Department of Medical Sciences
“Regina Apostolorum” Hospital
Anaemia is a common occurrence in cancer patients. The recently published European Cancer Anaemia Survey (ECAS), conducted in 24 countries, enrolled 15,367 cancer patients.(1) Overall, 66% of patients with solid tumours and 72% of patients with haematological malignancies were anaemic (haemoglobin [Hb] level <12g/dl) at some point during the six-month observation period. Patients treated with platinum-based chemotherapy agents are at especially high risk for developing anaemia. Reported transfusion rates in these cases range from 47% to 100%, depending on the cumulative dose of platinum and on other risk factors, particularly a low baseline Hb level (<11g/dl) or a reduction in the Hb level of 1 to 2g/dl after the first cycle of chemotherapy.(2)
Apart from the myelosuppressive effects of radiotherapy and chemotherapy, cancer-related anaemia appears to result from a range of factors, such as chronic inflammation, blood losses, nutritional deficiencies, haemolysis, bone marrow infiltration by malignant cells and a decrease of bone marrow responsiveness to erythropoietin.(3) Compensatory erythropoietin production is typically inadequate for the degree of anaemia seen in cancer patients.(4)
The clinical consequences of anaemia range from fatigue, weakness and drowsiness to impaired mental function, respiratory distress and cardiac decompensation. The negative impact of these effects on patients’ quality of life (QoL) is substantial.(5) In addition, anaemia may compromise patients’ tolerance of treatments, resulting in the need to reduce duration or intensity.(5–7) Diagnostic workup in anaemic patients aims at identifying correctable causes of anaemia. If no specific treatment is available, red blood cell transfusions or stimulants of erythropoiesis may be indicated.
Blood transfusion has been the mainstay of therapy in the treatment of anaemia of cancer. However, as public and clinical awareness of bloodborne infections has increased, patients and healthcare providers have become increasingly concerned about the administration of blood. These concerns have had an effect on blood collection and consequently on the availability of blood for transfusion.(8) Adverse reactions, such as fever, chills and allergic reactions, are associated with approximately 20% of blood transfusions.(9) Moreover, patients requiring repeated transfusions over long periods may experience iron or fluid overload. The long-term effects on cell-mediated and humoral immunity in transfusion recipients are less clear and are likely to be complex. Several retrospective analyses have indicated that patients who receive transfusions during treatment for diseases as diverse as colorectal, cervical and laryngeal cancer have higher recurrence rates and decreased survival compared with those who are not transfused.(10,11) However, no high-quality prospective data are available. Although indications for blood transfusions are determined by clinical considerations, current guidelines suggest their use only for patients with severe (Hb level <8g/dl) anaemia.
Three erythropoietic agents are currently licensed for the treatment of moderate (Hb level 8–10g/dl) chemotherapy- induced anaemia (see Table 1). Epoetin alfa contains the same amino acid sequence as endogenous human erythopoietin (EPO) and has a half-life of approximately 4–11 hours in healthy individuals after intravenous administration.(12) Epoetin beta was introduced in Europe in 1997 but is not marketed in the USA. It differs from epoetin alfa only in terms of glycosylation and sialic acid content. Darbepoetin alfa is a recombinant human EPO (rhEPO) modified by the addition of two N-glycosylation sites, thus giving it an approximately threefold longer half-life than epoetin alfa.(13) Both epoetins and darbepoetin alfa appear to be similarly effective as endogenous EPO in stimulating the maturation of erythroid progenitors to mature erythrocytes.
Several clinical trials of rhEPO in cancer patients with chemotherapy-associated anaemia have been conducted and reviewed in a systematic meta-analysis. Epoetin therapy reduced the risk of receiving red blood cell transfusions by an average of 33% (relative risk: 0.67, 95% confidence interval [CI]: 0.62 to 0.73), whereas the relative risk for haematological response (increase in Hb level of 2g/dl or more or an increase in haematocrit of 6% or more, unrelated to blood transfusion) for rhEPO versus control was 3.60 (95% CI: 3.07 to 4.23). Recent trials have shown similar efficacy of the longer-acting darbepoetin alfa compared with epoetins.(14,15) However, direct comparison between epoetin alfa and darbepoetin alfa is based on limited evidence,(16) which does not allow definitive conclusions about relative efficacy and cost-effectiveness.
