While carcinoids frequently synthesize, and secrete serotonin into the circulation, and 5-HIAA is a common biomarker in the carcinoids, measurement of 5-HIAA in non-carcinoid PanNET patients (i.e. no hormone-related symptoms or nonfunctional) is not routinely recommended by international guidelines. The incidence of serotonin-producing PanNETs may be underestimated, with potential impact on clinical outcome when serotonin levels remain elevated. We sought to characterize 5-HIAA and CgA levels in PanNET patients who participated in the large placebo-controlled phase III CLARINET Study.
Evaluable data available for urinary 5-HIAA and serum CgA for patients with PanNET in CLARINET study were analyzed. Urinary 5-HIAA and Serum CgA were assessed at baseline and every 12 weeks thereafter through Week 96. Changes in urinary 5-HIAA and serum CgA levels were calculated using a non-parametric Wilcoxon 2-sample test. Biochemical response for urinary 5-HIAA or serum CgA was defined as baseline >upper limit of normal (ULN, 41.6 µmol/d 5-HIAA; 98.1 µg/L CgA) and ≥50% decrease from baseline or a decrease to a value ≤ULN on study.
91/204 patients in CLARINET had PanNETs. Evaluable data for urinary 5-HIAA and serum CgA concentrations were available in 79 and 88 patients, respectively. A substantial number of patients with PanNET had elevated (>ULN) urinary 5-HIAA levels (21/79; 27%) and/or serum CgA (63/88; 72%). Among the 21 PNET patients with baseline 5-HIAA >ULN, biochemical response was achieved in 85% (11/13) lanreotide-treated patients compared with 63% (5/8) in patients on placebo at the last available value (p = 0.33). Among patients with baseline CgA >ULN, biochemical response was achieved in 66% (19/29) of lanreotide vs. 18% (6/34) of placebo-treated patients (p = 0.0002). Limited sample sizes precluded robust analysis for statistically significant differences in the lanreotide vs. the placebo group among patients with elevated biomarkers at baseline and biochemical response.
The percentage of patients with elevated urinary 5-HIAA was unexpected. The concept of PanNET and secretion of serotonin may need to be redefined. The potential of 5-HIAA and CgA as biomarkers of response and follow-up in nonfunctioning PanNET is alluring, but requires further study. Data from additional prospective studies are needed to impact clinical practice guidelines.
Clinical trial identification
Legal entity responsible for the study
Ipsen Biopharmaceuticals r A.T. Phan: Consultant/Advisor: Ipsen, Novartis; speakers’ bureau: Celgene, Genentech, Eli Lilly, Ipsen, Novartis; research support: Incyte, Ipsen, Lexicon, Novartis, Sanofi. E.M. Wolin: Consultant/Advisor: Celgene, Ipsen, Novartis, Pfizer; research support: Ipsen (Inst), Novartis (Inst), Pfizer (Inst). N. Liyanage: Employee of Ipsen. B. Mirakhur: Employee of Ipsen Biopharmaceuticals. S. Pitman Lowenthal: Employee of Ipsen Biopharmaceuticals. A. Vinik: Const/Advisor: Isis, Merck, Neurometrix, Pamlab, Pfizer; speakers bureau: Merck, Pamlab; research support: BMS, Celgene, Eli Lilly, Medivation, Newlink Genetics, Novartis, Pharmaceutical Research Associates, Polaris, PRA International, Tercica, XBiotech. G.A. Fisher, Jr: Consultant/Advisor: Genentech, Ipsen; research support: BMS, Celgene, Lilly, Ipsen, Medivation, Newlink Genetics, Novartis, Pharmaceutical Research Associates, Polaris, PRA International, Tercica, XBiotech; stock ownership: Seattle Genetics. M. Pavel: Consultant/Advisor: Ipsen, Lexicon, Novartis, Pfizer; research support: Novartis.