There are 2 EPOs currently registered in Singapore: epoetin alfa (Eprex®, Johnson & Johnson) and epoetin beta (Recormon®, Roche). Both products are indicated for the treatment of anaemia in patients associated with renal failure; to increase yield of autologous blood collection; and for use in prevention and treatment of anaemia in cancer patients. Recent emerging safety concerns of the possibility that some clinical uses of EPOs in patients with cancer may be associated with unanticipated risks, including an increased risk of thrombotic vascular events and/or an adverse effect on tumour progression and duration of survival have prompted HSA and its Pharmacovigilance Advisory Committee (PVAC) to review the use of EPOs in cancer patients. Several international regulatory authorities have also discussed the risk-benefit profile of EPOs in cancer patients due to this emerging safety concern. The review was triggered by the following articles published in The Lancet.
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The ENHANCE study
Henke et al1 conducted a double-blind, placebo controlled trial to test the hypothesis that correction of anaemia in subjects receiving radiation therapy for the treatment of head and neck carcinoma could possibly improve tumour control. Patients were randomised to receive either epoetin beta (Recormon®) or placebo. The mean haemoglobin (Hb) concentrations after 4 weeks of treatment were 12.3 g/dL for the placebo arm and 14.8 g/dL for epoetin beta arm. The adjusted relative risk of death was 1.39 for epoetin beta patients (95% CI 1.05–1.84). In the actuarial analysis, patients receiving treatment with placebo survived a median of 928 days compared to 605 days in the epoetin beta group (p=0.09).
Vascular disorders (hypertension, haemorrhage, venous thrombosis/pulmonary embolism, cardiovascular accidents) developed in 5% of the placebo group and in 11% of the epoetin beta arm. Henke et al concluded that epoetin beta treatment was associated with an adverse effect on mortality and tumour progression.
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The Breast Cancer Erythropoietin Trial (BEST)
Results showed the frequencies of deaths were higher in epoetin alfa-treated subjects (32%; 148/469) compared to placebo group (24%; 115/470). Most of the between-group difference in mortality was observed within the first 4 months after randomisation. Thrombotic vascular events (TVEs) could have been a significant contributing factor to the differences in survival rates between the 2 treatment groups. [Amongst patients who died within 4 months of study entry, 2 subjects in the placebo vs 11 subjects in the epoetin alfa group had evidence of a TVE proximate death].
Treatment with EPOs has been associated with some increase in the risk for TVEs, and it is assumed that such events may become more frequent when subjects are treated beyond the correction of anaemia.
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Clinical practice guidelines
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Advisory
i) that the licensed indication of EPOs for prevention of anaemia in cancer patients is no longer appropriate.
ii) that the target Hb concentration in cancer patients if treated with EPOs should be up to 12 g/dL.
HSA is working with the affected drug companies to make the necessary changes in the products' package insert.
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References
- Lancet 2003; 362:1255-1260.
- Lancet Oncology 2003; 4:459-460.
- J Clin Oncol 2002; 20:4083.
- Eur J Cancer; 40:2201.
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