Systematic review of the role of targeted therapy in metastatic neuroendocrine tumors

Background: Targeted therapies [interferon (IFN), vascular endothelial growth factor (VEGF) inhibitors, and somatostatin analogs (SSA)] have become an integral part of the neuroendocrine tumor (NET) treatment paradigm. We systematically reviewed the available literature to assess the overall beneficial and negative effects of targeted therapy on progression-free survival (PFS), overall survival (OS), response rate (RR), and toxicity. Methods: Randomized controlled trials (RCT) were identified from MEDLINE, Embase, other major databases, and an electronic search of major conferences. Abstract review, quality assessment, and data abstraction were performed independently by 2 investigators. Meta-analyses were conducted using the generic inverse variance method with a random-effects model, with studies pooled according to drug class and/or control arm for clinical homogeneity. Results: Fifteen RCT [SSA, n = 2; mammalian target of rapamycin (mTOR)/VEGF inhibitors, n = 4; IFN, n = 3; targeted therapy added to everolimus, n = 2, and other, n = 4] investigating 2,790 patients were included. Overall, targeted agents improved PFS (HR 0.54; 95% CI 0.40-0.73) but not OS (HR 0.86; 95% CI 0.72-1.01). SSA improved PFS (HR 0.41; 95% CI 0.29-0.58) but not OS (HR 1.00; 95% CI 0.58-1.74). mTOR/VEGF inhibitors improved PFS (HR 0.48; 95% CI 0.32-0.72) but not OS (HR 0.82; 95% CI 0.58-1.17). Targeted therapies added to everolimus or IFN did not improve either PFS or OS. The RR overall was improved (OR 2.85; 95% CI 1.77-4.59) but toxicity was increased (meta-analysis not performed). Conclusions: The addition of targeted therapies improves PFS but not OS in NET. The evidence is strongest for VEGF inhibitors and SSA. There is an ongoing need for well-designed RCT to inform the optimal use of targeted therapies in NET.