BMJ  2007;334:648-649 (31 March), doi:10.1136/bmj.39163.536852.80

Editorials

Erythropoiesis stimulating agents

May not be safe in people with cancer

In February 2007, new concerns surfaced over the safety of agents that stimulate erythropoiesis when used to treat anaemia in patients with cancer. These concerns quickly gained the attention of the oncology community and the popular press. Most major newspapers carried this story¹ because of the widespread clinical use of these agents and the high volume of advertising by the drugs' corporate sponsors aimed directly at the consumer.²

Safety concerns relate to the possibility that erythropoiesis stimulating agents are associated with increased tumour growth and worse survival in some patients with cancer. On 9 March 2007, a black box warning was added to the labelling of darbepoetin alfa and epoetin alfa in the United States. This instructed doctors to use the lowest dose possible to avoid red blood cell transfusions, and not to allow haemoglobin concentrations to exceed 120 g/l.³ The Food and Drug Administration has announced a special meeting of the Oncology Drugs Advisory Committee on 10 May 2007 to discuss this matter further.

Both randomised and open label trials have shown that patients with anaemia associated with cancer chemotherapy who are treated with erythropoiesis stimulating agents need fewer transfusions, have higher haemoglobin concentrations, and possibly have higher quality of life than those who are not treated.⁴ Most of the early theoretical concerns about erythropoietin's potential to alter tumour behaviour dissipated by the time a meta-analysis in 2005 found no difference in survival with erythropoiesis stimulating agents than with supportive care alone or placebo.⁴

Two studies suggesting specific risks for cancer patients from erythropoiesis stimulating agents first appeared in 2003, but were largely dismissed because of limitations in trial design and conduct.⁵ The first study found a higher rate of tumour progression and worse survival in patients with head and neck cancer treated with epoetin beta compared with placebo.⁶ The second trial, in patients with metastatic breast cancer, was terminated early because of higher mortality in people taking epoetin alfa (8.7% v 3.4%), a difference that became evident after only four months of treatment.⁷ These findings raised concerns—some of which focused on thromboembolism rather than tumour growth—but overall were considered inconclusive, especially given the robust safety record with epoetin accumulated over the previous decade. Importantly, the target haemoglobin range in these two studies (140-155 g/l and 120-140 g/l, respectively) was higher than that normally used with erythropoietin or recommended by professional society guidelines.⁸ In light of these results, the Oncology Drugs Advisory Committee held a meeting in 2004 and recommended label changes for epoetin alfa and darbepoetin alfa that warn about excessive rises in haemoglobin concentrations and urge specifically against trying to raise them above 120 g/l.

More recently, a growing number of studies have been terminated early or have reported worrying preliminary results, which suggests that the 2003 results were not spurious. A Danish trial of 522 patients with head and neck cancer receiving radiotherapy, which was stopped early after an interim analysis in November 2006, found a 10% increase in locoregional disease progression and a trend towards worse survival in the darbepoetin arm.⁹ A Canadian study of epoetin alfa in patients with incurable non-small cell lung cancer was terminated after only 70 of the 300 planned patients were treated because of worse survival in the epoetin alfa arm (63 v 129 days).¹⁰ An Amgen sponsored study of 989 patients with cancer who were not receiving chemotherapy found more deaths in the darbepoetin alfa arm (48.5% v 46%; P=0.006). In addition, Roche suspended a randomised phase II trial of its novel erythropoietin stimulating drug, CERA, in patients with non-small cell lung cancer who were receiving chemotherapy, because of an unexpected number of deaths that were initially thought to be unrelated to drug treatment.¹¹

None of these studies have yet been presented in full, and each will be carefully scrutinised when this occurs. Coming in the wake of a recent randomised study that showed worse outcomes in patients with anaemia secondary to chronic renal failure when treated to achieve a higher haemoglobin value rather than a lower one, these new results increase concern about using these drugs outside current prescribing guidelines.¹² A NICE appraisal is in development¹³ and the literature review was inconclusive on several key points. The guidance statement has gone through several appeals already, and recent data will certainly affect its conclusion.

Future development of CERA is now uncertain. Some investors are worried—for instance, the value of the common stock of Amgen, the leading manufacturer of these drugs—with sales of darbepoetin and epoetin worth $6.6bn (£3.4bn; 5bn) last year—dropped 20% between 22 January and 9 March.¹ The consequences of these developments on reimbursement for use of erythropoiesis stimulating agents by third party payers are unpredictable.

