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

Abstract

Background

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.

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 different treatment options (including placebo) and rank the treatments according to their efficiency 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 In addition, we checked trial registries for ongoing or unpublished eligible trials and manually searched for abstracts from scientific and clinical meetings.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‐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).

Authors' conclusions

The findings from this study suggest that a range of efficient therapies with different safety profiles is available for people with NETs.

Author(s)

Martin A Walter, Cédric Nesti, Marko Spanjol, Attila Kollár, Lukas Bütikofer, Viktoria L Gloy, Rebecca A Dumont, Christian A Seiler, Emanuel R Christ, Piotr Radojewski, Matthias Briel, Reto M Kaderli

Abstract

Plain language summary

Treatment options for neuroendocrine tumours 

Review question 

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.

Background 

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.

Study characteristics 

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.

Key results 

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).

Author(s)

Martin A Walter, Cédric Nesti, Marko Spanjol, Attila Kollár, Lukas Bütikofer, Viktoria L Gloy, Rebecca A Dumont, Christian A Seiler, Emanuel R Christ, Piotr Radojewski, Matthias Briel, Reto M Kaderli

Reviewer's Conclusions

Authors' conclusions 

Implications for practice 

Clinical decisions should be based on the best available evidence. The present results provide a comprehensive overview of the existing evidence on NET therapies as well as the best possible comparison of therapies that have not been directly compared in RCTs. Using this approach, the certainty of evidence is incorporated into the results to assist in decision‐making. Safety and efficacy results should both be incorporated into the treatment decision, while in addition the safety results may aid in the decision to establish preventive measures and increase the surveillance for known toxic effects. 

However, based on the evidence presented in this review, the results do not allow us to suggest a fixed sequence of therapies or therapy modalities for people with GI‐NET and pNET in the course of disease. 

Implications for research 

The present results may guide future research by highlighting necessary head‐to‐head comparisons and facilitating their trial design. Specifically, bevacizumab plus a somatostatin analogue, dactolisib, everolimus plus bevacizumab plus a somatostatin analogue, sunitinib and surufatinib have only been compared with one other active therapy in pNET to date, while bevacizumab plus a somatostatin analogue, everolimus, everolimus plus a somatostatin analogue, surufatinib, streptozocin plus fluorouracil and 177‐Lu‐DOTATATE plus a somatostatin analogue have only been compared with one other active therapy in GI‐NETs.

Sunitinib and everolimus have been compared only with placebo in pNETs and GI‐NETs respectively and, to our knowledge, head‐to‐head comparisons with active therapies in RCTs have not yet been performed. When designing such head‐to‐head comparisons, the estimated associations from our network meta‐analysis can help to select the reference therapy and approximate the required patient numbers. Particularly, because the present results identified eight therapies in pNETs and 6 therapies in GI‐NETs with higher efficacy than placebo, comparisons with placebo as a reference are discouraged for the future. Because of their proven efficacy and central role in current comparisons, somatostatin analogues represent the logical reference compound for further RCTs. Moreover, the quality assessment of currently available RCTs revealed that further studies should incorporate blinding to avoid overestimation of effects and improve the overall quality of evidence in the field.

In addition, this study demonstrates the need for more research in assessing adverse events and effects on quality of life for NET therapies.

Finally, an important research topic would be a randomised evaluation of different sequences of therapies and therapy modalities in order to determine whether certain therapy modalities (i.e. 177‐Lu‐DOTATATE) are more efficient early or late in the course of disease .

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