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Pharmaceutical Erythropoietin Use in Patients With Cancer: Is It Time to Abandon Ship or Just Drop Anchor?

      Pharmaceutical erythropoietins, also known as erythropoiesis-stimulating agents (ESAs), include epoetin alfa, epoetin beta, and darbepoetin alfa. Epoetin alfa is marketed in the United States as either Epogen (Amgen Inc, Thousand Oaks, CA) or Procrit (Ortho Biotech Products LP, Bridgewater, NJ, a subsidiary of Johnson & Johnson, New Brunswick, NJ). The same drug is marketed in Europe and Canada as Eprex by other affiliates of Johnson & Johnson. Epoetin beta is marketed in Europe as NeoRecormon (Roche Pharmaceuticals, Basel, Switzerland). Darbepoetin alfa is marketed in the United States and other countries as Aranesp (Amgen Inc, Thousand Oaks, CA). All 3 drugs are recombinant forms of native erythropoietin (Epo) and are approved by the Food and Drug Administration (FDA) for the treatment of symptomatic anemia associated with chronic renal failure (CRF), for cancer chemotherapy restricted to non-myeloid malignancies, and for zidovudine therapy in patients infected with the human immunodeficiency virus. In addition, epoetin alfa is licensed for use as a prophylactic measure to reduce the need for allogeneic blood transfusions during elective noncardiovascular surgery.
      Both native and pharmaceutical Epos are glycated proteins with a peptide core of 165 amino acids. Differences in carbohydrate content are responsible for their different plasma half-lives and dosing frequencies.
      • Bunn HF
      New agents that stimulate erythropoiesis.
      Native Epo is produced primarily by peritubular fibroblasts of the renal cortex with secondary and substantially lesser contributions from the liver and other organs. Hypoxia is the main trigger for endogenous Epo production; the process is mediated by hypoxia-inducible transcription factors that originate in the cytoplasm and enter the nucleus to bind to the hypoxia-response elements of EPO-enhancer DNA sequences.
      • Koury MJ
      Erythropoietin: the story of hypoxia and a finely regulated hematopoietic hormone.
      Epo is the growth factor that is primarily responsible for the terminal proliferation and differentiation of erythroid progenitors. Its mechanism of action involves binding to the Epo receptor (EpoR), JAK-STAT signaling, and prevention of apoptosis in erythroid precursors.
      • Koury MJ
      Erythropoietin: the story of hypoxia and a finely regulated hematopoietic hormone.
      In the current issue of Mayo Clinic Proceedings, Wish and Coyne
      • Wish JB
      • Coyne DW
      Use of erythropoiesis-stimulating agents in patients with anemia of chronic kidney disease: overcoming the pharmacological and pharmacoeconomic limitations of existing therapies.
      provide a balanced and comprehensive look at current issues regarding the use of ESAs in patients with CRF. The FDA first approved epoetin alfa in 1989 for patients with CRF. From the beginning, the agency has had safety concerns regarding the overzealous use of the drug and has specified a hemoglobin target concentration of 10 to 12 g/dL. In support of the FDA's concerns, a controlled trial in 1998 showed an increased rate of death and nonfatal myocardial infarction when Epo was used to target a higher hemoglobin level in CRF patients with a history of heart disease.
      • Besarab A
      • Bolton WK
      • Browne JK
      • et al.
      The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin.
      This observation was validated by a more recent randomized study of 1432 Epo-treated patients with CRF, in which patients who were assigned to a target hemoglobin level of 13.5 g/dL experienced significantly more adverse events (deaths, chronic heart failure, myocardial infarctions, strokes) than those who were assigned a target hemoglobin level of 11.3 g/dL.
      • Singh AK
      • Szczech L
      • Tang KL
      • CHOIR Investigators
      • et al.
      Correction of anemia with epoetin alfa in chronic kidney disease.
      Furthermore, targeting a higher hemoglobin concentration did not result in better quality of life (QOL). These findings are supported by a more recent meta-analysis of 9 randomized studies comparing the effects of different hemoglobin targets in more than 5000 patients with CRF; patients with higher hemoglobin concentrations displayed significantly higher rates of allcause mortality, arteriovenous access thrombosis, and suboptimal blood pressure control.
      • Phrommintikul A
      • Haas SJ
      • Elsik M
      • Krum H
      Mortality and target haemoglobin concentrations in anaemic patients with chronic kidney disease treated with erythropoietin: a meta-analysis.
      Erythropoietin therapy also corrects or prevents anemia in patients with cancer who are undergoing chemotherapy and has the potential to improve QOL for patients with baseline hemoglobin levels of less than 10 g/dL.
