Treatment efficacy in a metastatic small intestinal neuroendocrine tumour grade 2 cohort

Abstract

Small intestinal neuroendocrine tumours (Si-NET) are often studied as a uniform group. Proliferation index Ki-67 influences prognosis and determines tumour grade. We hypothesized that Si-NET grade 2 (G2), which have a higher Ki-67 than G1 tumours, might benefit less from established treatments for metastatic disease. We conducted a retrospective cohort study of 212 patients with metastatic Si-NET G2 treated in two Swedish hospitals during 20 years (2000-2019). Median cancer-specific survival (CSS) on first-line somatostatin analogues (SSA) was 77 months. Median progression-free survival (PFS) was 12.4 months when SSA was given as monotherapy, and 19 months for all patients receiving first-line SSA. PFS after SSA dose escalation was 6 months in patients with radiological progression. Treatment efficacies of SSA and peptide-receptor radionuclide treatment (PRRT) were studied separately in patients with Ki-67 of 3-5%, 5-10% and 10-20%. For SSA, PFS was significantly shorter at higher Ki-67 levels (31, 18 and 10 months, respectively) while there was only a minor difference in PFS for PRRT (29, 25 and 25 months). Median PFS for sequential treatment with interferon-alpha (IFNa), everolimus and chemotherapy was 6, 5 and 9 months. IFNa seemed to be effective in tumours with low somatostatin-receptor expression. In conclusion, established treatments appeared effective in Si-NET G2, despite their higher proliferation index compared to G1 tumours. However, efficacy of SSA but not PRRT was reduced at higher Ki-67 levels. SSA dose escalation provided limited disease stabilization.

Investigating Carcinoid Tumor Oncogenesis through the lens of Developmental Dynamics involved in Small Intestinal Neuroendocrine Cells

“…Furthermore, the activation of tumorigenic signaling pathways is a plausible consequence of damaged Nkx2.2, with downstream genes and TFs promoting cell survival, proliferation, and evasion of apoptosis. In the context of gut motility and secretion regulation, where neuroendocrine cells in uenced by Nkx2.2 play a role, damaged Nkx2.2 could impact downstream genes involved in the regulation of gut motility and secretion, thereby contributing to gastrointestinal dysfunction [159]. Finally, the potential alteration in neural-progenitor cell maintenance due to damaged Nkx2.2 suggests downstream effects on genes regulating the maintenance of neural progenitor cells, in uencing the pool of cells available for subsequent differentiation.…”