Effect of Lanreotide Depot/Autogel on Urinary 5-Hydroxyindoleacetic Acid and Plasma Chromogranin A Biomarkers in Nonfunctional Metastatic Enteropancreatic Neuroendocrine Tumors

Oncologist. 2019 Apr;24(4):463-474. doi: 10.1634/theoncologist.2018-0217. Epub 2018 Oct 24.


Background: Urinary 5-hydroxyindoleacetic acid (5-HIAA) is an established biomarker in neuroendocrine tumors and carcinoid syndrome; however, its role in nonfunctional neuroendocrine tumors is not defined. We present post hoc data on urinary 5-HIAA and plasma chromogranin A (CgA) from the CLARINET study.

Methods: Patients with well- or moderately differentiated, nonfunctioning, locally advanced or metastatic enteropancreatic neuroendocrine tumors were randomized to deep subcutaneous lanreotide depot/autogel 120 mg or placebo once every 28 days for 96 weeks. Tumor response, evaluated centrally (RECIST 1.0), and progression-free survival (PFS) were assessed by treatment and biochemical response, defined as (a) baseline >upper limit of normal (ULN, 41.6 μmol per day 5-HIAA; 98.1 μg/L CgA) and (b) ≥50% decrease from baseline and to ≤ULN value on study.

Results: Forty-eight percent (82 of 171; lanreotide, n = 45; placebo, n = 37) and 66% (129 of 195; lanreotide, n = 65; placebo, n = 64) of randomized patients had 5-HIAA and CgA > ULN at baseline. Among patients with >ULN baseline values who did not progress after 96 weeks of treatment, significantly greater reductions in 5-HIAA and CgA were observed in lanreotide-treated versus placebo-treated patients throughout the study (all p < .05). PFS was significantly prolonged among 5-HIAA responders versus nonresponders (median not reached vs. 16.2 months, p < .0001; hazard ratio [HR] = 0.21, 95% confidence interval [CI], 0.09-0.48) and CgA responders versus nonresponders (median not reached vs. 16.2 months, p = .0070; HR = 0.30, 95% CI, 0.12-0.76), regardless of treatment arm. PFS was also significantly prolonged among lanreotide-treated 5-HIAA responders versus nonresponders (p = .0071) but was not significantly different among placebo-treated 5-HIAA responders versus nonresponders. There were no significant differences in PFS between lanreotide-treated CgA responders versus nonresponders or between placebo-treated CgA responders versus nonresponders.

Conclusions: The 5-HIAA findings are noteworthy because they occurred in patients with nonfunctioning enteropancreatic neuroendocrine tumors. Monitoring 5-HIAA and CgA may be useful when treating patients with nonfunctional neuroendocrine tumors.

Implications for practice: Current guidelines focus only on the monitoring of 5-hydroxyindoleacetic acid (5-HIAA) in the diagnosis and management of functional neuroendocrine tumors with carcinoid syndrome. The current post hoc analysis of patients with nonfunctional enteropancreatic neuroendocrine tumors in the CLARINET study demonstrated that measuring and following both 5-HIAA and chromogranin A as biomarkers of disease progression may be useful in the management of patients with nonfunctional neuroendocrine tumors.


背景。尿 5‐羟基吲哚乙酸 (5‐HIAA) 是一种神经内分泌瘤和类癌综合征的确定生物标志物;但是,其在非功能性神经内分泌瘤中的作用尚未确定。我们提供了来自 CLARINET 研究的尿 5‐HIAA 和血浆嗜铬粒蛋白 A (CgA) 的事后分析数据。

方法。我们为分化良好或中度分化、无功能、局部晚期或转移性肠胰神经内分泌瘤患者随机分配深层皮下兰瑞肽储库型控释注射/凝胶注射 120 mg 或安慰剂,每 28 天一次,持续 96 周。治疗和生化反应评估了集中评估的肿瘤反应 (RECIST 1.0) 和无进展生存期 (PFS),定义为 (a) 基线 > 正常值上限(ULN, 5‐HIAA 41.6 μmol每天; CgA 98.1 μg / L)和 (b) 基线起≥50% 减少,至研究的≤ULN值。

结果。48%(82 / 171 ;兰瑞肽, n = 45;安慰剂, n = 37)和 66%(129 / 195 ; 兰瑞肽,n = 65;安慰剂, n = 64) 的随机挑选患者出现 5‐HIAA 和 CgA > 基线 ULN。在治疗 96 周后病情没有进展的 >基线ULN值患者中,在整个研究中观察到兰瑞肽治疗对比安慰剂治疗患者的 5‐HIAA 和 CgA 显着大幅下降(均为p < 0.05)。5‐HIAA 应答者对比无应答者的 PFS 显著延长 [未达到中值vs. 16.2 个月,p < 0.000 1;风险比(HR) = 0.21,95% 置信区间(CI), 0.09‐0.48], CgA 应答者对比无应答者(未达到中值vs. 16.2 个月,p = 0.007 0;HR = 0.30,95% CI,0.12‐0.76),不论治疗方案。兰瑞肽治疗的 5‐HIAA 应答者对比无应答者的 PFS 也显著延长 (p = 0.007 1),但安慰剂治疗的 5‐HIAA 应答者对比无应答者的 PFS 无显著差异。兰瑞肽治疗或安慰剂治疗的 CgA 应答者与无应答者之间的PFS 无显著差异。

结论。5‐HIAA 的研究结果是值得关注的,因为它们发生在非功能性肠胰神经内分泌肿瘤患者中。在治疗非功能性神经内分泌肿瘤患者时,监测 5‐HIAA 和 CgA 可能会有用。

对实践的启示:当前指导方针只关注诊断和治疗伴有类癌综合征的功能性神经内分泌肿瘤中的 5‐羟基吲哚乙酸 (5‐HIAA) 监测。目前 CLARINET 研究中对非功能性肠胰神经内分泌肿瘤患者的事后分析表明,测量与跟踪作为疾病进展的生物标志物的 5‐HIAA 和嗜铬粒蛋白 A,可能会对治疗非功能性神经内分泌肿瘤患者有用。

Keywords: 5‐Hydroxyindoleacetic acid; Lanreotide; Neuroendocrine tumor; Plasma chromogranin A.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / therapeutic use
  • Biomarkers, Tumor / analysis*
  • Chromogranin A / blood*
  • Female
  • Follow-Up Studies
  • Gastrointestinal Neoplasms / blood
  • Gastrointestinal Neoplasms / drug therapy
  • Gastrointestinal Neoplasms / secondary*
  • Gastrointestinal Neoplasms / urine
  • Humans
  • Hydroxyindoleacetic Acid / urine*
  • International Agencies
  • Male
  • Middle Aged
  • Neuroendocrine Tumors / blood
  • Neuroendocrine Tumors / drug therapy
  • Neuroendocrine Tumors / secondary*
  • Neuroendocrine Tumors / urine
  • Pancreatic Neoplasms / blood
  • Pancreatic Neoplasms / drug therapy
  • Pancreatic Neoplasms / pathology*
  • Pancreatic Neoplasms / urine
  • Peptides, Cyclic / therapeutic use*
  • Prognosis
  • Retrospective Studies
  • Somatostatin / analogs & derivatives*
  • Somatostatin / therapeutic use
  • Survival Rate


  • Antineoplastic Agents
  • Biomarkers, Tumor
  • Chromogranin A
  • Peptides, Cyclic
  • lanreotide
  • Somatostatin
  • Hydroxyindoleacetic Acid

Supplementary concepts

  • Non functioning pancreatic endocrine tumor