phenotyping campaigns.

ABSTRACTTwo large-scale mouse gene knockout phenotyping campaigns have provided extensive data on the functions of thousands of mammalian genes. The ongoing International Mouse Phenotyping Consortium (IMPC), with the goal of examining all ∼20,000 mouse genes, has examined 5115 genes since 2011, and phenotypic data from several analyses are available on the IMPC website (www.mousephenotype.org). Mutant mice having at least one human genetic disease-associated phenotype are available for 185 IMPC genes. Lexicon Pharmaceuticals' Genome5000™ campaign performed similar analyses between 2000 and the end of 2008 focusing on the druggable genome, including enzymes, receptors, transporters, channels and secreted proteins. Mutants (4654 genes, with 3762 viable adult homozygous lines) with therapeutically interesting phenotypes were studied extensively. Importantly, phenotypes for 29 Lexicon mouse gene knockouts were published prior to observations of similar phenotypes resulting from homologous mutations in human genetic disorders. Knockout mouse phenotypes for an additional 30 genes mimicked previously published human genetic disorders. Several of these models have helped develop effective treatments for human diseases. For example, studying Tph1 knockout mice (lacking peripheral serotonin) aided the development of telotristat ethyl, an approved treatment for carcinoid syndrome. Sglt1 (also known as Slc5a1) and Sglt2 (also known as Slc5a2) knockout mice were employed to develop sotagliflozin, a dual SGLT1/SGLT2 inhibitor having success in clinical trials for diabetes. Clinical trials evaluating inhibitors of AAK1 (neuropathic pain) and SGLT1 (diabetes) are underway. The research community can take advantage of these unbiased analyses of gene function in mice, including the minimally studied ‘ignorome’ genes.

Burden of carcinoid heart disease in patients initiating treatment for carcinoid syndrome.

262 Background: Carcinoid heart disease (CaHD) develops as a complication of uncontrolled carcinoid syndrome (CS) due to overproduction of serotonin. Delayed diagnosis or control of CS may result in a greater prevalence of cardiac involvement. The objective of this study was to determine the burden of CaHD in patients initiating somatostatin analogs (SSA) for CS. Methods: This retrospective study investigated claims for commercially insured adults receiving SSA for CS between 2010 and 2016. Claims were evaluated for markers of CaHD such as tricuspid or pulmonary valve-related disease. Eligible patients had ≥ 1 medical claim for CS, had initiated SSA treatment, were continuously enrolled in their health plan for 30 days prior to SSA initiation and for ≥ 1 year, had no sign of acromegaly, and did not participate in a clinical trial during the study period. Patients were followed as long as they were observed in the dataset. Descriptive statistics examined demographic and treatment characteristics and costs for patients with (cases) and without (controls) a marker for CaHD during the study period. Results: A total of 654 patients with CS met the study criteria, of which 38% (n = 248) already had ≥ 1 marker for CaHD prior to initiating SSA treatment. At least 1 CaHD marker was identified in 46% (n = 185) of patients (cases) during the follow-up period. Except for age, all demographic characteristics were similar between cases and controls (n = 221). Cases were significantly older than controls (mean 67 vs. 64 years, p = 0.004). Average follow-up was 26 months (SD 22.0) for cases and 35 months (SD 24.8) for controls. Average time to observation of first CaHD marker for cases was 16 months (SD 16.7) after SSA initiation; most (84%) had ≥ 2 CaHD markers. Markers of right heart involvement were present in 20% of cases, and aortic or mitral valve involvement in 15% and 24%, respectively. Annual per patient expenditures were significantly higher for cases versus controls (mean [SD]: $51,825 [$70,423] vs $29,068 [$56,454], respectively). Conclusions: This study revealed that CaHD is common among patients with CS both before and after initiating SSA treatment. Early diagnosis and control of CS is necessary to reduce the burden of CaHD.

