This article appears in the following Annals of Oncology issue: ESMO Clinical Recommendations [View the issue table of contents]
ESMO clinical recommendations |
Erythropoiesis-stimulating agents in cancer patients: ESMO Recommendations for use
1 Department of Medical Oncology, Ziekenhuis Antwerpen Middelheim, Antwerp, Belgium
2 Department of Medical Oncology, S. Maria Hospital, Terni, Italy
* Correspondence to: ESMO Guidelines Working Group, ESMO Head Office, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; E-mail: clinicalrecommendations{at}esmo.org
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definition of anemia |
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 Top definition of anemia anemia in patients with...indications for the use...comparison between ESAsrecommendations in relation to...cancer therapy outcomesafety and tolerabilitypharmaco-economic considerationsnotereferences |
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Anemia is defined as a reduction of the hemoglobin (Hb) concentration, red-cell count or packed cell volume below normal levels.
Mild anemia is defined as an Hb concentration of 
11.9 g/dl and 
10 g/dl, moderate anemia as Hb of 9.9 and 8.0 g/dl and severe anemia as Hb <8.0 g/dl.
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anemia in patients with non-myeloid malignancies |
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Topdefinition of anemiaanemia in patients with...indications for the use...comparison between ESAsrecommendations in relation to...cancer therapy outcomesafety and tolerabilitypharmaco-economic considerationsnotereferences |
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Anemia of cancer is present in 40% of patients with non-myeloid malignancies. It is mild in 30%, moderate in 9% and severe in 1%. Overall incidence of anemia during chemo- or radiotherapy is 54% (mild 39%, moderate 14% and severe 1%). The incidence is highest in patients with lung (71%) or gynecological (65%) cancer and increases with the number of chemotherapy cycles.
Causes of anemia in cancer patients might be patient (e.g. hemoglobinopathies, thalassemia, diminished nutritional status with deficiencies); disease (bone marrow infiltration, bleeding, hypersplenism, anemia of chronic disease) or treatment related (extensive radiotherapy; bone marrow and renal toxicity secondary to chemotherapy; drug-induced hemolysis).
Treatment-related anemia is graded according to the National Cancer Institute-Common Toxicity Criteria of Adverse Events (CTCAE v3) (Hb grade 0: within normal limits; grade 1: lower normal limit to 10.0 g/dl; grade 2: 8.0 to <10.0 g/dl; grade 3: 6.5 to <8.0 g/dl; grade 4: <6.5 g/dl).
In patients with anemia, it is necessary to take a thorough history with emphasis on drug exposure; to review the peripheral blood smear, do a reticulocyte count and if necessary to perform a bone marrow examination; to evaluate iron, folate and vitamin B12 status; to assess occult blood loss and renal insufficiency. Coombs testing should be considered in patients with chronic lymphocytic leukemia, non-Hodgkin lymphoma and in patients with a history of autoimmune disease; endogenous erythropoietin (EPO) concentrations may predict response in patients with myelodysplasia.
All causes of anemia should be taken into account and, if possible, corrected before the use of erythropoiesis-stimulating agents (ESAs) [A].
Anemia has a negative impact on the quality of life (QoL) [I] and is an important factor in cancer-related fatigue.
It also constitutes a negative prognostic factor for overall survival in most types of cancer [I].
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indications for the use of ESAs |
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Topdefinition of anemiaanemia in patients with...indications for the use...comparison between ESAsrecommendations in relation to...cancer therapy outcomesafety and tolerabilitypharmaco-economic considerationsnotereferences |
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anemic patients with non-myeloid malignancies
The indication of ESAs is the treatment of symptomatic chemotherapy-induced anemia in adult patients with non-myeloid malignancies. The aim is to prevent transfusions and their possible complications (iron overload, transmission of infection, immune suppression related to transfusions) and possibly to improve health-related QoL (HRQoL) by increasing the Hb level.
- In patients treated with chemotherapy and an Hb concentration of 10 g/dl, treatment with ESAs might be considered to increase Hb to <12 g/dl or to prevent a further decline in Hb [I, A].
- In patients treated with chemotherapy and an Hb concentration of 10–12.0 g/dl, treatment with ESAs could be considered in the case of symptoms or to prevent a further decline in Hb [I, A]. However, this is an off-label indication.
- In patients not treated with chemotherapy, there is no indication for the use of ESAs since there might be an increased risk of death when ESAs are administered to a target Hb of 12 g/dl [I, A].
- In patients treated with curative intent, ESAs should be used with caution [D].
Treatment recommendations are given in Table 1.
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- If the Hb increase is at least 1 g/dl above baseline after 4 weeks of treatment, the dose may remain the same or may be decreased by 25–50%.
- If the Hb increase is <1 g/dl above baseline, the dose of selected ESA should be increased (Table 1). If after an additional 4 weeks of therapy, the Hb has increased 1 g/dl the dose may remain the same or may be decreased by 25–50%.
- In the case of response, treatment with ESAs should be discontinued 4 weeks after the end of chemotherapy.
- If the Hb increase is <1 g/dl above baseline after 8–9 weeks of therapy, response to ESAs therapy is unlikely and treatment should be discontinued.
- If the Hb rises by >2 g/dl per 4 weeks or if the Hb exceeds 12 g/dl, the dose should be reduced by
25–50%.
- If the Hb exceeds 12 g/dl, therapy should be discontinued until Hb falls below 12 g/dl and then reinstituted at a dose 25% below the previous dose.
