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Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Apr 2012. | This topic last updated: Apr 10, 2012.

INTRODUCTION — Anemia is a common complication in patients with malignancy. Anemia can impair the patient's functional status, diminish physiologic reserve, and cause fatigue that can be disabling. (See "Cancer-related fatigue: Prevalence, screening and clinical assessment" and "Cancer-related fatigue: Treatment" and "Hematologic consequences of malignancy: Anemia and bleeding", section on 'Definitions'.)

In addition to causing symptoms, the presence of anemia has been linked to an adverse prognosis in several malignancies. This has been attributed in part to a poorer response to anticancer treatment, since ionizing radiation and some forms of chemotherapy are dependent upon adequate tissue oxygen levels for cytotoxicity. These observations have been used to provide an additional rationale for aggressively treating anemia in patients receiving cancer therapy.

Multiple factors can cause or contribute to anemia in patients with malignancy. (See "Hematologic consequences of malignancy: Anemia and bleeding".)

  • As can occur with other chronic inflammatory conditions, some cancer patients have an anemia that is a consequence of the disease and unrelated to treatment. This type of anemia is typically mild (ie, hemoglobin [HGB] level >10 g/dL), and the symptoms may be difficult to distinguish from those caused by the underlying malignancy. Occasionally, anemia may be more severe, impairing functional status, diminishing physiologic reserve, and reducing QOL. (See "Anemia of chronic disease (anemia of chronic inflammation)".)
  • Anemia is often exacerbated by myelosuppressive cancer treatment, particularly in patients who are undergoing intensive chemotherapy or combined modality treatment with both chemotherapy and radiation therapy (RT) [1-5].
  • In addition to direct effects of the malignancy or its treatment, other causes of anemia may coexist in these patients (eg, blood loss, hemolysis, deficiencies of iron, folate, or vitamin B12). These causes should be actively sought, and when present, treated appropriately. (See "Approach to the adult patient with anemia", section on 'Multiple causes of anemia'.)

The definitive therapy for cancer-related anemia is eradication of the underlying malignancy. However, in many cases, this is not possible and short-term red blood cell (RBC) support may be needed.

Erythropoiesis-stimulating agents (ESAs) were initially used to treat anemia in patients with chronic renal failure, including those on hemodialysis. (See "Erythropoietin for the anemia of chronic kidney disease among predialysis and peritoneal dialysis patients" and "Erythropoietin for the anemia of chronic kidney disease in hemodialysis patients".)

Subsequent trials indicated that ESAs were also effective in patients with cancer and cancer treatment-related anemia, but their use has become controversial because of data linking ESA use to an excess of thromboembolic events, inferior survival and worse cancer outcomes.

This topic review will focus primarily on the efficacy and risks associated with the erythropoiesis stimulating agents (ESAs) epoetin alfa and darbepoetin alfa in anemic patients with non-hematologic malignancies. The issues surrounding the use of ESAs for patients with hematologic malignancies such as myelodysplastic syndrome (MDS) are more complex and discussed separately. (See "Treatment of the complications of multiple myeloma", section on 'Anemia' and "Overview of the complications of chronic lymphocytic leukemia", section on 'Chemotherapy induced anemia' and "Prognosis and treatment of primary myelofibrosis" and "Management of the complications of the myelodysplastic syndromes", section on 'Erythropoiesis stimulating agents'.)

OVERVIEW OF TREATMENT OPTIONS FOR ANEMIA IN CANCER PATIENTS — Definitive therapy for cancer-related anemia is eradication of the underlying malignancy. However, in many cases, this is not possible. Successful treatment of the malignancy with combinations of surgery, chemotherapy, and/or radiation therapy (RT) may, in the long term, improve the HGB level. However, short-term red blood cell (RBC) support may be needed.

Transfusion — Red blood cell (RBC) transfusions are almost universally successful in raising HGB levels. Transfusions can often ameliorate the patient's symptoms rapidly and improve health-related QOL. Exceptions include patients unable to be transfused because of the presence of multiple alloantibodies and those who refuse transfusions based on religious beliefs. (See "The approach to the patient who refuses blood transfusion".)

The use of RBC transfusions to treat anemia is discussed in more detail separately. (See "Use of red blood cells for transfusion" and "Indications for red cell transfusion in the adult".)

ESAs: epoetin and darbepoetin — Clinical trials have established that epoetin and darbepoetin are effective in raising HGB levels and decreasing transfusion requirements in a substantial number of patients with chemotherapy-induced anemia. Both ESAs appear to be equivalent with regard to efficacy and safety [6,7]. (See 'ESAs: efficacy, side effects, and clinical use' below.)

However, use of these agents in patients with cancer has become controversial because of data linking ESA use to an excess of thromboembolic events, inferior survival (particularly when used in patients whose anemia is unrelated to chemotherapy) and worse cancer outcomes. While there is general agreement that ESAs are not indicated in anemic cancer patients who are not receiving chemotherapy (with the exception of lower-risk myelodysplastic syndromes and those patients with coexistent renal failure), whether ESAs should be avoided in patients who are receiving myelosuppressive chemotherapy with the intent of cure remains controversial. (See 'Effect on disease control and survival' below and 'Thromboembolic risk' below and "Erythropoietin for the anemia of chronic kidney disease among predialysis and peritoneal dialysis patients" and "Erythropoietin for the anemia of chronic kidney disease in hemodialysis patients".)

ESAs versus transfusion — For patients with symptomatic anemia induced by chemotherapy HGB levels can be raised with either ESAs or RBC transfusions. In addition to the issues raised above, many other factors influence the choice of one or the other of these approaches, including the following:

  • Clinical responses to transfusion occur almost immediately, while meaningful responses to ESAs may take weeks to months. Patients with advanced malignancy may have a relatively short life expectancy, and prompt relief of symptoms is important. In these circumstances, transfusion may be particularly appropriate in severely symptomatic patients.
  • Transfusion is now associated with a lower risk of infection (eg, human immunodeficiency virus, hepatitis C) because of improvements in donor screening, compared to the risk when the ESAs were originally developed (table 1). (See "Laboratory testing of donated blood".)
  • Each unit of transfused RBCs contains 200 to 250 mg of iron. Since the body has no physiologic mechanism to induce iron loss, a patient requiring 25 units of packed RBC will have accumulated five to six grams of excess body iron and may show signs of iron overload. (See "Iron overload syndromes other than hereditary hemochromatosis", section on 'Transfusional iron overload'.)
  • ESAs have particular advantages for patients who are averse to RBC transfusions or who do not have ready access to an appropriate facility for transfusion. (See "The approach to the patient who refuses blood transfusion", section on 'Alternative courses of action'.)
  • The relative costs of ESAs versus transfusions [8], along with insurance coverage and blood availability issues [9], may become important factors in determining which approach will be used.

The relative risks and benefits of ESAs versus RBC transfusion in patients undergoing cancer chemotherapy are outlined in the table (table 2).

