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. Author manuscript; available in PMC: 2011 Aug 15.
Published in final edited form as: Am J Hematol Oncol. 2008 Aug 1;7(8):327–332.

Risks of Venous Thromboembolism and Mortality Associated With Erythropoiesis-Stimulating Agents for the Treatment of Cancer-Associated Anemia

Athena T Samaras 1, Charles L Bennett 1
PMCID: PMC3156058  NIHMSID: NIHMS132667  PMID: 21850277

Findings from our recently published meta-analysis demonstrate increased risks of venous thromboembolism and mortality with the administration of erythropoiesis-stimulating agents (ESAs) to treat anemic cancer patients.1 ESAs, which are supportive care drugs that include recombinant erythropoietin and darbepoetin, were approved in 1993 and 2002, respectively, for the treatment of chemotherapy-induced anemia.2,3 Following their approval, concerns regarding increased risk of tumor progression and venous thromboembolism (VTE) have been raised.4 In 2003, two trials identified poorer survival among ESA-treated breast cancer patients receiving chemotherapy and head and neck cancer patients receiving radiotherapy.5,6 Additionally, two systematic overviews published in 2006 found increased VTE risks associated with ESAs but did not identify mortality risks.7,8 We therefore conducted a meta-analysis to comprehensively evaluate venous thromboembolism and mortality risks associated with ESA use.

Methods

The Cochrane 2006 systematic overview served as the primary data source for this analysis, and studies reported more recently were added. The 2006 Cochrane overview evaluated 42 trials with 8,167 patients for overall survival and 38 trials with 6,769 patients for VTE.9 Our meta-analysis excluded one trial that was included in the Cochrane overview because it evaluated patients with myelodysplastic syndrome rather than cancer and added 13 new trials (n=5,369 patients).10-22 Mortality and VTE rates were extracted from a total of 51 clinical trials with 13,611 patients and 38 trials with 8,172 patients, respectively. Data sources included published trials and systematic reviews as well presentations from the 2007 FDA Oncologic Drugs Advisory Committee meeting. Trials included were both independent and industry sponsored. Effect estimates for hazard rates (HR), relative risks (RR), and 95% confidence intervals (CIs) were derived.1

Results

Results from the mortality analysis identified a 10% increased risk of mortality associated with the use of ESAs for anemic cancer patients (HR=1.10; 95% CI, 1.01-1.20). Moreover, a 57% increased risk of VTE was noted with the use of ESAs for this indication (RR: 1.57; 95% CI, 1.31-1.87). These associations were not dominated by a small number of studies; the largest 8 trials each contributed 5% to 9% of the total patients included.1

Trials included in this analysis varied with respect to study drug, sample size, treatment duration, concomitant treatments, and cancer types. Epoetin alfa or epoetin beta, two variations of erythropoietin, were evaluated in 40 trials and darbepoetin was evaluated in 11 trials. A median of 223 patients were included, ranging from 30 to 939 patients. Additionally, the duration of ESA treatment ranged from 6 to 52 weeks. The trials included patients who experienced cancer-related anemia as well as treatment-related anemia. While 28 trials included patients who were concomitantly receiving chemotherapy, other trials included concomitant treatments of radiotherapy (3 trials), chemoradiotherapy (7 trials), and palliative radiotherapy (1 trial). Three trials did not report concomitant treatments, and patients from 7 trials evaluating cancer-related anemia did not receive concomitant treatment. Twenty-six trials evaluated single disease populations including lung cancer, breast cancer, head and neck cancer, cervical cancer, ovarian cancer, lymphoma, and multiple myeloma.1

Discussion

This analysis confirmed previous findings of an increased risk of VTE associated with ESAs for the treatment of anemic cancer patients and also identified a statistically significant increased risk of mortality for use of ESAs within this setting. Given that ESAs are widely used within the oncology setting as a supportive care drug, these findings have important clinical and policy implications. Risks regarding ESA administration to cancer patients have been addressed by notifications disseminated by the FDA and ESA manufacturers, basic science reports, and the FDA Oncologic Drugs Advisory Committee.

In January 2008, the FDA released an advisory describing increased risks of tumor promotion and decreased survival based on findings from the PREPARE (preoperative epirubicin, paclitaxel, darbepoetin alfa) study including patients with advanced breast cancer and the GOG-191 (National Cancer Institute Gynecologic Oncology Group) study including patients with cervical cancer.23 Three safety notifications have been distributed by ESA manufacturers. In March 2007, ESA manufacturers added a black box warning for the first time to the FDA-approved package insert, describing increased VTE and cardiovascular and mortality risks.24 Manufacturers revised the black box warning for ESAs in November 2007 and again in March 2008. In November 2007, the warning indicated that randomized trials identified more rapid cancer progression and shortened overall survival among patients with advanced breast, head and neck, lymphoid, and non□small cell lung cancer. The warning also indicated that ESAs should only be used to treat anemia that occurs in patients with cancer while they are undergoing chemotherapy.25 In March 2008, the revision described faster tumor growth and increased mortality risks with ESAs versus controls based on the aforementioned FDA advisory.26

Debate exits regarding the identification of erythropoietin and erythropoietin receptor expression in a wide range of solid human tumor types.27,28 The specific effect(s) of ESAs in patients may depend upon tumor type. Additionally, erythropoietin may act as a proangiogenic factor, potentially aiding the tumor's ability to recruit a blood supply.29 Many provocative issues remain to be clarified regarding the specific action(s) of ESAs on human cancer cells.

