title: Systematic Review and Meta-Analysis on the Role of Chemotherapy in Advanced and Metastatic Neuroendocrine Tumor (NET).
abstract: OBJECTIVE
  In the era of somatostatin analogues and targeted therapies, the role of chemotherapy in NET remains largely undefined. This systematic review aimed to assess the effect of chemotherapy on response rates (RR), progression-free survival (PFS), overall survival (OS) and toxicity compared to other chemotherapies/systemic therapies or best supportive care in patients with advanced or metastatic NET.
  
  
  METHODS
  Randomised controlled trials (RCTs) from 1946 to 2015 were identified from MEDLINE, EMBASE, other databases and conference proceedings. Review of abstracts, quality assessment and data abstraction were performed independently by two investigators. Meta-analyses were conducted using Mantel-Haenszel analysis with random-effects modelling.
  
  
  RESULTS
  Six RCTs comparing standard streptozotocin plus 5-fluorouacil (STZ/5FU) chemotherapy to other chemotherapy regimens, and 2 comparing this to interferon (IFN) were included. Only 1 study was considered at low risk of bias. STZ/5-FU was no different to other chemotherapies in response rate [RR 0.96; 95% confidence interval (CI) 0.72-1.27], PFS (RR 0.95; CI 0.81-1.13), or OS (RR 1.03; CI 0.77-1.39). IFN may produce higher response than STZ/5FU (RR 0.20; CI 0.04-1.13), but event rates were small and survival was no different. Interferon was associated with higher overall haematological (RR 0.47; CI 0.27-0.82) and lower overall renal toxicity (RR 3.61; CI 1.24-10.51).
  
  
  CONCLUSIONS
  Strong evidence is lacking in the area of chemotherapy in neuroendocrine tumors. There is currently no evidence that one chemotherapeutic regimen is significantly better than the other, nor is interferon better than chemotherapy. There is an urgent need to design RCTs comparing modern chemotherapy to other agents in NET.
authors.affiliation: Department of Medical Oncology, Gosford Hospital, Gosford, Australia.|Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.
authors.forename: Matthew H
authors.initials: MH
authors.lastname: Wong
authors.affiliation: Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.|Department of Medical Oncology, Royal North Shore Hospital, Sydney, Australia.
authors.forename: David L
authors.identifier: http://orcid.org/0000-0002-7773-3144
authors.initials: DL
authors.lastname: Chan
authors.affiliation: Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.|Department of Medical Oncology, Royal North Shore Hospital, Sydney, Australia.|Northern Cancer Institute, Sydney, Australia.
authors.forename: Adrian
authors.initials: A
authors.lastname: Lee
authors.affiliation: Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.|Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: Bob T
authors.initials: BT
authors.lastname: Li
authors.affiliation: Department of Medical Oncology, Royal North Shore Hospital, Sydney, Australia.
authors.forename: Sumit
authors.initials: S
authors.lastname: Lumba
authors.affiliation: Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.|Department of Medical Oncology, Royal North Shore Hospital, Sydney, Australia.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Clarke
authors.affiliation: Department of Gastrointestinal Surgery, Royal North Shore and Macquarie University Hospitals, Sydney, Australia.
authors.forename: Jaswinder
authors.initials: J
authors.lastname: Samra
authors.affiliation: Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.|Department of Medical Oncology, Royal North Shore Hospital, Sydney, Australia.
authors.forename: Nick
authors.initials: N
authors.lastname: Pavlakis
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018572:Disease-Free Survival; D005472:Fluorouracil / Q000627:therapeutic use*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D009362:Neoplasm Metastasis; D018358:Neuroendocrine Tumors / Q000188:drug therapy*; D016032:Randomized Controlled Trials as Topic; D013004:Somatostatin / Q000031:analogs & derivatives; D013311:Streptozocin / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D013004:Somatostatin; D013311:Streptozocin; D007372:Interferons; D005472:Fluorouracil