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This is an updated systematic review of 57 trials and 9353 cancer patients from articles, abstracts, and reports published between January 1, 1985, and April 30, 2005, on the effects of epoetin alfa and beta (i.e., epoetin) and darbepoetin alfa (i.e., darbepoetin). We included randomized controlled trials comparing epoetin or darbepoetin plus red blood cell transfusion with red blood cell transfusion alone for prophylaxis or treatment of anemia in cancer patients with or without concurrent antineoplastic therapy. The Cochrane Library, MEDLINE, EMBASE, and conference proceedings were searched. Effect estimates and 95% confidence intervals (CIs) were calculated with fixed-effects models. Treatment with epoetin or darbepoetin statistically significantly reduced the risk for red blood cell transfusions (relative risk [RR] = 0.64, 95% CI = 0.60 to 0.68; 42 trials and 6510 patients) and improved hematologic response (RR = 3.43, 95% CI = 3.07 to 3.84; 22 trials and 4307 patients). Treatment with epoetin or darbepoetin increased the risk of thrombo-embolic events (RR = 1.67, 95% CI = 1.35 to 2.06; 35 trials and 6769 patients). Uncertainties remain as to whether and how epoetin or darbepoetin affects overall survival (hazard ratio = 1.08, 95% CI = 0.99 to 1.18; 42 trials and 8167 patients). Caution is advised when using epoetin or darbepoetin in combination with thrombogenic chemotherapeutic agents or for cancer patients who are at high risk for thrombo-embolic events.

Objectives: to assess the effectiveness and cost-effectiveness of epoetin alpha, epoetin beta and darbepoetin alpha (referred to collectively in this report as epo) in anaemia associated with cancer, especially that attributable to cancer treatment. Data sources: electronic databases were searched from 2000 (1996 in the case of darbepoetin alpha) to September 2004. Review methods: using a recently published Cochrane review as the starting point, a systematic review of recent randomised controlled trials (RCTs) comparing epo with best standard was conducted. Inclusion, quality assessment and data abstraction were undertaken in duplicate. Where possible, meta-analysis was employed. The economic assessment consisted of a systematic review of past economic evaluations, an assessment of economic models submitted by the manufacturers of the three epo agents and development of a new individual sampling model (the Birmingham epo model). Results: in total 46 RCTs were included within this systematic review, 27 of which had been included in the Cochrane systematic review. All 46 trials compared epo plus supportive care for anaemia (including transfusions), with supportive care for anaemia (including transfusions), alone. Haematological response (defined as an improvement by 2 g/dl(-1)) had a relative risk of 3.4 [95% confidence interval (CI) 3.0 to 3.8, 22 RCTs] with a response rate for epo of 53%. The trial duration was most commonly 16-20 weeks. There was little statistical heterogeneity in the estimate of haematological response, and there were no important differences between the subgroups examined. Haemoglobin (Hb) change showed a weighted mean difference of 1.63 g/dl(-1) (95% CI 1.46 to 1.80) in favour of epo. Treatment with erythropoietin in patients with cancer-induced anaemia reduces the number of patients who receive a red blood cell transfusion (RBCT) by an estimated 18%. Health-related quality of life (HRQoL) data were analysed using vote counting and qualitative assessment and a positive effect was observed in favour of an improved HRQoL for patients on epo. Published information on side-effects was of poor quality. New trials provided further evidence of side-effects with epo, particularly thrombic events, but it is still unclear whether these could be accounted for by chance alone. The results of the previous Cochrane review had suggested a survival advantage for epo (HR 0.84, 95% CI 0.69 to 1.02), based on 19 RCTs. The update, based on 28 RCTs, suggests no difference (HR 1.03, 95% CI 0.88 to 1.21). Subgroup analysis suggested some explanations for this heterogeneity, but it is difficult to draw firm conclusions without access to the substantial amounts of missing or unpublished data, or more detailed results from some of the trials with heterogeneous patient populations. The conclusions are, however, broadly in line with those of a Food and Drug Administration (FDA) safety briefing, which recommended that patients with a haemoglobin above 12 g/dl(-1) should not be treated; the target rate of rise in Hb should not be too great, and further carefully conducted trials are required to determine which subgroups of patients may be harmed by the use of these products, in particular through the stimulation of tumour activity. Five published economic evaluations identified from the literature had inconsistent results, with estimates ranging from a cost per quality-adjusted life-year (QALY) under pound 10,000 through to epo being less effective and more costly than standard care. The more favourable evaluations assumed a survival advantage for epo. The three company models submitted each relied on assumed survival gains to achieve relatively low cost per QALY, from pound 13,000 to pound 28,000, but generated estimates from pound 84,000 to pound 159,000 per QALY when no survival gain was assumed. Each of these models relied on Hb levels alone driving utility, and each assumed gradual normalisation of Hb in the standard treatment arm after the end of treatment. The Birmingham epo model followed the company models in regard to the relationship between Hb levels and utility, and also assumed normalisation in the base case. With no survival gain, the incremental cost per QALY was pound 150,000, falling to pound 40,000 when the lower, more favourable, confidence interval for survival was used. Conclusions: epo is effective in improving haematological response and reducing RBCT requirements, and appears to have a positive effect on HRQoL. The incidence of side-effects and effects on survival remains highly uncertain. However, if there is no impact on survival, it seems highly unlikely that epo would be considered a cost-effective use of healthcare resources. The main target for further research should be improving estimates of impact on survival, initially through more detailed secondary research, such as the individual patient data meta-analysis started by the Cochrane group. Further trials may be required, and have been recommended by the FDA, although many trials are in progress, completed but unreported or awaiting mature follow-up. The Birmingham epo model developed as part of this project contains new features that improve its flexibility in exploring different scenarios; further refinement and validation would therefore be of assistance. Finally, further research to resolve uncertainty about other parameters, particularly quality of life, adverse events, and the rate of normalisation, would also be beneficial