Androgens — Androgen use (eg, testosterone, fluoxymesterone) for the treatment of anemia has declined markedly since ESAs became available; androgens are now rarely used to treat cancer-related anemia. Side effects which have limited the application of androgens include acne, virilization in women, priapism in men, peliosis hepatis, liver enzyme abnormalities, an elevated risk of hepatocellular carcinoma, and stimulation of the growth of prostate cancer. (See "Non-iron pharmacologic adjuvants to erythropoiesis stimulating agent therapy in dialysis patients", section on 'Androgens'.)

ESAS: EFFICACY, SIDE EFFECTS, AND CLINICAL USE — Randomized clinical trials have consistently demonstrated that use of ESAs raises HGB levels and reduces the frequency of red blood cell transfusions in anemic cancer patients who are receiving chemotherapy [10,11]. With few exceptions [12,13], most of these trials have not shown that ESAs prolong survival, or improve quality of life (QOL) or patient-reported outcomes (PRO), including fatigue. Furthermore, these trials have also raised questions about serious side effects, including an increased incidence of thromboembolic events and the possibility of adverse cancer outcomes.

Meta-analyses — Multiple meta-analyses have addressed issues of benefit and adverse effects from ESAs [10,14-19]. Key findings have included the following:

  • ESAs significantly reduced the use of RBC transfusions (relative risk [RR] 0.64, 95% CI 0.60 to 0.68) in one analysis [10]. Patients treated with an ESA received one unit less of red blood cells on average than the control group, and the number needed to treat (NNT) to completely spare one patient from red cell transfusions was about six patients, when only higher quality studies were considered.
  • The risk of venous thromboembolism (VTE) was increased in patients receiving ESAs (7.5 versus 4.9 percent in patients not receiving ESAs, relative risk 1.57 [95% CI 1.31 to 1.87]) [15]. As with the earlier meta-analysis cited above, this report did not address whether higher target HGB levels were associated with a greater risk of VTE events. (See 'Threshold and target hemoglobin levels' below.)

    Additional information on thromboembolic risk is provided below. (See 'Thromboembolic risk' below.)

    The impact of ESAs on survival was addressed in an individual patient data (IPD) meta-analysis of 13,933 cancer patients from 53 trials [19]. ESA use significantly increased on-study mortality by 17 percent and overall mortality by 6 percent (95% CI 0 to 12 percent). However, when the analysis was restricted to patients receiving chemotherapy, there was only a trend toward higher on-study (10 percent) and overall mortality (4 percent, 95% CI -3 to 11 percent), neither of which was statistically significant. There was no evidence of a different impact of ESAs in any subpopulation tested (including the type of malignancy). Additional information on the effect on disease control and survival is provided below. (See 'Effect on disease control and survival' below.)

    These findings are in keeping with published guidelines from the American Society of Clinical Oncology and American Society of Hematology, which state that patients who are not receiving chemotherapy should not receive ESAs. (See 'ASH/ASCO guidelines' below and 'Use in patients not receiving chemotherapy' below.)

Thromboembolic risk — As noted above, randomized trials and systematic reviews demonstrate a significantly increased risk of thromboembolism in patients receiving ESAs.

In two separate meta-analyses, the relative risk (RR) for VTE in patients who received versus did not receive an ESA was approximately 1.57 and 1.69, respectively [15,20]. The pooled event rates of thromboembolic events were 7 (range 1 to 30 percent) versus 4 (range 0 to 23) percent for epoetin and controls, respectively, whereas the rates were 5 versus 3 percent in one published darbepoetin trial [20].

Specific risk factors for thromboembolism have not been defined in these trials, and clinicians must use caution and clinical judgment when considering the use of one of these agents. Established general risk factors for thromboembolism include a history of thromboses, surgery, and prolonged periods of immobilization or limited activity. Some disease and treatment regimens have also been associated with a higher risk of thromboembolic events (eg, multiple myeloma treated with thalidomide or lenalidomide and doxorubicin or corticosteroids). (See "Drug-induced thrombosis and vascular disease in patients with malignancy".)

Effect on disease control and survival — The presence of anemia has been linked to shortened survival in a variety of solid tumors [21-25], an effect attributed, in part, to a poorer response to anticancer treatments dependent upon oxygen delivery for their cytotoxicity (eg, ionizing radiation and some forms of chemotherapy). It was hypothesized that normalizing HGB levels through the use of ESAs might reduce the degree of tumor hypoxia, thus improving the response to chemotherapy and/or RT and prolonging disease-free and overall survival.

This hypothesis was generally supported by observational studies, which suggested that raising HGB levels to >12 or >14.5 g/dL improved survival in non-small cell lung cancer and head and neck cancer, respectively [26,27]. (See "Methods to overcome radiation resistance in head and neck cancer".)

However, several trials using this approach in various solid tumors have raised concerns about possible increased mortality with ESAs:

  • Head and neck cancer — The use of ESAs to raise HGB levels during treatment in patients with head and neck cancer has been directly evaluated in four randomized, placebo-controlled trials. The goal was to maintain HGB at levels or above 12 to 14 g/dL in women and 15 to 16 g/dL in men, both before and during curative radiotherapy for stage III or IV head and neck cancer. These target HGB levels are substantially higher than those recommended by professional society guidelines or approved by the United States FDA [28-31]. (See 'Threshold and target hemoglobin levels' below.)

    Three trials [32-34] reported inferior locoregional control rates and/or worse overall survival in the groups treated with epoetin compared to placebo, while the fourth reported no adverse effects on survival or tumor outcomes [35]. These trials are discussed in more detail elsewhere. (See "Methods to overcome radiation resistance in head and neck cancer".)
  • Breast cancer — Three trials have addressed the use of ESAs as a component of breast cancer treatment. The two larger trials, including one conducted in an adjuvant setting, suggested that the use of ESAs was associated with significantly higher mortality [36,37], while a third trial did not [38].

    To illustrate, the PREPARE trial used darbepoetin to keep or raise HGB levels above 12 g/dL in women with early stage breast cancer receiving either standard or dose-intense neoadjuvant chemotherapy. The group receiving darbepoetin had inferior three-year disease-free (74 versus 80 percent) and overall survival (88 versus 92 percent); neither difference was statistically significant [37].

