Carcinoid syndrome: Patient outcomes from a European Neuroendocrine Tumour Society (ENETs) centre of excellence

Background: Carcinoid syndrome (CS), characterised by flushing, diarrhoea, wheeze and fibrotic valvulopathy, arises in patients (pts) with advanced NETs due to serotonin and kallikrein secretion.Methods: Sequential pts with advanced well-differentiated gastroenteropancreatic NETs (GEP-NETs) treated at The Christie (1998-2017) with ≥1 carcinoid symptom(s) and raised serum/urinary 5-hydroxyindoleacetic acid (5-HIAA) were identified. Ratio of 5-HIAA/upper limit normal (ULN) was calculated. Progression-free (PFS) and overall survival (OS) were estimated (Kaplan-Meier method) and prognostic factors identified (Cox proportional hazards model).Results: Of 882 pts, 139 (16%) had CS: median (med) age 64 yrs, 55% male, 80% performance status (PS) 0-1, 13% PS 2; 65% had small bowel primary, 10% large bowel, 4% pancreas, 0.7% gastric, 21% unknown primary (consistent with GEP-NET origin). Tumour grade (G) was 1 in 45%; G2 in 29%; symptoms included diarrhoea (91%), flushing (89%), wheeze (22%), and carcinoid heart disease (CHD; 35%). Fifty-seven (41%) had primary resection, and 121 (87%) had liver metastases. In first line, 66% received a somatostatin analogue (SSA), 20% debulking surgery, 14% other. Med baseline 5-HIAA levels were 8.45 x ULN (urinary: 10.56 x ULN, serum: 6.07 x ULN). Med follow-up was 45.7 months (mo). Med PFS and OS were 27.0 (95%CI 17.2-33.9) and 65.4 (95%CI 50.4-76.4) mo. On univariate analysis, small bowel primary (P = 0.045), liver metastases (P = 0.03), Ki-67 (P < 0.01) and 5-HIAA baseline ratio (P < 0.001) were prognostic for PFS; and age (P < 0.01), PS (P < 0.01), primary in situ (P < 0.001), CHD (P = 0.03), Ki-67 (P = 0.03), baseline 5-HIAA ratio (P < 0.001) and use of SSA vs surgery (P = 0.02) were prognostic for OS. On multivariable analysis, high Ki-67 (HR 1.06, 95%CI 1.00-1.12, P = 0.049) and baseline 5-HIAA ratio (HR 1.03, 95%CI 1.01-1.05, P = 0.001) were prognostic for worse PFS. Primary in situ (HR 2.23, 95%CI 1.09-4.54, P = 0.03) and high baseline 5-HIAA ratio (HR 1.02, 95%CI 1.00-1.04, P = 0.04) were prognostic for worse OS. Change in 5-HIAA at 6 mo was not prognostic for PFS (P = 0.42) or OS (P = 0.60).Conclusions: Baseline 5-HIAA ratio, but not change from baseline to 6 months, was prognostic for PFS and OS. Treatment optimisation is pivotal.