Putting economic and regulatory questions aside, how might erythropoiesis stimulating agents stimulate growth of tumours? This question is the subject of ongoing study and debate. Leading possibilities include changes in the oxygen tension in the tumour microenvironment, with subsequent changes in neoangiogenesis and cell growth; alteration in the rheology of blood in tumour microvasculature; and stimulation of functional erythropoietin receptors on neoplastic cells, if such receptors are present. Current literature on tumour cell erythropoietin receptors is clouded by use of flawed antibodies that also detect unrelated peptides, and studying tumour microvasculature in real time is technically challenging, so these questions are unanswerable at present.¹⁴

What should clinicians do while waiting for clarification? Treatment with erythropoiesis stimulating agents undoubtedly spares some patients with cancer from red cell transfusions,⁴ which carry important risks of their own. The only other effective treatments for anaemia associated with cancer are androgenic hormones, which are much less effective and have a broad range of undesirable systemic effects. Erythropoiesis stimulating agents should therefore be used in patients being treated for cancer who are likely to need a transfusion (such as those with a haemoglobin concentration <100 g/l) and in those who have severe symptoms from anaemia. But we should not use these drugs just to increase haemoglobin concentrations, and we must be honest with patients who have anaemia associated with cancer about the uncertainties of benefits for quality of life compared with risks, as well as possible increases in the risk of thromboembolism or a worse overall outcome.

Division of Hematology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA

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Competing interests: None declared.

Provenance and peer review: Commissioned; not externally peer reviewed.

References

1. Pollack A. Studies show anemia drugs may harm cancer patients. New York Times 27 Feb 2007. http://query.nytimes.com/gst/fullpage.html?res=9F07E3DA1E3EF934A15751C0A9619C8B63&sec=health&spon=&pagewanted=1
2. Crawford J. Erythropoietin: high profile, high scrutiny. J Clin Oncol Epub 20 March 2007.
3. Anonymous. Erythropoiesis-stimulating agents (ESAs). www.fda.gov/cder/drug/advisory/RHE2007.htm
4. Bohlius J, Langensiepen S, Schwarzer G, Seidenfeld J, Piper M, Bennett C, et al. Recombinant human erythropoietin and overall survival in cancer patients: results of a comprehensive meta-analysis. J Natl Cancer Inst 2005;97:489-98.[Abstract/Free Full Text]
5. Steensma DP, Loprinzi CL. Erythropoietin use in cancer patients: a matter of life and death? J Clin Oncol 2005;23:5865-8.[Free Full Text]
6. Henke M, Laszig R, Rube C, Schafer U, Haase KD, Schilcher B, et al. Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 2003;362:1255-60.[CrossRef][ISI][Medline]
7. Leyland-Jones B, Semiglazov V, Pawlicki M, Pienkowski T, Tjulandin S, Manikhas G, et al. Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 2005;23:5960-72.[Abstract/Free Full Text]
8. Rizzo JD, Lichtin AE, Woolf SH, Seidenfeld J, Bennett CL, Cella D, et al. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol 2002;20:4083-107.[Abstract/Free Full Text]
9. Overgaard J. Danish Head and Neck Cancer Group: DAHANCA 10. 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. .http://frejacms.au.dk/dahanca/get_media_file.php?mediaid=125
10. Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, Smith C, et al. Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol Epub 20 March 2007.
11. Mitchell S. Roche weathers a hard week. United Press International. www.upi.com/healthbusiness/view.php?storyid=20070223-052736-4559r.
12. Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006;355:2085-98.[Abstract/Free Full Text]
13. National Institute for Health and Clinical Excellence. Erythropoetin (alpha and beta) and darbepoetin for the treatment of cancer-treatment induced anaemia. http://guidance.nice.org.uk/page.aspx?o=appraisals.inprogress.anaemia9#keydocs
14. Brown WM, Maxwell P, Graham AN, Yakkundi A, Dunlop EA, Shi Z, et al. Erythropoietin receptor expression in non-small cell lung carcinoma: a question of antibody specificity. Stem Cells 2007;25:718-22.[Abstract/Free Full Text]

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Rapid Responses:

Read all Rapid Responses

FDA Black Box warning applies equally to Chronic Kidney Disease

Stanley Shaldon
bmj.com, 31 Mar 2007 [Full text]

Response to Dr Shaldon

David P Steensma
bmj.com, 10 Apr 2007 [Full text]