An Italian multicentre 2-step study in patients with MANECs of the gastro-entero-pancreatic tract treated with chemotherapy.

Background. Mixed adeno-neuroendocrine carcinomas (MANECs) are very rare malignancies. Due to their biological and clinical heterogeneity there is not a universally shared clinical approach. Materials and Methods. Clinical records of patients with advanced MANEC of the gastro-enteropancreatic (GEP) tract from 4 Italian referral centres were retrospectively analysed. All the surgical specimens were centrally reviewed by a team of expert pathologists. Clinical and biological data were correlated with outcomes. Results. Fifty-one patients with histological diagnosis of GEPMANEC between 1995 and 2016 were included. Primary sites were colo-rectal in 32 patients, esophago-gastro-duodenal in 14, and pancreato-biliary in 5. At diagnosis (surgery) 74% were locally advanced. Seventy-one % developed distant metastases (24% sinchronous, 47% metachronous). Twenty-two % of patients (50% stomach) received pre-operative chemotherapy, 27% adjuvant (50% colo-rectal), and 12% peri-operative (45%, 50%, 80% fluoropyrimidines-based respectively). A first line therapy (57% fluoropyrimidines/oxaliplatin) was offered to the 45% patients. Patients with a <55% Ki67 index in the NEC component had a significant longer OS than those with a ≥ 55% Ki67 (P=0.0004) regardless of the type of therapy. In the whole cohort, the median OS was 1.2 years (95% CI 0.8-1.6). Conclusion. This analysis suggested that the prognosis of GEP-MANECs is mainly driven by the NEC-component regardless of treatments. Since its descriptive design and various clinical management, it cannot either suggest a specific therapy or a real impact of chemotherapy on prognosis. However it produced solid hypotheses for future prospective-interventional studies in selected populations.