Antiproliferative Effect of Above-Label Doses of Somatostatin Analogs for the Management of Gastroenteropancreatic Neuroendocrine Tumors

Abstract

<b><i>Background:</i></b> Above-label doses of somatostatin analogs (SSAs) are increasingly utilized in the management of inoperable/metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs), progressing on standard 4-weekly regimens. <b><i>Objective:</i></b> To evaluate the antiproliferative effect of 3-weekly SSA administration in a retrospective GEP-NET cohort. <b><i>Methods:</i></b> Patients with advanced GEP-NET, treated with long-acting release (LAR) octreotide 30 mg or lanreotide Autogel 120 mg at a 3-weekly interval, after disease progression on standard 4-weekly doses, were retrospectively identified. Clinicopathologic and treatment response data were collected. Progression-free survival (PFS; dose escalation to radiographic progression or death) was estimated with the Kaplan-Meier method. Factors associated with PFS were identified with the Cox proportional-hazards model. <b><i>Results:</i></b> The inclusion criteria were fulfilled by 105 patients. Octreotide LAR was administered to 60 (57%) and lanreotide Autogel to 45 (43%). Indications for dose escalation were breakthrough carcinoid symptoms (58%), radiographic progression (35%) and/or increasing biomarkers (11%). Diarrheal and/or flushing symptomatic improvement was identified in 37/67 cases (55%) and 30/55 cases (55%) with available data, respectively. The disease control rate (radiographic partial response or stable disease) was achieved in 53 patients (50%). Median PFS was 25.0 months (95% CI 16.9–33.1). Patients with radiographic progression <12 months from 4-weekly SSA initiation had worse PFS after dose escalation (7.0 vs. 17.0 months, <i>p</i> = 0.002). In multivariate analysis, pancreatic NETs, a Ki-67 index ≥5% and multiple extrahepatic metastases were independently associated with inferior PFS. <b><i>Conclusions:</i></b> Above-label doses of SSAs may offer a considerable prolongation of PFS and could be utilized as a bridge to other more toxic treatments. Patients with small bowel/colorectal primaries, a Ki-67 index <5% and absence of/limited extrahepatic metastases are more likely to benefit from this approach.

Efficacy and safety of high-dose lanreotide autogel in patients with progressive pancreatic or midgut neuroendocrine tumours: CLARINET FORTE phase 2 study results

“…A recent retrospective analysis of above-label doses of octreotide LAR (30 mg/3 weeks) or LAN (120 mg/3 weeks) administered to 105 patients with advanced, progressive GEP-NETs on standard treatment included a multivariate analysis in which Ki-67 5e20% was independently associated with PFS duration (HR: 3.96 [95% CI 1.18e13.32] versus Ki-67 <3%; p Z 0.03) [16]. Our data suggest that patients with panNET and Ki-67 10% might benefit from increased SSA dose when experiencing the progressive disease.…”

“…Other studies support an increase in SSA dose to control progressive disease, including two retrospective studies of patients with progressive GEP-NETs treated with LAN or octreotide LAR at increased administered doses or reduced dosing intervals [14,16]. In addition, a prospective phase 2 study of dose escalation of LAN (180 mg every 28 days) in 32 patients with progressive thoracic or GEP-NETs reported a disease control rate of 47% at 12 months and median time to progression of 11 months [17].…”

Somatostatin Analogue Therapy in MEN1-Related Pancreatic Neuroendocrine Tumors from Evidence to Clinical Practice: A Systematic Review

“…Focusing specifically on pNENs, many studies have showed the SSAs’ efficacy in controlling the symptoms related to the hormone secretion of functional tumors, approximately in 50–100% of cases [ 23 , 24 ]. Similarly, several retrospective studies [ 25 , 26 , 27 , 28 , 29 ] and also a phase III randomized clinical trial [ 22 ] have clearly demonstrated the activity of SSAs in tumor growth control. The CLARINET study enrolled patients with advanced non-functioning GEP-NENs (except for two patients with gastrinoma in each group of treated and placebo arms), with a Ki-67 index < 10%, and that were indium-111 pentetreotide scan-positive.…”

Carcinoid Heart Disease: How to Diagnose and Treat in 2020?

“…The best results were observed in subjects with small intestine/colorectal primaries, Ki-67 below 5%, and no/ limited extrahepatic metastases. 32 In certain subjects, especially asymptomatic with small carcinoid burden and 5-HIAA levels within normal limits, initial watchful waiting might be adopted. Nonetheless, in all subjects with substantial serotonin production, it is reasonable to initiate the therapy with somatostatin analogs.…”

“…The best results were observed in subjects with small intestine/colorectal primaries, Ki-67 below 5%, and no/limited extrahepatic metastases. 32 …”