Cancer, meta-analysis and reporting biases: the case of erythropoiesis-stimulating agents

Abstract

Reporting and publication bias is a well-known problem in meta-analysis and healthcare research. In 2002 we conducted a meta-analysis on the effects of erythropoiesis-stimulating agents (ESAs) on overall survival in cancer patients, which suggested some evidence for improved survival in patients receiving ESAs compared with controls. However, a meta-analysis of individual patient data conducted several years later showed the opposite of our first meta-analysis, that is, evidence for increased on-study mortality and reduced overall survival in cancer patients receiving ESAs. We aimed to determine whether the results of our first meta-analysis could have been affected by publication and reporting biases and, if so, whether timely access to clinical study reports and individual patient data could have prevented this. We conducted a hypothetical meta-analysis for overall survival including all studies and study data that could have been available in 2002, at the time when we conducted our first meta-analysis. Compared with our original meta-analysis, which suggested an overall survival benefit for cancer patients receiving ESAs [hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.67‒0.99], our hypothetical meta-analysis based on the results of all studies conducted at the time of the first analysis did not show evidence for a beneficial effect of ESAs on overall survival (HR 0.97, 95% CI 0.83‒1.12). Thus we have to conclude that our first meta-analysis showed misleading overall survival benefits due to publication and reporting biases, which could have been prevented by timely access to clinical study reports and individual patient data. Unrestricted access to clinical study protocols including amendments, clinical study reports and individual patient data is needed to ensure timely detection of both beneficial and harmful effects of healthcare interventions.

Putting Evidence Into Practice: An Update of Evidence-Based Interventions for Cancer-Related Fatigue During and Following Treatment

“…A target hemoglobin level of 11-12 g/dl was associated with the greatest reduction in CRF and improvement in other quality-of-life outcomes (Eton & Cella, 2011). Although ESAs are generally well tolerated, the use of these agents specifically for the management of fatigue must be considered in light of safety issues, including an elevated risk for thromboembolic complications and decreased survival, particularly when ESAs are used in patients with cancer who are not receiving chemotherapy Bormanis et al, 2013;Boulaamane et al, 2013;Gao, Ma, & Lu, 2013;Tonia et al, 2012;Tonia, Schwarzer, & Bohlius, 2013;Wauters & Vansteenkiste, 2012). National clinical practice guidelines (Lichtin, 2011;NCCN, 2015;Rizzo et al, 2010) and the recommendations of the U.S. Food and Drug Administration (2013) should guide decisions about treatment initiation, discontinuation, monitoring, and management in patients receiving ESAs.…”

Putting Evidence Into Practice: An Update of Evidence-Based Interventions for Cancer-Related Fatigue During and Following Treatment

“…A target hemoglobin level of 11-12 g/dl was associated with the greatest reduction in CRF and improvement in other quality-of-life outcomes (Eton & Cella, 2011). Although ESAs are generally well tolerated, the use of these agents specifically for the management of fatigue must be considered in light of safety issues, including an elevated risk for thromboembolic complications and decreased survival, particularly when ESAs are used in patients with cancer who are not receiving chemotherapy Bormanis et al, 2013;Boulaamane et al, 2013;Gao, Ma, & Lu, 2013;Tonia et al, 2012;Tonia, Schwarzer, & Bohlius, 2013;Wauters & Vansteenkiste, 2012). National clinical practice guidelines (Lichtin, 2011;NCCN, 2015;Rizzo et al, 2010) and the recommendations of the U.S. Food and Drug Administration (2013) should guide decisions about treatment initiation, discontinuation, monitoring, and management in patients receiving ESAs.…”

Planning and reporting of quality-of-life outcomes in cancer trials

“…implications Failure to report pre-specified outcomes can seriously bias published evidence [26], especially because positive findings are more likely to be reported than negative findings [17]. For instance, a meta-analysis of cancer trials suggested that administration of erythropoiesis-stimulating agents prolonged survival, while an updated individual patient data meta-analysis that included previously unpublished outcome data showed no significant effect [27].…”

