Elsevier

The Lancet Oncology

Volume 18, Issue 4, April 2017, Pages 525-534
The Lancet Oncology

Articles
Frequency of carcinoid syndrome at neuroendocrine tumour diagnosis: a population-based study

https://doi.org/10.1016/S1470-2045(17)30110-9Get rights and content

Summary

Background

Neuroendocrine tumours (NETs) can secrete bioactive amines into the bloodstream, causing carcinoid syndrome, with symptoms including flushing and diarrhoea. However, carcinoid syndrome frequency in the NET population has never been rigorously assessed, nor has its relationship to presenting clinicopathological characteristics. This analysis assessed the proportion of patients with NETs and carcinoid syndrome in the USA and associated clinical factors.

Methods

We identified patients (≥65 years of age) from the Surveillance, Epidemiology, and End Results-Medicare database, excluding those with pancreatic tumours or small-cell or large-cell lung cancer, as well as those without complete data. We assessed the incidence of patients with at least two insurance claims of flushing, diarrhoea, or carcinoid syndrome during the 3 months before and after NET diagnosis. We compared demographic and clinical characteristics between patients with and without carcinoid syndrome using χ2 tests. We used the Cochran-Armitage trend test to identify trends in carcinoid syndrome incidence and Cox regression to assess the relationship between carcinoid syndrome and survival.

Findings

Between April 1, 2000, and Dec 31, 2011, 9512 eligible patients were diagnosed with NETs, of whom 1786 (19%) had carcinoid syndrome. The number of patients with NETs and carcinoid syndrome increased from 50 (11%) of 465 patients in 2000 to 160 (19%) of 854 in 2011 (p<0·0001). The proportion of patients with carcinoid syndrome compared with those without did not differ significantly with respect to age at diagnosis (p=0·65), geographical region (p=0·054), or urban versus rural status (p=0·53). Patients with carcinoid syndrome were more frequently female than male (p=0·0003). Race was associated with a significant difference in the reported incidence of carcinoid syndrome (p<0·0001), as was tumour grade, stage, and primary tumour site (all p<0·0001). Patients with carcinoid syndrome had a shorter overall survival (median 5 years [95% CI 4·5–5·4]) than did those without carcinoid syndrome (5·6 years [5·4–5·9]; hazard ratio 1·102 [1·016–1·194]; p=0·019). Use of octreotide (p<0·0001) and chemotherapy (p=0·003) were more common in patients with carcinoid syndrome than in those without it, whereas surgery was used more frequently in patients without carcinoid syndrome (p=0·009); use of radiotherapy was not significantly associated with the presence of carcinoid syndrome at diagnosis (p=0·07).

Interpretation

This population-based analysis reveals that carcinoid syndrome is significantly associated with tumour grade, stage, and primary tumour site, and leads to shorter survival compared with those patients without carcinoid syndrome. An improved understanding of the heterogeneity of presenting symptoms among patients with NETs might permit more tailored assessment and management than at present and enable future research into the effect of carcinoid syndrome control on patient survival.

Funding

Ipsen.

Introduction

Neuroendocrine tumours (NETs) are rare malignancies that can develop from a diffuse network of neuroendocrine cells throughout the body. Their incidence is increasing, with Surveillance, Epidemiology, and End Results (SEER) data showing a five-times increase from 1973 to 2004 and an annual incidence of 5·25 per 100 000 people in the USA in 2004.1 This increase is probably multifactorial and related to improvements in detection and diagnosis, as well as a true rise in incidence. Given the indolent nature of well differentiated NETs, many patients live for more than 5 years with metastatic disease and have symptoms for substantial periods of time.

Extrapancreatic NETs are historically known as carcinoids because of their carcinoma-like histology. These NETs can secrete bioactive amines causing carcinoid syndrome.2 These symptoms consist of wheezing, skin flushing, diarrhoea, and fibrotic valvular heart disease.3 Consistent with observations that serotonin is a product of the enterochromaffin cells4 considered the non-malignant counterparts of gastrointestinal NETs, serotonin secretion is associated with carcinoid syndrome in patients with NETs.5 Similarly, urinary excretion of the downstream serotonin metabolite 5-hydroxyindoleacetic acid is elevated in patients with carcinoid syndrome, more so than that of serum serotonin, which fluctuates substantially.6 Hormone secretion and associated symptoms can be reduced but not eliminated in most patients using somatostatin analogues, such as octreotide.7, 8, 9

Research in context

Evidence before this study

A search of PubMed between Jan 1, 2000, and Oct 15, 2016, with the Medical Education Subject Headings “malignant carcinoid syndrome/epidemiology” and “carcinoid tumor”, with no language restrictions, revealed 44 publications. Two studies included more than 150 patients. One study included 2001 patients and the other included 3379 patients with pancreatic neuroendocrine tumours (NETs) and 8088 patients with gastrointestinal NETs. Carcinoid syndrome was estimated to occur in 3·2% of patients in the larger study using retrospective questionnaires and 21·4% of patients in the other study.