    The use of epoetin and darbepoetin in patients undergoing adjuvant chemotherapy for breast cancer is discussed elsewhere. (See "Side effects of adjuvant chemotherapy for early stage breast cancer", section on 'Fatigue and anemia'.)
  • Cervical cancer — The benefit of using ESAs during chemoradiotherapy was studied in Gynecologic Oncology Group (GOG) trial 0191, in which women with locally advanced cervical cancer undergoing RT with weekly cisplatin were randomly assigned to HGB maintenance at 10 g/dL versus aggressive intervention to raise HGB levels to 12 to 13 g/dL (through transfusion and epoetin) [39]. The study was closed prematurely because of an increase in the number of thromboembolic events in the epoetin/transfusion arm (11 of 57 versus 4 of 52 controls). Although there were no deaths from thromboembolic events, the three-year progression-free survival (58 versus 66 percent) and overall survival (60 versus 74 percent) were both inferior in the epoetin group. (See "Invasive cervical cancer: Management of stages IB2, bulky IIA2, and locally advanced disease", section on 'Impact of anemia and its correction during treatment'.)
  • Small cell lung cancer — In contrast to these results, the use of ESAs did not adversely affect survival in a double-blind trial enrolling 600 patients with small cell lung cancer. Patients were randomly assigned to receive darbepoetin (300 microg once weekly for four weeks, then once every three weeks) or placebo [40]. Darbepoetin or placebo was withheld if the HGB was ≥14 g/dL and reinitiated if the HGB fell to <13 g/dL. All patients were previously untreated and were receiving chemotherapy with either cisplatin plus etoposide or carboplatin plus etoposide. For patients treated with darbepoetin there was no significant difference in survival compared to placebo (median overall survival 40 weeks on both arms, hazard ratio [HR] 0.93 for darbepoetin, 95% CI 0.78 to 1.11). There was a significantly lower risk of requiring transfusion during treatment in those receiving darbepoetin (17 versus 39 percent with placebo, HR 0.40, 95% CI 0.29 to 0.55).

Target HGB levels were supraphysiologic in all of these trials. The risks of shortened survival and inferior tumor control have neither been excluded nor confirmed when ESAs are dosed to a target HGB value <12 g/dL.

The results of meta-analyses examining the survival impact of ESA use are described above. In the most influential of these, when the analysis was restricted to patients receiving chemotherapy, there was only a nonstatistically significant trend toward higher on study (10 percent) and overall mortality (4 percent, 95% CI -3 to 11 percent) [17]. (See 'Meta-analyses' above.)

Potential mechanisms — The reasons for poorer outcomes in cancer patients receiving ESA treatment are unclear. One potential mechanism by which ESA therapy might result in negative outcomes is through promotion of thromboembolic events [41]. However, in the trials described above, the incidence of thromboembolic and other adverse events was only minimally elevated and insufficient to explain the observed differences in survival [32,42]. In addition, the events would not explain the reduction in survival related to enhanced tumor progression in some of the studies. (See 'Thromboembolic risk' above.)

Another proposed potential mechanism to explain more rapid disease progression and shortened survival following treatment with ESAs is the presence of erythropoietin receptors (EPO-Rs) on the surface of tumor cells, which may promote angiogenesis, tumor growth, tumor cell survival, and/or resistance to treatment [43-48]. A possible stimulatory effect of ESAs on tumor growth has been suggested [34], particularly since, in one of the trials, the worse outcomes were limited to epoetin-treated patients whose tumors expressed the erythropoietin receptor (EPO-R) [49].

However, other laboratory and clinical results raise questions about the significance of these observations [41]:

  • There is a lack of compelling evidence for functional EPO-R expression in tumor cells, and for pharmacologically relevant ESA-mediated EPO-R signaling in tumor cell lines and tissues [50-52].
  • Several studies suggest that all of the commercially available antibodies used to define the presence of EPO-R prior to 2010 also stain non-specific peptides such as heat shock proteins [53,54]. This lack of specificity for the antibodies used to detect EPO-R has implications for interpretation of much of the published literature evaluating EPO-R expression on tumor cells. A newer antibody, A82, introduced in 2010, may be more specific for EPO-R [55].

For these reasons, the clinical significance of tumor cell expression of EPO-R in patients receiving ESAs remains uncertain and this issue requires further evaluation [41,46].

Finally, there is some evidence that indirect, non-EPO-R-mediated effects of ESAs may contribute to mechanisms of tumor regulation (including endothelial cell and platelet activation and resulting neovasculogenesis) [56-61]. However, the role that neovascularization plays in tumor progression during ESA therapy remains to be determined [41].

Use in patients treated with curative intent: recommendations of EMA, FDA, ASCO/ASH, and NCCN — Preliminary results from many of the trials described above led the European Medicines Agency to recommend in June 2008 that blood transfusions are preferred over ESAs in cancer patients who have chemotherapy-related anemia and a "reasonably long life expectancy" [62].

Review of the same data also led the US Food and Drug Administration (FDA) to mandate a label change for ESAs, stating that their use was not indicated in patients receiving myelosuppressive chemotherapy when the anticipated outcome was cure [63]. However, they did not restrict this recommendation to patients being treated for breast, head and neck, or cervical cancer. (See 'United States FDA' below.)

Furthermore, to ensure that patients receiving ESAs in the setting of cancer are informed about the risks before they begin treatment, regardless of the intent of therapy, the US FDA has mandated a risk evaluation and mitigation strategy (REMS) risk management program, termed APPRISE (Assisting Provides and Cancer Patients with Risk Information for the Safe Use of ESAs) for use of ESAs in patients with cancer [64]. (See 'APPRISE: the US FDA Risk Evaluation and Mitigation Strategy program' below.)

Despite these mandates, whether use of ESAs should be avoided in patients receiving myelosuppressive chemotherapy with the intent of cure remains controversial, particularly in view of the 2009 pooled analysis that failed to find an adverse impact of darbepoetin on death or disease progression in patients with chemotherapy induced anemia [17], and the fact that no study has evaluated outcomes of ESA therapy by subgroups defined by chemotherapy intent. Furthermore, determination of the goal of treatment requires clinical judgment of an individual patient’s circumstances. (See 'Summary: patient selection for ESAs' below and 'Meta-analyses' above.)

While the most recent NCCN guidelines for cancer and chemotherapy-related anemia state that ESAs are not indicated in patients for whom the cancer treatment goal is cure [30], updated guidelines for the use of ESAs from the American Society of Hematology/American Society of Clinical Oncology (ASH/ASCO) do not differentiate between patients receiving potentially curative cancer therapy and those undergoing palliative cancer treatment [6,7]. (See 'Recommendations from expert groups' below.)

Threshold and target hemoglobin levels — An excessively high hemoglobin level, either prior to treatment with an ESA or as an ESA treatment target, may have contributed to adverse outcomes in the above clinical trials, either by increasing the incidence of thromboembolic events or by accelerating tumor growth [32,36,65-67]. In many of these trials, HGB target levels were in the range of 13 to 15 g/dL.

When ESAs are used in patients with end-stage renal disease (ESRD), higher target HGB levels increase the incidence of thrombotic and vascular events. Studies evaluating target HGB levels in patients with ESRD are discussed separately. (See "Anemia of chronic kidney disease: Target hemoglobin/hematocrit for patients treated with erythropoietic agents", section on 'Target levels'.)