BACKGROUND: Anaemia associated with cancer and cancer therapy is an important clinical factor in the treatment of malignant diseases. Therapeutic alternatives are recombinant human erythropoiesis stimulating agents (ESAs) and red blood cell transfusions. OBJECTIVES: To assess the effects of ESAs to either prevent or treat anaemia in cancer patients. SEARCH METHODS: This is an update of a Cochrane review first published in 2004. We searched the Central Register of Controlled Trials (CENTRAL), MEDLINE and EMBASE and other databases. Searches were done for the periods 01/1985 to 12/2001 for the first review, 1/2002 to 04/2005 for the first update and to November 2011 for the current update. We also contacted experts in the field and pharmaceutical companies. SELECTION CRITERIA: Randomised controlled trials on managing anaemia in cancer patients receiving or not receiving anti‐cancer therapy that compared the use of ESAs (plus transfusion if needed). DATA COLLECTION AND ANALYSIS: Several review authors assessed trial quality and extracted data. One review author assessed quality assessment and extracted data, a second review author checked for correctness. MAIN RESULTS: 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). AUTHORS' CONCLUSIONS: 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.

Background: Epoetin (EPO), darbepoetin (DARB) and red blood cell transfusions (RBCT) are therapeutic alternatives to treat anemia associated with cancer and cancer therapy. Results of randomized controlled trials (RCTs) conflict, and some question the safety of EPO and DARB. Previously, we systematically reviewed this topic (Bohlius et al, JNCI 2005). Since then many new studies became available necessitating an update the prior systematic review. Objectives: To determine the effectiveness and safety of recombinant human erythropoietin and darbepoetin to prevent or alleviate anemia in cancer patients (pts), and to compare current and previous results of systematic review. Methods: Included RCTs compared EPO or DARB plus RBCT if needed with observation plus RBCT for prophylaxis or treatment of anemia in cancer patients receiving or not receiving antineoplastic therapy. Patients had solid tumors or hematological malignancies including MDS. Endpoints were rates of RBCT, hematological response (defined as transfusion free Hb increase of 2 g/dL), tumor response, overall survival and thrombo embolic events. Medical databases (Cochrane Library, MEDLINE, EMBASE) and conference proceedings were searched (first review:1985–2001, update up to 04/2005). We included full-text and abstract publications plus unpublished data. Data extraction and quality assessment were in duplicate. Results: The update included 57 trials with 9,353 patients. Use of EPO or DARB significantly reduced the relative risk (RR) of RBCTs (RR 0.64; 95%-CI 0.60–0.68; 42 trials, n = 6,510). On average, participants in the EPO/DARB groups received one unit of blood less than controls (weighted mean difference −1.05; 95% CI− 1.32 −0.78; 14 trials, n = 2,353). Hb response (baseline Hb < 12 g/dL) was more likely in the EPO/DARB group (RR 3.43; 95%-CI 3.07–3.84; 22 trials, n = 4,307). Thrombo embolic complications were more frequent in patients receiving EPO/DARB: RR 1.67 (95%-CI 1.35–2.06; 35 trials, n = 6,769). Uncertainties remain whether and how EPO/DARB affects tumor response (fixed effect RR 1.12; 95%-CI 1.01–1.23; random effects: RR 1.09; 95%-CI 0.94–1.26; 13 trials, n = 2,833) or overall survival (HR 1.08; 95%-CI 0.99–1.18; 42 trials, n = 8,167). Subgroup analyses comparing EPO and DARB did not identify clinically or statistically significant differences. This update confirms previous findings for transfusion rates and hematological response. In contrast, the update suggests EPO/DARB may reduce survival whereas the first review suggested possible benefits (HR 0.81; 95%-CI 0.67–0.99; 19 trials, n = 2,865). Factors possibly contributing to these conflicting results include mortality due to thrombo embolic complications and tumor progression but also methodological limitations such as baseline imbalances. Conclusion: EPO or DARB given to cancer pts reduces the relative risk for red blood cell transfusion and increases likelihood of hematological response. However, EPO/DARB also increases the risk of thrombo embolic complications. The impact on tumor response and survival is uncertain.

