Singapore - There are two erythropoietins (EPO) currently registered in Singapore: epoetin alfa (Eprex®) and epoetin beta (Recormon®). Both products are indicated for:

• 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 the health Sciences Authority 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 triggered by publication of the following studies.

The ENHANCE study (1), was a double-blind, placebo controlled trial to evaluate whether correction of anaemia in subjects receiving radiation therapy for the treatment of head and neck carcinoma improves tumour control. Patients were randomized to receive either epoetin beta or placebo. 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. It was concluded that epoetin beta treatment was associated with an adverse effect on mortality and tumour progression.

The Breast Cancer Erythropoietin Trial (BEST) was a randomized controlled trial of epoetin alfa versus placebo in patients with metastatic breast cancer receiving chemotherapy which was terminated prematurely (2). The trial was designed to test whether epoetin alfa would improve survival and quality of life. Results showed frequencies of deaths as higher in epoetin alfa-treated subjects (32%) compared to placebo (24%). Thrombotic vascular events (TVEs) could have been a significant contributing factor to the differences in survival rates between the two treatment groups. 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 (1, 2).

The American Society of Clinical Oncology, the American Society of Hematology (3), and the European Organization for Research and Treatment of Cancer (EORTC) (4) have separately developed evidence-based clinical practice guidelines for the use of EPOs in patients with cancer. Both sets of guidelines recommended that cancer patients receiving chemotherapy and/or radiotherapy, treatment of EPOs if initiated should be at a Hb level of < 11 g/dL.

Based on the risk-benefit assessment of EPOs in cancer patients, the Pharmacovigilance Advisory Committee has recommended the following:

• that the licensed indication of EPOs for prevention of anaemia in cancer patients is no longer appropriate.

• that the target Hb concentration in cancer patients if treated with EPOs should be up to 12 g/dL.

References

1. Lancet, 362:1255-1260 (2003).

2. Lancet Oncology, 4: 459-460 (2003).

3. Journal of Clinical Oncology, 20: 4083 (2002).

4. European Journal of Cancer; 40: 2201 (2004).

5. HSA Product Safety Alert. 31 March 2005 at http://www.hsa.gov.sg/cda/safetyalerts

6. Epoetin alfa and blood clot formation in cancer patients. WHO Drug Information, 18(4): 285 (2004).