Article date: August 2008
Recombinant human erythropoietins (r-HuEPOs) stimulate erythropoiesis. They are indicated for the treatment of symptomatic anaemia in patients with chronic kidney disease. Some r-HuEPOs are also authorised for the treatment of patients with non-myeloid cancer who develop symptomatic anaemia due to chemotherapy. Carefully consider whether the benefit of administering recombinant erythropoietins outweighs the risk, and involve the patient in the decision.
You should also consider:
- tumour type and stage
- degree of anaemia
- the environment in which the patient is being treated
- the patient’s preference.
In December 2007, a Drug Safety Update article advised that r-HuEPOs should not be given to patients with cancer who do not fulfil the criteria in the authorised cancer indications, and that patients should be monitored closely to ensure that the lowest approved dose of r-HuEPO is used to adequately control of symptoms of anaemia. This advice was based mainly on data from five large controlled trials, which showed a consistent, unexplained statistically significant excess mortality in patients who had cancer-associated anaemia who received r-HuEPOs compared with controls. In these studies, r-HuEPOs had been given in a way that was not always consistent with prescribing recommendations: participants either did not have anaemia resulting from chemotherapy or haemoglobin was corrected to concentrations higher than 12 g/dL (7·5 mmol/L). Therefore, it was unclear what risks might apply to the use of r-HuEPOs to achieve haemoglobin concentrations lower than 12 g/dL (7·5 mmol/L) in patients with cancer who are receiving chemotherapy.
Further data has come to light for these medicines in cancer management.
New data for r-HuEPOs in cancer
A prematurely terminated studyand an interim analysis from an unpublished study give further information on mortality and tumour progression in patients with cancer who receive r-HuEPOs.
The Gynecologic Oncology Group study
This study1 compared the effect of maintaining haemoglobin concentration at 12 g/dL (7·5 mmol/L) or higher with r-HuEPO, with that of blood transfusion when haemoglobin concentration fell below 10 g/dL (6·2 mmol/L) on progression-free survival, overall survival, and local disease control in women who were receiving concurrent weekly cisplatin and radiotherapy for carcinoma of the cervix.
The study was terminated prematurely, with less than 25% of the planned number of patients (n=109), because of concerns about thromboembolic events in the r-HuEPO group. The r-HuEPO group were treated to maintain haemoglobin concentration between 12 g/dL (7·5 mmol/L) and 14 g/dL (8·7 mmol/L). 11 of 57 patients in this group had thromboembolism compared with four of 52 in the control group; none of the thromboembolic events was fatal. Median follow-up was 37 months (range 10–50). Progression-free survival at 3 years was lower in the r-HuEPO group than in the control group (58% vs 65%, respectively). Overall survival at 3 years was lower in the r-HuEPO group than in the control group (61% vs 75%, respectively).
This study was a randomised, open-label trial in women with primary breast cancer who were randomly assigned one of two chemotherapy regimens for 24 weeks before surgery with or without radiotherapy. Patients in both treatment groups were also randomly allocated either darbepoetin alfa or no r-HuEPO. Darbepoetin alfa was given to maintain a haemoglobin concentration of 12 g/dL (7·5 mmol/L). Tumours were assessed every 12 weeks during chemotherapy, and follow-up was every 3 months for 2 years after the end of surgery or radiotherapy. 733 patients were analysed.
14% of patients who received darbepoetin alfa died compared with 10% of patients who received no r-HuEPO. Tumour progression was recorded for 25% of patients who received darbepoetin alfa compared with 19% of patients in the control group.
Neither study showed a statistically significant elevated risk associated with r-HuEPO treatment. However, their outcomes corroborate findings from previous studies of an increased risk of tumour progression and reduced overall survival associated with r-HuEPO in cancer settings. In the unpublished analysis, darbepoetin alfa was given in a way that resembles the authorised use for r-HuEPOs.
The risk of tumour progression associated with r-HuEPOs and their effect on overall survival in patients with cancer continues to be investigated. Further data should become available in due course, enabling further characterisation of the apparent risks.
Advice for healthcare professionals includes:
- available evidence suggests that use of r-HuEPOs in patients with cancer is associated with reduced overall survival and a negative effect on progression-free survival
- data currently available does not allow definitive conclusion that the risk outweighs the benefit in their authorised indication in patients with cancer
- owever, data does suggest that blood transfusion should be the preferred option for the management of anaemia in patients with cancer, particularly in those who are receiving adjuvant chemotherapy or who are being treated with curative intent
- blood transfusion may also be preferable in patients with advanced or metastatic cancer who have a good survival prognosis
- the decision to administer r-HuEPOs should be based on an informed risk-benefit assessment with the participation of the patient, which takes into account: tumour type and stage; degree of anaemia; life-expectancy; the environment in which the patient is being treated; and the patient’s preference
See the press release by the European Medicines Agency
Summaries of product characteristics
Letter sent to healthcare professionals July 2008
Article citation: Drug Safety Update Aug 2008, vol 2 issue 1: 3.