      • Seidenfeld J
      • Piper M
      • Flamm C
      • et al.
      Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials.
      However, as is the case in patients with CRF, such treatment also increases the risk of thromboembolic complications in patients with cancer
      • Bohlius J
      • Wilson J
      • Seidenfeld J
      • et al.
      Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients.
      • Khorana AA
      • Francis CW
      • Culakova E
      • Lyman GH
      Risk factors for chemotherapy-associated venous thromboembolism in a prospective observational study.
      • Wun T
      • Law L
      • Harvey D
      • Sieracki B
      • Scudder SA
      • Ryu JK
      Increased incidence of symptomatic venous thrombosis in patients with cervical carcinoma treated with concurrent chemotherapy, radiation, and erythropoietin.
      ; it should be noted that Epo enhances platelet reactivity and that low-dose aspirin therapy might not prevent Epo-associated thrombosis.
      • Stohlawetz PJ
      • Dzirlo L
      • Hergovich N
      • et al.
      Effects of erythropoietin on platelet reactivity and thrombopoiesis in humans.
      • Kooistra MP
      • van Es A
      • Marx JJ
      • Hertsig ML
      • Struyvenberg A
      Low-dose aspirin does not prevent thrombovascular accidents in low-risk haemodialysis patients during treatment with recombinant human erythropoietin.
      Certain tumor cells and endothelial cells have also been shown to express EpoR, thus raising the possibility of Epo treatment-associated augmentation of neoplastic growth and angiogenesis.
      • Hardee ME
      • Arcasoy MO
      • Blackwell KL
      • Kirkpatrick JP
      • Dewhirst MW
      Erythropoietin biology in cancer.
      • Pajonk F
      • Weil A
      • Sommer A
      • Suwinski R
      • Henke M
      The erythropoietin-receptor pathway modulates survival of cancer cells.
      • Mohyeldin A
      • Dalgard CL
      • Lu H
      • et al.
      Survival and invasiveness of astrocytomas promoted by erythropoietin.
      • Feldman L
      • Wang Y
      • Rhim JS
      • Bhattacharya N
      • Loda M
      • Sytkowski AJ
      Erythropoietin stimulates growth and STAT5 phosphorylation in human prostate epithelial and prostate cancer cells.
      • Acs G
      • Chen M
      • Xu X
      • Acs P
      • Verma A
      • Koch CJ
      Autocrine erythropoietin signaling inhibits hypoxia-induced apoptosis in human breast carcinoma cells.
      • Batra S
      • Perelman N
      • Luck LR
      • Shimada H
      • Malik P
      Pediatric tumor cells express erythropoietin and a functional erythropoietin receptor that promotes angiogenesis and tumor cell survival.
      • Beleslin-Cokic BB
      • Cokic VP
      • Yu X
      • Weksler BB
      • Schechter AN
      • Noguchi CT
      Erythropoietin and hypoxia stimulate erythropoietin receptor and nitric oxide production by endothelial cells.
      • Heeschen C
      • Aicher A
      • Lehmann R
      • et al.
      Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization [published correction appears in Blood. 2004;103(12):4388].
      This particular scenario is highlighted by recent reports of decreased survival and suboptimal tumor control in Epo-treated patients with cancer
      • Henke M
      • Laszig R
      • Rube C
      • et al.
      Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial.
      • Wright JR
      • Ung YC
      • Julian JA
      • et al.
      Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia.
      • Temkin SM
      • Hellmann M
      • Serur E
      • Lee YC
      • Abulafia O
      Erythropoietin administration during primary treatment for locally advanced cervical carcinoma is associated with poor response to radiation.
      • Leyland-Jones B
      • Semiglazov V
      • Pawlicki M
      • et al.
      Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study.
      and in patients whose tumor cells expressed EpoR.
      • Saintigny P
      • Besse B
      • Callard P
      • et al.
      Erythropoietin and erythropoietin receptor coexpression is associated with poor survival in stage I non-small cell lung cancer.
      • Leo C
      • Horn LC
      • Rauscher C
      • et al.
      Expression of erythropoietin and erythropoietin receptor in cervical cancer and relationship to survival, hypoxia, and apoptosis.
      • Acs G
      • Xu X
      • Chu C
      • Acs P
      • Verma A
      Prognostic significance of erythropoietin expression in human endometrial carcinoma.
      In one of the first controlled studies addressing this particular issue (published in 2003), Henke et al
      • Henke M
      • Laszig R
      • Rube C
      • et al.
      Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial.
      randomized 351 patients with anemia and with surgically resected head and neck cancer to receive epoetin beta or placebo during curative radiotherapy. Both overall survival and local-regional disease control were significantly inferior in the Epo-treated cohort. In a subsequent study published in 2006,
      • Henke M
      • Mattern D
      • Pepe M
      • et al.
