Persistent low urinary excretion of 5-HIAA is a marker for favourable survival during follow-up in patients with disseminated midgut carcinoid tumours

doi:10.1016/j.ejca.2007.07.025

European Journal of Cancer

Volume 43, Issue 18, December 2007, Pages 2651-2657

https://doi.org/10.1016/j.ejca.2007.07.025 Get rights and content

Abstract

Survival of patients with disseminated midgut carcinoid tumours varies. We investigated which factors predict survival at referral and during follow-up, with emphasis on urinary 5-hydroxyindolacetic acid (5-HIAA) levels.

Between 1992 and 2003, 76 patients were studied; urine was prospectively collected over a 24 h period every 3 months in order to measure 5-HIAA levels. Uni- and multivariate analyses were performed.

Median follow-up was 55 months with a median survival of 54 months. Prognostic factors for poor survival were high age, high gamma-glutamyltransferase levels and greatly increased 5-HIAA levels (>20 mmol/mol creatinine) The Hazard Ratio (HR) of a greatly increased 5-HIAA level was 3.33 (95% confidence interval (CI) 1.66–6.66, p = 0.001).

In a multivariate survival analysis with the 5-HIAA level as time dependent covariable, the HR for the 5-HIAA level was 1.007 (95% CI 1.004–1.010, p = 0.000).

In conclusion, patients with persistent moderately increased urinary 5-HIAA levels (⩽ 20 mmol/mol creatinine) have favourable outcome.

Introduction

Midgut carcinoid tumours are rare, slowly growing neuroendocrine tumours (NET) originating in the small intestine and proximal colon. They are derived from enterochromaffin cells and capable of secreting serotonin.¹ The World Health Organisation nowadays classifies these tumours as well differentiated neuroendocrine carcinomas of the small bowel.² However, the term midgut carcinoid tumour is still being used for those tumours originating from the enterochromaffine cells, with serotonin secretion and associated with the carcinoid syndrome. In patients with disseminated midgut carcinoid tumours, an increased urinary 5-hydroxyindolacetic acid (5-HIAA) level, the metabolite of serotonin, is found.³ The urinary 5-HIAA level is used as a diagnostic test and is used in the evaluation of disease progression and treatment.4, 5 Treatment of patients with disseminated midgut carcinoid tumours is primarily palliative and aimed at ameliorating symptoms, improving quality of life and prolonging survival. This can be achieved by somatostatin analogues,⁶ interferon,⁷ targeted radionuclide therapy⁸ and in selective patients by surgery.⁹ Treatment leads, in the majority of patients, to a reduction of the urinary 5-HIAA levels but rarely in objective tumour responses. Recently, however, several targeted drugs such as sunitinib, bevacizumab and mTOR inhibitors showed signs of antitumour activity in these tumours.10, 11, 12, 13, 14 This raised the interest in the course of the disease in order to decide, in the future, when during this protracted disease to start which drug.

Survival varies greatly between these patients and it is difficult to predict the course of an individual patient. In a large population based study, 5 year survival rate was 44.1% for patients with disseminated midgut carcinoid tumours.¹⁵ In several studies prognostic factors were studied (Table 1).9, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37 Unfavourable factors for survival are high urinary 5-HIAA levels at first visit in referral centres, high plasma Chromogranin A (CgA) levels, the presence of liver or lymph node metastases, carcinoid heart disease, tumour size, histological grade of differentiation and old age (Table 1). With the exception of the study of Turner and colleagues no studies are available that focussed on biochemical parameters during follow-up to predict survival.³⁴ Given the numerous drugs that seem to become available for these tumours it would be extremely helpful, in addition to radiological tumour measurements, to have a marker available that indicates prognosis during follow-up. This could guide selection of patients that potentially might benefit from intervention with newer agents. Therefore, the aim of the present study was to determine factors that predict survival of patients with disseminated midgut carcinoid tumours at referral and during follow-up with the emphasis on the urinary 5-HIAA level.

Section snippets

Patients

Between January 1992 and December 2003 all patients with a disseminated midgut carcinoid tumour who were referred for treatment at the Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, were studied. The diagnosis of a disseminated midgut carcinoid tumour was based on the review of operation reports, the pathology specimens, thoracoabdominal computed tomography, somatostatin scintigraphy and increased levels of 5-HIAA in a 24 h urine collection (upper

Patients

A total of 76 patients, 33 male and 43 female patients, all Caucasian, were included. Table 2 shows the characteristics of patients at referral. Nine patients (11.8%) developed carcinoid heart disease during follow-up. Patients with carcinoid heart disease had higher urinary 5-HIAA levels at referral, 52.8 mmol/mol creatinine (range 8.5–252.0 mmol/mol creatinine) compared to patients without carcinoid heart disease, 18.6 mmol/mol creatinine (range 1.3–418.4 mmol/mol creatinine) (p = 0.085).

