Prognostic and predictive factors of platinum-based chemotherapy in gastroenteropancreatic neuroendocrine neoplasms G3

Data on gastroenteropancreatic neuroendocrine neoplasms (NEN) G3 (well-differentiated neuroendocrine tumors (NET G3) and neuroendocrine carcinoma (NEC) are limited. NET G3 are highly heterogeneous tumors, containing tumors that are both well and poorly differentiated. The assumption was reflected in the current 2019 WHO classification. Patients were identified from hospital databases between 2016 and 2019 with the diagnosis of NEN G3 confirmed by synaptophysin (Syn) and/or chromogranin A (CgA) positivity, GEP primary or unknown primary, Ki-67 index >20% or poorly differentiated morphology. Mixed tumors (MANEC) were included. Response to chemotherapy was analyzed according to the following criteria: start and end date of chemotherapy, best response (local radiological review based on RECIST 1.0), progression-free survival (PFS) and overall survival (OS) using Kaplan–Meier analysis and comparisons were performed using the log-rank test. A p-value of < 0.05 was considered statistically significant. Cox proportional hazard models were developed using relevant clinicopathologic variables to determine the association of each parameter with PFS and OS. All statistical analyses were performed using the (Statistica ver. 13.1) (StatSoft, Poland). Two hundred twenty-one patients were analyzed (27 NET G3, 14 MANEC, and 180 NEC). The mean age of patients was 64.1±9.1 years. Women to men ratio was 1:1.8. Tumor origin included gastric (20%), duodenum and Vateri Ampullae (11%), pancreas (32%), ileum (12%) and colon-rectum (39,9%). The primary tumor was resected in 80 (36%) patients. Metastatic disease was evident at diagnosis in 90% (liver metastases: 69%). The median time of follow-up of those patients alive was 14.5 (range 1.1–124.7) months. Median Ki-67 index was 70% (30% in NET G3, 60% in MANEC and 80% in NEC; P 25%), Ki-67 index, platelet count, lactate dehydrogenase, and primary tumor location were prognostic for response and survival. Patients were significantly younger in the NET G3 cohort (P=0.001) and were significantly more likely to have a functional tumor compared to NEC (P=0.003). Primary localization was more often in the pancreas (65%) for NET G3, while colorectal NEC was more common than colorectal NET G3. Multivariate analyses identified performance status as the strongest prognostic factor in the NEC cohort. A Ki-67 threshold of 50% was predictive for response to first-line platinum-based chemotherapy. Tumors with a Ki-67 index < 50% were much less responsive to platinum-based chemotherapy (response rate, 10% vs 48%), but the patients with those tumors had a significantly longer survival compared with the patients who had higher Ki-67 levels. In conclusion, NET G3 and NEC are characterized by significant differences in Ki-67 index and outcomes. While platinum-based chemotherapy is effective in NEC, it seems to have limited value in NET G3.