      Do erythropoietin receptors on cancer cells explain unexpected clinical findings.
      the authors suggested that tumor expression of EpoR could potentially explain the adverse outcome seen in Epo-treated patients.
      Currently, some studies endorse and some refute the above-mentioned observations by Henke et al. For example, findings from another randomized study first reported in 2003 by Leyland-Jones et al
      • Leyland-Jones B
      • Semiglazov V
      • Pawlicki M
      • et al.
      Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study.
      • Leyland-Jones B
      • BEST Investigators and Study Group
      Breast cancer trial with erythropoietin terminated unexpectedly.
      involved 939 patients with metastatic breast cancer who received epoetin alfa or placebo in the first 12 months of their first-line chemotherapy to maintain normal hemoglobin concentration. The study was terminated early because of a significantly worse 12-month survival rate in Epo-treated patients who displayed increased rates of disease progression and thrombotic and vascular events. More recently, Wright et al
      • Wright JR
      • Ung YC
      • Julian JA
      • et al.
      Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia.
      designed a study to investigate the effects of epoetin alfa therapy on the QOL of 300 patients with anemia and advanced non-small cell lung cancer. This study was also terminated early after accrual of the first 70 patients because of a significantly worse median survival seen in Epo-treated patients. The FDA has also been notified (December 2006) of an interim analysis of a Danish Head and Neck Cancer Study Group's randomized trial of patients receiving radiation therapy; treatment with darbepoetin alfa, as opposed to placebo, was associated with significantly inferior local-regional disease control (http://www.fda.gov/ola/2007/esa062607.html). In the same report, the agency mentioned notification (January 2007) of another large (N=989), randomized, multicenter study of patients with cancer and anemia (hemoglobin ≤11 g/dL) who were not receiving chemotherapy; despite a conservative target hemoglobin concentration of 12 g/dL, treatment with darbepoetin alfa resulted in excess mortality. In contrast, many other studies involving both hematologic and nonhematologic malignancies found no survival disadvantage associated with Epo therapy.
      • Crawford J
      • Robert F
      • Perry MC
      • Belani C
      • Williams D
      • Anemia Prevention in NSCLC Group
      A randomized trial comparing immediate versus delayed treatment of anemia with once-weekly epoetin alfa in patients with non-small cell lung cancer scheduled to receive first-line chemotherapy.
      • Machtay M
      • Pajak TF
      • Suntharalingam M
      • et al.
      Radiotherapy with or without erythropoietin for anemic patients with head and neck cancer: a randomized trial of the Radiation Therapy Oncology Group (RTOG 99-03) [published online ahead of print August 23, 2007].
      • Baz R
      • Walker E
      • Choueiri TK
      • et al.
      Recombinant human erythropoietin is associated with increased overall survival in patients with multiple myeloma.
      • Aapro M
      • Coiffier B
      • Dunst J
      • Osterborg A
      • Burger HU
      Effect of treatment with epoetin beta on short-term tumour progression and survival in anaemic patients with cancer: a meta-analysis.
      • Grote T
      • Yeilding AL
      • Castillo R
      • et al.
      Efficacy and safety analysis of epoetin alfa in patients with small-cell lung cancer: a randomized, double-blind, placebo-controlled trial.
      • Hedenus M
      • Vansteenkiste J
      • Kotasek D
      • Austin M
      • Amado RG
      Darbepoetin alfa for the treatment of chemotherapy-induced anemia: disease progression and survival analysis from four randomized, double-blind, placebo-controlled trials.
      • Jadersten M
      • Montgomery SM
      • Dybedal I
      • Porwit-MacDonald A
      • Hellstrom-Lindberg E
      Long-term outcome of treatment of anemia in MDS with erythropoietin and G-CSF.
      • Osterborg A
      • Brandberg Y
      • Hedenus M
      Impact of epoetin-beta on survival of patients with lymphoproliferative malignancies: long-term follow up of a large randomized study.
      • Rades D
      • Tribius S
      • Yekebas EF
      • et al.
      Epoetin alfa improves survival after chemoradiation for stage III esophageal cancer: final results of a prospective observational study.
      • Bohlius J
      • Langensiepen S
      • Schwarzer G
      • et al.
      Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis.
      • Littlewood TJ
      • Nortier J
      • Rapoport B
      • Epoetin Alfa Study Group
      • et al.
      Epoetin alfa corrects anemia and improves quality of life in patients with hematologic malignancies receiving non-platinum chemotherapy.
      • Sartelet H
      • Fabre M
      • Castaing M
      • et al.
