Carcinoid syndrome-Symptoms and therapeutic approaches.

The carcinoid syndrome (CS) is a constellation of symptoms attributed to hypersecretion of amines, prostaglandins and polypeptides. The cardinal symptoms of CS are flushing, diarrhea and bronchospasm; however, CS may present with various symptoms and signs, as: Skin: cutaneous flushes, cyanosis, pellagra, Gastrointestinal: diarrhea, nausea, abdominal cramps, vomiting, Heart: tricuspid and pulmonic valve thickening causing right heart failure, edema, Respiratory: wheezing, dyspnea.

Health care resource use and costs among patients with carcinoid syndrome in France: Analysis of the National Health Insurance Database.

OBJECTIVES: Carcinoid syndrome (CS) develops in approximately 20% of patients with neuroendocrine tumours (NET). This study described healthcare resource utilization and its associated costs among patients with NET and CS, using the French national health care data system. METHODS: Patients were included if they had a hospital stay associated with the code E34.0 "CS" and at least one delivery of a somatostatin analogue (SSA) between 01/01/2012 and 31/12/2016. The end of the analysis was either 31/12/2017 or the date of death, whichever occurred first. Mean overall costs were described by item of expenditure and by periods. RESULTS: 646 patients were included: 64yo, 55% men, 64% and 15% had NET from the small-intestine or lung, respectively. Among them, 309 patients were incident and 271 died during the study period. Mean overall cost per person per month (PPPM) was €2,892: €3,273 for the first year following diagnosis, €2,574 in "middle-years" and €5,039 within the year preceding death. The two most costly expenditure items were drugs (€1,695 PPPM) and hospital stays (€870 PPPM). CONCLUSION: The first year following diagnosis and the year preceding death are the two periods representing the highest costs for CS care in France. Successful disease management may contribute to lower costs in the intermediate period.

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.

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.

Arterial function, biomarkers, carcinoid syndrome and carcinoid heart disease in patients with small intestinal neuroendocrine tumours.

PURPOSE: Carcinoid heart disease (CHD) is a life-threatening complication of carcinoid syndrome (CS) characterised by tricuspid regurgitation (TR). However, there is an unmet need for earlier diagnosis of CHD. We cross-sectionally assessed the prevalence and potential predictive or diagnostic markers for CS and CHD in a contemporary cohort of patients with small intestinal neuroendocrine tumours (SI-NETs). METHODS: Biochemical characteristics, hepatic tumour load, measures of arterial and endothelial function, atherosclerosis, and transthoracic echocardiography were analysed in a prospective cross-sectional setting. RESULTS: Among the 65 patients studied, 29 (45%) had CS (CS+ ), and 3 (5%) CHD. CS+ was characterised by significantly higher hepatic tumour load, S-5-HIAA and fP-CgA, higher frequency of diarrhoea and flushing, and more frequent PRRT compared to CS- (for all, P < 0.05). Central systolic, central mean, and central end-systolic blood pressures were significantly higher in CS+ than in CS- (for all, P < 0.05). Subjects with grades 2-4 TR had higher hepatic tumour burden, fP-CgA, and S-5-HIAA compared to those with grades 0-1 TR, but measures of vascular function did not differ. fP-CgA (P = 0.017) and S-5-HIAA (P = 0.019) but not proBNP increased significantly according to the severity of TR. CONCLUSION: Although CS is common, the prevalence of CHD was found to be lower in a contemporary cohort of SI-NET patients than previously anticipated. Measures of arterial or endothelial function or carotid atherosclerosis do not identify subjects with mild TR. Echocardiography remains the most sensitive means to diagnose CHD in CS patients with high tumour burden and elevated CgA and 5-HIAA.

Recent Advances in the Diagnosis and Management of Carcinoid Syndrome.

