title: Dose efficiency of erythropoiesis-stimulating agents for the treatment of patients with chemotherapy-induced anemia: a systematic review.
abstract: BACKGROUND
  Erythropoiesis-stimulating agents (ESAs) increase red blood cell production in patients with chemotherapy-induced anemia (CIA). In Europe, short-acting ESAs (epoetin alfa, epoetin beta, epoetin zeta, and epoetin theta) and a long-acting ESA (darbepoetin alfa) are available to treat CIA.
  
  
  OBJECTIVE
  This systematic review aimed to determine potential dose efficiency associated with the use of different ESAs for the treatment of CIA according to European labeling.
  
  
  METHODS
  A systematic review of ESA studies with starting doses according to European labeling was conducted according to published methodology. Measures of dose efficiency were defined as mean weekly doses to achieve target hemoglobin level or final dose and dose adjustments (dose increase, decrease, or withheld). Electronic databases and grey literature sources were searched up to July 2012. Data were selected for analysis using an evidence hierarchy and quantitatively analyzed to assess statistical homogeneity. Where pooling of data was not appropriate, a narrative summary with descriptive statistics (medians and ranges) was reported.
  
  
  RESULTS
  Fifty-five studies met the inclusion criteria. Twenty-five studies considered to represent the highest level of evidence were extracted and included in the analysis. The analysis showed a high degree of statistical heterogeneity, often precluding meta-analysis. The patients included in the analysis were representative of those encountered in clinical practice, and patient characteristics were similar between the short-acting and the darbepoetin alfa groups. Mean weekly doses appeared ~30% lower with darbepoetin alfa versus short-acting ESAs (median, 136.5 μg or 27,300 IU [range, 21,560-38,260 IU] vs 38,230 IU [range, 31,634-42,714 IU], respectively), resulting in a mean weekly dose ratio of 1:280. Darbepoetin alfa patients appeared to need fewer dose increases compared with short-acting ESAs (pooled, 0.75%; I(2) = 21% vs median 26.6% [range, 7.6%-44.6%]) and more dose decreases (median, 74% [range, 57%-75%] vs 22% [range, 2.8%-59%]). A similar percentage of darbepoetin alfa and short-acting ESA patients required a dose to be withheld (20% and 33% [2 studies] vs median 33.2% [range, 12.6%-51.1%]).
  
  
  CONCLUSIONS
  Statistical heterogeneity between studies was high, although clinically the studies represented medical practice. Without randomized clinical trials directly comparing darbepoetin alfa and short-acting ESAs, these findings are tentative and future research is warranted. This review shows that good-quality, reliable data from head-to-head trials are lacking. The best available evidence comes from prospective ESA-arm data. Mean weekly doses, dose increases, and dose decreases suggest a dose efficiency for darbepoetin alfa compared with short-acting ESAs.
authors.affiliation: Kleijnen Systematic Reviews Ltd, Escrick, York, United Kingdom. Electronic address: carol@systematic-reviews.com.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Forbes
authors.affiliation: Kleijnen Systematic Reviews Ltd, Escrick, York, United Kingdom.
authors.forename: Gillian
authors.initials: G
authors.lastname: Worthy
authors.affiliation: Kleijnen Systematic Reviews Ltd, Escrick, York, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Harker
authors.affiliation: Kleijnen Systematic Reviews Ltd, Escrick, York, United Kingdom; School for Public Health and Primary Care (CAPHRI), Maastricht University, Maastricht, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Kleijnen
authors.affiliation: Health Economics, Amgen (Europe) GmbH, Zug, Switzerland.
authors.forename: Lucie
authors.initials: L
authors.lastname: Kutikova
authors.affiliation: Services d'oncologie, Hôpital Avicenne, Bobigny, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Zelek
authors.affiliation: Department of Medical Oncology, University Hospital Ghent, Ghent, Belgium.
authors.forename: Simon
authors.initials: S
authors.lastname: Van Belle
mesh_terms: D000740:Anemia / Q000139:chemically induced / Q000188:drug therapy*; D000068256:Darbepoetin alfa / Q000008:administration & dosage; D016208:Databases, Factual; D000068817:Epoetin Alfa / Q000008:administration & dosage; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000008:administration & dosage; D006397:Hematinics / Q000008:administration & dosage*; D006801:Humans; D008875:Middle Aged; D011446:Prospective Studies; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D006397:Hematinics; D011994:Recombinant Proteins; C103998:epoetin beta; C555712:epoetin theta; C530192:epoetin zeta; D004921:Erythropoietin; D000068256:Darbepoetin alfa; D000068817:Epoetin Alfa
keywords: chemotherapy-induced anemia; darbepoetin; epoetin; erythropoiesis-stimulating agent