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Original Investigation
February 14, 2019

Therapeutic Options for Neuroendocrine Tumors: A Systematic Review and Network Meta-analysis

Author Affiliations
  • 1Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
  • 2Department of Nuclear Medicine, University Hospital, University of Geneva, Geneva, Switzerland
  • 3Department of Medical Oncology, Bern University Hospital, University of Bern, Bern, Switzerland
  • 4Clinical Trials Unit Bern, Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland
  • 5Department of Endocrinology, Diabetes, and Metabolism, Basel University Hospital, University of Basel, Basel, Switzerland
  • 6Institute for Clinical Epidemiology and Biostatistics, Department of Clinical Research, Basel University Hospital, University of Basel, Basel, Switzerland
  • 7Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
JAMA Oncol. 2019;5(4):480-489. doi:10.1001/jamaoncol.2018.6720
Key Points

Question  What is the available evidence on therapies for neuroendocrine tumors?

Findings  This systematic review and network meta-analysis identified 30 relevant randomized clinical trials comprising 3895 patients with neuroendocrine tumors assigned to 22 different therapies. A network meta-analysis identified 7 therapies for pancreatic neuroendocrine tumors and 5 therapies for gastrointestinal neuroendocrine tumors with a broad range of different toxic effects and higher efficacy than placebo.

Meaning  There appears to be a range of efficient therapies with different safety profiles available for patients with neuroendocrine tumors.

Abstract

Importance  Multiple therapies are currently available for patients with neuroendocrine tumors (NETs), yet many therapies have not been compared head-to-head within randomized clinical trials (RCTs).

Objective  To assess the relative safety and efficacy of therapies for NETs.

Data Sources  PubMed, Embase, the Cochrane Central Register of Controlled Trials, trial registries, meeting abstracts, and reference lists from January 1, 1947, to March 2, 2018, were searched. Key search terms included neuroendocrine tumors, gastrointestinal neoplasms, therapy, and randomized controlled trial.

Study Selection  Randomized clinical trials comparing 2 or more therapies in patients with NETs (primarily gastrointestinal and pancreatic) were evaluated. Thirty RCTs met the selection criteria.

Data Extraction and Synthesis  Pairs of independent reviewers screened studies, extracted data, and assessed the risk of bias. A network meta-analysis with a frequentist approach was used to compare the efficacy of therapies; the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was used.

Main Outcomes and Measures  Disease control, progression-free survival, overall survival, adverse events, and quality of life.

Results  The systematic review identified 30 relevant RCTs comprising 3895 patients (48.4% women) assigned to 22 different therapies for NETs. These therapies showed a broad range of risk for serious and nonserious adverse events. The network meta-analyses included 16 RCTs with predominantly a low risk of bias; nevertheless, precision-of-treatment estimates and estimated heterogeneity were limited. The network meta-analysis found 7 therapies for pancreatic NETs: everolimus (hazard ratio [HR], 0.35 [95% CI, 0.28-0.45]), everolimus plus somatostatin analogue (HR, 0.35 [95% CI, 0.25-0.51]), everolimus plus bevacizumab plus somatostatin analogue (HR, 0.44 [95% CI, 0.26-0.75]), interferon (HR, 0.37 [95% CI, 0.16-0.83]), interferon plus somatostatin analogue (HR, 0.31 [95% CI, 0.13-0.71]), somatostatin analogue (HR, 0.46 [95% CI, 0.33-0.66]), and sunitinib (HR, 0.42 [95% CI, 0.26-0.67]), and 5 therapies for gastrointestinal NETs: bevacizumab plus somatostatin analogue (HR, 0.22 [95% CI, 0.05-0.99]), everolimus plus somatostatin analogue (HR, 0.31 [95% CI, 0.11-0.90]), interferon plus somatostatin analogue (HR, 0.27 [95% CI, 0.07-0.96]), Lu 177–dotatate plus somatostatin analogue (HR, 0.08 [95% CI, 0.03-0.26], and somatostatin analogues (HR, 0.40 [95% CI, 0.21-0.78]) with higher efficacy than placebo and suggests an overall superiority of combination therapies.

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

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