Carcinoid syndrome, a paraneoplastic condition linked with the release of multiple humoral factors, affects around 30-40% of patients with well-differentiated neuroendocrine tumours. Carcinoid syndrome has a major and unfavourable impact on patients' quality of life; it raises costs when compared to non-functioning neuroendocrine tumours; and it causes patients' lifestyles to alter, such as food, job, physical activity, and social life. Somatostatin analogues have been the first-line therapy for individuals with neuroendocrine tumours and carcinoid disease for decades. While these drugs give considerable relief from carcinoid syndrome symptoms, clinical progression is unavoidable, necessitating further research into newer treatment measures. Carcinoid tumours are sometimes difficult to diagnose because of their vague or nonspecific symptoms. There have been several advancements in all aspects of carcinoid syndrome, as well as novel therapeutics, in the previous few years. New epidemiological studies show that it is becoming more common; increasing insights into the pathogenesis of its various clinical manifestations and its natural history: definition of prognostic factors; new methods to verify its presence; the development of new drugs to treat its various manifestations, both initially and in somatostatin-refractory cases; and an increased understanding of the pathogenesis, natural history, and management of the disease. An all language literature search was conducted on MEDLINE, COCHRANE, EMBASE, and Google Scholar till November 2021. The following search strings and Medical Subject Headings (MeSH) terms were used: "Recent advances", "Carcinoid syndrome", "Neuroendocrine Neoplasms" and "Carcinoid heart disease". We comprehensively reviewed the literature on the pathogenesis, clinical features, and newer treatment modalities for Carcinoid Syndrome. Recent advancements in research and management have resulted from advances in our understanding of the aetiology of carcinoid syndrome. The development of molecular indicators of aggressiveness improved serum tumour markers, and the molecular aetiology of carcinoid heart disease are all possible because of advances in molecular biology. We conducted a comprehensive review to update knowledge regarding the pathophysiology, diagnostic protocols, and current and newer treatments for carcinoid syndrome, which presently requires a multidisciplinary approach, due to the complexity of the illness's aetiology, diagnosis, and therapy.

Clinical Features and Prognosis of Patients with Carcinoid Syndrome and Carcinoid Heart Disease: A Retrospective Multicentric Study of 276 Patients.

INTRODUCTION: Carcinoid syndrome is the most frequent functional syndrome of neuroendocrine neoplasia. It is characterized by flushing, diarrhea, wheezing, hypotension, and exanthema and may cause carcinoid heart disease. METHODS: We assessed clinical characteristics and prognosis of patients with carcinoid syndrome and carcinoid heart disease in 276 patients from 3 referral centers. RESULTS: Carcinoid syndrome patients had a mean age of 57 years (range 21-84) and a normal BMI of 24.9 (SD 4.5; range 13.8-39.6). Most primaries were of small bowel or unknown primaries with distant metastasis in 94.6%. Flushing was the most frequent symptom in 74.3% of patients, followed by diarrhea in 68.8%, and wheezing in 40.9%. Pain was described by 45.3%, weakness by 23.5%, and weight loss of >10% in 6 months by 30.1% of patients. Carcinoid heart disease was diagnosed in 37.3% of patients (n = 104) by echocardiography and involved predominantly in the tricuspid valve. Combinations with other valve defects were common. Somatostatin analogs were taken by 80.4% of patients and 17% needed additional loperamide/opium tincture. Surgery and peptide receptor radiotherapy were most frequent treatments. The median survival of patients with carcinoid syndrome after diagnosis was 9 years. Prognosis was significantly impaired by male sex and diagnosis of carcinoid heart disease but surprisingly significantly increased by the presence of symptoms flushing and weakness. DISCUSSION/CONCLUSION: Carcinoid syndrome is associated with extensive disease and primaries in small bowels or of unknown primary. Weight loss, weakness, and pain are frequent, and carcinoid heart disease is diagnosed in more than one-third of patients.

A prospective study of carcinoid crisis with no perioperative octreotide.

BACKGROUND: Carcinoid crises, defined as the sudden onset of hemodynamic instability in patients with neuroendocrine tumors undergoing operation, are associated with significantly increased risk of postoperative complications. Octreotide has been used prophylactically to reduce crisis rates as well as therapeutically to treat crises that still occur. However, studies using octreotide still report crisis rates of 3.4% to 35%, leading to the questioning of its efficacy. METHODS: Patients with neuroendocrine tumors undergoing operation between 2017 to 2020 with no perioperative octreotide were prospectively studied. Clinicopathologic data were compared by χ2 test for discrete variables and by Mann-Whitney U test for continuous variables. RESULTS: One hundred and seventy-one patients underwent 195 operations. Crisis was documented in 49 operations (25%), with a mean duration of 3 minutes. Crisis was more likely to occur in patients with small bowel primary tumors (P = .012), older age (P = .015), and carcinoid syndrome (P < .001). Those with crises were more likely to have major postoperative complications (P = .003). CONCLUSION: Completely eliminating perioperative octreotide resulted in neither increased rate nor duration compared with previous studies using octreotide. We conclude perioperative octreotide use may be safely stopped, owing to inefficacy, though the need for an effective medication is clear given continued higher rates of complications.

Value of a patient-reported-outcome measure of carcinoid syndrome symptoms.

