Erythropoietin or Darbepoetin for patients with cancer - meta-analysis based on individual patient data

Bohlius, Julia; Schmidlin, Kurt; Brillant, Corinne; Schwarzer, Guido; Trelle, Sven; Seidenfeld, Jerome; Zwahlen, Marcel; Clarke, Mike; Weingart, Olaf; Kluge, Sabine; Piper, Margaret; Napoli, Maryann; Rades, Dirk; Steensma, David P.; Djulbegoviĉ, Benjamin; Fey, Martin F.; Ray‐Coquard, Isabelle; Moebus, Volker; Thomas, Gillian; Untch, Michael; Schumacher, Martin; Egger, Matthias; Engert, Andreas

doi:10.1002/14651858.cd007303.pub2

Cited by 101 publications

(86 citation statements)

References 248 publications

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“…Heinze et al (27) used an extensive Austrian registry of transplant recipients to ask the what the impact of anemia associated with renal transplantation was. There was a graded relationship between worse anemia and patient survival-itself not so surprising-but also a worrying increase in mortality seen in rHuEPO-treated patients with Hb values Ͼ14 g/dl (26).…”

Section: A "Perfect Storm"mentioning

confidence: 96%

“…At the same time (in the same year, 2009), two large metaanalyses of the use of rHuEPOs in patients with cancer (a potentially very "lucrative" anemia market) both highlighted limited symptomatic benefit offset by safety and mortality concerns (cancer is known to be a state in which increased coagulability potentiates thrombosis [25,26]). A total of 13,933 patients with cancer from 53 trials were analyzed; 1530 patients died during study and 4993 died overall.…”

Section: A "Perfect Storm"mentioning

confidence: 99%

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2009

Goldsmith¹

2010

Clinical Journal of the American Society of Nephrology

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The recombinant human erythropoietins and allied proteins (epoetin alfa, attempted copies and biosimilar variants of epoetin alfa, epoetin beta, epoetin delta, epoetin zeta, epoetin theta, epoetin omega, darbepoetin alfa, and methoxy-polyethylene glycol-epoetin beta) are among the most successful and earliest examples of biotechnologically manufactured products to be used in clinical medicine. This article charts a brief history of their use in clinical medicine, mainly dealing with chronic kidney disease, paying special attention to how these agents were introduced into clinical medicine and what has happened subsequently; in 2009, there were several developments that could be regarded as a "perfect storm" in terms of the long-term use of these compounds in chronic kidney disease and oncology and, likely, elsewhere. We are now very much at a "crossroads," where mature reflection is required, because with the latest trials and meta-analyses, these therapies seem not only expensive but also very much a clinical tradeoff (increased risk of adverse effects versus a small gain in fatigue scores). How we arrived at this crossroads is a useful illustration of how easy it is, without properly designed randomized, controlled trials, to assume that clinical benefit must follow therapeutic interventions.Clin J Am Soc Nephrol 5: 929 -935, 2010.

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Section: A "Perfect Storm"mentioning

confidence: 96%

Section: A "Perfect Storm"mentioning

confidence: 99%

2009

Goldsmith¹

2010

Clinical Journal of the American Society of Nephrology

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“…16 Subsequently, between 2006 and 2010, hemodialysis patients saw modest declines in mean hemoglobin and ESA doses, whereas transfusion rates were unchanged. [17][18][19] These changes were spurred by several factors: reexamination of ESA safety issues first raised by the 1998 Normal Hematocrit Trial 1,20 2,24 More recently in 2011, the US Centers for Medicare and Medicaid Services instituted a partially capitated payment system for dialysis services that included both ESAs and IVI, which were previously separately billable. 25 This provided financial incentives for dialysis providers to reduce utilization of high-cost items like ESAs by increasing use of lower-cost IVI.…”

Section: Secular Trendsmentioning

confidence: 99%

Considerations and Challenges in Defining Optimal Iron Utilization in Hemodialysis

Charytan

Pai

Chan

et al. 2015

Journal of the American Society of Nephrology

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Trials raising concerns about erythropoiesis-stimulating agents, revisions to their labeling, and changes to practice guidelines and dialysis payment systems have provided strong stimuli to decrease erythropoiesis-stimulating agent use and increase intravenous iron administration in recent years. These factors have been associated with a rise in iron utilization, particularly among hemodialysis patients, and an unprecedented increase in serum ferritin concentrations. The mean serum ferritin concentration among United States dialysis patients in 2013 exceeded 800 ng/ml, with 18% of patients exceeding 1200 ng/ml. Although these changes are broad based, the wisdom of these practices is uncertain. Herein, we examine influences on and trends in intravenous iron utilization and assess the clinical trial, epidemiologic, and experimental evidence relevant to its safety and efficacy in the setting of maintenance dialysis. These data suggest a potential for harm from increasing use of parenteral iron in dialysisdependent patients. In the absence of well powered, randomized clinical trials, available evidence will remain inadequate for making reliable conclusions about the effect of a ubiquitous therapy on mortality or other outcomes of importance to dialysis patients. Nephrology stakeholders have an urgent obligation to initiate well designed investigations of intravenous iron in order to ensure the safety of the dialysis population.

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“…Both guidelines are extremely reserved regarding the use of ESAs in patients receiving radiotherapy. So are several meta-analyses [2,28,29]. Th e association between haemoglobin levels, tumour oxygenation, and eff ectiveness of radiotherapy remains complex and requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Challenges of anemia correction during radiotherapy and chemoradiation

Rades

Schild

2012

memo

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Th e eff ect of radiotherapy depends on optimal tumour oxygenation, as tumour hypoxia impairs the production of radiation-induced cytotoxic free radicals resulting in less tumour cell kill. Th e range of haemoglobin levels optimal for tumour oxygenation is 12-14 g/dl in women and 13-15 g/dl in men. It appears reasonable to elevate the haemoglobin level in anaemic cancer patients into this optimal range. Th is may be achieved with red blood cell transfusions (RBCT) or erythropoiesis stimulating agents (ESAs). However, RBCT have had negligible or even negative eff ect on patient outcome, possibly because RBCT induce immunosuppression or result in haemoglobin levels too high for optimal tumour oxygenation. Several randomized trials have demonstrated that patients irradiated for head-and-neck cancer had worse outcomes with ESAs than the control group. However, in the majority of these trials, over-treatment with ESAs resulted in haemoglobin levels above the optimal range. Tumour oxygenation is impaired by inappropriately high haemoglobin levels due to increased blood viscosity and decreased tumour cell perfusion. Th is concept is supported by the fi ndings of prospective studies in cervix cancer and esophageal cancer patients. In these studies the ESA administration was withheld at a haemoglobin level of 14 g/dl resulting in a positive eff ect of ESAs on treatment outcome. In summary, the eff ect of RBCT and particularly of ESAs during radiotherapy remains unclear. Further randomized trials are required. Until such trials are available, one should follow the ASCO and ESMO guidelines that are very conservative regarding the administration of ESAs during radiotherapy and chemoradiation.

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Erythropoietin or Darbepoetin for patients with cancer - meta-analysis based on individual patient data

Abstract: 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 101 publications

References 248 publications

2009

2009

Considerations and Challenges in Defining Optimal Iron Utilization in Hemodialysis

Challenges of anemia correction during radiotherapy and chemoradiation

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