Treatment of Advanced Gastro-Entero-Pancreatic Neuro-Endocrine Tumors: A Systematic Review and Network Meta-Analysis of Phase III Randomized Controlled Trials

Simple Summary The most effective and safest approach for the treatment of advanced gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) remains unknown. A systematic review was done to clarify this point. A network meta-analysis was used to overcome the multiarm problem. Our study confirmed that somatostatin analogs (SSAs) alone remain the best choice for well-differentiated GEP-NENs. Lu-177-Dotatate plus SSA is a valid alternative for midgut NENs since it has been shown to be slightly more efficacious but yielding a higher risk for toxicity than SSAs. Several new therapies have been approved to treat advanced gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) in the last twenty years. In this systematic review and meta-analysis, we searched MEDLINE, ISI Web of Science, and Scopus phase III randomized controlled trials (RCTs) comparing two or more therapies for unresectable GEP-NENs. Network metanalysis was used to overcome the multiarm problem. For each arm, we described the surface under the cumulative ranking (SUCRA) curves. The primary endpoints were progression-free survival and grade 3-4 of toxicity. We included nine studies involving a total of 2362 patients and 5 intervention arms: SSA alone, two IFN-alpha plus SSA, two Everolimus alone, one Everolimus plus SSA, one Sunitinib alone, one Lu-177-Dotatate plus SSA, and one Bevacizumab plus SSA. Lu-177-Dotatate plus SSA had the highest probability (99.6%) of being associated with the longest PFS. This approach was followed by Sunitinib use (64.5%), IFN-alpha plus SSA one (53.0%), SSA alone (46.6%), Bevacizumab plus SSA one (45.0%), and Everolimus +/- SSA one (33.6%). The placebo administration had the lowest probability of being associated with the longest PFS (7.6%). Placebo or Bevacizumab use had the highest probability of being the safest (73.7% and 76.7%), followed by SSA alone (65.0%), IFN-alpha plus SSA (52.4%), Lu-177-Dotatate plus SSA (49.4%), and Sunitinib alone (28.8%). The Everolimus-based approach had the lowest probability of being the safest (3.9%). The best approaches were SSA alone or combined with Lu-177-Dotatate.

Automated summary

SSAs alone remain the best choice for treating well-differentiated GEP-NENs, while Lu-177-Dotatate plus SSA is a valid alternative for midgut NENs.