The data in anemic cancer patients are less extensive, and the relationship between baseline and target HGB levels and the incidence of thrombotic and vascular events remains uncertain [68,69]:

  • An association between target HGB and VTE was suggested in an open label study of epoetin-alfa conducted in patients receiving adjuvant chemotherapy for breast cancer, 77 of 1785 patients evaluable for safety were diagnosed with a clinically relevant thromboembolic event, 55 of whom had baseline HGB levels >12 g/dL [68].
  • In a meta-analysis of 12 randomized trials totaling 2297 cancer patients in which epoetin beta was compared to placebo (all but three involving chemotherapy), the overall risk for a thromboembolic event was significantly increased (HR 1.62; 95% CI 1.13 to 2.31) in patients receiving epoetin compared to placebo, while the risk of death was not significantly increased (HR 1.13; 95% CI 0.87 to 1.46) [69,70]. There was no increased risk for thromboembolic events or inferior survival when the HGB initiation level was >11 g/dL [69].
    However, when the analysis was restricted to the four studies with long-term follow up, there was an adverse effect on survival when epoetin was initiated at a baseline HGB >11 g/dL (HR 1.24; 95% CI 1.00 to 1.53), but not at lower levels.

    In the analysis based on maximum-achieved HGB level during treatment, there was no evidence for an increased risk of thromboembolic events or mortality when maximum HGB levels were >13 g/dL as compared to lower levels in the entire cohort of 12 trials [69]. Again, when the analysis was restricted to the four trials with long-term follow-up, there was a statistically significant, higher mortality rate in patients with a maximum HGB in the 10 to 13 g/dL range compared to patients with a maximum HGB <10 g/dL, but the mortality rate was not elevated in those patients with a maximal HGB of >13 g/dL.

    The results of this analysis need to be interpreted with caution because of methodologic limitations and potential confounders. As an example, for the subgroup of patients with a maximum achieved HGB ≥13 g/dL, the comparison was between those patients who were treated to beyond 13 g/dL with epoetin, and those who either achieved HGB ≥13 g/dL without treatment or who were enrolled with baseline HGB ≥13 g/dL. On the assumption that an increase in HGB independent of epoetin treatment is a good prognostic factor, these analyses would be biased in favor of the control group.

In its 2010 updated guidelines for use of ESAs in adult patients with cancer, the ASCO/ASH expert panel concluded that the use of ESAs to decrease transfusions is recommended for patients with chemotherapy induced anemia and a hemoglobin concentration that has decreased to <10 g/dL; the optimal level at which to initiate ESA therapy in patients with anemia and a HGB level between 10 and 12 g/dL cannot be determined from the available data [6,7]. Furthermore, given that an optimal target HGB could not be definitively determined from the available literature, the panel recommended that HGB should be increased to the lowest concentration needed to avoid transfusion, a level that may vary by patient and condition. (See 'Recommendations from expert groups' below.)

Use in patients not receiving chemotherapy — Off-label use of ESAs in cancer patients not receiving chemotherapy was frequent in the past [71]. However, results from large clinical trials suggest that ESAs are not beneficial in this setting, and may be harmful [67,72,73].

The largest was a double-blind phase III trial, in which 989 patients with nonmyeloid malignancy and anemia were randomly assigned to receive either darbepoetin (6.75 microg/kg every four weeks) or placebo for 16 weeks [72]. All patients had a HGB ≤11 g/dL and were not receiving chemotherapy. Treatment was withheld if the HGB level was >13 g/dL, and reinstated with a 25 percent dose reduction once the HGB was <12 g/dL.

Key findings included the following:

  • The study's primary endpoint, a reduction in the incidence of first RBC transfusion during weeks 5 to 17, was not reached following treatment with darbepoetin (19 versus 24 percent with placebo; p = 0.07).
  • There was a significant increase in mortality with darbepoetin during the study or long-term follow-up (median time to death 37 versus 47 weeks, HR 1.22, 95% CI 1.03 to 1.45).
  • Cardiovascular and thromboembolic adverse events were more frequent in the darbepoetin group (9.7 versus 7.7 percent).

Based upon these results, ESAs are NOT recommended for the treatment of anemia that is unrelated to chemotherapy in patients with malignancy. Use of ESAs in patients with lower-risk myelodysplastic syndromes to avoid transfusion is an exception to this recommendation [6,7]. (See 'United States FDA' below and 'ASH/ASCO guidelines' below and "Management of the complications of the myelodysplastic syndromes", section on 'Erythropoiesis stimulating agents'.)

Variability in and predictors of response to ESAs — Not all patients with chemotherapy-induced anemia benefit from use of an ESA. Up to 15 to 20 percent still require RBC transfusions, and only 50 to 70 percent have a HGB increment of ≥1 g/dL after 8 to 12 weeks of ESA therapy [73,74].

There are a number of other settings in which ESAs may not be effective, including:

  • A common cause of reduced responsiveness to ESAs is an impaired supply of iron to developing erythroid cells. Sufficient stores of bioavailable iron are required to achieve and maintain target HGB levels with ESAs. The concomitant use of parenteral iron may augment erythropoiesis by ensuring adequate delivery of iron to red cell precursors [75,76]. (See 'Iron monitoring and supplementation' below.)
  • With extensive malignant involvement of the bone marrow, there may be an insufficient number of erythropoietic elements to respond to the ESAs.
  • Although most patients with anemia due to cancer have a serum erythropoietin level that is inappropriately low for the degree of anemia [77], some cancer patients synthesize large amounts of endogenous erythropoietin in response to anemia (ie, >500 U/L). These patients are unlikely to respond to pharmacological doses of an ESA, although there are no data addressing this issue in patients receiving chemotherapy for solid tumors. Furthermore, a 2003 meta-analysis highlighted the lack of sensitivity or specificity of erythropoietin levels in selecting anemic cancer patients for ESA treatment [78]. (See 'Minimum requirements' below.) Patients with lower-risk myelodysplastic syndromes (MDS) may be an exception, as serum erythropoietin levels >500 U/L strongly predict lack of ESA response in the MDS setting [79].
  • In patients with anemia of chronic disease, the bone marrow may respond poorly to ESAs because of the presence of erythropoiesis-inhibiting cytokines (eg, TNF-alpha, IL-6) [80]. (See "Anemia of chronic disease (anemia of chronic inflammation)", section on 'Pathogenesis'.)
  • Cases of pure red cell aplasia due to anti-erythropoietin antibodies have been reported in patients treated with ESAs; ninety percent are in patients treated with Eprex, an epoetin alfa product used outside of the US. (See "Pure red cell aplasia due to anti-erythropoietin antibodies".)

The ASCO/ASH expert panel on use of ESAs in adult patients with cancer concluded that starting doses and dose modifications of ESAs after response or nonresponse should follow the US FDA-approved labeling guidelines (table 3), and that ESAs should be discontinued after eight weeks in nonresponders (ie, a <1 to 2 g/dL increase in HGB, or no diminution of transfusion requirements) [6,7]. (See 'Threshold and target hemoglobin levels' above and 'United States FDA' below.)

INDICATIONS FOR ESA THERAPY

Recommendations from expert groups

ASH/ASCO guidelines — Clinical practice guidelines for use of ESAs from the American Society of Hematology (ASH) and the American Society of Clinical Oncology (ASCO) were updated in 2010 [6,7]: (See 'Use in patients not receiving chemotherapy' above and "Management of the complications of the myelodysplastic syndromes", section on 'Erythropoiesis stimulating agents'.)

