[Rich66]

Neoplasia. 2007 Dec;9(12):1122-9.
Effects of recombinant erythropoietin on breast cancer-initiating cells.

Phillips TM, Kim K, Vlashi E, McBride WH, Pajonk F.
Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, 10833 LeConte Ave, Los Angeles, CA 90095-1714, USA.
BACKGROUND: Cancer anemia causes fatigue and correlates with poor treatment outcome. Erythropoietin has been introduced in an attempt to correct these defects. However, five recent clinical trials reported a negative impact of erythropoietin on survival and/or tumor control, indicating that experimental evaluation of a possible direct effect of erythropoietin on cancer cells is required. Cancer recurrence is thought to rely on the proliferation of cancer initiating cells (CICs). In breast cancer, CICs can be identified by phenotypic markers and their fate is controlled by the Notch pathway. METHODS: In this study, we investigated the effect of erythropoietin on CICs in breast cancer cell lines. Levels of erythropoietin receptor (EpoR), CD24, CD44, Jagged-1 expression, and activation of Notch-1 were assessed by flow cytometry. Self-renewing capacity of CICs was investigated in sphere formation assays. RESULTS: EpoR expression was found on the surface of CICs. Recombinant human Epo (rhEpo) increased the numbers of CICs and self-renewing capacity in a Notch-dependent fashion by induction of Jagged-1. Inhibitors of the Notch pathway and PI3-kinase blocked both effects. CONCLUSIONS: Erythropoietin functionally affects CICs directly. Our observation may explain the negative impact of recombinant Epo on local control and survival of cancer patients with EpoR-positive tumors.

PMID: 18084619 [PubMed - indexed for MEDLINE]




Clin Cancer Res. 2009 Sep 1;15(17):5552-9. Epub 2009 Aug 25.
Erythropoietin receptor expression and correlation to tamoxifen response and prognosis in breast cancer.

Larsson AM, Jirström K, Fredlund E, Nilsson S, Rydén L, Landberg G, Påhlman S.
Center for Molecular Pathology, Department of Laboratory Medicine, University Hospital MAS, Malmö, Sweden.
PURPOSE: The main function of erythropoietin (EPO) is to stimulate erythropoiesis. EPO receptors (EPOR) are expressed in other cell types, including tumor cells, suggesting that the EPO/EPOR pathway governs additional cellular processes besides erythropoiesis. Recombinant EPO (rhEPO) is frequently given to anemic cancer patients, although data on clinical outcome are conflicting. In an attempt to understand these clinical data, we analyzed EPO and EPOR expression in breast cancer and evaluated EPOR as a putative prognostic and predictive marker in breast cancer patients treated with tamoxifen. EXPERIMENTAL DESIGN: EPO mRNA/protein and EPOR mRNA were quantified by PCR and ELISA, respectively. Tissue microarrays containing 500 breast tumors from premenopausal women randomized to tamoxifen or no adjuvant treatment were evaluated for EPOR expression by immunohistochemistry. Predictive and prognostic information was evaluated using Kaplan-Meier curves and log-rank tests to estimate recurrence-free survival (RFS). RESULTS: EPO and EPOR were expressed in cultured cells, and breast tumor specimens expressed EPOR at varying levels. Tamoxifen treatment significantly increased RFS in patients with estrogen receptor-positive/progesterone receptor-positive (ER(+)/PR(+)) tumors with low EPOR expression (P = 0.001) but had no effect on RFS in patients with tumors with high EPOR expression (P = 0.98). In the untreated cohort, RFS was significantly improved for patients with ER(+) tumors with high EPOR expression. CONCLUSION: EPOR is abundantly expressed in breast cancer specimens. The fact that high expression of EPOR is related to an impaired tamoxifen response in ER(+)/PR(+) tumors and to improved survival in untreated patients suggests that EPOR expression in breast cancer affects tumor behavior.

PMID: 19706814 [PubMed - indexed for MEDLINE]




Annu Rev Med. 2009;60:181-92.
Erythropoietin in cancer patients.

Glaspy JA.
Division of Hematology-Oncology, Department of Medicine, School of Medicine, University of California, Los Angeles, California 90095, USA. jglaspy@mednet.ucla.edu
Therapy with erythropoiesis-stimulating agents (ESAs) is associated with well-documented benefits to anemic cancer patients undergoing chemotherapy, most importantly a reduction in the likelihood of needing red cell transfusions. One challenge in supportive cancer care is a relative resistance to ESAs, requiring high doses with a significant rate of nonresponse. Recent advances in our understanding of iron metabolism in patients with chronic illness and the results of clinical trials indicate that parenteral iron improves ESA response in this setting. Another issue is the safety of ESA treatment in cancer patients. There is an increased risk of venous thrombosis that must be considered in clinical decision making. There are also recent data raising concerns that ESAs may enhance tumor progression or decrease patient survival. Although the preponderance of the data suggests that ESAs do not alter survival when used to treat chemotherapy-induced anemia, large well-controlled trials addressing this issue are needed.

PMID: 18980468 [PubMed - indexed for MEDLINE]


Am J Health Syst Pharm. 2009 Jul 1;66(13):1180-5.
Use of erythropoietin-stimulating agents in breast cancer patients: a risk review.

