We reviewed the evidence on safety and efficacy of therapies for neuroendocrine tumours (NETs) in the gastrointestinal tract and the pancreas to provide a ranking of these treatment options.
NETs are a varied group of rare cancers, which can occur anywhere in the body. However, most neuroendocrine tumours derive from the gastrointestinal tract or the pancreas. There are many types of NETs with different growth rates and symptoms. While some NETs produce excess hormones, others do not release hormones, or not enough to cause symptoms. The treatment options, as well as their combinations and sequencing, depend on the type of tumour, its location, aggressiveness, and whether it produces excess hormones.
Until now, no clear recommendations could be given about which NET therapies were the most effective and caused the fewest adverse events. We used statistical methods to compare all therapies with each other based on the available information.
We included 22 randomised controlled trials (studies in which participants are randomly assigned to treatment groups), published before 11 December 2020, with a total of 4299 people. There were differences in tumour location (gastrointestinal and pancreatic), tumour type, sample size, treatments, and quality of the research between the studies.
This analysis suggests, in general, a superiority of combination therapies, including somatostatin-like medications, in both gastrointestinal and pancreatic NETs. However, in pancreatic NETs, everolimus was the most effective therapy with the highest certainty of evidence compared to the other treatments. Furthermore, the results indicate that NET therapies have a broad range of risk for adverse events and effects on quality of life. Because disease is often advanced at presentation and treatment is often given with the intent to control and shrink disease, rather than be ultimately curative, treatment adverse events and quality of life are key considerations.
Quality of evidence
We rated the certainty of the evidence as high to low for the different therapies. An overall ranking of the treatments (and combinations) was not possible. In order to make an informed decision, advantages and disadvantages of each therapy, including its risks for adverse events and effects on quality of life, have to be balanced against each other. Evidence from this network meta-analysis (and underlying 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).
The findings from this study suggest that a range of efficient therapies with different safety profiles is available for people with NETs.
Several available therapies 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.
To evaluate the safety and efficacy of therapies for NETs, to guide clinical decision-making, and to provide estimates of relative efficiency of the different treatment options (including placebo) and rank the treatments according to their efficiency based on a network meta-analysis.
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.
We evaluated randomised controlled trials (RCTs) comparing two or more therapies in people with NETs (primarily gastrointestinal and pancreatic).
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.
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-of-treatment 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 0.46]), interferon plus somatostatin analogue (HR, 0.34 [95% CI, 0.14 to 0.80]), everolimus 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]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.48 [95% 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 0.77]); and six therapies for gastrointestinal NETs: 177-Lu-DOTATATE plus somatostatin analogue (HR, 0.07 [95% CI, 0.02 to 0.26]), everolimus plus somatostatin analogue (HR, 0.12 [95%CI, 0.03 to 0.54]), bevacizumab plus somatostatin analogue (HR, 0.18 [95% CI, 0.04 to 0.94]), interferon plus somatostatin analogue (HR, 0.23 [95% CI, 0.06 to 0.93]), surufatinib (HR, 0.33 [95%CI, 0.12 to 0.88]), 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 analogues.
The results 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 underlying 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).