Abstract: This update of the systematic review includes a total of 91 trials with 20,102 participants. Use of ESAs significantly reduced the relative risk of red blood cell transfusions (risk ratio (RR) 0.65; 95% confidence interval (CI) 0.62 to 0.68, 70 trials, N = 16,093). On average, participants in the ESAs group received one unit of blood less than the control group (mean difference (MD) -0.98; 95% CI -1.17 to -0.78, 19 trials, N = 4,715). Haematological response was observed more often in participants receiving ESAs (RR 3.93; 95% CI 3.10 to 3.71, 31 trials, N = 6,413). There was suggestive evidence that ESAs may improve Quality of Life (QoL). There was strong evidence that ESAs increase mortality during active study period (hazard ratio (HR) 1.17; 95% CI 1.06 to 1.29, 70 trials, N = 15,935) and some evidence that ESAs decrease overall survival (HR 1.05; 95% CI 1.00 to 1.11, 78 trials, N = 19,003). The risk ratio for thromboembolic complications was increased in patients receiving ESAs compared to controls (RR 1.52, 95% CI 1.34 to 1.74; 57 trials, N = 15,498). ESAs may also increase the risk for hypertension (fixed-effect model: RR 1.30; 95% CI 1.08 to 1.56; random-effects model: RR 1.12; 95% CI 0.94 to 1.33, 31 trials, N = 7,228) and thrombocytopenia/haemorrhage (RR 1.21; 95% CI 1.04 to 1.42; 21 trials, N = 4,507). There was insufficient evidence to support an effect of ESA on tumour response (fixed-effect RR 1.02; 95% CI 0.98 to 1.06, 15 trials, N = 5,012). ESAs reduce the need for red blood cell transfusions but increase the risk for thromboembolic events and deaths. There is suggestive evidence that ESAs may improve QoL. Whether and how ESAs affects tumour control remains uncertain. The increased risk of death and thromboembolic events should be balanced against the potential benefits of ESA treatment taking into account each patient’s clinical circumstances and preferences. More data are needed for the effect of these drugs on quality of life and tumour progression. Further research is needed to clarify cellular and molecular mechanisms and pathways of the effects of ESAs on thrombogenesis and their potential effects on tumour growth.

Plain-language summary: - More people who received epoetin or darbepoetin died during and up to 30 days after the end of study compared with people who took placebo or underwent standard treatment. The increased risk for people taking epoetin or darbepoetin was 17%. One hundred and fourteen out of 1,000 persons receiving epoetin or darbepoetin died, compared with 98 out of 1,000 persons not receiving epoetin or darbepoetin. We could not identify particular characteristics of people or treatment strategies that increased or decreased the risk for dying. - Concerning long-term survival people taking epoetin or darbepoetin were 5% more at risk for dying than people taking placebo or receiving standard treatment. - People receiving epoetin or darbepoetin rated their fatigue symptoms to be an average of 2.08 points improved on a scale of 0-52 points after 3-4 months, compared with people taking placebo or having standard treatment. This improvement, however, is less than the 3.0 point increase which is considered to be the minimum required for the patient to feel a difference in his experience of fatigue-related symptoms using this scale. - People taking epoetin or darbepoetin rated their fatigue and anaemia symptoms had to be an average of 6.14 points improved after three to four months, on a scale of 0-80 points. This improvement is considered to reflect a positive change in the way patients experience their fatigue and anaemia related symptoms, as it is more than four to five points of increase which is the minimum required for this scale. - Seven people out of 100 who took epoetin or darbepoetin suffered a thromboembolic event such as stroke and myocardial infarction compared with five people out of 100 who did not receive epoetin or darbepoetin. - Six out of 100 people receiving epoetin or darbepoetin developed high blood pressure compared with four out of 100 people who took placebo or had standard care.