Abstract

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.

Abstract

Purpose: To update American Society of Hematology/American Society of Clinical Oncology recommendations for use of erythropoiesis-stimulating agents (ESAs) in patients with cancer. Methods: An Update Committee reviewed data published between January 2007 and January 2010. MEDLINE and the Cochrane Library were searched. Results: The literature search yielded one new individual patient data analysis and four literature-based meta-analyses, two systematic reviews, and 13 publications reporting new results from randomized controlled trials not included in prior or new reviews. Recommendations: For patients undergoing myelosuppressive chemotherapy who have a hemoglobin (Hb) level less than 10 g/dL, the Update Committee recommends that clinicians discuss potential harms (eg, thromboembolism, shorter survival) and benefits (eg, decreased transfusions) of ESAs and compare these with potential harms (eg, serious infections, immune-mediated adverse reactions) and benefits (eg, rapid Hb improvement) of RBC transfusions. Individual preferences for assumed risk should contribute to shared decisions on managing chemotherapy-induced anemia. The Committee cautions against ESA use under other circumstances. If used, ESAs should be administered at the lowest dose possible and should increase Hb to the lowest concentration possible to avoid transfusions. Available evidence does not identify Hb levels >= 10 g/dL either as thresholds for initiating treatment or as targets for ESA therapy. Starting doses and dose modifications after response or nonresponse should follow US Food and Drug Administration-approved labeling. ESAs should be discontinued after 6 to 8 weeks in nonresponders. ESAs should be avoided in patients with cancer not receiving concurrent chemotherapy, except for those with lower risk myelodysplastic syndromes. Caution should be exercised when using ESAs with chemotherapeutic agents in diseases associated with increased risk of thromboembolic complications. Table 1 lists detailed recommendations.

Abstract

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.

Abstract

To support evidence-based clinical guidelines on erythropoietin use for anemia in oncology, we conducted systematic reviews of controlled trials on four patient groups. These were patients with treatment- related anemia; patients with disease-related anemia; patients transplanted with allogeneic hematopoietic stem cells; and those transplanted with autologous hematopoietic stem cells. Two reviewers followed a prospective protocol to select studies, abstract relevant outcomes, evaluate study quality, and conduct meta-analysis where data sufficed. For treatment-related anemia, meta-analysis of available evidence (22 trials; N = 1,927) demonstrated reduced odds of transfusion after erythropoietin, but higher-quality trials reported smaller odds reductions. In several trials, erythropoietin improved quality of life for groups with mean baseline hemoglobin < or = 10 g/d L. However, evidence was insufficient to determine whether initiating erythropoietin treatment earlier for newly anemic patients reduced the odds of transfusion or improved quality of life more than waiting until hemoglobin approached l0 g/dL. Limited evidence (6 trials; N= 693) suggested that erythropoietin decreased the risk of transfusion for patients with disease-related anemia. For those undergoing allotransplants, evidence (7 trials; N = 493) showed erythropoietin modestly decreased time to red cell engraftment and transfusions. Studies on erythropoietin after autologous transplants (6 trials; N = 321) did not support a beneficial effect of erythropoietin.