Crouch Z, DeSantis ER.
Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA.
PURPOSE: The treatment of cancer-induced anemia with erythropoietin-stimulating agents (ESAs) is reviewed. SUMMARY: Before the introduction of ESAs, the only treatment option for cancer-related anemia was red blood cell (RBC) transfusion. The use of ESAs in multiple disease states has been well established and is now considered first-line treatment for many forms of anemia. Chang et al. evaluated the effect of epoetin alfa (40,000 units administered subcutaneously every week) and standard-of-care therapy on quality of life (QOL), transfusion requirements, and hemoglobin levels in 354 patients with breast cancer who had a baseline hemoglobin concentration of <15 g/dL. The authors concluded that early initiation of treatment with epoetin alfa in patients with breast cancer is effective in maintaining hemoglobin levels, reducing transfusions, and improving QOL. Leyland-Jones et al. conducted a study evaluating the effects of early intervention with epoetin alfa (40,000 units administered subcutaneously every week) on survival and QOL of mainly nonanemic patients with metastatic breast cancer. In contrast to Chang et al., this study was discontinued because of lower overall survival rates within the epoetin alfa group. In 2008, the Food and Drug Administration issued a black-box warning for both epoetin alfa and darbepoetin alfa. The warning acknowledges that ESAs have shortened overall survival and time to disease progression in patients with advanced breast cancer who are given these agents to achieve a target hemoglobin concentration of > or =12 g/dL. CONCLUSION: When used in patients with cancer-induced anemia, ESAs should only be given at the lowest dose possible to prevent RBC transfusions. During treatment, hemoglobin levels should be monitored closely and ESA doses need to be adjusted accordingly.

PMID: 19535656 [PubMed - indexed for MEDLINE]






Br J Cancer. 2009 Dec 15;101(12):1961-71. Epub 2009 Sep 29.
Epoetin-beta treatment in patients with cancer chemotherapy-induced anaemia: the impact of initial haemoglobin and target haemoglobin levels on survival, tumour progression and thromboembolic events.

Aapro M, Osterwalder B, Scherhag A, Burger HU.
Institut Multidisciplinaire d'Oncologie, Clinique de Genolier, 1, route du Muids, Genolier CH-1272, Switzerland. maapro@genolier.net
Comment in:

• Br J Cancer. 2009 Dec 15;101(12):1947-8.

BACKGROUND: Epoetin-beta 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-beta 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-beta 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-beta was used within its licensed indication (Hb initiation < or = 10 g dl(-1)) or the EORTC recommended level of 11 g dl(-1). An increased risk of TEEs is seen for all Hb-initiation level strata and a detrimental impact on survival is seen when initiating epoetin-beta therapy at Hb levels >11 g dl(-1). We observe no association between high target Hb levels (> or = 13 g dl(-1)) and an increased risk of mortality, disease progression or TEEs with epoetin-beta compared with control. CONCLUSION: The results of this analysis indicate that epoetin-beta therapy has no detrimental impact on survival or tumour progression when initiated at Hb levels up to 11 g dl(-1). Furthermore, there is no evidence to suggest that high Hb values achieved during epoetin-beta therapy are associated with an increased mortality, disease progression or TEE rate.

PMID: 19997109 [PubMed - indexed for MEDLINE]



Acta Haematol. 2011;125(1-2):55-67. Epub 2010 Dec 8.
Twist and shout: one decade of meta-analyses of erythropoiesis-stimulating agents in cancer patients.

Bohlius J, Tonia T, Schwarzer G.
Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland.

FREE TEXT
Abstract

Anemia associated with cancer and cancer therapy is a common and important issue in the treatment of patients with malignant disease. Conventionally, blood transfusions are used to treat severe cancer-related anemia. Short- and long-acting preparations of recombinant human erythropoiesis-stimulating agents (ESAs) offer an alternative treatment option. Multiple studies and subsequent meta-analyses have demonstrated that ESA treatment increases hemoglobin levels and reduces the likelihood of transfusion for a proportion of treated patients. However, studies that attempted to evaluate whether ESAs improve tumor response and survival have generated conflicting evidence. Results of smaller trials reporting improved survival outcomes were contradicted by large randomized controlled trials that reported more deaths in patients receiving ESAs. In addition, there is strong evidence that cancer patients receiving ESAs have an increased risk of thromboembolic and cardiovascular events. We herein review the main meta-analyses published in the field, their strengths and weaknesses, their contribution to patient management and future perspectives for systematic reviews.
Copyright © 2010 S. Karger AG, Basel.
PMID: 21150188 [PubMed - in process]Free Article

The findings of several meta-analyses on ESAs in cancer patients demonstrate that ESAs reduce the risk for RBCT and increase the risk for TVEs and mortality. There is an ongoing debate whether or not ESAs increase mortality in cancer patients receiving chemotherapy as well. However, the currently available data are insufficient to exclude an increased risk for death in cancer patients undergoing chemotherapy and receiving ESAs. In clinical practice, the increased risks of death and TVEs should be balanced against the benefits of treatment with ESAs, taking into account each patient’s clinical circumstances and preferences.

Amgen's troubles keep compounding; Aranesp studies reveal greater risks

Posted 5:00 PM 11/11/09

See full article from DailyFinance: http://srph.it/cE2OUB

Aranesp (darbepoetin alfa) is an injectable drug that stimulates the production of red blood cells in the body. Often, patients who undergo dialysis or chemotherapy develop severe anemia that leaves them weak. Aranesp helps them recover from the tough treatments faster and reduces the need for transfusions. Amgen's drug Epogen and Johnson & Johnson's (JNJ) Procrit belong to the same family of drugs, called erythropoiesis-stimulating agents (ESAs).
Concerns over these drugs have been mounting in recent years after a series of studies found that high doses can lead to increased risks of heart attack, stroke, heart failure and tumor growth in some patients. As a result, in 2007, the Food and Drug Administration issued a black-box warning -- the strongest warning possible about potential side affects -- for Aranesp, Epogen and Procrit. Aranesp sales have declined in recent years as a result.
Less than two weeks ago, a new study published in The New England Journal of Medicine raised fresh safety concerns about the widely used anemia medicine. The study found that Aranesp nearly doubled the risk of stroke in people with diabetes and chronic kidney problems who are not yet sick enough to need dialysis.