Carcinoid heart disease in patients with advanced small-intestinal neuroendocrine tumors and carcinoid syndrome: a retrospective experience from two European referral centers

Abstract

Background: Up to 50% of patients with advanced small-intestinal neuroendocrine tumors (SI-NETs) and carcinoid syndrome (CS) develop carcinoid heart disease (CHD). However, the true frequency and prognostic markers for CHD in CS are lacking. We described the real-world management of patients in two NET referral centers in this clinical context and relationships between clinical features, including CHD and overall survival (OS).

Patients and methods: This is a retrospective analysis of patients with stage IV SI-NET and CS, treated at the European Institute of Oncology in Milan and Uppsala University in Sweden between 2015 and 2021. CHD was defined as at least one moderate right-sided heart valve defect. Median OS and cumulative incidence of CHD were estimated from the diagnosis of metastatic disease, and the association between clinical parameters with both OS and occurrence of CHD was evaluated.

Results: We included 165 patients, with 97% having low-intermediate-grade SI-NETs and 86% having synchronous liver metastases. Ninety-eight patients (59%) became refractory to full label dose of somatostatin analogues and 25% developed a CHD. At CHD diagnosis, baseline urine 5-hydroxyindoleacetic acid (24-h u5-HIAA) value and plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) value were known in 76% of patients. Moderate-to-severe tricuspid insufficiency was the most common alteration of CHD. Prognosis was significantly impaired by CHD (multivariable hazard ratio for OS = 2.85, P < 0.001). The median OS from the CHD diagnosis was 4.5 years [95% confidence interval (CI) 2.1-7.2 years], and the 5-year survival rate was 34% (95% CI 13% to 57%).

Conclusions: In our study population of SI-NET patients with CS, more than half had a refractory carcinoid syndrome (RCS) and one-quarter developed a CHD, with a negative impact on OS. Therefore, it is recommended to screen and monitor patients with CS for CHD, ideally with a combination of u5-HIAA, NT-proBNP values, and echocardiography at CS baseline, preferably in NET referral centers.

Keywords: carcinoid heart disease; carcinoid syndrome; neuroendocrine tumor; small intestinal.

Figure 1

Overall survival in the whole study population (N = 165, A), and among patients with carcinoid heart disease (N = 41, B). (A) The OS function was defined as the time from metastatic NET diagnosis until death or last contact, and was estimated using the Kaplan–Meier method. With a median follow-up of 4.2 years (IQR 2.6-6.5 years), 33% of our patients died. Since the diagnosis of metastatic disease, the 1-year OS rate was 97.5% (95% CI 93.4% to 99.0%) and the 5-year OS rate was 69.2% (95% CI 60.0% to 76.7%). The median OS of the whole study population was 8.9 years (95% CI 6.7-11.8 years). (B) For patients with CHD, the OS from CHD diagnosis was also calculated. Forty-six percent of the CHD patients died. The 1-year OS rate was 81.9% (95% CI 65.7% to 91.0%), and just one-third was alive at 5 years [5-year OS rate: 34.4% (95% CI 13.2% to 57.0%)]. The median OS of the CHD patients was 4.5 years (95% CI 2.1-7.2 years). CHD, carcinoid heart disease; CI, confidence interval; IQR, interquartile range; NET, neuroendocrine tumor; OS, overall survival.

Figure 2

Cumulative incidence function of carcinoid heart disease (N = 165). The CIF of carcinoid heart disease estimated according to method described by Kalbfleisch and Prentice, considering death as a competing event. The CIF of CHD in the whole study population at 1, 3, 5, and 8 years were 15.3% (95% CI 10.2% to 21.2%), 17.9% (95% CI 12.4% to 24.2%), 24.3% (95% CI 17.5% to 31.7%), and 30.2% (95% CI 21.7% to 39.0%), respectively. CHD, carcinoid heart disease; CI, confidence interval; CIF, cumulative incidence function; NET, neuroendocrine tumor.