OBJECTIVE: Literature on patient-reported outcomes (PRO) of carcinoid syndrome symptoms (CSS) is scarce. We used a patient-reported outcome measure (PROM) to evaluate CSS, the domains of daily life impacted by CSS, the main symptoms that affect daily life, its change according to clinical, biological and morphological evolution, and the risk factors for a poor PRO-CSS score. METHODS: Patients completed the PRO-CSS, EORTC-QLQ30, and GI-NET21 questionnaires at the time of their clinical, laboratory, and morphological assessments in a multicentre French cohort study from February 2019 to May 2020. RESULTS: In total, 147 patients with metastatic ileal (n =126), lung (n =20), or unknown primitive neuroendocrine tumour but high 5-hydroxyindole-3-acetic acid level (n =1) were included; 42 (32%) received an above-label dose of somatostatin analogues. Fifty-one (35%) patients had a poor PRO-CSS score. Travelling and food restriction were the two main domains affected. Diarrhoea (mean: 2.3/5 on Likert scale), imperiousness (mean of 2.5/5), fatigue (2.2/5), abdominal pain (1.7/5), and flushing episodes (1.5/5) were the main symptoms affecting daily life. The PRO-CSS score was not correlated to the clinical assessment performed by physicians at the baseline and during the follow-up. Patients with a poor PRO-CSS score had a higher tumour burden. CONCLUSIONS: PROM-CSS may help physicians make an objective assessment of CSS and its impact in daily practice; this tool could become a key evaluation criterion in clinical trials focusing on CSS.

Carcinoid Heart Disease: Prognostic Value of 5-Hydroxyindoleacetic Acid Levels and Impact on Survival: A Systematic Literature Review.

BACKGROUND: Carcinoid heart disease (CHD) can develop in patients with carcinoid syndrome (CS), itself caused by overproduction of hormones and other products from some neuroendocrine tumours. The most common hormone is serotonin, detected as high 5-hydroxyindoleacetic acid (5-HIAA). This systematic literature review summarises current literature on the impact of CHD on survival, and the relationship between 5-HIAA levels and CHD development, progression, and mortality. METHODS: MEDLINE, Embase, Cochrane databases, and grey literature were searched using terms for CHD, 5-HIAA, disease progression, and mortality/survival. Eligible articles were non-interventional and included patients with CS and predefined CHD and 5-HIAA outcomes. RESULTS: Publications reporting on 31 studies were included. The number and disease states of patients varied between studies. Estimates of CHD prevalence and incidence among patients with a diagnosis/symptoms indicative of CS were 3-65% and 3-42%, respectively. Most studies evaluating survival found significantly higher mortality rates among patients with versus without CHD. Patients with CHD reportedly had higher 5-HIAA levels; median urinary levels in patients with versus without CHD were 266-1,381 versus 67.5-575 µmol/24 h. Higher 5-HIAA levels were also found to correlate with disease progression (median progression/worsening-associated levels: 791-2,247 µmol/24 h) and increased odds of death (7% with every 100 nmol/L increase). CONCLUSIONS: Despite the heterogeneity of studies, the data indicate that CHD reduces survival, and higher 5-HIAA levels are associated with CHD development, disease progression, and increased risk of mortality; 5-HIAA levels should be carefully managed in these patients.

Work productivity burden and indirect costs associated with carcinoid syndrome diarrhea.

Objectives: We estimated the indirect costs of work productivity burden from carcinoid syndrome diarrhea (CSD) among employed, insured adults in the United States. Methods: Retrospective cohort study of patients ≥18 years old with CS who did and did not have CSD (2014-2016). Eligible patients had continuous health plan enrollment for ≥12 months prior to their first CS claim and for ≥30 days after. Univariate analyses of clinical and work productivity outcomes and indirect costs were conducted. Multivariate analyses examined associations of CSD with work productivity measures, controlling for baseline characteristics. Results: A total of 1,880 patients with CS were eligible, including 577 with CSD and 1,303 with CS only. Baseline characteristics were generally similar. Patients with CSD missed half of eligible workdays (median 56%, 146/260); those with CS-only missed one-third (38%, 100/260). Work productivity was lower and the associated costs were higher in the presence of CSD. Patients with CSD had more absenteeism, short-term disability, and lost workdays which translated into incremental mean costs of $16,679 greater than those with CS only. Conclusion: Indirect costs related to work productivity losses among adults with CSD are significant, which further add to the burden of CSD to society.

Direct costs of carcinoid syndrome diarrhea among adults in the United States.