The value of supplemental erythropoietin in patients with cancer-related anaemia is now being judged not only by its effects on the haemoglobin or haematocrit, but also by its influence on QoL. A recent review identified 41 studies addressing QoL improvement in epoetin therapy, with 36 reporting statistically significant improvements in QoL.(17) In the majority of these studies, patients who achieved a haemoglobin response experienced greater improvements in QoL than nonresponders.
The most consistent adverse events of treatment with erythropoietic agents are thrombotic; they may occur irrespective of the increase in haemoglobin. However, current data do not provide conclusive evidence that treatment with erythropoietic agents increases the risk for thromboembolic events or related complications in cancer patients.(18) The incidence of hypertension was also reported higher following erythropoietic protein therapy in several studies, but this was not statistically significant.(18) A controversial issue with respect to the safety of rhEPO arose from two recent studies(19,20) in which the drug was given to maintain Hb concentrations in a range higher than those recommended by current guidelines (12–13g/dl), as well as by the label information for the various products. The results of these studies showed a significantly higher death rate in the epoetin groups, compared with the placebo groups. Both trials have been widely discussed and criticised for the high target Hb in the epoetin group, a high percentage of protocol violators and imbalances in baseline characteristics between treatment and control groups. Nevertheless, the fact that the EPO receptor is expressed in several cancer cell lines(21–23) leaves the concern of possible stimulation of tumour cell growth by these drugs.
Patients treated with rhEPO may develop iron deficiency. Evidence from a prospective, open-label, randomised trial demonstrated a higher percentage of patients with haematopoietic response if iron was administered intravenously, compared with no iron supplementation or oral iron supplementation (68 vs 25 and 36%, respectively; p<0.01).(24) However, guidelines for optimal timing and periodicity of monitoring and the optimal dosing regimen for iron repletion are not available.
Several important questions on the optimal use of rhEPO remain to be answered. Current guidelines recommend epoetin as a treatment option in cancer patients with chemotherapy-associated anaemia if the Hb levels have declined to 10g/dl.(17,25) For anaemic patients with declining Hb levels which are still in the range of >10 to <11g/dl, the decision to use epoetin should be based on clinical circumstances like advanced age, comorbid conditions and degree of symptoms from anaemia. These recommendations also apply for patients with multiple myeloma, non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia experiencing chemotherapy-associated anaemia if cytoreductive treatment has failed to induce a haemoglobin response. In addition, rhEPO appears to be effective in low-risk myelodysplastic syndrome patients with low endogenous EPO levels. At present, due to limited evidence, no recommendations for cancer patients with radiotherapy- associated anaemia can be given.(17)
Although several studies have reported predictive factors for response to erythropoietic agents, none has been validated in prospective trials.(26)
Finally, studies of cost-effectiveness, particularly compared with transfusion therapy, have been challenging to conduct and analyse, and have generated ambiguous results. At present there is insufficient evidence on which to assess the cost-effectiveness of EPO in the treatment of cancer-related anaemia.
Cancer-related fatigue is a multifactorial and prevalent problem. Erythropoietic agents are a class of drugs with an enormous potential for the treatment of this condition. However, their use needs to be optimised in terms of cost-effectiveness, indications need to be redefined and issues regarding the safety need to be clarified.
To resolve these issues, the design of new randomised clinical trials with a stronger methodology is a major priority. At the present time, erythropoietic agents should be used only according to current guidelines.
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American Society of Clinical Oncology
European Society of Medical Oncology
NCCN – National Comprehensive Cancer Network