Biochemical Responses in Symptomatic and Asymptomatic Patients with Neuroendocrine Tumors: Pooled Analysis of Two Phase 3 Trials

Neuroendocrine tumors (NETs) are associated with elevated 5-hydroxyindoleacetic acid (5-HIAA) and chromogranin A (CgA) levels. This study aimed to analyze relationships between urinary 5-HIAA and plasma CgA levels and clinical outcomes. Centrally assessed biomarker levels and correlations with progression-free survival (PFS) and carcinoid syndrome (CS) symptom control were evaluated in a pooled analysis of CLARINET (96-week randomized, double-blind, placebo-controlled) and ELECT (16-week randomized, double-blind, placebo-controlled, 32-week initial open label and ≥2 year long-term extension open label) studies of adults with NETs, with (ELECT) or without (CLARINET) CS at 97 institutions. Patients were treated with subcutaneous lanreotide depot 120 mg monthly. Of 319 pooled patients, 86% and 95% had baseline 5-HIAA and CgA data, respectively, with 47% and 74% having levels greater than the upper limit of normal (ULN). PFS was longer among patients who experienced a decrease in biomarker levels at week 12, with statistical significance reached in the CgA cohort (not reached vs. 14.4 months; P<.0001). A large proportion (87%) of patients without symptoms of CS in the CLARINET study had detectable levels of 5-HIAA (48% >ULN). In ELECT, patients with CS who received lanreotide and experienced a biochemical response (≥50% decrease from baseline) achieved greater symptom control. This pooled analysis of two randomized, placebo-controlled trials demonstrated that 5-HIAA and CgA are secreted as biochemical biomarkers in many patients with NETs, regardless of clinical syndromes. Significant biochemical response was associated with improved clinical outcomes, as measured by improved PFS or improved CS symptom control. 5-HIAA = 5-hydroxyindoleacetic acid; CgA = chromogranin A; CI = confidence interval; CLARINET = Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors; CS = carcinoid syndrome; ELECT = Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment; HR = hazard ratio; ITT = intention-to-treat; NET = neuroendocrine tumor; PanNET = pancreatic NET; PFS = progression-free survival; PPI = proton pump inhibitor; SSA = somatostatin analogue; ULN = upper limit of normal.

Oral Ondansetron Offers Effective Antidiarrheal Activity for Carcinoid Syndrome Refractory to Somatostatin Analogs.

Somatostatin analogs (SSAs) are standard for symptomatic patients with neuroendocrine tumors (NETs). However, most patients experience tachyphylaxis, and limited options exist for this so-called "refractory carcinoid syndrome." Recently, 5-HT3 antagonist ondansetron has been associated with reduction of bowel movement in a small series. The aim of this analysis was to assess effectiveness of ondansetron for symptomatic treatment of carcinoid syndrome. We have analyzed patients given ondansetron as bridging therapy for refractory carcinoid syndrome. The dose was 2 × 8 mg for 5 days, followed by reduction to 1 × 8 mg in case of benefit. A total of 14 patients with small bowel NETs metastatic to the liver were identified. All patients had been treated with SSAs for a median time of 18 months before aggravation of diarrhea. One patient had to be excluded because of an underlying infectious cause of diarrhea. The median number of daily bowel movements was 7 (range, 5-13) before initiation of therapy. At this time, seven patients had stable disease, whereas six patients showed radiological progression with symptomatic breakthrough. All 13 patients were scheduled for salvage therapy. Remarkably, in 85% (11/13) ondansetron resulted in a clinically relevant decrease of bowel movements to a median of 3 (1-4). The median time of ondansetron intake was 29 days (7 days to 29 months). In four patients, diarrhea recurred after initial improvement at an interval of 22-43 days, whereas the remaining seven had an ongoing benefit, including two long-term responders who refused further therapy because of pronounced decrease of symptoms (ondansetron for 14+ and 29+ months). Ondansetron offers symptomatic relief in the majority of patients. Although there was no influence on 5-HIAA levels, evidence from two patients suggests prolonged benefit. Somatostatin analogs are standard treatment in patients with carcinoid syndrome and have an overall response rate of up to 50%. This symptomatic benefit, however, is lost in many patients because of the development of tachyphylaxis or tumor progression. Patients with this "refractory carcinoid syndrome" pose a therapeutic challenge and are sometimes faced with a detrimental effect on quality of life. In this article, the authors suggest the 5-HT3 receptor antagonist ondansetron as potential symptomatic therapy for patients with refractory diarrhea due to carcinoid syndrome. Although the number of patients in this retrospective series is limited, treatment was easily applicable, feasible, and safe and resulted in an ongoing symptomatic benefit in 85% of patients, including two long-term responders.

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

PurposeIn 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/m2) 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. MethodsAssessment of the occurrence of weight change ≥3% at week 12 was prespecified in the statistical analysis plan. FindingsIn 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. ImplicationsUp 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.