Added value of this study

This study used prospective databases to identify 9512 patients with extrapancreatic NETs and used claims data to identify those with carcinoid syndrome. To our knowledge, it is the largest, most rigorous analysis of the epidemiology of carcinoid syndrome and associated clinicopathological factors. Nearly 20% of patients with NETs had carcinoid syndrome in our study, which was associated with tumour grade, stage, and primary tumour site. Carcinoid syndrome was also associated with survival.

Implications of all the available evidence

This work highlights the prognostic importance of prioritisation of the diagnosis of carcinoid syndrome in patients with NETs and raises potential future research questions regarding the survival benefit of carcinoid syndrome control. Patients with carcinoid syndrome might need more aggressive tumour monitoring and management than might patients without, and a deeper understanding of tumour serotonin synthesis than at present might provide additional actionable insights into tumour biology.

However, the frequency of carcinoid syndrome among patients with NETs has not been systematically assessed. Although previous studies10, 11, 12, 13 have attempted to estimate this frequency, the wide range identified (3–74%) suggests methodological limitations and the need to establish a more accurate incidence than at present in the broad NET patient population. Indeed, previous analyses were small retrospective studies from single centres or relied on surveys, with potential ascertainment bias.

Although the reported frequency of carcinoid syndrome among patients with NETs has been inconsistent, the effect of carcinoid syndrome on patient quality of life is clear.2, 14, 15, 16 Patients with NETs and carcinoid syndrome show marked impairments in multiple areas, namely fatigue, general health, and physical function, compared with both the general population15, 16 and with patients with NETs without overt carcinoid syndrome,2 using metrics such as the Patient-Reported Outcomes Measurement Information System (PROMIS) 29 and 36-Item Short Form Health Survey (SF-36). Additionally, findings from small studies6, 17, 18 have suggested that potentially because of subclinical niacin deficiency from tumour consumption of tryptophan to produce serotonin, even patients with NETs on therapeutic somatostatin analogues have modest subjective and objective cognitive impairments.19, 20 Given the importance of understanding the symptom burden of this growing patient population, this study used SEER-Medicare, a large, population-based database, to examine trends in the incidence of carcinoid syndrome and associated symptoms. We compared demographic and clinical characteristics between patients with and without carcinoid syndrome to establish factors associated with NETs and carcinoid syndrome. We also assessed treatment selection and patient outcomes.

Section snippets

Study design and patients

The data source used for this study is the SEER registry linked with Medicare claims data. The SEER programme of the National Cancer Institute provides information about cancer statistics, including tumour characteristics, patient demographics, and cause of death information for people diagnosed with cancer in the USA. The SEER registries cover approximately 28% of the US population and, when linked to Medicare claims data, provide detailed patient information, such as neighbourhood

Results

Between April 1, 2000, and Dec 31, 2011, 27 702 patients in the SEER-Medicare database were diagnosed with NETs, of whom 9512 were eligible for this analysis (figure 1). We assessed the proportion of patients with newly diagnosed NETs who were also diagnosed with carcinoid syndrome or its component symptoms for each year between 2000 and 2011 (figure 2). 1786 (19%) of 9512 were deemed to have carcinoid syndrome in the 6 months surrounding the diagnosis of NET. The number of patients diagnosed

Discussion

In this study of 9512 incident cases of NETs in patients 65 years of age and older diagnosed over more than a decade, the aggregate proportion of patients with symptoms indicating a carcinoid syndrome diagnosis was 19%, ranging from 229 (8%) of 2773 with lung NETs to 717 (32%) of 1494 with small-bowel NETs. To our knowledge, this work represents the first comprehensive epidemiological analysis of the incidence of carcinoid syndrome among patients newly diagnosed with NETs. Since nearly one in

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