The Role of Higher Doses of Somatostatin Analogs for Progressing Neuroendocrine Tumors

In a multicenter Italian study, researchers aimed to assess the results of somatostatin analogue treatment at non-conventional doses in patients with radiologic progression of neuroendocrine tumors.

Modified schedules of somatostatin analogs (SSAs) at doses higher than recommended may be a feasible treatment option for patients with well-differentiated progressive gastroenteropancreatic neuroendocrine tumors (NETs), according to study results published in The Journal of Clinical Endocrinology & Metabolism.

For patients with metastatic NETs, treatment with SSAs is used for the control of tumor growth and for symptoms related to hormone hypersecretion. Currently, there are 2 approved SSAs for clinical use, including lanreotide autogel 120 mg and octreotide long-acting release 30 mg, both given every 28 days.

In the current multicenter study, the researchers aimed to assess the results of SSA treatment at nonconventional doses (high-dose SSA) in patients with radiologic progression of NETs.

The retrospective study included all clinical data that was prospectively collected at 13 Italian centers from January 2004 to December 2017 from patients with NETs. All patients were diagnosed with a sporadic well-differentiated NET (grade 1 or 2) and had evidence of disease progression with SSA at standard doses before the start of high-dose SSA. Progression-free survival — the interval between the start of the therapy and the time of disease progression — and safety were the primary outcomes.

The study cohort included 140 patients (60% men; median age, 65 years). Most patients (n=97) had a gastrointestinal NET; the remainder had a pancreatic NET (n=43). According to World Health Organization (WHO) classification, 75 patients had grade 1 disease and 63 patients had grade 2 disease; data were missing in 2 cases.

High-dose SSA treatment was defined as increased dose intensity (lanreotide 180 mg or octreotide long-acting release 60 mg every 28 days; 7 patients) or increased dose density (lanreotide 120 mg or octreotide long-acting release 30 mg every 14 or 21 days; 133 patients).

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Overall, median progression-free survival with high-dose SSA after radiologic disease progression was 31 months (95% CI, 19.3-42.6 months). Using high-dose SSA as a second-line treatment was associated with significantly longer progression-free survival (57 months; 95% CI, 9.4-104.6 months) compared with reserving this treatment option as a third-line or later treatment (22 months; 95% CI, 13.0-31.0; P =.007).

There were no significant differences in progression-free survival according to sex, type of high-dose SSA (increased dose intensity or density), primary tumor site, disease extent, liver metastatic pattern, whether the primary tumor was resected or not, presence of hormone hypersecretion, or grade of NET.

On multivariate analysis, the association of use of high-dose SSA as a third- or further-line therapy was independently associated with a higher risk for tumor progression or death (hazard ratio, 2.12; 95% CI, 1.28-3.51; P =.004). Disease-control rate was 84.3%: 12 patients (8.6%) achieved partial response and 106 (75.7%) had stable disease.

High-dose SSA treatment was safe overall and well tolerated and no patients interrupted SSA treatment because of the occurrence of adverse events.

Study limitations included the retrospective design, lack of a systematic tumor reassessment at progression, possible selection bias as patients treated with high-dose SSA are usually those with more indolent NETs, and the small percentage of patients treated with increased dose intensity for high-dose SSA.

“[High-dose] SSA can be a feasible option in selected NETs, characterized by low proliferation index and limited or slow progression. To further clarify [high-dose] SSA usefulness, a phase II study of Lanreotide Autogel 120 mg every 14 days in [patients with gastroenteropancreatic] NET with their tumor progressing on Lanreotide Autogel 120 mg every 28 days is ongoing,” the researchers concluded.

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Lamberti G, Faggiano A, Brighi N, et al. Non-conventional doses of somatostatin analogs in patients with progressing well differentiated neuroendocrine tumor [published online September 23, 2019]. J Clin Endocrinol Metab. doi:10.1210/clinem/dgz035