  • ESAs should NOT be used for patients with cancer and anemia not associated with chemotherapy. Use of ESAs in patients with lower-risk myelodysplastic syndromes to avoid transfusion is an exception to this recommendation.
  • Before any decision regarding use of ESAs is made, appropriate history, physical examination, and diagnostic tests are indicated to identify alternative causes of anemia aside from chemotherapy or the underlying malignancy (table 4).
  • Clinicians should carefully weigh the risks of thromboembolism in patients who are being considered for ESAs, particularly those with a heightened risk for thromboembolic events (eg, prior history of thromboses, surgery, prolonged periods of immobilization or limited activity, multiple myeloma treated with thalidomide or lenalidomide with doxorubicin or a corticosteroid).
  • Use of an ESA is recommended as a treatment option for patients with chemotherapy-associated anemia and a HGB level that has decreased below 10 g/dL. The optimal level at which to initiate ESA therapy in patients with anemia and HGB between 10 and 12 g/dL cannot be definitively determined from the available literature. Whether or not to initiate treatment with an ESA in such patients must be determined by clinical judgment, consideration of the risks and benefits of ESAs, and patient preferences.
  • An optimal target HGB cannot be definitively determined from the available literature. HGB levels should be increased to the lowest concentration needed to avoid transfusion, which may vary by patient and condition. Modification to reduce the ESA dose is appropriate when HGB reaches a level sufficient to avoid transfusion, or if the increase exceeds 1 g/dL in any two-week period. FDA-approved dose modification guidelines for ESA use in adults are presented in the table (table 3).

    The FDA-approved labeling also indicates that ESAs should be withheld if hemoglobin exceeds a level needed to avoid transfusion, but the label does not specify a specific hemoglobin value [81]. However, Centers for Medicare and Medicaid Services (CMS) restricts coverage of ESAs to patients with hemoglobin <10 g/dL and recommends further that therapy be discontinued once the hemoglobin is ≥10 g/dL. (See 'Regulatory and fiscal policies' below.)
  • Treatment with an ESA should be discontinued if there is no response to treatment within six to eight weeks, as evidenced by a rise in hemoglobin of less than 1 to 2 g/dL or no decrease in transfusion requirement.

NCCN guidelines — The most recent update of indications for ESAs in the management of cancer and chemotherapy-related anemia from the National Comprehensive Cancer Network (NCCN) can be summarized as follows [30]:

  • ESAs are not indicated for anemia unrelated to chemotherapy.
  • For anemia related to myelosuppressive chemotherapy, ESAs are not indicated if the cancer treatment goal is cure.
  • ESAs may be appropriate for anemic patients receiving palliative myelosuppressive chemotherapy who do not need immediate correction of anemia.
  • If considering the use of ESAs, evaluate for risk factors for thrombosis (eg, history of thromboembolism, heritable mutation, hypercoagulability, elevated prechemotherapy platelet count, hypertension, steroids, prolonged immobilization, recent surgery, certain therapies for multiple myeloma, hormonal agents).
  • FDA indications, dosing and dosing adjustments should be used as a guideline for use of ESAs. (See 'United States FDA' below.)

Regulatory and fiscal policies

United States FDA — In 2007 and 2008, the results of various trials led the US Food and Drug Administration (FDA) to clarify several aspects of the usage of ESAs in patients with cancer.

  • Patients not receiving chemotherapy — A black box safety alert from the FDA indicates that treating the anemia of cancer with an ESA in patients who are not receiving chemotherapy offers no benefit and may cause serious harm [82,83]. As noted above, ESAs increase mortality in cancer patients not receiving chemotherapy or radiation therapy when administered to a target hemoglobin of >12 g/dL. The updated 2010 guidelines from ASH and ASCO are consistent with FDA-approved labeling [6,7]. (See 'Use in patients not receiving chemotherapy' above.)
  • Patients receiving chemotherapy — As a result of safety information obtained from studies described above, black box warnings and labeling revisions for ESAs were issued by the FDA:

  • The lowest possible dose of ESAs should be used that will gradually increase the hemoglobin concentration to the lowest level sufficient to avoid blood transfusions.
  • ESAs increase the risk for death and for serious cardiovascular events when administered to a target hemoglobin >12 g/dL.
  • ESAs are not indicated in patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure [63].
  • Treatment with ESAs should not begin until the hemoglobin level drops to ≤10 g/dL. ESAs should be withheld if hemoglobin exceeds a level needed to avoid transfusion but a specific hemoglobin value was not specified. The 2008 mandate removed previously approved language from the package insert that allowed earlier initiation of ESAs, or treatment to a higher hemoglobin target, if the patient was unable to tolerate anemia due to a comorbid condition.

The safety and efficacy of ESA use within these confines was shown in a small randomized trial in which 186 patients receiving chemotherapy for lung or gynecological cancer who had a hemoglobin ≤10g/dL were randomly assigned to ESA use (epoetin beta 36,000 units or placebo weekly for 12 weeks) with weekly doses held for hemoglobin levels >10 g/dL and sustained levels >12 g/dL avoided [84]. Transfusions were significantly less common in the ESA group (5 versus 20 percent of patients), and the incidence of thromboembolic events was similar, as was the one-year overall survival. While this trial provides some reassurance that the risk of thromboembolic events is not increased when ESAs are dosed according to established guidelines, it was not adequately powered to detect the magnitude of differences in survival or disease progression that have been noted with ESAs in much larger trials.

European Medicines Agency — The same data that led the United States FDA to restrict approval for ESAs to palliative settings prompted the European Medicines Agency to recommend in June 2008 that blood transfusions are preferred over ESAs in cancer patients who have chemotherapy-related anemia and a "reasonably long life expectancy" (otherwise not defined) [62].

Medicare and Medicaid — CMS has restricted its coverage for ESAs in response to the controversies and safety concerns surrounding their use in patients with cancer. ESA use is currently limited to patients with chemotherapy-induced anemia whose hemoglobin level is <10 g/dL. Furthermore, treatment with ESAs is not reimbursed once the hemoglobin level has risen to ≥10 g/dL. CMS left coverage decisions about ESA use in MDS up to regional carriers, so there is geographic variability in reimbursement policies for ESA use in patients with MDS.

APPRISE: the US FDA Risk Evaluation and Mitigation Strategy program — To ensure that patients receiving ESAs in the setting of cancer (regardless of the intent of therapy) are informed about the risks before they begin treatment, the US FDA approved a Risk Evaluation and Mitigation Strategy (REMS) risk management program, termed APPRISE (Assisting Provides and Cancer Patients with Risk Information for the Safe Use of ESAs) on February 16, 2010 [64]. The program requires hospitals and physicians prescribing ESAs for cancer patients to register and maintain enrollment in the REMS program, complete training on the use of ESAs in patients with cancer, and provide written documentation of the discussion with patients as to the risks of stroke, heart attack, blood clots, heart failure, tumor progression, and death, prior to instituting ESAs. Enrollment began March 24, 2010.

