Second-line treatment in patients (pts) with advanced extra-pulmonary poorly differentiated neuroendocrine carcinoma (EP-PD-NEC): A systematic review and meta-analysis

Background: There is no standard second-line treatment for pts with advanced EP-PD-NEC. This study explored data evaluating second-line treatment in these pts.Methods: A search of Medline and Embase identified studies reporting survival and/or response data for pts with EP-PD-NEC receiving second-line therapy. Association between baseline factors (age, gender, ECOG performance status, primary tumour location, morphology, grade 3/4 haematological toxicity and Ki-67) and response rate (RR), progression-free (PFS) and overall survival (OS) were assessed with a mixed effects meta-regression weighted by individual study sample size. Due to a small sample size, associations were reported quantitatively based on magnitude of beta coefficient rather than statistical significance.Results: Of 83 identified studies, 20 were eligible, including 4 prospective and 16 retrospective studies (16 different regimens used and multiple regimens in 2 studies). Analysis comprised 595 pts, with a median number of 20 pts in each study (range 5-100). Median age was 59 years (range 53-66). Median RR was 18% (range 0-50; 0% for single-agent everolimus, temozolomide, topotecan; 50% with amrubicin), median PFS was 2.5 months (range 1.15-6.0) and median OS was 7.64 months (range 3.2-22). Studies with a higher proportion of pts with a liver/biliary primary had higher RR (β=0.65) and those with a higher proportion of pts with a Ki-67>55% had lower RR (β=-0.73) and shorter OS (β=-0.82).Conclusion: Second-line therapy for pts with advanced EP-PD-NEC has limited efficacy. High Ki-67 is associated with worse treatment outcomes. Prospective randomised studies are warranted to enable exploration of new treatment strategies.