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Alfonso Domínguez-Gil Hurlé*
Dr rer nat
*Department of Pharmacy
University Hospital at Salamanca
**University Clinic Tübingen
Cancer patients often experience anaemia that can severely diminish their quality of life because of related symptoms such as fatigue.(1) Two main treatment options are allogenic red blood cell transfusion and therapy with erythropoiesis- stimulating agents (ESAs). The recent European Cancer Anaemia Survey demonstrated that many anaemic patients do not receive treatment.(2)
Before 1990, transfusion was the only treatment option.(3) Concerns about transfusions, such as infection risk and transfusion reactions, have led to strategies designed to optimise and limit its use.(4)
ESAs stimulate the differentiation of precursors into erythrocytes to produce red blood cells. Three ESAs are now commercially available, including epoetin alfa and epoetin beta, both introduced in the 1990s, and darbepoetin alfa, which was launched in 2001.(4) Darbepoetin alfa has additional sugar residues that prolong the half-life in vivo and increase biological activity, compared with recombinant human erythropoietin (rHuEPO) and epoetin alfa.(5–7) Recently, a half-life of over 70 hours has been reported for darbepoetin alfa when administered every three weeks (Q3W).(8) ESAs have substantially improved anaemia management.
Evidence-based guidelines on ESA use
Defining the optimal use of ESAs, however, is important considering their cost, and evidence-based guidelines play an important role in this. Two major evidence-based guidelines that reflect American practice include the American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) anaemia guidelines,(4) as well as the National Comprehensive Cancer Network (NCCN) clinical practice guidelines on cancer- and treatment-related anaemia.(3) The ASCO guidelines are based on data published between 1985 and 1999; they include few data on ESA use.(4) Nevertheless, many of the recommendations on ESA use are supported by more recent evidence and remain valid. The NCCN guidelines(3) provide a treatment algorithm to follow for anaemia in cancer patients in the form of decision trees to guide treatment.
Having guidelines based on European practices is important. The European Organisation for Research and Treatment of Cancer (EORTC) taskforce published European-based guidelines in October 2004 (an update should be available in the coming few months).(9) These guidelines address questions about current use of ESAs, such as when to initiate therapy and target haemoglobin level. The authors focus on evidence relating to ESA use, assuming other factors (eg, iron deficiency, bleeding or nutritional defects or haemolysis) that may induce anaemia have been corrected before starting ESA therapy.
Use of ESAs
Each guideline reports evidence that ESAs effectively increase haemoglobin levels, reduce transfusion requirements and improve quality of life for cancer patients with anaemia. The guidelines also describe optimal use of ESAs. A very brief summary of the guidelines is provided in Table 2. Issues of particular relevance to hospital pharmacies are also discussed.
When to initiate therapy
Deciding when to initiate therapy is important. Anaemia is often classified as mild, moderate or severe; how these grades are defined varies slightly according to source (see Table 1). These grades, however, do not relate to clinical symptoms or well-being;(10) even mild-to-moderate anaemia can adversely affect patient quality of life.(10)
Each guideline states that starting treatment should depend on both haemoglobin levels and associated symptoms. EORTC guidelines(9) suggest ESA initiation at a haemoglobin level of 9–11g/dl. By comparison, the NCCN guidelines(3) advise considering ESA therapy for cancer patients with symptomatic anaemia and haemoglobin levels of 10–11g/dl, in particular if haemoglobin levels are <10g/dl, and in asymptomatic anaemic patients with a haemoglobin level <11.0g/dl if risk factors for symptomatic anaemia, such as fatigue and cardiac symptoms, are present. Comorbidities such as a history of cardiac disease should also be assessed, as anaemia represents a greater risk to such patients.(11) Similarly, the ASCO/ASH guidelines recommend ESA treatment at haemoglobin levels <10g/dl. The guidelines state that clinical circumstances should dictate when to use ESAs in this haemoglobin range.(4)
When first introduced, rHuEPO was administered three times per week (TIW), although once-weekly (QW) dosing at 450IU/kg is approved in some European countries.(12)
The European SPC recommends administering darbepoetin once Q3W,(13) suggesting weekly administration as an alternative. Data supporting a Q3W dosing regimen for darbepoetin alfa was recently presented at the annual meeting of the European Haematology Association and has been subsequently published.(14) In this phase III, noninferiority trial, a fixed dose of darbepoetin alfa 500µg Q3W was at least as effective as a weight-based weekly dose. As described in the EORTC and NCCN guidelines, studies have shown that darbepoetin alfa was effective when used QW,(15,16) Q2W(17–19) or Q3W.(8,20)
Frequency of dosing can be an important consideration. Clinic visits for anaemia treatment have a major impact on quality of life for patients and their caregivers.(21) Among the complaints, patients report that clinic visits affect paid time at work and time with friends and family; caregivers often need to provide transportation because of clinic visits.(21) Less frequent clinic visits can also benefit doctors, by freeing up time to spend on other essential duties.(21)
Initial dose and dose adjustments
The EORTC guidelines recommend starting darbepoetin alfa dosing at 2.25µg/kg/week and epoetin alfa dosing at 30,000–40,000IU/week. The EORTC guidelines state that fixed doses, often used in clinical practice,(9) are as effective as weight-based doses.(14) For example, in a noninferiority trial, darbepoetin alfa (500µg Q3W) was at least as effective as weekly dosing (2.25µg/kg/week), with the incidence of transfusions (week 5 to end of treatment period) being comparable between the arms (23% versus 30%). Incidence of patients achieving target haemoglobin levels (11–13g/dl) was 84% vs 77%, respectively.(14) The EORTC guidelines found limited data to support dose increases, which has positive economic implications.