Treatment with ESAs in patients with chemotherapy-induced anemia increases Hb levels with an overall weighted mean difference of 1.63 g/dl [95% confidence interval (CI): 1.46–1.80 g/dl] compared with controls [I]. ESAs also reduce significantly the relative risk of receiving red blood cell transfusions (RBCTs) by 36% [relative risk (RR) 0.64, 95% CI 0.60–0.68]. Patients with solid tumors and patients who are on platinum-based chemotherapy seem to benefit more than patients with other tumor types and receiving other tumor therapies [I].
HRQoL as measured by different evaluation tools is improved by ESAs in some studies [II], although it is not clear how these results translate into utility gains.
Continuing ESA treatment beyond 6–8 weeks in the absence of response defined as a rise in Hb concentration of <1–2 g/dl or no diminution of transfusion requirement is not beneficial [I, A].
The Hb concentration should not exceed 12 g/dl [II, B].
myelodysplastic syndromes
In patients with low-risk myelodysplastic syndromes based on bone marrow blast percentage, number of cytopenias and cytogenetic analysis, ESAs [± granulocyte-colony stimulating factor (G-CSF)] can be used to improve anemia (off-label indication). In randomized studies, ESAs induced a better Hb response rate (27.3%) compared with controls (6.7%) (odds ratio: 5.2; 95% CI: 2.5–10.8) [II]. Patients with a higher average baseline serum EPO concentration (500 u/l) have a smaller Hb change [II] and a lower rate of Hb response (27.3%) than groups with a lower baseline serum EPO concentration (34.9%).
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comparison between ESAs |
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Topdefinition of anemiaanemia in patients with...indications for the use...comparison between ESAsrecommendations in relation to...cancer therapy outcomesafety and tolerabilitypharmaco-economic considerationsnotereferences |
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There is no difference between different ESAs in relation to effectiveness and safety [I].
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recommendations in relation to iron |
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Topdefinition of anemiaanemia in patients with...indications for the use...comparison between ESAsrecommendations in relation to...cancer therapy outcomesafety and tolerabilitypharmaco-economic considerationsnotereferences |
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Baseline and periodic monitoring of iron, total iron binding capacity, transferrin saturation or ferritin levels are necessary [B]. In anemic patients with iron deficiency, intravenous iron substitution leads to higher Hb increment in comparison with oral or no iron substitution [II, A].
Iron supplementation also appears to reduce the numbers of patients receiving RBCTs [I].
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cancer therapy outcome |
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Topdefinition of anemiaanemia in patients with...indications for the use...comparison between ESAsrecommendations in relation to...cancer therapy outcomesafety and tolerabilitypharmaco-economic considerationsnotereferences |
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The influence of ESAs on tumor response and overall survival in anemic cancer patients remains unclear. Several randomized trials have demonstrated decreased survival times and poorer loco-regional control or progression-free survival but the design of these studies aimed at Hb levels >12 g/dl and included patients with a baseline Hb level of >10 g/dl [II].
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safety and tolerability |
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Topdefinition of anemiaanemia in patients with...indications for the use...comparison between ESAsrecommendations in relation to...cancer therapy outcomesafety and tolerabilitypharmaco-economic considerationsnotereferences |
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ESAs should not be used in patients with a known hypersensitivity to ESAs or any of the excipients and in patients with poorly controlled hypertension [B]. Their effect on patients with impaired liver function is unknown and they should be used with caution in patients with liver disease [D].
The relative risk for thromboembolic events is increased by 67% in patients treated with ESAs compared with placebo (RR 1.67; 95%CI: 1.35–2.06) [I]. The use of ESAs should be carefully reconsidered in patients with a high risk of thromboembolic events such as a previous history of thrombosis, surgery, prolonged immobilization or limited activity and in patients with multiple myeloma and treated with thalidomide or lenalidomide in combination with doxorubicin and corticosteroids [D]. There are no data on the preventive use of anticoagulants or aspirin.
Pure red cell aplasia (PRCA) caused by neutralizing anti-EPO antibodies has been observed in association with ESAs in patients with chronic renal failure [V], although no PRCA has been reported in cancer patients [II, B].
Other side-effects of ESAs are rare allergic reactions including dyspnea, skin rash and urticaria; arthralgia; peripheral edema; and mild and transient injection site pain [I].
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pharmaco-economic considerations |
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Topdefinition of anemiaanemia in patients with...indications for the use...comparison between ESAsrecommendations in relation to...cancer therapy outcomesafety and tolerabilitypharmaco-economic considerationsnotereferences |
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Use of ESAs profoundly increases health care costs [I] and the cost per quality-adjusted life-year (QALY) is estimated to be 208 000 Euros since there seems to be no survival benefit [II].
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note |
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Topdefinition of anemiaanemia in patients with...indications for the use...comparison between ESAsrecommendations in relation to...cancer therapy outcomesafety and tolerabilitypharmaco-economic considerationsnotereferences |
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Levels of evidence [I–IV] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the authors and the ESMO faculty.
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footnotes |
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Approved by the ESMO Guidelines Working Group: December 2006, last update July 2008. This publication supercedes the previously published version—Ann Oncol 2008; 19 (Suppl 2): ii113–ii115.
Conflict of interest: Prof. Schrijvers has reported that he is member of the Advisory Board of Johnson and Johnson; Dr Roila has reported no conflicts of interest.
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references |
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