Prognostic and Predictive Role of Body Composition in Metastatic Neuroendocrine Tumor Patients Treated with Everolimus: A Real-World Data Analysis

Abstract

Neuroendocrine tumors (NETs) are rare neoplasms frequently characterized by an upregulation of the mammalian rapamycin targeting (mTOR) pathway resulting in uncontrolled cell proliferation. The mTOR pathway is also involved in skeletal muscle protein synthesis and in adipose tissue metabolism. Everolimus inhibits the mTOR pathway, resulting in blockade of cell growth and tumor progression. The aim of this study is to investigate the role of body composition indexes in patients with metastatic NETs treated with everolimus. The study population included 30 patients with well-differentiated (G1-G2), metastatic NETs treated with everolimus at the IRCCS Romagnolo Institute for the Study of Tumors (IRST) "Dino Amadori", Meldola (FC), Italy. The body composition indexes (skeletal muscle index [SMI] and adipose tissue indexes) were assessed by measuring on a computed tomography (CT) scan the cross-sectional area at L3 at baseline and at the first radiological assessment after the start of treatment. The body mass index (BMI) was assessed at baseline. The median progression-free survival (PFS) was 8.9 months (95% confidence interval [CI]: 3.4-13.7 months). The PFS stratified by tertiles was 3.2 months (95% CI: 0.9-10.1 months) in patients with low SMI (tertile 1), 14.2 months (95% CI: 2.3 months-not estimable [NE]) in patients with intermediate SMI (tertile 2), and 9.1 months (95% CI: 2.7 months-NE) in patients with high SMI (tertile 3) (p = 0.039). Similarly, the other body composition indexes also showed a statistically significant difference in the three groups on the basis of tertiles. The median PFS was 3.2 months (95% CI: 0.9-6.7 months) in underweight patients (BMI ≤ 18.49 kg/m²) and 10.1 months (95% CI: 3.7-28.4 months) in normal-weight patients (p = 0.011). There were no significant differences in terms of overall survival. The study showed a correlation between PFS and the body composition indexes in patients with NETs treated with everolimus, underlining the role of adipose and muscle tissue in these patients.

Keywords: NET; adipose tissue; body composition; everolimus; mTOR inhibitors; muscle tissue; neuroendocrine tumors.

Figure 1

mTORC1 complex is involved in lipid synthesis and metabolism: Everolimus plus NFKBP-12 has a negative effect.

Figure 2

Flow diagram of patients identified and included in the final analysis. NET, neuroendocrine tumor; EVE, everolimus; CT, computed tomography.

Figure 3

Evaluation of body composition. An axial CT image segmented into the skeletal muscle area (SKM in red), visceral adipose tissue area (VAT in yellow) and subcutaneous adipose tissue area (SAT in green). Total adipose tissue area (TAT) is identified from VAT + SAT. (A) and (B) differ from body composition.

Figure 4

Indexes variation measured before and after the start of everolimus-based treatment.

Figure 5

Correlation between PFS and SMI (A), VATI (B), SATI (C) and TATI (D).

Figure 6

mTOR pathway is involved not only in tumor progression but also in lipid metabolism and lypolysis. Adapted from “mTOR Signaling Pathway”, by BioRender.com (2020). Retrieved from https://app.biorender.com/biorender-templates (accessed on 15 June 2022).