The FDA Oncologic Drugs Advisory Committee met in March 2008 to discuss findings regarding the use of ESAs in the cancer setting and to vote on policy recommendations for this indication. The committee members voted that ESAs should not be used for patients receiving potentially curative therapies. Additionally, the committee voted to restrict the use of ESAs from breast or head and neck cancer patients based on findings of increased risks within these populations.30

In conclusion, our meta-analysis confirms the risks associated with ESA use for anemic cancer patients that have been addressed by several regulatory organizations, scientific findings, and an FDA advisory committee. The exact mechanism by which ESAs may affect survival of cancer patients is incompletely understood, yet associated risks are apparent. Our findings, in conjunction with other safety advisories, suggest that ESA use within the cancer setting should follow a doctor and patient discussion of associated risks. ♦

Acknowledgments

Supported by grants from the National Cancer Institute (1R01CA 102713-01 and P 30 CA60553).

Author disclosures: Dr Bennett has previously served as a consultant to Amgen and has received grant support from Amgen.

References

  • 1.Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA. 2008;299:914–924. doi: 10.1001/jama.299.8.914. [DOI] [PubMed] [Google Scholar]
  • 2.Vansteenkiste J, Pirker R, Massuti B, et al. Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst. 2002;94:1211–1220. doi: 10.1093/jnci/94.16.1211. [DOI] [PubMed] [Google Scholar]
  • 3.Henry DH, Brooks BJ, Jr, Case DC, Jr, et al. Recombinant human erythropoietin therapy for anemic cancer patients receiving cisplatin chemotherapy. Cancer J Sci Am. 1995;1:252–260. [PubMed] [Google Scholar]
  • 4.Steinbrook R. Erythropoietin, the FDA, and oncology. N Engl J Med. 2007;356:2448–2451. doi: 10.1056/NEJMp078100. [DOI] [PubMed] [Google Scholar]
  • 5.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. Lancet. 2003;362:1255–1260. doi: 10.1016/S0140-6736(03)14567-9. [DOI] [PubMed] [Google Scholar]
  • 6.Leyland-Jones B. BEST Investigators and Study Group. Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol. 2003;4:459–460. doi: 10.1016/s1470-2045(03)01163-x. [DOI] [PubMed] [Google Scholar]
  • 7.Bohlius J, Wilson J, Seidenfeld J, et al. Erythropoietin or darbepoetin for patients with cancer. Cochrane Database Syst Rev. 2006;3:CD003407. doi: 10.1002/14651858.CD003407.pub4. DOI: 10.1002/14651858.CD003407.pub4. [DOI] [PubMed] [Google Scholar]
  • 8.Seidenfeld JPM, Bohlius J, Weingart O, et al. Comparative Effectiveness Review No. 3. Agency for Healthcare Research and Quality; Rockville, MD: 2006. Comparative effectiveness of epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment. http://www.effectivehealthcare.ahrq.gov/reports/final.cfm. Accessed April 28, 2008. [PubMed] [Google Scholar]
  • 9.Bohlius J, Wilson J, Seidenfeld J, et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst. 2006;98:708–714. doi: 10.1093/jnci/djj189. [DOI] [PubMed] [Google Scholar]
  • 10.Oncologic Drugs Advisory Committee FDA Briefing Document. Continuting reassessment of the risks of erythropoiesis-stimulating agents (ESAs) administered for the treatment of anemia associated with cancer chemotherapy. May 10, 2007. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4301b2-02-FDA.pdf. Accessed April 11, 2008.
  • 11.Amgen DA 145 Study 2007 April 19; http://wwwext.amgen.com/media/media_pr_detail.jsp?year=2007&releaseID=987476. Accessed: January 9, 2008.
  • 12.Overgaard J, Hoff C, Sand Hansen H, et al. Randomized study of the importance of novel erythropoiesis stimulating protein (Aranesp) for the effect of radiotherapy in patients with primary squamous cell carcinoma of the head and neck (HNSCC): the Danish Head and Neck Cancer Group DAHANCA 10 randomised trial. Eur J Cancer Suppl. 2007;5:7. Abstract. [Google Scholar]
  • 13.Charu V, Belani CP, Gill AN, et al. Efficacy and safety of every-2-week darbepoetin alfa in patients with anemia of cancer: a controlled, randomized, open-label phase II trial. Oncologist. 2007;12:727–737. doi: 10.1634/theoncologist.12-6-727. [DOI] [PubMed] [Google Scholar]
