Asphericity of Somatostatin Receptor Expression in Neuroendocrine Tumors: An Innovative Predictor of Outcome in Everolimus Treatment?

Christoph Wetz,Imke Schatka,Christian Furth,Holger Amthauer,Henning Jann,Michael Kreissl,Marino Venerito,Julian Rogasch,Philipp Genseke

doi:10.3390/diagnostics10090732

Abstract

Background: in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET), the mTOR inhibitor everolimus is associated with significant improvement in progression-free survival (PFS). This study evaluated the lesional asphericity (ASP) in pretherapeutic somatostatin receptor (SSR) imaging as the first imaging-based prognostic marker for PFS. Methods: this retrospective bicentric cohort study included 30 patients (f = 13, median age, 66.5 (48–81) years) with pretherapeutic [111In-DTPA0]octreotide scintigraphy (Octreoscan®). ASP of functional volumes of up to three leading lesions per patient (n = 74) was calculated after semiautomatic, background-adapted segmentation. Uni- and multivariable Cox regression regarding PFS for clinical factors and the maximum ASP per patient was obtained. Results: all 30 patients showed metachronous or progressive liver metastases. ASP, primary tumor site, metastases pattern, and prior peptide receptor radionuclide therapy (PRRT) were significantly associated with PFS in univariable Cox regression. Only ASP > 12.9% (hazard ratio (HR), 3.33; p = 0.024) and prior PRRT (HR, 0.35; p = 0.043) remained significant in multivariable Cox. Median PFS was 6.7 months for ASP > 12.9% (95% confidence interval (CI), 2.1–11.4 months) versus 14.4 (12.5–16.3) months for ASP ≤ 12.9% (log-rank, p = 0.028). Conclusion: pretherapeutic ASP of SSR positive lesions independently predicted PFS for treatment with everolimus in GEP-NET. ASP may supplement risk-benefit assessment before patient inclusion to treatment.

Highlights

Neuroendocrine tumors (NET) of the bronchopulmonary or gastroenteropancreatic system (GEP-NET) are classified as a rare and heterogeneous tumor entity with substantially rising incidence over the last two decades [1,2]
Three large phase III placebo-controlled randomized trials showed the efficacy of everolimus in patients with well-differentiated lung- and gastrointestinal (GI)-NET (RADIANT-2 and RADIANT-4) [3,5] as well as in patients with advanced pancreatic tumors (P)-NET (RADIANT-1 and RADIANT-3) [4,7]
This study examined if ASP of NET lesions in somatostatin receptor (SSR) imaging before initiation of everolimus treatment could predict progression-free survival (PFS)

Summary

Introduction

Neuroendocrine tumors (NET) of the bronchopulmonary (lung-) or gastroenteropancreatic system (GEP-NET) are classified as a rare and heterogeneous tumor entity with substantially rising incidence over the last two decades [1,2]. Three large phase III placebo-controlled randomized trials showed the efficacy of everolimus in patients with well-differentiated lung- and gastrointestinal (GI)-NET (RADIANT-2 and RADIANT-4) [3,5] as well as in patients with advanced pancreatic tumors (P)-NET (RADIANT-1 and RADIANT-3) [4,7]. RADIANT trials demonstrated an improved progression-free survival (PFS) in patients with advanced NET when combining everolimus with somatostatin analogs (SSA), regardless of previous SSA exposure [3,6,7]. Based on these results, the European Neuroendocrine Tumor Society (ENETs) guidelines recommend everolimus as a second-line therapy for advanced P-NEN and as a third-line therapy for GI-NEN [8]

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Conclusion