Editor—We wrote the assessment report of riluzole in motor neurone disease, which was commissioned by the health technology assessment programme for the National Institute for Clinical Excellence (NICE).1,2 We believe that a superficial reading of the advice recently issued by NICE on this subject may not give an adequate understanding of the evidence base for this treatment.3,4 The evidence in favour of riluzole for use in the amyotrophic lateral sclerosis form of motor neurone disease is very weak. The pooled effect estimates for survival outcomes are not conventionally significant, but of greater concern is the disagreement between the trials about the direction and the size of the treatment effect; this apparent heterogeneity remains unexplained. A European public assessment report from the European Agency for the Evaluation of Medicinal Products also expressed concern about the use of riluzole, in view of the limited evidence of an effect on survival without evidence of a slowing in the rate of deterioration of functional status.5 The opinion concludes that there are therefore remaining uncertainties on the product in the management of amyotrophic lateral sclerosis. No further trial data have become available since this time. In the interests of patients we make the following plea to the clinical community. Ensure that consent to treatment is fully informed and that patients know of the uncertainty about any survival benefit, the modest size of any benefit that might exist, the lack of evidence that functional deterioration is slowed, the toxicity associated with treatment, and the nature of the additional monitoring required for the treatment rather than the disease. Approach an experienced organisation in the public sector with regard to designing a large randomised trial. Ideally this should include placebo, newer agents, or new combinations if appropriate, and investigate the lower dose of riluzole 25 mg twice daily. One trial compared different doses and reported a dose response effect, but this claim is in error; there is no evidence that 25 mg twice daily is any less effective than 50 mg twice daily, and it may have a more favourable toxicity profile. Resist the temptation to use this agent outside the licensed indication. There is pressure to use riluzole for motor neurone diseases other than amyotrophic lateral sclerosis, despite an incomplete understanding of the pathophysiology of these diseases (including amyotrophic lateral sclerosis) or the mechanism of action of riluzole, and a complete absence of any trial data in such patients. Consider the need for trials in other forms of motor neurone disease.

Objectives: To systematically review the effectiveness and cost-effectiveness of palivizumab for the prevention of respiratory syncytial virus (RSV) in children and examine prognostic factors to determine whether subgroups can be - identified with important differences in cost-effectiveness. Data sources: Bibliographic databases were searched from inception to March 2007 for literature on the effectiveness and cost-effectiveness of prophylaxis with palivizumab. Review methods: The literature was systematically reviewed and current economic evaluations were analysed to identify which parameters were driving the different cost-effectiveness estimates. A probabilistic decision-analytical model was built to assess the cost-effectiveness of prophylaxis with palivizumab for children at risk of RSV infection and the parameters populated with the best estimates thought most applicable to the UK. We also constructed a new model, the Birmingham Economic Evaluation (BrumEE). Cost-effectiveness analyses were undertaken from both NHS and societal perspectives. Results: Two randomised controlled trials (RCTs) were identified. Prophylaxis with palivizumab for preterm infants without chronic lung disease (CLD) or children with CLD resulted in a 55% reduction in RSV hospital admission: 4.8% (48/1002) in the palivizumab group and 10.6% (53/500) in the no prophylaxis group (p = 0.0004). Prophylaxis with palivizumab was associated with a 45% reduction in hospitalisation nate RSV among children with coronary heart disease (CHD). Hospitalisation rates for RSV were 5.3% (34/639) in the palivizumab group and 9.7% (63/ 648) in the no prophylaxis group (p = 0.003). Of existing economic evaluations, 3 systematic reviews and 18 primary studies were identified. All the systematic reviews concluded that the potential costs of palivizumab were far in excess of any potential savings achieved by decreasing hospital admission rates, and that the use of palivizumab was unlikely to be cost-effective in all children for whom it is recommended, but that its continued use for particularly high-risk children may be justified. The incremental cost-effectiveness ratios (ICERs) of the primary studies varied 17-fold for life-years gained (LYG), from £25,800/LYG to £404,900/LYG, and several-hundred-fold for quality-adjusted life years (QALYs); from £3200/QALY to £1,489,700/QALY for preterm infants without CLD or children with CLD. For children with CHD, the ICER varied from £5300/LYG to £7900/LYG and from £7500/QALY to £68,700/QALY. An analysis of what led to the discrepant ICERs showed that the assumed mortality rate for RSV infection was the most important driver. The results of the BrumEE confirm that palivizumab does not reach conventional levels of cost-effectiveness in any of the licensed indications if used for all eligible children. Conclusions: Prophylaxis with palivizumab is clinically effective for the reducing the risk of serious lower respiratory tract infection caused by RSV infection and requiring hospitalisation in high-risk children, but if used unselectively in the licensed population, the ICER is double that considered to represent good value for money in the UK- The BrumEE shows that prophylaxis with palivizumab may be cost-effective (based on a threshold of £30,000/QALY) for children with CLD when the children have two or more additional risk factors. Future research should initially focus on reviewing systematically the major uncertainties for patient subgroups with CLD and CHD and then on primary research to address the important uncertainties that remain. © Queen's Printer and Controller of HMSO 2008. All rights reserved.