  • 14.Debus J, Hindermann S, Morr H, et al. Epoetin alfa (EPO) and survival in patients with non-resectable NSCLC: interim results. German Medical Science. http://www.egms.de/en/meetings/dkk2006/06dkk257.shtml. Accessed April 11, 2008. [Google Scholar]
  • 15.Gordon DH, Nichols G, Ben-Jacob A, et al. Treating anemia of cancer with darbepoetin alfa administration every 4 weeks: final results from a phase 2, randomized, double-blind, placebo-controlled study in cancer patients not receiving chemotherapy and/or radiotherapy. Presented at: American Society of Hematology; Orlando, FL. December 9, 2006; Abstract 1304. [Google Scholar]
  • 16.Moebus V, Lueck H, Thomssen C, et al. The impact of epoetin-alpha on anemia, red blood cell (RBC) transfusions, and survival in breast cancer patients (pts) treated with dose-dense sequential chemotherapy: mature results of an AGO phase III study (ETC trial) J Clin Oncol. 2007;25(June 20 suppl) Abstract 569. [Google Scholar]
  • 17.Glaspy J, Smith R, Aapro M, et al. Results from a phase III, randomized, double-blind, placebo-controlled study of darbepoetin alfa for the treatment of anemia in patients not receiving chemotherapy or radiotherapy. Paper presented at: Proceedings from the American Association for Cancer Research Annual Meeting; Los Angeles, CA. April 14-28, 2007. [Google Scholar]
  • 18.Wilkinson PM, Antonopoulos M, Lahousen M, et al. Epoetin alfa in platinum-treated ovarian cancer patients: results of a multinational, multicentre, randomised trial. Br J Cancer. 2006;94:947–954. doi: 10.1038/sj.bjc.6603004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Taylor KB, Ganly P, Charu V, et al. Randomized, double-blind, placebo-controlled study of darbepoetin alfa every 3 weeks for the treatment of chemotherapy-induced anemia. Paper presented at: Blood (ASH Annual Abstract Meeting); Atlanta, GA. December 12, 2005; Abstract 3556. [Google Scholar]
  • 20.Mystakidou K, Kalaidopoulou O, Katsouda E, et al. Evaluation of epoetin supplemented with oral iron in patients with solid malignancies and chronic anemia not receiving anticancer treatment. Anticancer Res. 2005;25:3495–3500. [PubMed] [Google Scholar]
  • 21.Strauss HG, Haensgen G, Dunst J, et al. Effects of anemia correction with epoetin beta in patients receiving radiochemotherapy for advanced cervical cancer. Int J Gynecol Cancer. 2008;18:515–524. doi: 10.1111/j.1525-1438.2007.01032.x. [DOI] [PubMed] [Google Scholar]
  • 22.Blohmer J-U, Wurschmidt F, Petry U, et al. Results with sequential adjuvant chemo-radiotherapy with vs without epoetin alfa for patients with high-risk cervical cancer: results of a prospective, randomized, open and controlled AGO and NOGGO-intergroup study. Paper presented at: European Cancer Conference; Copenhagen, Denmark. September 21-25, 2003; Abstract 477PD. [Google Scholar]
  • 23.US Food and Drug Administration Press Release: FDA receives new data on risks of anemia drugs consistent with previous data on tumor growth and death. http://www.fda.gov/bbs/topics/NEWS/2008/NEW01769.html. Accessed April 11, 2008.
  • 24.US Food and Drug Administration Drugs at FDA. March 2007 Label. http://www.fda.gov/cder/foi/label/2007/103234s5122lbl.pdf. Accessed April 18, 2008.
  • 25.US Food and Drug Administration Drugs at FDA. November 2007 Label. http://www.fda.gov/cder/foi/label/2007/103234s5158lbl.pdf. Accessed April 18, 2008.
  • 26.US Food and Drug Administration Drugs at FDA. March 2008 Drug Label. http://www.fda.gov/cder/foi/label/2008/103234s5164lbl.pdf. Accessed April 18, 2008.
  • 27.Hardee ME, Arcasoy MO, Blackwell KL, et al. Erythropoietin biology in cancer. Clin Cancer Res. 2006;12:332–339. doi: 10.1158/1078-0432.CCR-05-1771. [DOI] [PubMed] [Google Scholar]
  • 28.Elliott S, Busse L, Bass MB, et al. Anti-Epo receptor antibodies do not predict Epo receptor expression. Blood. 2006;107:1892–1895. doi: 10.1182/blood-2005-10-4066. [DOI] [PubMed] [Google Scholar]
  • 29.Hardee ME, Cao Y, Fu P, et al. Erythropoietin blockade inhibits the induction of tumor angiogenesis and progression. PLoS ONE. 2007;2:e549. doi: 10.1371/journal.pone.0000549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Pollack A. Panel seeks new limits on anemia drugs. The New York Times. http://www.nytimes.com/2008/03/14/business/14anemia.html?_r=1&ref=business&oref=slogin. Accessed April 11, 2008.

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