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) tumours, 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 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 (IFNα), everolimus and chemotherapy was 6, 5 and 9 months. IFNα 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.

Keywords: Ki-67; PRRT; Si-NET; grade 2; interferon; peptide receptor radionuclide treatment; small intestinal neuroendocrine tumours; somatostatin analogues; somatostatin receptor negative.

Figure 1

Treatment sequencing for all medical treatments and SSA dose escalations. Each vertical column represents a line of treatment; the height of each node is proportional to the number of patients treated, and the width of links between nodes to the number of patients transitioning between consecutive lines of treatment. SSA, somatostatin analogues; esc, escalation of SSA; IFNα, interferon-alpha; PRRT, peptide receptor radionuclide therapy; eve, everolimus; chemo, chemotherapy; SD, standard dose of SSA (30 mg octreotide LAR/120 mg lanreotide autogel); w, weeks.

Figure 2

(A) Multivariable analysis of prognostic factors for cancer-specific survival (CSS) after initiation of treatment with first-line somatostatin analogues at below-label or standard doses. Chromogranin A is expressed as times the upper limit of normal (×ULN). A lower starting dose, increasing Ki-67 and chromogranin A, age ≥65 years and a performance status ≥1 are associated with higher risk of cancer-specific death. (B) CSS for patients with Ki-67 ≤5% and 5–10%. Only the 5–10% subgroup seems to benefit from the higher starting dose. Patients with Ki-67 >10% were not formally analysed, as only four patients were treated with a below-label dose in this subgroup. HR, hazard ratio; CI, confidence interval; PRRT, peptide receptor radionuclide therapy. A full colour version of this figure is available at https://doi.org/10.1530/ERC-22-0316.

Figure 3

Cancer-specific (CSS) and progression-free survival (PFS) for somatostatin analogues (SSA) and peptide receptor radionuclide treatment (PRRT) by Ki-67 at 5% and 10% cut-offs. Efficacy of treatment with SSA but not with PRRT seems to diminish with increasing Ki-67. A full colour version of this figure is available at https://doi.org/10.1530/ERC-22-0316.

Figure 4

Cancer-specific and progression-free survival by somatostatin receptor (SSTR) status for patients treated with somatostatin analogues (SSA) as monotherapy or combination treatment and with interferon-alpha (IFNα), after adjusting for the difference in Ki-67 in a cox model. HR, hazard ratio; CI, confidence interval. A full colour version of this figure is available at https://doi.org/10.1530/ERC-22-0316.

Figure 5

(A) Reduction of chromogranin A (CgA) was seen almost exclusively in tumours with low/negative somatostatin receptor expression, treated with interferon-alpha (IFNα), single or in combination, but not in those treated with somatostatin analogues (SSA). (B) Progression-free survival was significantly longer for patients treated with IFNα (single or in combination with SSA) compared to patients treated with only SSA. A full colour version of this figure is available at https://doi.org/10.1530/ERC-22-0316.