      Expression of erythropoietin and its receptor in neuroblastomas.
      • Mittelbronn M
      • Capper D
      • Bunz B
      • et al.
      De novo erythropoietin receptor (EPO-R) expression in human neoplastic glial cells decreases with grade of malignancy but is favourably associated with patient survival.
      • Hoogsteen IJ
      • Peeters WJ
      • Marres HA
      • et al.
      Erythropoietin receptor is not a surrogate marker for tumor hypoxia and does not correlate with survival in head and neck squamous cell carcinomas.
      For example, Amgen recently announced the results of the so-called 145 Study, a randomized study of darbepoetin alfa in 600 patients with small cell lung cancer receiving platinum-containing chemotherapy (www.amgen.com/media/media_pr_detail.jsp?releaseID=987476). The study showed that survival and mortality were not negatively affected by the drug. Similarly, another recent study randomly assigned 141 patients with anemia and with head and neck cancer who were receiving radiation therapy to additional treatment with epoetin alfa or no additional treatment; no difference was noted in either local-regional tumor control or overall survival between the 2 groups.
      • Crawford J
      • Robert F
      • Perry MC
      • Belani C
      • Williams D
      • Anemia Prevention in NSCLC Group
      A randomized trial comparing immediate versus delayed treatment of anemia with once-weekly epoetin alfa in patients with non-small cell lung cancer scheduled to receive first-line chemotherapy.
      Where do we go from here? First, I believe that the time has come to reassess the benefit of Epo therapy in patients with cancer and to determine whether the magnitude of that benefit is sufficient to justify the potential risk of the therapy. After all, an alternative exists—red blood cell transfusions remain an effective method of treating anemia, and modern transfusion practices have minimized the occurrence of transfusion-associated complications.
      • Tanneberger S
      • Melilli G
      • Strocchi E
      • Frenquelli C
      • Pannuti QF
      Use of red blood cell transfusion in palliative care services: is it still up to date or is cancer-related anaemia controlled better with erythropoietic agents? [letter].
      Second, it must be acknowledged that definitive conclusions about the safety and overall efficacy of Epo therapy cannot be drawn from currently available evidence. Third, we must resist the temptation to make generalizations; valid interpretation of study results requires emphasis on the specific tumor types studied and the target hemoglobin levels used. Nevertheless, the burden of proof is now on the drug manufacturers; if they wish to alleviate persisting concerns regarding drug safety, they should pursue additional large-scale controlled trials accompanied by relevant laboratory correlative studies (eg, EpoR expression by tumor cells and pretreatment and post-treatment platelet and coagulation function tests). Appropriate study end points in this regard should include survival, tumor progression, and cardiovascular events in addition to QOL assessment.
      In the meantime, it is prudent to avoid Epo therapy in any patient whose pretreatment hemoglobin concentration is 10 g/dL or more. In addition, on the basis of currently available clinical and experimental evidence, I have reservations about using the drug in the setting of solid tumors, even if the hemoglobin level is lower than 10 g/dL. I also worry about the lack of adequate safety data from controlled clinical trials in myeloid disorders (eg, myelodysplastic syndrome), in terms of both leukemic transformation rate and incidence of cardiovascular events.
      • Casadevall N
      • Durieux P
      • Dubois S
      • et al.
      Health, economic, and quality-of-life effects of erythropoietin and granulocyte colony-stimulating factor for the treatment of myelodysplastic syndromes: a randomized, controlled trial.
      • Italian Cooperative Study Group for rHuEpo in Myelodysplastic Syndromes
      A randomized double-blind placebo-controlled study with subcutaneous recombinant human erythropoietin in patients with low-risk myelodysplastic syndromes.
      In this regard, a recent retrospective study of 311 patients with primary myelofibrosis unexpectedly revealed a significant association between leukemic transformation and history of Epo therapy (unpublished Mayo Clinic study to be presented at the American Society of Hematology 49th Annual Meeting, December 8-11, 2007, Atlanta, GA). Finally, it should be noted that the FDA has issued a series of public health advisories (November 2006, February 2007, and March 2007) regarding the pharmaceutical uses of Epo that include a new boxed warning underscoring the aforementioned risks in patients with cancer (www.fda.gov/cder/drug/infopage/RHE/default.htm). The FDA strongly recommends, and I agree, that Epo should be prescribed in the lowest dosage that can secure a sufficiently high hemoglobin level to render blood transfusion unnecessary (ie, 9-10 g/dL). However, a higher level (10-12 g/dL) of hemoglobin can reasonably be targeted on a case-by-case basis, provided that the patient is fully informed of the associated risks and that a potential improvement in QOL can be clearly documented.

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