Effect of Once-Weekly Epoetin Beta on Survival in Patients With Metastatic Breast Cancer Receiving Anthracycline- and/or Taxane-Based Chemotherapy: Results of the Breast Cancer—Anemia and the Value of Erythropoietin (BRAVE) Study

Aapro, Matti; Leonard, Robert; Barnadas, Agustí; Marangolo, M.; Untch, Michael; Malamos, Nikolaos; Mayordomo, J. I.; Reichert, Dietmar; Pedrini, José Luiz; Ukarma, Lidia; Scherhag, Armin; Burger, Hans-Ulrich

doi:10.1200/jco.2007.11.5378

Cited by 103 publications

(65 citation statements)

References 24 publications

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“…Importantly, this updated meta-analysis also includes long-term follow-up data from more recent studies and largely confirms the results of the earlier metaanalysis of nine controlled studies (n ¼ 1413) (Aapro et al, 2006), which did not include the recently completed studies by Henke et al (2003); Aapro et al (2008) and Strauss et al (2008). Moreover, this update confirms the safety of epoetin-b in terms of overall Figure 1 Kaplan -Meier curves of (A) overall survival and (B) time to progression in the pooled population of 12 controlled studies.…”

Section: Discussionsupporting

confidence: 63%

“…Other studies were, however, designed to assess the effects of epoetin-b on survival and/or disease progression (Henke et al, 2003;Aapro et al, 2008) or Hb response to treatment (Strauss et al, 2008). Long-term follow-up information, up to 60 months, was available for overall survival in four studies (Henke et al, 2003;Ö sterborg et al, 2005;Aapro et al, 2008;Strauss et al, 2008) and for tumour progression in three studies (Henke et al, 2003;Aapro et al, 2008;Strauss et al, 2008). All reported adverse events were also reviewed against a prespecified list of TEEs, the definition of which was consistently applied across all studies.…”

Section: Methodsmentioning

confidence: 99%

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Effect of treatment with epoetin-β on survival, tumour progression and thromboembolic events in patients with cancer: an updated meta-analysis of 12 randomised controlled studies including 2301 patients

2008

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Epoetin-b is used to treat patients with metastatic cancer undergoing chemotherapy to alleviate the symptoms of anaemia, reduce the risk of blood transfusions and improve quality of life. This meta-analysis of 12 randomised, controlled studies evaluated the impact of epoetin-b on overall survival, tumour progression and thromboembolic events (TEEs). A total of 2297 patients were included in the analysis (epoetin-b, n ¼ 1244; control, n ¼ 1053; 65% solid and 35% nonmyeloid haematological malignancies). A prespecified subgroup analysis assessed the effects in patients with a baseline Hbp11 g dl À1 , corresponding to current European Organisation for Research and Treatment of Cancer (EORTC) guidelines. No statistically significant effect on mortality was observed with epoetin-b vs control, both overall (hazard ratio (HR) ¼ 1.13; 95% CI: 0.87, 1.46; P ¼ 0.355) and in patients with baseline Hbp11 g dl À1 (HR ¼ 1.09; 95% CI: 0.80, 1.47; P ¼ 0.579). A trend for a beneficial effect on tumour progression was seen overall (HR ¼ 0.85; 95% CI: 0.72, 1.01; P ¼ 0.072) and in patients with an Hbp11 g dl À1 (HR ¼ 0.80; 95% CI: 0.65, 0.99; P ¼ 0.041). An increased frequency of TEEs was seen with epoetin-b vs control (7 vs 4% of patients); however, TEEs-related mortality was similar in both groups (1% each). The results of this meta-analysis indicate that when used within current EORTC treatment guidelines, epoetin-b has no negative impact on survival, tumour progression or TEEs-related mortality.

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Section: Discussionsupporting

confidence: 63%

Section: Methodsmentioning

confidence: 99%

Effect of treatment with epoetin-β on survival, tumour progression and thromboembolic events in patients with cancer: an updated meta-analysis of 12 randomised controlled studies including 2301 patients

2008

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“…It should be noted that alongside the beneficial effects of EPO, a concern that EPO treatment for anemia might adversely affect the prognosis in certain cases of solid tumor cancers (Aapro et al, 2008;Henke et al, 2006;Longmore, 2007) has been raised. In that respect although EPO-Rs were found in certain solid tumors (Acs et al, 2003;Arcasoy et al, 2002;Yasuda et al, 2003), their functionality is still controversial Jeong et al, 2008;Laugsch et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

