title: Chemotherapy for advanced non-pancreatic well-differentiated neuroendocrine tumours of the gastrointestinal tract, a systematic review and meta-analysis: A lost cause?
abstract: BACKGROUND
  Chemotherapy is well-established in the treatment of patients with well-differentiated neuroendocrine tumours (NETs) arising from the pancreas (pNETs); however, its role in patients with gastrointestinal non-pancreatic NETs (non-pNETs) is uncertain. This systematic review assesses the evidence for the role of chemotherapy in well-differentiated non-pNET patients.
  
  
  METHODS
  Eligible studies (identified using MEDLINE) were those reporting response and/or survival data for patients with well-differentiated non-pNETs receiving systemic chemotherapy. The primary end-point was overall-response (OR) rate; secondary end-points were progression-free survival (PFS), overall survival (OS), disease-stabilization (DS) and disease-control (DC) rates.
  
  
  RESULTS
  Of 6434 studies screened, 20 were eligible: one randomised phase III trial, 2 randomised phase II studies, 10 single-arm phase II trials and 7 retrospective analyses including a total of 264 patients (median of 11 patients per study, range 6-49); and employing multiple chemotherapy schedules. The mean "median PFS" and "median OS" were 16.9 months (95%-confidence interval (CI) 3.8-30.04) and 32.2 months (95%-CI 10.4-54.2), respectively. The non-weighted mean OR, DS and DC rates were 11.5% (95%-CI 5.8-17.2), 56.5% (95%-CI 38.1-74.9) and 70.7% (95%-CI 54.9-86.5), respectively. In studies including both pNETs and non-pNET patients, meta-analysis showed a lower OR-rate in the non-pNET patients when compared to pNETs [odds ratio (OR) 0.35 (95% CI 0.18-0.66)]; however significance was lost when high-risk bias studies were excluded in a sensitivity analysis [OR 0.45 (95% CI 0.19-1.07); p-value 0.07].
  
  
  CONCLUSIONS
  Studies were of evidence level-C with heterogeneous populations and treatments; and small patient numbers. Well-designed, prospective studies are needed to adequately evaluate the role of chemotherapy in this setting.
authors: Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
authors: Angela
authors: A
authors: Lamarca
authors: Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
authors: Emma
authors: E
authors: Elliott
authors: Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
authors: Jorge
authors: J
authors: Barriuso
authors: Manchester Academic Health Sciences Centre, Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors: Alison
authors: A
authors: Backen
authors: Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Manchester Academic Health Sciences Centre, Institute of Cancer Sciences, University of Manchester, Manchester, UK.
authors: Mairéad G
authors: MG
authors: McNamara
authors: Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK.
authors: Richard
authors: R
authors: Hubner
authors: Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK; Manchester Academic Health Sciences Centre, Institute of Cancer Sciences, University of Manchester, Manchester, UK. Electronic address: juan.valle@christie.nhs.uk.
authors: Juan W
authors: JW
authors: Valle
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000069287:Capecitabine / Q000008:administration & dosage; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018572:Disease-Free Survival; D005472:Fluorouracil / Q000008:administration & dosage; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000473:pathology; D019275:Radiopharmaceuticals / Q000627:therapeutic use; D013004:Somatostatin / Q000031:analogs & derivatives*; D013311:Streptozocin / Q000008:administration & dosage; D000077204:Temozolomide
chemical_list: D000970:Antineoplastic Agents; D019275:Radiopharmaceuticals; D013004:Somatostatin; D013311:Streptozocin; D000069287:Capecitabine; D003606:Dacarbazine; D007372:Interferons; D005472:Fluorouracil; D000077204:Temozolomide
keywords: Chemotherapy; Clinical trials; Neuroendocrine tumours; Non-pancreatic; Pancreatic; Well-differentiated