Discussion

To our knowledge, this is the first study to demonstrate that the urinary 5-HIAA level is an independent prognostic factor both at referral and during follow-up for patients with a disseminated midgut carcinoid tumour. Patients with a greatly increased urinary 5-HIAA level at referral (>20 mmol/mol creatinine) had a median survival of 33 months compared to 90 months for patients with a moderately increased level (⩽20 mmol/mol creatinine). Next to the urinary 5-HIAA level we found that high age

Conflict of interest statement

None declared.

Acknowledgement

We are indebted to G. Sieling for dedicated database management of all our patients.

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5-Hydroxyindole-3-acetic acid (5-HIAA) is regarded as a biomarker for diagnosis of carcinoid tumors, and it is of great significance to developing a precision assay for monitoring 5-HIAA levels. In this work, gold nanoparticles loading on the surface of MOF-199 (Au NPs/MOF-199) is prepared to propose a surface enhanced Raman scattering (SERS) assay for 5-HIAA. When 4-mercaptopyridine (4-MPy) is used as a SERS probe, on Au NPs/MOF-199, limit of detection (LOD) at 10⁻⁹ mol/L can be achieved. In addition, Au NPs/MOF-199 substrate with good preparation reproducibility shows long-term storage stability at 4 °C. Under optimal condition, the Au NPs/MOF-199-based SERS method is applied to determine 5-HIAA in serum. The concentration linear range is from 10⁻⁹ to 10⁻⁵ mol/L and LOD is of 6.40 × 10⁻¹¹ mol/L. Much importantly, Au NPs/MOF-199 substrate exhibits specific response toward 5-HIAA against other metabolites in the serum due to the capturing selectivity from porous MOF-199. The recoveries obtained on spiked human serum samples locate in the span from 94.30% to 106.00% with RSD of 4.01–7.43%. Au NPs/MOF-199-based SERS sensing strategy is a promising avenue for on-field monitoring biomedical species for clinic diagnosis purpose.
Biochemical responses in symptomatic and asymptomatic patients with neuroendocrine tumors: Pooled analysis of two phase 3 trials
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Citation Excerpt :
The utility of 5-HIAA in patients with NETs is controversial, with conflicting results regarding the potential utility of 5-HIAA as a prognostic marker of survival. Elevated urinary 5-HIAA has been correlated with severe CS symptoms as well as worse survival (2,13,14). In patients with midgut NETs, increases in 5-HIAA >5,000 μg/L have been predictive of shorter survival (15).
Objective: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
Abbreviations: 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
Prognostic utility of 24-hour urinary 5-HIAA doubling time in patients with neuroendocrine tumors
2018, Endocrine Practice
Objective: New clinical prognostic tools are needed to select the population of patients with neuroendocrine tumors (NETs) that have a high risk of disease progression and disease-specific mortality (DSM). Biochemical biomarker doubling time (DT) is used clinically for prognosis prediction in several solid malignancies. The aim of the current study was to determine whether 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA) level DT has any prognostic utility in patients with NETs.
Methods: Patients with NETs were enrolled in a prospective study with comprehensive biochemical analysis. The current analysis included 90 subjects with increasing 5-HIAA levels in two consecutive measurements. DT was calculated using the Schwartz equation. The primary outcome measures were DSM and disease progression.
Results: 5-HIAA DT of <434 days was associated with a higher rate of DSM (P =.02), with positive and negative predictive values for DSM of 75 and 77%, respectively. The difference in DSM was accounted for mainly by patients with small intestine or unknown primary NET (P =.01). In addition, a shorter 5-HIAA DT in patients with small intestine or unknown primary NET was associated with a higher risk of disease progression both in univariate (P =.001) and multivariable analyses (hazard ratio, 15.8; 95% confidence interval, 1.3 to 198.0; P =.03).
Conclusion: 5-HIAA DT may be used as a risk stratification tool in patients with small intestine NET or NET of unknown primary after it is validated in an independent cohort and can assist in identifying patients with a high risk for disease progression and DSM.
Abbreviations: CT = computed tomography; DSM = disease-specific mortality; DT = doubling time; 5-HIAA = 5-hydroxyindoleacetic acid; MRI = magnetic resonance imaging; NET = neuroendocrine tumor; NETUP = neuroendocrine tumor of unknown primary; PET = positron emission tomography; PFS = progression-free survival; PNET = pancreatic neuroendocrine tumor; ROC = receiver operating characteristic; SINET = small-intestine neuroendocrine tumor
Role of palliative resection of the primary tumour in advanced pancreatic and small intestinal neuroendocrine tumours: A systematic review and meta-analysis
2017, European Journal of Surgical Oncology
Citation Excerpt :
Of the thirteen papers that quoted survival outcomes for the surgical and non-surgical groups, six quoted an adjusted hazard ratio from a multivariable cox regression model (Table 2). Three studies (Huttner,19 Du14 and van der Hort-Schrivers23) additionally quoted hazard ratios from univariable analysis, which were consistent with the multivariable results (HR: 0.47 vs. 0.41, 0.39 vs. 0.34 and 0.58 vs. 0.61 respectively). Hence, the meta-analysis was based on the multivariable results in order to maximise the number of studies available for analysis.
This study aimed to evaluate the impact on overall survival following palliative surgery to remove the primary lesion in unresectable metastatic small intestinal (SI-NET) and pancreatic neuroendocrine tumours (P-NET).
A systematic review of the literature and meta-analysis was performed. MEDLINE and Embase databases were searched to identify articles comparing patients undergoing palliative primary tumour resection without metastatectomy vs. no resection. Relevant articles were identified in accordance with PRISMA guidelines. The primary outcome was overall survival. Included studies were evaluated for heterogeneity and publication bias.
13 studies met the inclusion criteria, of which 6 presented data suitable for meta-analysis. No randomised controlled trials were identified. Analysis of pooled multivariate hazard ratios demonstrated significantly longer overall survival in patients undergoing resection of both P-NETs (HR 0.43; 95% CI: 0.34–0.57, p < 0.001) and SI-NETs (HR 0.47; 95% CI: 0.35–0.55, p = 0.007). The increase in median survival in patients treated surgically relative to non-surgically ranged from 14 to 46 months in P-NET, and 22–112 months in SI-NET. The number needed to treat in order that one additional patient was alive at five years, ranged from 3.0 to 4.2, and 1.7 to 7.7 respectively.
Meta-analysis demonstrates that palliative resection of primary SI-NETs and P-NETs in the setting of unresectable metastatic disease can increase survival. Although these results should be interpreted with caution due to potential selection and publication bias, the data supports consideration of surgery, particularly in patients with low tumour burdens and good functional status.
Prognostic and predictive biomarkers in neuroendocrine tumours
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Neuroendocrine tumours are extremely heterogeneous malignancies. Despite marked heterogeneity in clinical course and prognosis, few biomarkers exist to help predict prognosis and guide treatment. Many tumour-based biomarkers (Ki-67, mitotic count, genetic/epigenetic changes and microRNAs) exist, but only Ki-67 and mitotic count have strong evidence to support their routine use. Blood-based markers are easily repeatable, but currently established biomarkers (chromogranin A and urinary 5-HIAA) are difficult to measure accurately in practice. Structural imaging is used routinely via the TNM system. Functional imaging such as ⁶⁸Ga-based and FDG PET may become valuable biomarkers with their increasing availability, aided by ongoing quantitative research. Multiple nomograms have been proposed to integrate the above factors, but most have not been prospectively validated and are difficult to use in practice. Further research should aim to establish robust new biomarkers and integrate existing ones to help optimise NET treatment.
Urinary 5-Hydroxyindolacetic Acid Measurements in Patients with Neuroendocrine Tumor-Related Carcinoid Syndrome: State of the Art
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Persistent low urinary excretion of 5-HIAA is a marker for favourable survival during follow-up in patients with disseminated midgut carcinoid tumours