In addition to providing the FDA-approved medication guide [85,86], ASCO/ASH guidelines suggest that health care providers discuss specific issues with patients considering ESA therapy, as outlined in the table (table 5) [6,7].

Summary: patient selection for ESAs

Minimum requirements — ESAs are indicated for the treatment of anemia in patients with non-myeloid malignancies when the anemia is due to chemotherapy. In keeping with guidelines from ASH/ASCO, cancer patients with anemia should meet all of the following criteria before being treated with an ESA:

  • Anemia should be symptomatic. Correctable causes of the anemia should be ruled out or treated, if present, prior to the use of an ESA.
  • The patient's anemia should be due to chemotherapy for a non-hematologic malignancy. Current clinical trial evidence, professional society guidelines, and product approval indications do NOT support the use of ESAs for the treatment of anemia due to malignancy in the absence of chemotherapy. Use of ESAs in patients with lower-risk myelodysplastic syndrome (MDS) to avoid transfusions is an exception to this recommendation. (See 'Use in patients not receiving chemotherapy' above and "Management of the complications of the myelodysplastic syndromes", section on 'Erythropoiesis stimulating agents'.)
  • ESAs should be instituted only if hemoglobin is ≤10 g/dL prior to therapy [63]. However, in keeping with ASH/ASCO guidelines, the decision to use an ESA for patients with highly symptomatic anemia and a hemoglobin level between 10 and 12 g/dL should be determined by clinical judgment, consideration of the risks and benefits of ESAs, and patient preferences [6,7]. (See 'Threshold and target hemoglobin levels' above.)
  • Clinicians should carefully weigh the risks of thromboembolism in patients who are being considered for ESAs, particularly those with a heightened risk for thromboembolic events (eg, prior history of thromboses, surgery, prolonged periods of immobilization or limited activity, multiple myeloma treated with thalidomide or lenalidomide with doxorubicin or a corticosteroid). The presence of uncontrolled hypertension is a contraindication to the use of ESAs.

Intent of therapy — FDA-mandated labeling changes for ESAs in July 2008 state that these drugs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure [63]. This decision was based upon data from randomized trials suggesting worse outcomes in patients with early, potentially curable breast, head and neck, and cervical cancer who received ESAs compared to those who did not receive ESAs. In all of the trials, target hemoglobin levels were ≥12 g/dL. Furthermore, a meta-analysis found no association between darbepoetin use and risk of death or disease progression in patients with chemotherapy-induced anemia, the approved indication for ESAs [87]. (See 'Effect on disease control and survival' above.)

In our view, whether ESAs should be avoided in patients receiving chemotherapy for a potentially curable cancer remains controversial. Updated guidelines for the use of ESAs from ASH/ASCO do not differentiate between patients receiving potentially curative cancer therapy and those undergoing palliative cancer treatment, stating that no study has evaluated outcomes of ESA therapy by subgroups defined by chemotherapy intent [6,7]. Given the general uncertainty about outcomes in patients being treated for cancer, whether individuals are receiving curative or palliative-intent therapy is not always a clear distinction.

The FDA mandate neither prohibits nor prevents health care providers from prescribing ESAs in this situation. We suggest that the benefits and risks of ESAs be discussed with patients who meet the minimum requirements as outlined above regardless of the intent of therapy. If after discussion with a well-informed patient, the risks are felt to be counterbalanced by the benefits of avoiding transfusion or reducing the chemotherapy dose(s), then use of ESAs is appropriate.

ESA FORMULATIONS AND DOSING

Epoetin alfa — When epoetin alfa was initially approved for patients with chemotherapy-associated anemia, a starting dose of 100 to 150 units/kg administered subcutaneously (SC) was recommended three times weekly along with supplemental oral iron. Responders were expected to show an increase in the reticulocyte count within one week and a rise in the hemoglobin concentration of at least 0.5 g/dL by two to four weeks [88,89].

However, a subsequent meta-analysis of data from four randomized trials in 604 patients with non-myeloid malignancies concluded that up to 46 percent of those without a rise in hemoglobin by two to four weeks ultimately respond to ESA therapy [78]. Accordingly, most patients are treated for 8 to 12 weeks before treatment is considered a failure.

The FDA-approved starting dose for epoetin is 150 U/kg three times weekly or 40,000 U weekly (table 3). When a weekly single dose schedule was employed in anemic patients, results were similar to three times weekly administration, with an increase in mean hemoglobin concentration, a reduction in transfusion requirement, and an improvement in quality of life measures for patients receiving chemotherapy [90] or chemoradiotherapy [91].

Less frequent administration of higher doses of epoetin is similarly effective but more convenient. Alternative schedules include:

  • Every two weeks — In a trial of 298 anemic patients with non-myeloid malignancies undergoing chemotherapy, 80,000 units of epoetin given SC once every two weeks demonstrated similar hemoglobin increases, transfusion rates, and safety outcomes compared to patients treated with 40,000 units once every week [92].
  • Every three weeks — Another study randomly assigned 365 patients to receive three weekly doses of 40,000 units of epoetin, and then either 120,000 units of epoetin every three weeks or to continue 40,000 units of epoetin weekly [74]. This study found no difference in transfusion endpoints or adverse events including thromboembolism, but observed a lower end-of-study hemoglobin in the treatment arm receiving 120,000 units every three weeks.

If hemoglobin levels have not increased by six to eight weeks in the setting of adequate iron stores, the schedule can be intensified or the dose raised (table 3). FDA-approved labeling guidelines suggest not continuing ESAs beyond eight weeks in the absence of a response (a <1 to 2 g/dL increase in HGB or no diminution in transfusion requirements). (See 'Iron monitoring and supplementation' below.)

Darbepoetin — Darbepoetin is indicated for the treatment of chemotherapy-induced anemia in non-myeloid malignancies. Darbepoetin is effective when given as infrequently as once every three to four weeks [93-96].

Darbepoetin is a biochemically distinct form of erythropoietin that is produced in Chinese hamster ovary cells using recombinant DNA technology. Darbepoetin has a longer in vivo half-life than erythropoietin and a modestly lower EPO-R binding activity (figure 1). These properties are due to an altered glycosylation pattern compared to native erythropoietin, while the protein sequence of darbepoetin is the same as that of epoetin. (See "Darbepoetin alfa for the management of anemia in chronic kidney disease".)

The activity of darbepoetin in patients with chemotherapy-induced anemia was illustrated by a double-blind trial in 314 anemic patients (hemoglobin ≤11.0 g/dL) receiving chemotherapy for lung cancer [97]. Patients were randomly assigned to weekly darbepoetin (initial dose 2.25 microg/kg SC) or placebo. Key findings included the following:

  • Fewer patients treated with darbepoetin required transfusion during the first 28 days of treatment (27 versus 52 percent with placebo, mean difference 25 percent, 95 % CI: 14 to 36 percent).
  • The rate of hematopoietic response (defined by an increase in hemoglobin level ≥2.0 g/dL or a hemoglobin ≥12.0 g/dL) was higher in patients treated with darbepoetin (66 versus 24 percent with placebo, mean difference 42 percent, 95% CI: 31 to 53 percent).
  • More patients showed a ≥25 percent improvement in a quality of life measurement, the FACT-fatigue score (32 versus 19 percent, mean difference 13 percent, 95% CI: 2 to 23 percent) (table 6).