Target haemoglobin levels for ESA therapy are not well defined for patients with cancer. As the EORTC guidelines indicate, no prospective, randomised study has specifically addressed the correlation between target haemoglobin level and clinical benefit. Nevertheless, haemoglobin levels and quality of life in cancer patients treated with ESA are correlated, with the maximal incremental gain in quality of life occurring when haemoglobin levels are 11–13g/dl. (9,22–24) ESA treatment should be withheld when haemoglobin concentrations exceed 13g/dl.
Patient characteristics for response
Not all cancer patients with anaemia respond to ESA therapy; response rates reported in the literature vary greatly, partly due to differences in the definition of “response”. The EORTC guidelines report that 24–75% of patients receiving ESA therapy achieve an increase in haemoglobin that is significantly greater than that seen in control patients.(9) Understanding which factors predict response could reduce the cost of treatment, but predicting response is poorly understood.(25) Table 3 shows baseline characteristics of patients that may have an impact on response to ESA therapy.
A patient’s iron status can influence response to erythropoietin.(25) Iron is necessary for the production of red blood cells, so functional iron deficiency can limit erythropoiesis, even when erythropoietin levels are sufficient. To optimise the benefit of ESA therapy, it is therefore important to assess iron status in patients before and during therapy and correct as necessary. The EORTC guidelines for anaemia assume that any iron deficiency is corrected before treatment with ESAs. The various guidelines acknowledge a lack of published supporting evidence but suggest that providing iron replacement, as required, may maximise symptom improvement for patients on ESAs.
The EORTC guidelines evaluated evidence for pure red cell aplasia (PRCA), thromboembolic events and hypertension in patients treated with ESA. No statistically significant increase in any of these events was demonstrated in any of the clinical trials reviewed. However, a meta-analysis of pooled data from 16 randomised controlled trials revealed a 1.55-fold elevated risk for thromboembolic events and 1.25-fold elevated risk for hypertension. PRCA has been reported, primarily in patients with renal failure and anaemia, although a few cases of PRCA associated with neutralising anti-erythropoietin antibodies have been reported in oncology patients.
Some studies suggest that many tumours express erythropoietin receptors, raising the question of whether erythropoietin may stimulate tumour growth. A recent publication, however, has raised questions about the antibodies used to detect erythropoietin receptors in these previous studies. In particular, these antibodies were found to be unspecific for erythropoietin receptors.(26) Conversely, correction of anaemia in cancer patients could, in theory, improve survival.
Survival outcomes have been mixed. The EORTC guidelines discuss the various observations of survival.(9) Of the studies they mention, 11 demonstrated no improvement or a trend for improved survival in the ESA group, while one reported a statistically significant increase in survival. Two other studies reported a higher rate of disease progression with ESA-treated patients to target haemoglobin levels greater than 12g/dl. A recent systematic review reporting the results of a meta-analysis of 27 trials concluded that the data suggest, but do not definitively prove, improved overall survival among patients treated with an ESA.(27)
Using the guidelines in clinical practice
Evidence-based guidelines are extremely helpful in providing the information needed to optimise therapy, but all too often they have little influence on clinical practice. To achieve best practice treatment, evidence-based recommendations must be incorporated into institution-specific policies that are integrated into the daily practice of all healthcare professionals within that institution. Institution guidelines must address issues such as identifying who to treat and when, selecting an appropriate drug and dose regimen, deciding which parameters should be monitored during therapy, and determining when to modify or stop treatment. They must also take into consideration current practice, economic factors and convenience for patients, caregivers and healthcare professionals. Examples of implementation of institution-based guidelines on ESA use were described by Adamson et al.(28) Engaging the healthcare providers and developing training were important for the implementation. The health system pharmacy plays a pivotal role in implementing the guidelines for inpatients. During implementation of the guidelines across the healthcare systems, it is important to address concerns over the change in dosing schedule from the oncology staff and on issues such as iron supplementation.
In summary, EORTC guidelines suggest that the goal of erythropoietic therapy is to avoid transfusions and increase patients’ quality of life.(9) Treatment with ESAs should be initiated when haemoglobin levels are between 9 and 11g/dl, with exact timing determined by clinical symptoms, with a goal to achieve a target haemoglobin range of 12–13g/dl.(9)
The EORTC, NCCN and ASCO/ASH evidence-based guidelines on the use of erythropoietin in cancer patients with anaemia provide valuable information that can be used to optimise patient care and costs of treatment. To apply this information in clinical practice, hospital/institution guidelines must be developed and implemented. Pharmacists can play an important role in implementing guidelines to ensure best practice use of ESA protein drugs.