Abstract

Objectives: Anemia is relatively common in patients with either hematologic or solid tissue malignancies. When cancer treatment or the disease itself decreases production of or impairs response to endogenous erythropoietin, epoetin treatment may correct the resulting anemia. This systematic review compares outcomes of managing anemia with epoetin (and red blood cell [RBC] transfusion used as necessary) with using RBC transfusion alone. Four groups of patients with malignancy are included: 1. Patients with anemia or at risk of anemia resulting primarily from cancer therapy. 2. Patients with anemia resulting primarily from their malignant disease and who may also be receiving cancer therapy. Patients who are anemic as a result of bone marrow ablation prior to: 3. Allogeneic stem-cell transplantation. 4. Autologous stem-cell transplantation. Search Strategy: The MEDLINE®, CancerLit, and EMBASE databases were searched from 1985 through 1998 and Current Contents on Diskette and Medscape Oncology through October 1999 for the terms: erythropoietin (Medical Subject Heading [MeSH®]); epoetin alfa (MeSH®); erythropoietin (tw); epoetin (tw); Epogen (tw); Procrit (tw); Eprex (tw); Marogen (tw); Recormon (tw); epo (tw); Anemia/drug therapy (MeSH®; included all subheadings); Anemia/therapy (MeSH®; included all subheadings); Anemia/diet therapy (MeSH®; included all subheadings). The search was then limited to neoplasmsor myelodysplastic syndromesand studies on human subjects. The yield was 2,943 references. Selection Criteria: This systematic review is limited to controlled trials comparing the outcomes of managing anemia with and without the use of epoetin in one of the four patient populations of interest. Uncontrolled trials were excluded. Data Collection and Analysis: We used a prospectively designed protocol conducted by two independent reviewers, with disagreements resolved by consensus. The meta-analysis used a random effects model to combine data on odds of transfusion in patients with anemia due primarily to cancer therapy. Main Results: For patients with anemia resulting primarily from cancer therapy, epoetin reduces the odds of transfusion. The overall number needed to treat (NNT) is 4.4 (95 percent confidence interval [CI], 3.6 to 6.1), which suggests four to five patients must be treated to spare one patient from transfusion. Sensitivity analysis found a smaller magnitude of risk reduction for double-blinded compared with unblinded studies. A large, double-blinded randomized trial, not yet published, found improvement in quality-of-life scores with epoetin. Assessment of the study methodology and clinical significance of the findings awaits publication of the full report. The most robust evidence that epoetin improves outcomes is from trials in patient groups with baseline hemoglobin (Hb) at or below 10 g/dL. The evidence is not adequate to determine whether outcomes are superior when epoetin treatment is initiated at higher hemoglobin thresholds. As many as one-half of all patients did not achieve a hematologic response to epoetin. Thus, nonresponding patients may account for much of the transfusion use in the epoetin arms of these trials. To achieve the most efficient use of epoetin, more systematic evidence is needed on patient characteristics that predict responsiveness and on early indicators of response. Anemia primarily a result of malignancy included patients with multiple myeloma, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and myelodysplastic syndromes. Epoetin increases Hb levels and achieves statistically significant hematologic response rates in these patients. The evidence on transfusion outcomes is sparse but suggests a favorable effect of epoetin. Hematologic response rates appear to be lower for patients with myelodysplastic syndrome; higher doses of epoetin may be necessary to achieve response. For patients undergoing allogeneic stem-cell transplantation, epoetin decreased time to RBC engraftment by 1 to 2 weeks and may decrease the number of RBC units transfused. No reduction in lengt

Abstract

Epoetin treatment offers an attractive but costly alternative to red blood cell transfusion for managing anemia associated with cancer therapy. The goal of this review is to facilitate more efficient use of epoetin by 1) quantifying the effects of epoetin on the likelihood of transfusion and on quality of life in patients with cancer treatment-related anemia and 2) evaluating whether outcomes are superior when epoetin treatment is initiated at higher hemoglobin thresholds. Two independent reviewers followed a prospective protocol for identifying studies. Outcomes data were combined with the use of a random-effects meta-analysis model. Double-blind, randomized, controlled trials that minimized patient exclusions were defined as higher quality for sensitivity analysis; randomized but unblinded trials and trials with excessive exclusions were included in the metaanalysis but were defined as lower quality. Twenty-two trials (n = 1927) met inclusion criteria, and 12 (n = 1390) could be combined for estimation of odds of transfusion. Epoetin decreased the percentage of patients transfused by 9%-45% in adults with mean baseline hemoglobin concentrations of 10 g/dL or less (seven trials; n = 1080), by 7%-47% in those with hemoglobin concentrations greater than 10 g/dL but less than 12 g/dL (seven trials; n = 431), and by 7%-39% in those with hemoglobin concentrations of 12 g/dL or higher (five trials; n = 308). In sensitivity analysis, the combined odds ratio for transfusion in epoetin-treated patients as compared with controls was 0.45 (95% confidence interval (CI) = 0.33 to 0.62) in higher quality studies and 0.14 (95% CI = 0.06 to 0.31) in lower quality studies. The number of patients needed to treat to prevent one transfusion is 4.4 for all studies, 5.2 for higher quality studies, and 2.6 for lower quality studies. Only studies with mean baseline hemoglobin concentrations of 10 g/dL or less reported statistically significant effects of epoetin treatment on quality of life; quality-of-life data were insufficient for meta-analysis. No studies addressed epoetin's effects on anemiarelated symptoms. We conclude that epoetin reduces the odds of transfusion for cancer patients undergoing therapy. Evidence is insufficient to determine whether initiating epoetin earlier spares more patients from transfusion or results in better quality of life than waiting until hemoglobin concentrations decline to nearly 10 g/d L.