BACKGROUND: The burden of carcinoid syndrome (CS) among patients with neuroendocrine tumors is substantial and has been shown to result in increased healthcare resource use and costs. The incremental burden of CS diarrhea (CSD) is less well understood, particularly among working age adults who make up a large proportion of the population of patients with CS. AIM: To estimate the direct medical costs of CSD to a self-insured employer in the United States. METHODS: CS patients with and without CSD were identified in the IBM® MarketScan® Database, including the Medicare Supplemental Coordination of Benefits database. Eligible patients had ≥ 1 medical claim for CS with continuous health plan enrollment for ≥ 12 mo prior to their first CS diagnosis and for ≥ 30 d after, no claims for acromegaly, and no clinical trial participation during the study period (2014-2016). Baseline demographic and clinical characteristics, including comorbidities and treatment, were analyzed using descriptive statistics. Measures of healthcare resource use and costs were compared between patients with and without CSD, including Emergency Department (ED) visits, hospital admissions and length of stay, physician office visits, outpatient services, and prescription claims, using univariate and multivariate analyses to evaluate associations of CSD with healthcare resource use and costs, controlling for baseline characteristics. RESULTS: Overall, 6855 patients with CS were identified of which 4,043 were eligible for the analysis (1352 with CSD, 2691 with CS only). Baseline demographic and clinical characteristics were similar between groups with the exception of age, underlying tumor type, and health insurance plan. Patients with CSD were older, had more comorbidities, and received more somatostatin analog therapy at baseline. Patients with CSD required greater use of healthcare resources and incurred higher costs than their peers without CSD, including hospitalizations (44% vs 25%) and ED visits (55% vs 31%). The total adjusted annual healthcare costs per patient were 50% higher (+ $23865) among those with CSD, driven by outpatient services (+ 56%), prescriptions (+ 48%), ED visits (+ 26%), physician office visits (+ 21%), and hospital admissions (+ 11%). CONCLUSION: The economic burden of CSD is greater than that of CS alone among insured working age adults in the United States, which may benefit from timely diagnosis and management.

Management of Diarrhea in Patients With Carcinoid Syndrome.

Neuroendocrine tumors (NETs) arise from enterochromaffin cells found in neuroendocrine tissues, with most occurring in the gastrointestinal tract. The global incidence of NETs has increased in the past 15 years, likely due to better diagnostic methods. Small-bowel NETs are frequently associated with carcinoid syndrome (CS). Carcinoid syndrome diarrhea occurs in 80% of CS patients and poses a substantial symptomatic and economic burden. Patients with CS diarrhea frequently suffer from diarrhea and flushing and report corresponding impairment in quality of life, requiring substantial changes in daily activities and lifestyle. Treatment paradigms range from surgical debulking to liver-directed therapies to treatment with somatostatin analogs, nonspecific anti-diarrheal agents, and a tryptophan hydroxylase inhibitor. Other causes of diarrhea, including steatorrhea, short bowel syndrome, and bile acid malabsorption, should be considered in NET patients with refractory diarrhea. More therapeutic options are needed for symptomatic management of patients with NETs, and better understanding of the pathophysiology can empower clinicians with improved patient care.

Telotristat ethyl: a novel agent for the therapy of carcinoid syndrome diarrhea.

Carcinoid syndrome (CS), characterized by diarrhea and flushing, is present in 20% of patients with neuroendocrine tumors at diagnosis and becomes more frequent with progression. The diarrhea of CS is caused mainly by tumoral secretion of serotonin. It may not be fully controlled by somatostatin analogs, the currently indicated drugs for symptomatic relief. Telotristat ethyl is a novel inhibitor of tryptophan hydroxylase, the rate-limiting enzyme in serotonin biosynthesis. Administration of the drug decreases diarrhea in patients with CS. Telotristat ethyl was approved in February 2017 (USA) and September 2017 (European Commission) for the treatment of CS diarrhea in adults inadequately controlled by somatostatin analog alone. This drug is expected to greatly improve the health and quality of life of patients with CS diarrhea.

Cost-effectiveness analysis of telotristat ethyl for treatment of carcinoid syndrome diarrhea inadequately controlled with somatostatin analogs.

