title: Effects of erythropoiesis-stimulating agents on fatigue- and anaemia-related symptoms in cancer patients: systematic review and meta-analyses of published and unpublished data.
abstract: BACKGROUND
  Erythropoiesis-stimulating agents (ESAs) reduce the need for red blood cell transfusions; however, they increase the risk of thromboembolic events and mortality. The impact of ESAs on quality of life (QoL) is controversial and led to different recommendations of medical societies and authorities in the USA and Europe. We aimed to critically evaluate and quantify the effects of ESAs on QoL in cancer patients.
  
  
  METHODS
  We included data from randomised controlled trials (RCTs) on the effects of ESAs on QoL in cancer patients. Randomised controlled trials were identified by searching electronic data bases and other sources up to January 2011. To reduce publication and outcome reporting biases, we included unreported results from clinical study reports. We conducted meta-analyses on fatigue- and anaemia-related symptoms measured with the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) and FACT-Anaemia (FACT-An) subscales (primary outcomes) or other validated instruments.
  
  
  RESULTS
  We identified 58 eligible RCTs. Clinical study reports were available for 27% (4 out of 15) of the investigator-initiated trials and 95% (41 out of 43) of the industry-initiated trials. We excluded 21 RTCs as we could not use their QoL data for meta-analyses, either because of incomplete reporting (17 RCTs) or because of premature closure of the trial (4 RCTs). We included 37 RCTs with 10581 patients; 21 RCTs were placebo controlled. Chemotherapy was given in 27 of the 37 RCTs. The median baseline haemoglobin (Hb) level was 10.1 g dl(-1); in 8 studies ESAs were stopped at Hb levels below 13 g dl(-1) and in 27 above 13 g dl(-1). For FACT-F, the mean difference (MD) was 2.41 (95% confidence interval (95% CI) 1.39-3.43; P<0.0001; 23 studies, n=6108) in all cancer patients and 2.81 (95% CI 1.73-3.90; P<0.0001; 19 RCTs, n=4697) in patients receiving chemotherapy, which was below the threshold (≥ 3) for a clinically important difference (CID). Erythropoiesis-stimulating agents had a positive effect on anaemia-related symptoms (MD 4.09; 95% CI 2.37-5.80; P=0.001; 14 studies, n=2765) in all cancer patients and 4.50 (95% CI 2.55-6.45; P<0.0001; 11 RCTs, n=2436) in patients receiving chemotherapy, which was above the threshold (≥ 4) for a CID. Of note, this effect persisted when we restricted the analysis to placebo-controlled RCTs in patients receiving chemotherapy. There was some evidence that the MDs for FACT-F were above the threshold for a CID in RCTs including cancer patients receiving chemotherapy with Hb levels below 12 g dl(-1) at baseline and in RCTs stopping ESAs at Hb levels above 13 g dl(-1). However, these findings for FACT-F were not confirmed when we restricted the analysis to placebo-controlled RCTs in patients receiving chemotherapy.
  
  
  CONCLUSIONS
  In cancer patients, particularly those receiving chemotherapy, we found that ESAs provide a small but clinically important improvement in anaemia-related symptoms (FACT-An). For fatigue-related symptoms (FACT-F), the overall effect did not reach the threshold for a CID.
authors.affiliation: Institute of Social and Preventive Medicine (ISPM), University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Bohlius
authors.affiliation: Institute of Social and Preventive Medicine (ISPM), University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Tonia
authors.affiliation: 1] Institute of Social and Preventive Medicine (ISPM), University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland [2] Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
authors.forename: E
authors.initials: E
authors.lastname: Nüesch
authors.affiliation: 1] Institute of Social and Preventive Medicine (ISPM), University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland [2] Department of Clinical Research, CTU Bern, University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Jüni
authors.affiliation: Department of Medical Oncology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland.
authors.forename: M F
authors.initials: MF
authors.lastname: Fey
authors.affiliation: Institute of Social and Preventive Medicine (ISPM), University of Bern, Finkenhubelweg 11, 3012 Bern, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Egger
authors.affiliation: Department of Medical Oncology, Inselspital, Bern University Hospital, 3010 Bern, Switzerland.
authors.forename: J
authors.initials: J
authors.lastname: Bernhard
mesh_terms: D000740:Anemia / Q000097:blood / Q000188:drug therapy*; D004920:Erythropoiesis / Q000187:drug effects; D005221:Fatigue / Q000097:blood*; D006397:Hematinics / Q000627:therapeutic use*; D006801:Humans; D009369:Neoplasms / Q000097:blood* / Q000188:drug therapy; D011788:Quality of Life; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D006397:Hematinics
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