The use of erythropoietin in cancer patients

teaser

Tariq I Mughal
MB(Lond) MD MRCP(UK) FACP
Professor
Department of Hematology and Medical Oncology
University of Massachusetts School of Medicine
Worcester, MA
USA
Guy’s & St Thomas’ Hospital
London
UK
E:[email protected]

Anaemia related to cancer probably occurs in up to two-thirds of all cancer patients, with the incidence being the highest for haematological malignancies.(1) Anaemia often develops insidiously; it has an adverse impact on the quality of life and may affect survival.(2,3)

Although there is little doubt that the presence of moderate- to-severe anaemia is associated with a reduced survival in patients with cancer, it is less clear whether anaemia itself is the proximate cause of reduced survival or whether it is instead a surrogate marker for other adverse prognostic features. Anaemia is an independent factor for recognised prognostic indices for various haematological malignancies, including chronic myeloid leukaemia, chronic lymphocytic leukaemia, multiple myeloma and Hodgkin lymphoma.(4)

Molecular pathogenesis
Many efforts have been directed towards understanding the molecular mechanisms resulting in the adverse impact of anaemia on the survival of cancer patients. For the most part, these remain poorly understood, but several useful observations have been made. Tumours with an increased hypoxic fraction are associated with an increase in levels of urokinase plasminogen activator, a potent enzyme that has a role in the maintenance of the extracellular matrix.

A popular hypothesis is that the induction of increased levels of urokinase plasminogen activator by hypoxia may allow the breakdown of extracellular matrix and therefore promote the metastatic process.(5) Alternative hypotheses, not mutually exclusive, include hypoxia affecting the hypoxia- inducible factor 1 alpha-vascular endothelial growth factor angiogenesis pathway that promotes tumour growth. In addition, many cancer cells harbour erythro­poietin (EPO) receptors, and EPO can affect the signal transduction pathways, which could result in inhibiting apoptosis and possibly promote tumour growth.(6)

Treatment of anaemia related to cancer
Up until 1990, red blood cell transfusions were the principal form of treatment of anaemia related to cancer. EPO has been used increasingly following the confirmation of its usefulness in correcting anaemia related to multiple myelomas.(7) Current experience confirms the effectiveness of EPO in the treatment of some patients with anaemia related to cancer.(8) Two recent meta-analyses confirmed the notion that EPO treatment improves anaemia and reduces the risks associated with red blood cell transfusions. The 2005 meta-analysis also demonstrated a trend (not statistically significant) that EPO treatment may result in an improvement of the overall survival.(9,10) This latter observation is in contrast to the results of two recent large randomised clinical trials that showed an inferior overall survival for the EPO-treated cohort.(11,12) Such observations have raised considerable questions about the potential biological effects of EPO on the underlying cancer. A detailed analysis of the two trials associated with an adverse survival with EPO is beyond the scope of this article, but several keynote issues can be highlighted. First, in both trials, patients had much higher haemoglobin (Hb) levels (even normal or near normal) at time of entry into the trial. In the Breast Cancer Erythropoietin Survival Trial (BEST), in contrast to most other trials, the primary endpoint was overall survival.(10) This trial, assessing the role of epoetin alfa, was terminated early by a data safety monitoring committee because of a trend towards higher mortality among patients receiving epoietin alfa.(13) There were considerable flaws in the methodology, and the trial merited much criticism. The second trial studied the role of epoietin beta in 351 patients undergoing radiation therapy for squamous cell carcinoma of the head and neck.(11) This trial showed that the recurrence rate among patients treated with EPO was higher than that among patients treated with placebo.

Different erythropoietic agents
At present, three erythropoietic agents are commercially available: epoetin alfa (Eprex; Epogen; Procrit), epoetin beta (Neocormin) and darbe­poietin alfa (Aranesp). All these agents differ in their biochemical structure, EPO-receptor affinity and serum half-life, which allows for alternative dosing and scheduling strategies.(14,15) In addition to the concerns raised by the BEST trial with regards to epoetin alfa and the German head-and-neck trial with regards to epoietin beta, much concern was aroused recently following the identification of epoetin alfa-associated red-cell aplasia.(16) Fortunately, following stringent changes in the storage and handling, the reported incidence of red cell aplasia apparently decreased significantly.(17) At present, no such adverse effects have been noted in patients receiving ­darbepoietin alfa for anaemia related to cancer.

