Dimitrios Papantoniou: Small Intestinal neuroendocrine tumours Grade 2: Studies of tumour biology and treatment

Abstract

Grade 2 small intestinal neuroendocrine tumours (G2 Si-NET) have higher proliferation index (PI) Ki-67 (3-20%) and more aggressive clinical course than more indolent G1 tumours. However they have not been studied separately. The aim of this thesis was to evaluate the efficiency of standard treatments and to explore prognostic markers in this population. 

In the first paper we showed that baseline chromogranin A (CgA) was associated with cancer-specific survival (CSS) irrespective of treatment, and with progression-free survival (PFS ) after peptide receptor radionuclide therapy (PRRT). Early CgA and 5-hydroxyindoleacetic acid (5-HIAA) reductions were prognostic of longer PFS after somatostatin analogues (SSA), but not after PRRT. In the second paper we found that treatment with SSA is effective in G2 Si-NET (median PFS 12.4m, similar to PFS for G1 patients in the PROMID trial). Dose intensification had modest effect. Importantly, in subgroups with lower (3-5%), intermediate (5-10%) and higher Ki-67 (10-20%), PFS for SSA declined with increasing Ki-67 (31, 18 and 10m) , whereas it was stable for PRRT (29, 25 and 25m). In the third paper, we evaluated an alternative estimation method of PI (phospho-histone H3, PHH3). Both Ki-67 and PHH3 separated groups of longer and shorter CSS (128 vs 95 and 149 vs 88m, HR: 1.18 and 1.16, respectively). PHH3 but not Ki-67-based PI was associated with PFS. A cut-off of >2 PHH3-estimated mitoses per 10 high-performance fields seemed to provide better discrimination. We finally investigated the prognostic value of inflammation scores after treatment with PRRT. We found that parameters based on CRP and albumin, but not derived neutrophil to lymphocyte ratio, were associated with overall survival. After adding inflammation markers to a model of standard prognostic factors, the model based on hypoalbuminemia had better prognostic power. 

Collectively, these studies confirm the efficacy of standard medical treatments in G2 Si-NET, but underline that SSA might be less effective in the higher Ki-67 subgroup. Additionally, they investigate the prognostic value of tumour markers, inflammation and proliferation parameters, which can be used for patient counseling and as stratification factors in future clinical trials.