Treatment for gastrointestinal and pancreatic neuroendocrine tumours: a network meta-analysis

Background Several a"aiiab|etherap/es for neuroendocrine tumours (NETs) have demonstrated efficacy in randomised controlled trials. However, translation of these results into improved care faces several challenges, as a direct comparison of the most pertinent therapies is incomplete. Objectives To evaluate the safety and efficacy of therapies for NETs, to guide clinical decision -making, and to provide estimates of relative efficiency of the differenttreatment options (including placebo) and rankthe treatments accordingto theirefficiency based on a network meta -analysis. Search methods We identified studies through systematic searches of the following bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (Ovid); and Embase from January 1947 to December 2020. In addition, we checked trial registries for ongoing or unpublished eligible trials and manually searched for abstracts from scientific and clinical meetings. Selection criteria We evaluated randomised controlled trials (RCTs) comparing two or more therapies in people with NETs (primarily gastrointestinal and pancreatic). Data collection and analysis Two review authors independently selected studies and extracted data to a pre -designed data extraction form. Multi -arm studies were included in the network meta -analysis using the R-package netmeta. We separately analysed two different outcomes (disease control and progression -free survival) and two types of NET (gastrointestinal and pancreatic NET) in four network meta -analyses. A frequentist approach was used to compare the efficacy of therapies. Main results We identified 55 studies in 90 records in the qualitative analysis, reporting 39 primary RCTs and 16 subgroup analyses. We included 22 RCTs, with 4299 participants, that reported disease control and/or progression -free survival in the network meta -analysis. Precision -oftreatment estimates and estimated heterogeneity were limited, although the risk of bias was predominantly low. The network meta -analysis of progression -free survival found nine therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.36 [95% CI, 0.28 to 0A6]), interferon plus somatostatin anaEogue (HR, 0.34 [950/o CI, 0.14 to 0.80]), evercilimus plus somatostatin analogue (HR, 0.38 [95% CI, 0.26 to 0.57]), bevacizumab plus somatostatin analogue (HR, 0.36 [95% CI, 0.15 to 0.89]>, interferon (HR, 0.41 [95% CI, 0.18 to 0.94]), sunitinib (HR, 0.42 [95% CI, 0.26 to 0.67]), evero1imus plus bevacizumab pEus somatostatin analogue (HR, 0.48 [950/o CI, 0.28 to 0.83]), surufatinib (HR, 0.49 [95% CI, 0.32 to 0.76]), and somatostatin analogue (HR, 0.51 [95% CI, 0.34 to 0.771); and six therapies for gastrointestinal NETs: 177-Lu-DOTATATE pEus somatostatin analogue (HR, 0.07 [95% CI, 0.02 to 0.261), everolim us plus somatostatin analogue (HR, 0.12 [95%C|, 0.03 to 0.54), bevacizumab plus somatostatin analogue (HR, 0.18 [95% Cl, 0.04 to 0.941), interferon plus somatostatin analogue (HR, 0.23 [950/o CI, 0.06 to 0.93]), surufatinib (HR, 0.33 [9.50/0CI, 0.12 to 0.881), and somatostatin analogue (HR, 0.34 [95% CI, 0.16 to 0.76]), with higher efficacy than placebo. Besides everolimus for pancreatic NETs, the results suggested an overall superiority of combination therapies, including somatostatin anaEogues. The resu1ts indicate that NET therapies have a broad range of risk for adverse events and effects on quality of life, but these were reported inconsistently. Evidence from this network meta -analysis (and underEying RCTs) does not support any particular therapy (or combinations of therapies) with respect to patient-centred outcomes (e.g. overall survival and quality of life). Authors' conclusions The findings from this study suggest that a range of efficient therapies with different safety profiles is available for people with NETs.