Somatostatin analogues according to Ki67 index in neuroendocrine tumours: an observational retrospective-prospective analysis from real life.

Antongiulio Faggiano,Fabiana Tatangelo,Gaetano De Rosa,Claudia Battista,Carmela Mocerino,Anna Chiara Carratù,Annamaria Mauro,Lucia Franca Tozzi,Silvana Leo,Giovannella Palmieri,Ferdinando Riccardi,Vincenzo Damiano,Annamaria Colao,Salvatore Tafuto,Elia Guadagno,Roberta Siciliano

doi:10.18632/oncotarget.6686

Abstract

Somatostatin analogues (SSAs) have shown limited and variable antiproliferative effects in neuroendocrine tumours (NETs). Whether tumour control by SSAs depends on grading based on the 2010 WHO NET classification is still unclear. The aim of this study is to evaluate the efficacy of long-acting SSAs in NETs according to Ki67 index.An observational Italian multicentre study was designed to collect data in patients with gastro-entero-pancreatic or thoracic NETs under SSA treatment. Both retrospective and prospective data were included and they were analysed in line with Ki67 index, immunohistochemically evaluated in tumour samples and graded according to WHO classification (G1 = Ki67 index 0-2%, G2 = Ki67 index 3-20%, G3 = Ki67 index > 20%).Among 601 patients with NET, 140 with a histologically confirmed gastro-entero-pancreatic or thoracic NET or NET with unknown primary were treated with lanreotide autogel or octreotide LAR. An objective tumour response was observed in 11%, stability in 58% and progression in 31%. Objective response and tumour stability were not significantly different between G1 and G2 NETs. Progression free survival was longer but not significantly different in G1 than G2 NETs (median: 89 vs 43 months, p = 0.15). The median PFS was significantly longer in NETs showing Ki67 < 5% than in those showing Ki67 ≥5% (89 vs 35 months, p = 0.005).SSA therapy shows significant antiproliferative effects in well differentiated low/intermediate-proliferating NETs, not only G1 but also in G2 type. A Ki67 index of 5% seems to work better than 3% to select the best candidates for SSA therapy.

Highlights

Somatostatin analogues (SSAs) represent a consolidated therapeutic approach in patients with neuroendocrine tumour (NET)
A Ki67 index of 5% was the best cutoff at the receiver operator characteristic (ROC) analysis to separate patients according to tumour progression, with a sensitivity and specificity of 65 and 69%, respectively (p = 0.004)
Published in 2009, the PROMID study has been a milestone in the therapy of NETs, because it was the first randomized prospective phase 3 trial investigating SSA therapy in NETs [3]

Summary

Introduction

Somatostatin analogues (SSAs) represent a consolidated therapeutic approach in patients with neuroendocrine tumour (NET). Octreotide and lanreotide have initially been shown effective in controlling endocrine syndromes associated with NETs [1, 2]. Their role as antiproliferative agents has clearly been demonstrated in randomized trials conducted in patients with well differentiated NETs [3, 4]. The CLARINET study (double-blind controlled study of Lanreotide anti-proliferative response in NET) performed in patients with non functioning well-/ moderately differentiated GEP NETs (70% G1, 30% G2 with Ki67 ranging 3-10%) and including 45% pNETs, confirmed a significant improvement of progression free survival (PFS) in patients treated with lanreotide Autogel as compared to those receiving placebo [4]

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