The FDA-approved starting dose for darbepoetin is 2.25 microgram/kg weekly or 500 micrograms every three weeks [95], subcutaneously (table 3). Other guidelines for the use of darbepoetin in patients with chemotherapy-induced anemia recommend an initial dose of 200 micrograms every two weeks, a dose and schedule that is included in NCCN guidelines [30]. Three randomized trials for the treatment of chemotherapy-induced anemia in patients with breast, lung, or gynecologic malignancy found this dose and schedule for darbepoetin achieved comparable clinical and hematologic outcomes compared to epoetin given at a dose of 40,000 units once per week [73,98,99].

As with epoetin, if there is no increase in the hemoglobin concentration after four weeks in the setting of adequate iron stores, the dose can be increased (table 3) [6,7]. Guidelines from ASCO/ASH recommend not continuing ESAs beyond eight weeks in the absence of a response (a <1 to 2 g/dL increase in HGB or no diminution in transfusion requirements) [6,7].

Iron monitoring and supplementation — As noted above, the availability of iron can limit the hemoglobin response following treatment with ESAs in patients with cancer-related anemia as well as in those with renal failure. (See 'Variability in and predictors of response to ESAs' above.)

Iron deficiency may develop quickly in treated patients who have borderline iron levels at the onset of therapy. Furthermore, even normal subjects and cancer patients with adequate iron stores may have difficulty adequately mobilizing iron to respond to erythropoietin therapy, a phenomenon which has been termed "functional iron deficiency" or iron-restricted erythropoiesis [100-105]. Anemic cancer patients treated with ESAs may have additional difficulties with iron mobilization, due to cytokine-mediated inhibition of the transfer of iron from macrophages to the developing erythron. (See "Anemia of chronic disease (anemia of chronic inflammation)", section on 'Pathogenesis'.)

The most widely available markers reflecting functional iron status of the body are transferrin saturation (serum iron divided by the total iron binding capacity [TIBC, transferrin]) and serum ferritin, although transferrin saturation is strongly influenced by daily variations in serum iron, and ferritin is an acute phase protein that may be increased during acute inflammation [104].

Nevertheless, these are the best markers of iron stores that are currently available, and serum iron, TIBC, and serum ferritin should be assayed at baseline in all anemic patients who are being considered for an ESA and in patients who fail to respond to ESA therapy within six to eight weeks. Iron should be given during ESA therapy, if necessary, in order to maintain a transferrin saturation of ≥20 percent and a serum ferritin level of ≥100 ng/mL.

Oral versus parenteral — Although some cancer patients will respond to the use of oral iron, such replacement has not been demonstrated to be consistently effective in patients receiving ESAs [75,76]. Parenteral iron, although less convenient for both the patient and staff, may augment erythropoiesis by providing iron in a more rapidly bioavailable form. (See "Iron balance in predialysis, peritoneal dialysis, and home hemodialysis patients" and "Use of iron preparations in hemodialysis patients".)

Multiple randomized trials in patients with chemotherapy-induced anemia have shown that parenteral iron supplementation (compared to either oral iron or no iron) increases the proportion of patients achieving an adequate hemoglobin response to ESA therapy and decreases the percentage of patients requiring transfusion [75,76,102,106,107]. This benefit has been seen both in iron-deficient and iron-replete patients. However, the benefit of parenteral as compared to oral iron has been called into question by the following results:

Two trials, including the largest randomized trial to date of ESA with or without parenteral iron conducted in 502 patients receiving chemotherapy who had a hemoglobin <11 g/dL, failed to show any benefit with the intravenous iron preparation compared to oral iron [108,109] or oral placebo [108].

A meta-analysis of eight trials comparing parenteral iron versus no iron or oral iron in anemic chemotherapy patients receiving ESAs (including the two negative trials cited above) concluded that the use of parenteral iron significantly reduced the risk of transfusion compared to no iron (relative risk 0.77, 95% CI 0.62-0.97), but the difference was not statistically significant when parenteral iron was compared to oral iron (RR 0.68, 95% CI 0.44-1.05) [110].

Widespread adoption of parenteral iron in patients receiving ESAs has been slow. In the past, anaphylactic reactions have been a major problem for IV iron administration, particularly with high-molecular weight iron dextran preparations (eg, ImFeron, which is no longer available, and DexFerrum, which is available). This problem has been reduced but not eliminated with the introduction of ferric gluconate (Ferrlecit), and iron sucrose (Venofer), and perhaps to a lesser extent, low molecular weight iron dextran (InFed). There appears to be little difference among these agents in terms of efficacy, although low molecular weight iron dextran is less costly.

Another issue is that in the United States, Medicare rules do not allow the administration of an ESA and parenteral iron on the same day.

NCCN guidelines recommend use of low molecular weight iron dextran (INfed) for the treatment of iron deficiency in patients intolerant or unresponsive to oral iron therapy and for cancer patients who are receiving ESAs [30]. However, in our view, this recommendation is surprising in view of the data on the better safety profile of Ferrlecit (ferric gluconate) and Venofer (iron sucrose). Furthermore, the newest preparation, ferumoxytol, allows for the infusion of 510 mg of IV iron as a single push infusion, in contrast to the limit of 125 mg for Ferrlecit and Venofer. The use of these agents is discussed separately. (See "Treatment of anemia due to iron deficiency", section on 'Intravenous iron'.)

Even with the availability of safer parenteral agents, whether all patients receiving ESAs require IV iron remains controversial, and clinical practice varies. Randomized trials suggest that 50 to 70 percent of patients will respond to ESAs alone or with the addition of oral iron. Given this fact, some clinicians reserve IV iron for patients who fail to respond to an ESA within five to six weeks. On the other hand, particularly in patients with marginal or low iron stores, use of IV iron could be considered a faster way to ensure adequate iron stores than oral iron, and this might lead to the lowest possible dose of an ESA. NCCN guidelines suggest IV iron in this setting, as long as active infection is excluded [30].

Updated guidelines from the ASH/ASCO expert panel state that the evidence is inadequate to consider IV iron as the standard of care in patients with chemotherapy-associated anemia [6,7]. They cite the heterogeneity across the trials in patient population, use of concomitant chemotherapy, ESA and iron formulations and schedules, control groups, and reported primary outcomes, the lack of standardization of transfusion use, the lack of blinding, and imbalances between the experimental and control groups (eg, more women with breast and gynecologic cancers), which could have led to greater degrees of iron deficiency in the groups receiving IV iron.