Abstract

Introduction

Section snippets

Patients

Patients

Discussion

Conflict of interest statement

Acknowledgement

Lancet

Lancet Oncol

Ann Oncol

Surgery

Gastroenterology

Surgery

Ann Oncol

J Am Coll Cardiol

Eur J Cancer

Histological typing of endocrine tumours

Discriminating capacity of indole markers in the diagnosis of carcinoid tumors

Clin Chem

Neuroendocrine tumor panel. NCCN clinical practice guidelines in oncology

Neuroendocrine tumors

Carcinoid heart disease

N Engl J Med

Treatment of the malignant carcinoid syndrome. Evaluation of a long-acting somatostatin analogue

N Engl J Med

Effects of leukocyte interferon on clinical symptoms and hormone levels in patients with mid-gut carcinoid tumors and carcinoid syndrome

N Engl J Med

Radiolabeled somatostatin analog [177Lu-DOTA0,Tyr3]octreotate in patients with endocrine gastroenteropancreatic tumors

J Clin Oncol

Effect of surgery on the outcome of midgut carcinoid disease with lymph node and liver metastases

World J Surg

Analysis of circulating biomarkers of sunitinib malate in patients with unresectable neuroendocrine tumors (NET): VEGF, IL-8, and soluble VEGF receptors 2 and 3

J Clin Oncol

A phase II clinical and pharmacodynamic study of temsirolimus in advanced neuroendocrine carcinomas

Br J Cancer

Improved progressio ee survival (PFS), and rapid, sustained decrease in tumor perfusion among patients with advanced carcinoid treated with bevacizumab

J Clin Oncol

Clinical and in vitro studies of imatinib in advanced carcinoid tumors

Clin Cancer Res

Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors

Cancer