title: The effectiveness and cost-effectiveness of erythropoiesis-stimulating agents (epoetin and darbepoetin) for treating cancer treatment-induced anaemia (including review of technology appraisal no. 142): a systematic review and economic model.
abstract: BACKGROUND
  Anaemia is a common side effect of cancer treatments and can lead to a reduction in quality of life. Erythropoiesis-stimulating agents (ESAs) are licensed for use in conjunction with red blood cell transfusions to improve cancer treatment-induced anaemia (CIA).
  
  
  OBJECTIVE
  To investigate the effectiveness and cost-effectiveness of ESAs in anaemia associated with cancer treatment (specifically chemotherapy).
  
  
  METHODS
  The following databases were searched from 2004 to 2013: The Cochrane Library, MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Web of Science, Cumulative Index to Nursing and Allied Health Literature, British Nursing Index, Health Management Information Consortium, Current Controlled Trials and ClinicalTrials.gov. The US Food and Drug Administration and European Medicines Agency websites were also searched. Bibliographies of included papers were scrutinised for further potentially includable studies.
  
  
  METHODS
  The clinical effectiveness review followed principles published by the NHS Centre for Reviews and Dissemination. Randomised controlled trials (RCTs), or systematic reviews of RCTs, of ESAs (epoetin or darbepoetin) for treating people with CIA were eligible for inclusion in the review. Comparators were best supportive care, placebo or other ESAs. Anaemia- and malignancy-related outcomes, health-related quality of life (HRQoL) and adverse events (AEs) were evaluated. When appropriate, data were pooled using meta-analysis. An empirical health economic model was developed comparing ESA treatment with no ESA treatment. The model comprised two components: one evaluating short-term costs and quality-adjusted life-years (QALYs) (while patients are anaemic) and one evaluating long-term QALYs. Costs and benefits were discounted at 3.5% per annum. Probabilistic and univariate deterministic sensitivity analyses were performed.
  
  
  RESULTS
  Of 1457 titles and abstracts screened, 23 studies assessing ESAs within their licensed indication (based on start dose administered) were included in the review. None of the RCTs were completely aligned with current European Union licenses. The results suggest a clinical benefit from ESAs for anaemia-related outcomes and an improvement in HRQoL scores. The impact of ESAs on AEs and survival remains highly uncertain, although point estimates are lower, confidence intervals are wide and not statistically significant. Base-case incremental cost-effectiveness ratios (ICERs) for ESA treatment compared with no ESA treatment ranged from £ 19,429 to £ 35,018 per QALY gained, but sensitivity and scenario analyses demonstrate considerable uncertainty in these ICERs, including the possibility of overall health disbenefit. All ICERs were sensitive to survival and cost.
  
  
  CONCLUSIONS
  The relative effectiveness of ESAs was not addressed; all ESAs were assumed to have equivalent efficacy. No studies were completely aligned with their European labelling beyond the starting dose evaluated. There is questionable generalisability given that the included trials were published >20 years ago and there have been many changes to chemotherapy as well as to the quality of supportive treatment. Trial quality was moderate or poor and there was considerable unexplained heterogeneity for a number of outcomes, particularly survival, and evidence of publication bias. Adjustments were not made to account for multiple testing.
  
  
  CONCLUSIONS
  ESAs could be cost-effective when used closer to licence, but there is considerable uncertainty, mainly because of unknown impacts on overall survival.
  
  
  BACKGROUND
  This study is registered as PROSPERO CRD42013005812.
  
  
  BACKGROUND
  The National Institute for Health Research Health Technology Assessment programme.
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK.
authors.forename: Louise
authors.initials: L
authors.lastname: Crathorne
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK.
authors.forename: Nicola
authors.initials: N
authors.lastname: Huxley
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK.
authors.forename: Marcela
authors.initials: M
authors.lastname: Haasova
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK.
authors.forename: Tristan
authors.initials: T
authors.lastname: Snowsill
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK.
authors.forename: Tracey
authors.initials: T
authors.lastname: Jones-Hughes
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Hoyle
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Briscoe
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Coelho
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK.
authors.forename: Linda
authors.initials: L
authors.lastname: Long
authors.affiliation: University of Exeter Medical School, Exeter, UK.
authors.forename: Antonieta
authors.initials: A
authors.lastname: Medina-Lara
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK.
authors.forename: Ruben
authors.initials: R
authors.lastname: Mujica-Mota
authors.affiliation: Royal Devon and Exeter Hospital, Exeter, UK.
authors.forename: Mark
authors.initials: M
authors.lastname: Napier
authors.affiliation: Peninsula Technology Assessment Group (PenTAG), University of Exeter Medical School, Exeter, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Hyde
mesh_terms: D000740:Anemia / Q000188:drug therapy* / Q000191:economics / Q000209:etiology; D003362:Cost-Benefit Analysis; D006397:Hematinics / Q000191:economics / Q000627:therapeutic use*; D006801:Humans; D018803:Models, Economic; D009369:Neoplasms / Q000188:drug therapy* / Q000191:economics; D019057:Quality-Adjusted Life Years; D013673:Technology Assessment, Biomedical
chemical_list: D006397:Hematinics