Lifshitz

Prutchi-Sagiv

Avneon

et al. 2009

Molecular Immunology

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Erythropoietin (EPO) is the main hormone that promotes proliferation and differentiation of erythroid progenitor cells via binding to its surface receptor (EPO-R). Recent studies suggest that this hormone may affect also other cell types, besides the red blood cell lineage. We have previously demonstrated that the immune system is a target of EPO; however, the direct target cells of EPO, as well as the molecular mechanisms underlying its role as an immunomodulator, are unknown. Here we present evidence for functional effects of EPO on dendritic cells (DCs), which are known to initiate the immune response. In-vivo experiments in EPO-injected mice and in transgenic mice over-expressing human EPO showed an increased splenic DC population with a higher cell surface expression of CD80 and CD86. Further analysis based on mouse models, showed that DCs derived in-vitro from bone marrow (BM-DCs) express EPO-R mRNA. In-vitro stimulation of these DCs with recombinant human EPO enhanced viability, upregulated CD80, CD86 and MHC class II and augmented the secretion of IL-12. Biochemical analysis of EPO mediated signaling in the BM-DCs showed activation of the AKT, MAPK and NF-kappaB pathways. EPO stimulation of the BM-DCs led to Tyr-phosphorylation of STAT3. The inability to detect EPO mediated activation of STAT5 in the BM-DCs, suggests that in DCs, STAT3 may play a more important role than STAT5 in EPO-R signaling. Taken together, our data support the premise that DCs are direct targets of EPO, thereby providing an insight to the immunomodulatory functions of EPO.

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“…For the meta-analysis, this information was analysed retrospectively by reviewers blinded to treatment assignment. Four of the studies, which did evaluate the effects of epoetin-b on survival and/or disease progression (Henke et al, 2003;Ö sterborg et al, 2005;Aapro et al, 2008b) or response to treatment (Strauss et al, 2008) provided long-term (up to 60 months) follow-up information for overall survival or tumour progression. For the assessment of TEEs, all reported adverse events were reviewed against a pre-specified list of TEEs, which was applied consistently across all studies.…”

Section: Methodsmentioning

confidence: 99%

“…We previously reported results of an updated meta-analysis of 12 randomised, controlled studies of epoetin-b conducted in 2301 patients undergoing cancer therapy (Aapro et al, 2008a) including three recently completed trials with longer term follow-up in patients with head and neck cancer (Henke et al, 2003), patients with metastatic breast cancer (Aapro et al, 2008b) and patients with cervical cancer (Strauss et al, 2008). The results of this metaanalysis based on individual patient level data showed no statistically significant difference between patients receiving epoetin-b or control (standard treatment) in terms of overall survival, a favourable trend with respect to the risk of disease progression for patients receiving epoetin-b and a higher risk of thromboembolic events associated with epoetin-b treatment (Aapro et al, 2008a).…”

mentioning

confidence: 99%

Epoetin-β treatment in patients with cancer chemotherapy-induced anaemia: the impact of initial haemoglobin and target haemoglobin levels on survival, tumour progression and thromboembolic events

et al. 2009

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BACKGROUND: Epoetin-b is used to treat patients with cancer undergoing chemotherapy to alleviate the symptoms of anaemia, reduce the risk of blood transfusions and improve quality of life (QoL). METHODS: This meta-analysis of all 12 randomised, controlled studies of epoetin-b evaluated the impact of therapy at different Hb-initiation levels and to different target Hb levels on overall survival, tumour progression and thromboembolic events (TEE). An analysis of risk factors pre-disposing patients to TEEs under epoetin-b therapy was also performed. A total of 2297 patients are included in the analysis. RESULTS: Analyses based on various Hb-initiation levels indicate no detrimental impact on survival (HR 0.99; 95% CI 0.70, 1.40) and a favourable impact on disease progression (HR 0.73; 95% CI 0.57, 0.94) when epoetin-b was used within its licensed indication (Hb initiation p10 g dl À1 ) or the EORTC recommended level of 11 g dl À1 . An increased risk of TEEs is seen for all Hb-initiation level strata and a detrimental impact on survival is seen when initiating epoetin-b therapy at Hb levels 411 g dl À1 . We observe no association between high target Hb levels (X13 g dl À1 ) and an increased risk of mortality, disease progression or TEEs with epoetin-b compared with control. CONCLUSION: The results of this analysis indicate that epoetin-b therapy has no detrimental impact on survival or tumour progression when initiated at Hb levels up to 11 g dl À1 . Furthermore, there is no evidence to suggest that high Hb values achieved during epoetin-b therapy are associated with an increased mortality, disease progression or TEE rate.

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Effect of Once-Weekly Epoetin Beta on Survival in Patients With Metastatic Breast Cancer Receiving Anthracycline- and/or Taxane-Based Chemotherapy: Results of the Breast Cancer—Anemia and the Value of Erythropoietin (BRAVE) Study

Cited by 103 publications

References 24 publications

Effect of treatment with epoetin-β on survival, tumour progression and thromboembolic events in patients with cancer: an updated meta-analysis of 12 randomised controlled studies including 2301 patients

Effect of treatment with epoetin-β on survival, tumour progression and thromboembolic events in patients with cancer: an updated meta-analysis of 12 randomised controlled studies including 2301 patients

Non-erythroid activities of erythropoietin: Functional effects on murine dendritic cells

Epoetin-β treatment in patients with cancer chemotherapy-induced anaemia: the impact of initial haemoglobin and target haemoglobin levels on survival, tumour progression and thromboembolic events

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