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Database of Abstracts of Reviews of Effects (DARE): Quality-assessed Reviews [Internet].

Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes

J Glaspy, J Crawford, J Vansteenkiste, D Henry, S Rao, P Bowers, JA Berlin, D Tomita, K Bridges, and H Ludwig.

Review published: 2010.

CRD summary

This meta-analysis concluded that treatment with erythropoiesis-stimulated agents was associated with a significant increase in the risk of a venous thromboembolic event, but no significant effects on mortality or disease progression. The authors' conclusions appeared appropriate given the evidence presented, but should be treated with some caution due to a lack of detail in some areas and possible language bias.

Authors' objectives

To evaluate the effects of erythropoiesis-stimulating agents (ESA) on survival, disease progression and risk of venous thromboembolic events in patients with cancer.

Searching

Studies were located from a 2006 Cochrane Review (Bohlius 2006) and additional searches from April 2005 to March 2008 of BIOSIS Previews, Current Contents, EMBASE and MEDLINE. Search terms were reported. Abstracts and posters from 1995 to 2007 from conferences of American Society of Clinical Oncology, American Society of Hematology, San Antonio Breast Cancer Symposium and European Society for Medical Oncology were searched. Only studies published in English were included. For studies conducted by Amgen and Centecor Ortho Biotech, data from internal databases were used provided the trials met the literature search criteria.

Study selection

Eligible studies were randomised controlled trials of cancer patients treated with an ESA (epoetin alpha, epoetin beta or darbepoetin alpha) plus transfusions compared with placebo or best standard care for anaemia treatment (such as transfusions without ESAs). Studies needed to report deaths or provide sufficient data to enable their calculation. Interim trial analyses and studies that examined iron use in cancer patients were included. Studies that allowed ESAs in the control group were excluded.

Nearly all studies were of adult patients with solid tumours and/or haematological malignancies; only one was of paediatric cancer patients. Cancer types varied widely and included breast, gynaecological, small and non-small cell lung cancer, head and neck, Hodgkin's lymphoma, non-myeloid and other solid tumours. The most common treatment setting was chemotherapy; only a few studies were of radiotherapy and treatment for anaemia of cancer.

The authors did not report how many reviewers performed the study selection.

Assessment of study quality

The authors did not state that they assessed validity.

Data extraction

Numbers of deaths and venous thromboembolic events were used to calculate odds ratios (OR) with 95% confidence intervals (CI). Individual patient data (IPD) were available for 16 of the industry sponsored studies and these were used to calculate hazard ratios. Where possible both odds ratios and hazard ratios were calculated as a sensitivity analysis.

The authors did not report how many reviewers performed data extraction.

Methods of synthesis

Results were pooled using a random-effects model. Analyses used data for up to one year of follow-up. Heterogeneity was measured with the I2 statistic. A number of sensitivity analyses were performed on chemotherapy trials: comparison of use of odds ratios with hazard ratios as the effect measure in studies with longer follow-up (more than six months); individual patient data combined using an unadjusted Cox's proportional hazards model stratified by study; and influence plots were used to explore the impact of individual studies. Results were presented overall and by primary cancer treatment (anaemia of cancer, radiotherapy, chemotherapy).

Results of the review

Sixty studies were included (15,323 patients): 41 were the original Cochrane review and 19 from the updated searches. Nine studies (1,901 patients) treated anaemia of cancer. Four studies (1,314 patients) were of radiotherapy. Forty-seven studies (12,108 patients) were of chemotherapy, of which 20 (8,145 patients) had long-term follow-up.

Mortality: There was no evidence of a difference between ESA treatment and controls for mortality (OR 1.06, 95% CI 0.97 to 1.15; 60 studies) and no heterogeneity (I2=0%). A similar lack of difference was seen for all chemotherapy studies combined and when the chemotherapy studies were split into subgroups based on mean entry haemoglobin levels, and for radiotherapy and anaemia of cancer studies. There was no evidence of a difference between ESA treatment and controls in the 20 chemotherapy studies with long-term follow-up data and in the 16 chemotherapy studies with individual patient data available. For those studies where both could be calculated, hazard ratios and odds ratios were very close.

Disease progression: There was no evidence of a difference between ESA treatment and controls for disease progression for all 26 studies that reported this outcome and the 21 studies of chemotherapy alone.

Venous thromboembolic events: ESA treatment increased the risk of a thromboembolic event (OR 1.48, 95% CI 1.28 to 1.72; 44 studies). There was no heterogeneity (I2=0%). Similar results were seen for the 35 chemotherapy studies alone and the 18 chemotherapy studies with long-term follow-up.

Further results that repeated previously reported meta-analyses were presented in the paper.

Authors' conclusions

Treatment with erythropoiesis-stimulating agents was associated with a significant increase in the risk of a venous thromboembolic event, but no significant effects on mortality or disease progression.

CRD commentary

This meta-analysis was based on an update of a previous Cochrane systematic review. Trial inclusion and exclusion criteria were reported. Studies were located from the previous review and from a new search to locate studies published subsequently. Efforts were made to locate unpublished studies. Only studies published in English were included, which risked language bias. There was no quality assessment and no reporting of any methods used to reduce mistakes in the review process (such as having more than one person independently select studies and extract data). The methods of meta-analysis seemed appropriate. Subgroup analyses were used to explore differences by type of cancer treatment. Very little detail of the included studies, such as patient age, duration of cancer, duration of treatment and length of follow-up was reported. The authors repeated analyses from previous similar meta-analyses and compared them to their findings and discussed possible reasons for any disagreements.

Amgen provided data and assisted with writing the paper. Two of the authors appeared to be employees of pharmaceutical companies.

The authors' conclusions appeared appropriate given the evidence presented, but should be treated with some caution due to the lack of detail in some areas and possible language bias.

Implications of the review for practice and research

Practice: The authors did not state any implications for practice.

Research: The authors stated that studies were needed to further explore the effect of erythropoiesis-stimulated agent use on survival and disease progression, determine what drove treatment-related mortality and identify patient risk factors. They further stated that important evidence would be provided from trials that were ongoing.

Funding

Not stated.

Bibliographic details

Glaspy J, Crawford J, Vansteenkiste J, Henry D, Rao S, Bowers P, Berlin JA, Tomita D, Bridges K, Ludwig H. Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes. British Journal of Cancer 2010; 102(2): 301-315. [PMC free article: PMC2816662] [PubMed: 20051958]

Indexing Status

Subject indexing assigned by NLM

MeSH

Anemia /drug therapy /etiology; Hematinics /therapeutic use; Humans; Neoplasms /complications /mortality; Survival Analysis; Treatment Outcome

AccessionNumber

12010001535

Database entry date

29/09/2010

Record Status

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.

CRD has determined that this article meets the DARE scientific quality criteria for a systematic review.

Copyright © 2014 University of York.

PMID: 20051958

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