AIMS: This study evaluated the cost-effectiveness of telotristat ethyl (TE) added to somatostatin analog octreotide (SSA + TE) compared to octreotide alone (SSA) in patients with carcinoid syndrome diarrhea (CSD) whose symptoms remain uncontrolled with SSA alone. MATERIALS AND METHODS: A deterministic Markov model evaluated the costs and quality-adjusted life-years (QALY) gained with SSA + TE vs SSA per a third-party US payer perspective. The model reflected clinical practice and resource use estimates based on current standards of care, with utility estimates based on similar symptoms from ulcerative colitis. Treatment efficacy was based on the phase III clinical trial of SSA + TE vs SSA alone [TELESTAR, NCT01677910]. According to TELESTAR, 44% of SSA + TE and 20% of SSA patients responded to therapy after 12 weeks. At each 4-week assessment period, SSA patients not adequately controlled received increasing doses of SSA and SSA + TE patients discontinued TE and moved to SSA only. Drug costs for adequately and not adequately controlled patients were $4,291.75 and $5,890.57 for SSA, respectively, and $9,456.07 and $5,890.57 for SSA + TE, respectively. RESULTS: The base-case analysis demonstrated lifetime QALYs of 1.67 at a cost of $495,125 for the SSA cohort and 2.33 ($590,087) for SSA + TE with an incremental QALY for SSA + TE of 0.66 for an additional $94,962. The incremental cost per QALY gained was $142,545. Sensitivity analyses demonstrated high probability (>99%) of SSA + TE being cost-effective at thresholds for rare diseases and orphan drugs of $300,000-$450,000. LIMITATIONS: The recent availability of TE precluded the incorporation of clinical and economic inputs based on real-world practice patterns. The scarcity of epidemiology and utility information for this rare condition required the use of some proxy estimates. CONCLUSIONS: This analysis demonstrated TE is a cost-effective treatment option when used on top of standard of care in CSD patients.

Development of a gastric carcinoid tumor following allogeneic hematopoietic stem cell transplantation for early T-cell precursor acute lymphoblastic leukemia.

Gastric carcinoid tumor is rarely diagnosed in children. We report a case of gastric carcinoid tumor that occurred after allogeneic HSCT. A 13-year-old girl with ETP acute lymphoblastic leukemia underwent allogeneic HSCT from a 7/8 HLA-matched unrelated donor. She presented with rashes, abdominal pain, and diarrhea, which were suggestive of GVHD, 7 months after HSCT. Immunosuppressive agents failed to resolve these symptoms well. After a series of evaluations, carcinoid syndrome caused by a gastric carcinoid tumor was diagnosed. The tumor was located in the antral region and resulted in partial gastric outlet obstruction. She received subtotal gastrectomy with regional lymph node dissection. However, she had a flare-up of GVHD 1 month after surgery, and immunosuppressive therapy was intensified accordingly. Although her GVHD was getting better, she developed respiratory syncytial viral pneumonia with rapid progression to respiratory failure. She died of multiple organ failure 2 months postoperatively. This is the first pediatric case of a gastric carcinoid tumor following allogeneic HSCT. Our case also highlights the necessity for pediatric transplant physicians to be aware of carcinoid syndrome caused by this rare tumor in the setting of GVHD with poor response to immunosuppressive agents.

Retrospective review of serotonergic medication tolerability in patients with neuroendocrine tumors with biochemically proven carcinoid syndrome.

BACKGROUND: Patients with carcinoid tumors frequently could benefit from the pharmacologic treatment of depression and anxiety. However, many prescribers avoid serotonergic medications due to the theoretical risk of exacerbating carcinoid syndrome. METHODS: The authors conducted a retrospective chart review of patients with carcinoid tumors and elevated serotonin levels (as measured by 24-hour urine 5-hydroxyindoleacetic acid [5-HIAA]) at Dana-Farber/Brigham and Women's Cancer Center who initiated treatment with serotonergic antidepressants after a carcinoid diagnosis from 2003 to 2016. Each medication regimen was categorized based on the presence of adverse interactions as defined by clinical worsening of symptoms of carcinoid syndrome in the absence of progressive disease that temporally correlated with a serotonergic medication trial. RESULTS: A total of 73 serotonergic regimens received by 52 patients were included in the primary analysis. Among these medication trials, 8.2% of the regimens (6 regimens) were categorized as being associated with a likely adverse interaction, 61.6% of the regimens (45 regimens) were categorized as having no adverse reaction, 9.6% of the regimens (7 regimens) were categorized as an unlikely adverse reaction, and 20.6% of the regimens (15 regimens) were categorized as unknown. It is interesting to note that none of the 73 trials resulted in a carcinoid crisis requiring emergency care or hospitalization. Only 3 patients discontinued serotonergic medications due to worsening carcinoid syndrome. CONCLUSIONS: Serotonergic medications appear to be a safe option for the treatment of depressive and anxiety symptoms in the majority of patients with neuroendocrine tumors and carcinoid syndrome. In the current study, <10% of patients developed a combination of flushing, diarrhea, and bloating after the initiation of serotonergic medications. Clinicians can begin with low doses, monitor these symptoms, and reduce the dose or discontinue the medication if necessary. Cancer 2017;123:2735-42. © 2017 American Cancer Society.