The efficacy of all erythropoietic agents in the correction of anaemia in some (but not all) patients with chemotherapy- associated anaemia is well established. The longer half-life of darbepoietin alfa, compared with the other agents, has led to several trials exploring its administration once every three weeks.(18) These studies confirmed its efficacy when administered in this manner, leading to EMEA approval; it is likely that FDA approval will follow shortly.

Current US and European guidelines
Currently, there are several international, national and indeed regional guidelines on the use of EPO for the treatment of anaemia related to cancer. In the USA, the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH) jointly recommend the use of EPO for patients with chemotherapy-related anaemia with a Hb level of less than 10g/dl.(19) These guidelines also suggested that, for selected patients, EPO treatment may be indicated for Hb levels of 10–12g/dl. The National Comprehensive Cancer Network (NCCN) and the European Organization for Research and Treatment of Cancer (EORTC) recently issued similar guidelines.(20,21) The various guidelines encourage the monitoring of the iron status, since functional iron deficiency can develop when intense erythro­poiesis results from EPO. There has been a suggestion, requiring further confirmatory studies, that parenteral iron enhances the response to EPO in patients with cancer receiving chemotherapy.(22)

Conclusion
Current experience confirms the effectiveness of EPO in the treatment of some patients with anaemia related to cancer. More information is, however, required on the potential biological effects of EPO on the underlying cancer, and in particular a potential overall survival benefit. A 2005 meta-analysis suggests a trend towards a possible survival advantage when EPO is used for cancer patients who are anaemic; in contrast, two large randomised studies where many patients with normal or near-normal Hb were recruited showed a possible survival disadvantage for EPO.

An immediate result from these two trials was to offer EPO only to patients with Hb levels of 12g/dl or less and, clearly, further clinical trials are needed to address the survival issue further. At present, the FDA’s MedWatch safety information programme recommends that the target Hb should not exceed 12g/dl and, if the rate of Hb increase exceeds 1g/dl during a two-week period, the EPO dose and schedule need to be modified. Many efforts are also being made to develop risk models for anaemic patients with cancer receiving conventional dose chemo‑therapy.(23)

References

1. Eur J Cancer 2004;40:2293-306.
2. Mughal TI. Anaemia in patients with cancer: an overview. In: Bokemeyer C, Ludwig H, editors. ESO Scientific Updates, Vol 6. Anaemia in cancer. Elsevier Science BV; 2001. p. 15-23.
3. J Clin Oncol 2005;23:5865-8.
4. Cancer 2001;91:2214-21.
5. J Natl Cancer Inst 2001;93:266-76.
6. Carcinogenesis 2003;24:1021-9.
7. N Engl J Med 1990, 322: 1693-9.
8. J Clin Oncol 2001;19:2865-74.
9. J Natl Cancer Inst 2001;93:1204-14.
10. J Natl Cancer Inst 2005;97:489-98.
11. J Clin Oncol 2005;23:5960-72.
12. Lancet 2003;362:1255-60.
13. Lancet Oncol 2003;4:458-60.
14. Hematol Oncol 2004;22:121-34.
15. Am J Health-Syst Pharm 2005;62:54-62.
16. N Engl J Med 2004;351:1403-8.
17. N Engl J Med 2005;352:511-2.
18. J Clin Oncol 2005;23:6941-8.
19. Blood 2002;100:2303-20.
20. Sabbattini P, on behalf of the NCCN anemia panel. NCCN clinical practice guidelines in oncology: cancer and treatment-related anemia, version 1.2005. Available from: http://www.nccn.org/physician_gls/f_guidelines.html
21. Eur J Cancer 2004;40:2201-16.
22. J Clin Oncol 2004; 22: 1301-7.
23. J Clin Oncol 2005;23 Suppl: Abstract 8122.