In our view, the observed increase in erythropoiesis seen when using ESAs in combination with parenteral iron needs to be balanced against the increased cost, need for a several hour visit to an infusion center, small risk of an adverse reaction to the parenteral iron preparation and the very small potential risk of aggravating total body iron overload. Other potential long-term biologic effects of iron overload remain largely undefined, but concerns for promotion of tumor growth, enhanced oxidative stress, and exacerbation of infection have been voiced [104].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS — Anemia in cancer patients may be due to the malignancy itself, myelosuppressive chemotherapy or radiation therapy, or any of the other causes of anemia that affect patients without cancer. (See "Hematologic consequences of malignancy: Anemia and bleeding".)

In the patient with cancer and chemotherapy-related anemia, erythropoiesis-stimulating agents (ESAs) may be used to reduce the need for red blood cell (RBC) transfusions. There is no clear evidence that these agents relieve the symptoms of anemia or improve QOL. Transfusion is a reasonable alternative, particularly if a rapid increase in hemoglobin (HGB) is needed. (See 'ESAs: efficacy, side effects, and clinical use' above and 'ESAs versus transfusion' above.)

The use of ESAs has been associated with an increased incidence of thromboembolic events and shortened survival, particularly when used in patients whose anemia is not due to myelosuppressive chemotherapy. Furthermore, randomized trials conducted in patients with potentially curable breast, head and neck, and cervical cancer raise the possibility that the use of ESAs might compromise tumor control and survival. In all of these trials, the target HGB level was >12 g/dL. (See 'Thromboembolic risk' above and 'Effect on disease control and survival' above.)

The following recommendations are for the use of ESAs in adult patients with non-hematologic malignancy.

Indications

  • Cancer patients who are being considered for treatment with ESAs should meet all of the following criteria (see 'Minimum requirements' above):

  • For patients with chemotherapy-induced anemia who meet all of these criteria, clinicians should discuss potential harms (thromboembolism, shorter survival) and benefits (decreased transfusions) of ESAs and compare them with potential harms (serious infection, immune-mediated adverse reactions) and benefits (rapid Hgb improvement) of RBC transfusions (table 2). In addition to providing patients with the FDA-approved medication guide [85,86], ASCO/ASH guidelines suggest that the clinician discuss a number of specific issues before prescribing ESAs (table 5).

    In general, we suggest the use of ESAs rather than transfusion for patients who meet all of the above criteria, and who do not have a heightened risk for thromboembolic events (eg, prior history of thromboses, surgery, prolonged periods of immobilization or limited activity, multiple myeloma treated with thalidomide or lenalidomide with doxorubicin or a corticosteroid) (Grade 2B).

    RBC transfusion is an appropriate alternative for patients whose clinical condition indicates the need for immediate correction of the hemoglobin level, for those in whom reducing the frequency of transfusion is not an important consideration, and in patients who have established general risk factors for thromboembolic events. (See 'Summary: patient selection for ESAs' above and "Use of red blood cells for transfusion" and "Indications for red cell transfusion in the adult".)
  • The decision to use an ESA for patients with highly symptomatic anemia and a hemoglobin level between 10 and 12 g/dL should be determined by clinical judgment, consideration of the risks and benefits of ESAs, and patient preferences [6,7]. (See 'Summary: patient selection for ESAs' above.)
  • Whether the use of ESAs should be restricted to patients receiving palliative rather than potentially curative chemotherapy is controversial. FDA-approved labeling states that ESAs are not indicated in patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure [63].

    However, updated guidelines for the use of ESAs from ASH/ASCO do not differentiate between patients receiving potentially curative cancer therapy and those undergoing palliative cancer treatment, stating that no study has evaluated outcomes of ESA therapy by subgroups defined by chemotherapy intent [6,7]. Furthermore, determination of the goal of treatment requires clinical judgment in many cases.

    We follow the ASCO/ASH guidelines and suggest that patients undergoing myelosuppressive chemotherapy for a potentially curative cancer be counseled as to the risks and benefits of ESA use versus RBC transfusion or chemotherapy dose reduction (table 2). The wording of the FDA-mandated labeling neither prohibits nor prevents health care providers from prescribing an ESA to patients being treated with curative intent if, after discussion with a well-informed patient, the risks of therapy with an ESA are felt to be outweighed by the benefits of avoiding red cell transfusion. Patients must be informed that such use of an ESA may not be reimbursed.
  • For patients with anemia due to a solid tumor or non-myeloid hematologic malignancy who are NOT receiving chemotherapy, we recommend NOT using an ESA to treat anemia (Grade 1B). The use of ESAs for patients with lower-risk myelodysplastic syndrome to avoid transfusions is one exception to this recommendation. (See 'Use in patients not receiving chemotherapy' above and 'Regulatory and fiscal policies' above and "Management of the complications of the myelodysplastic syndromes", section on 'Erythropoiesis stimulating agents'.)
  • ESAs should be used cautiously in patients with a high risk for thromboembolism, especially in the setting of malignancies that are associated with an elevated risk for thromboembolic complications (eg, multiple myeloma, treated with thalidomide and lenalidomide with either doxorubicin or corticosteroids). (See 'ESAs: efficacy, side effects, and clinical use' above and "Hypercoagulable disorders associated with malignancy".)

Choice of agent, dose titration, and supplemental iron

  • The ESAs epoetin and darbepoetin appear to be similarly effective. Darbepoetin may be more convenient, based upon a lower frequency of administration. (See 'ESA formulations and dosing' above.)
  • Starting doses and dose modifications after response or nonresponse should follow US FDA-approved labeling guidelines (table 3):

  • The approved starting dose of epoetin is 150 U/kg three times weekly or 40,000 U weekly, subcutaneously; the approved starting dose for darbepoetin is 2.25 microgram/kg weekly or 500 micrograms every three weeks, subcutaneously.
  • The dose should be adjusted in each patient to maintain the lowest hemoglobin level sufficient to avoid red cell transfusions; dose modification guidelines are presented in the table (table 3).
  • Updated guidelines from ASCO/ASH state that an optimal target HGB concentration cannot be definitively determined based on the available data. Modification to reduce the ESA dose is appropriate when the HGB reaches a level sufficient to avoid transfusion, or the increase exceeds 1 g/dL in any two week period. (See 'Threshold and target hemoglobin levels' above and 'Regulatory and fiscal policies' above.)

    In keeping with ASCO/ASH guidelines, we suggest discontinuing the ESA after eight weeks if the HGB has not increased by more than 1 to 2 g/dL or there is no diminution in the need for RBC transfusion [6,7].

  • For all patients treated with ESAs, we recommend that supplemental iron be given to maintain a transferrin saturation ≥20 percent and a serum ferritin ≥100 ng/mL (Grade 1B). Parenteral rather than oral iron might be considered for this purpose, but data are conflicting and inconclusive. IV iron might be preferred during ESA therapy in three settings: patients who have not had an adequate response to oral iron within five to six weeks, those who have demonstrated low or marginal iron levels, and those who cannot tolerate or refuse to take oral iron. (See 'Iron monitoring and supplementation' above and "Anemia of chronic disease (anemia of chronic inflammation)", section on 'Pathogenesis'.)

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