How Basic Scientists Help the Pharmaceutical Industry Market Drugs

“…Let's take the example of erythropoetin-stimulating agents (ESAs), which were licensed in the early 1990s for treating anemia in cancer patients and became widely used. Early published clinical studies and meta-analyses appeared to show a benefit of ESAs on mortality [11] . It is now known, however, that ESAs actually increase thromboembolic events, cardiovascular events, and overall mortality in cancer patients [12] ; disturbingly, knowledge of this risk was delayed by a decade because of publication and reporting biases [11] .…”

Putting Evidence Into Practice: An Update of Evidence-Based Interventions for Cancer-Related Fatigue During and Following Treatment

“…A target hemoglobin level of 11-12 g/dl was associated with the greatest reduction in CRF and improvement in other quality-of-life outcomes (Eton & Cella, 2011). Although ESAs are generally well tolerated, the use of these agents specifically for the management of fatigue must be considered in light of safety issues, including an elevated risk for thromboembolic complications and decreased survival, particularly when ESAs are used in patients with cancer who are not receiving chemotherapy Bormanis et al, 2013;Boulaamane et al, 2013;Gao, Ma, & Lu, 2013;Tonia et al, 2012;Tonia, Schwarzer, & Bohlius, 2013;Wauters & Vansteenkiste, 2012). National clinical practice guidelines (Lichtin, 2011;NCCN, 2015;Rizzo et al, 2010) and the recommendations of the U.S. Food and Drug Administration (2013) should guide decisions about treatment initiation, discontinuation, monitoring, and management in patients receiving ESAs.…”

Planning and reporting of quality-of-life outcomes in cancer trials

“…implications Failure to report pre-specified outcomes can seriously bias published evidence [26], especially because positive findings are more likely to be reported than negative findings [17]. For instance, a meta-analysis of cancer trials suggested that administration of erythropoiesis-stimulating agents prolonged survival, while an updated individual patient data meta-analysis that included previously unpublished outcome data showed no significant effect [27].…”

How Basic Scientists Help the Pharmaceutical Industry Market Drugs

“…Let's take the example of erythropoetin-stimulating agents (ESAs), which were licensed in the early 1990s for treating anemia in cancer patients and became widely used. Early published clinical studies and meta-analyses appeared to show a benefit of ESAs on mortality [11] . It is now known, however, that ESAs actually increase thromboembolic events, cardiovascular events, and overall mortality in cancer patients [12] ; disturbingly, knowledge of this risk was delayed by a decade because of publication and reporting biases [11] .…”

Putting Evidence Into Practice: An Update of Evidence-Based Interventions for Cancer-Related Fatigue During and Following Treatment

“…A target hemoglobin level of 11-12 g/dl was associated with the greatest reduction in CRF and improvement in other quality-of-life outcomes (Eton & Cella, 2011). Although ESAs are generally well tolerated, the use of these agents specifically for the management of fatigue must be considered in light of safety issues, including an elevated risk for thromboembolic complications and decreased survival, particularly when ESAs are used in patients with cancer who are not receiving chemotherapy Bormanis et al, 2013;Boulaamane et al, 2013;Gao, Ma, & Lu, 2013;Tonia et al, 2012;Tonia, Schwarzer, & Bohlius, 2013;Wauters & Vansteenkiste, 2012). National clinical practice guidelines (Lichtin, 2011;NCCN, 2015;Rizzo et al, 2010) and the recommendations of the U.S. Food and Drug Administration (2013) should guide decisions about treatment initiation, discontinuation, monitoring, and management in patients receiving ESAs.…”

Planning and reporting of quality-of-life outcomes in cancer trials

“…implications Failure to report pre-specified outcomes can seriously bias published evidence [26], especially because positive findings are more likely to be reported than negative findings [17]. For instance, a meta-analysis of cancer trials suggested that administration of erythropoiesis-stimulating agents prolonged survival, while an updated individual patient data meta-analysis that included previously unpublished outcome data showed no significant effect [27].…”

How Basic Scientists Help the Pharmaceutical Industry Market Drugs

“…Let's take the example of erythropoetin-stimulating agents (ESAs), which were licensed in the early 1990s for treating anemia in cancer patients and became widely used. Early published clinical studies and meta-analyses appeared to show a benefit of ESAs on mortality [11] . It is now known, however, that ESAs actually increase thromboembolic events, cardiovascular events, and overall mortality in cancer patients [12] ; disturbingly, knowledge of this risk was delayed by a decade because of publication and reporting biases [11] .…”