Review

Nature Clinical Practice Oncology (2006) 3, 152-164
doi:10.1038/ncponc0451  
Received 22 August 2005 | Accepted 15 January 2006

Cancer-related anemia and recombinant human erythropoietin—an updated overview

Julia Bohlius, Olaf Weingart, Sven Trelle and Andreas Engert*  About the authors

Correspondence *Department I of Internal Medicine, University Hospital of Cologne, Kerpener Strasse 62, D-50924 Cologne, Germany

Email a.engert@uni-koeln.de

Summary

For cancer patients, anemia can be a debilitating problem that negatively influences their overall quality of life and worsens their prognosis. The condition is caused either by the cancer itself or by cytotoxic treatment. Anemia is the primary indication for transfusion of red blood cells, but the development of recombinant human erythropoietins (epoetins) provides an alternative to red blood cell transfusions. Treatment with epoetins has been shown to reduce transfusion rates and increase hemoglobin response. There is some evidence that epoetins improve quality of life. It remains unclear, however, whether erythropoietin affects tumor growth and survival, and this area requires further investigation. Data from clinical trials suggest that erythropoietin increases the risk of thromboembolic complications. In the management of anemic patients, physicians should follow closely the dosing recommendations in products' package inserts or the ASCO/American Society of Hematology guidelines. Treatment of patients beyond the correction of anemia, however, has to be regarded as experimental and is potentially harmful, so should only be conducted in clinical trials.

Review criteria

Data for this review were obtained by searching the MEDLINE and EMBASE databases for articles using combinatorial search terms that included "erythropoietin", "epoetin alfa", "epoetin beta", and "darbepoetin alfa", as well as "recombinant", "myelodysplasia" and "neoplasms". In addition, conference proceedings from ASCO, ASH and ESMO were reviewed, and the largest studies from this search together with reference lists from other systematic reviews and guidelines were assessed. The abstracts of retrieved citations were reviewed and prioritized by study size and relative clinical and preclinical data. Full articles were obtained and references checked for additional material when appropriate.

Keywords:

anemia, cancer, darbepoetin, erythropoietin, thromboembolic

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Introduction

Anemia is defined as a deficiency in red blood cells (RBCs) and is a widely prevalent complication among cancer patients.1 The prevalence of anemia varies according to the type of neoplasia.2, 3 About 50% of patients with solid tumors present with anemia at diagnosis. Hematologic malignancies increase the likelihood of developing anemia; for example, 60–70% of patients with non-Hodgkin's lymphoma are anemic at the time of diagnosis.2 The National Cancer Institute suggested a classification for anemia based on hemoglobin (Hb) values (Table 1).3

Table 1 Grading of anemia according to the National Cancer Institute classification.
Table 1 - Grading of anemia according to the National Cancer Institute classification
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The pathophysiology of tumor anemia is multifactorial (Figure 1).4 Tumor-associated factors such as tumor bleeding, hemolysis, and deficiency in folic acid and vitamin B12, can be acute or chronic. In the advanced stages of hematologic malignancies, bone marrow involvement often leads to progressive anemia. In addition, interaction between tumor cell populations and the immune system can lead to the release of cytokines, especially interferon-gamma, interleukin-1 and tumor-necrosis factor-alpha. This release disrupts endogenous erythropoietin synthesis in the kidney and suppresses differentiation of erythroid precursor cells in the bone marrow. As a result, patients with tumor anemia can have relatively low levels of erythropoietin for the grade of anemia observed.5 Moreover, activation of macrophages can lead to a shorter erythrocyte half-life and a decrease in iron utilization. Cytostatic therapy and radiation further aggravates anemia in cancer patients. Platinum-based chemotherapy regimens might diminish endogenous erythropoietin production by damaging renal tubular cells,6 and myelotoxic anticancer drugs can compromise erythroid precursor cells. As a consequence, dose-intensified treatment regimens or shortened treatment intervals, as well as multimodal therapies, are associated with a higher degree of anemia. Mild or moderate (grade 1 and 2) anemia in patients with solid cancers could affect about 60% of patients after platinum-based chemotherapy.3 Severe (grade 3) anemia in elderly patients with hematologic malignancies can occur in up to 74% of patients with non-Hodgkin's lymphoma after standard CHOP (cyclophosphamide/doxorubicin/vincristine/prednisolone) treatment.3 In addition, some of the newer chemotherapeutic agents, such as taxanes or vinorelbine, are strongly myelosuppressive and can cause high degrees of anemia.3

Figure 1 Pathophysiology of anemia.
Figure 1 : Pathophysiology of anemia Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

BFU-E, erythropoietic burst formation; CFU-E, erythrocytic colony formation; EPO, erythropoietin; HIF-1, hypoxia-inducible factor-1; IFN-alpha,beta, interferon-alpha,beta; IFN-gamma, interferon-gamma; IL-1, interleukin-1; TNF, tumor-necrosis factor. Figure modified with permission from reference 86 © (1996) Marcel Dekker).

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Signs and symptoms of anemia

The clinical manifestation and severity of anemia vary considerably among individual patients. Moderate anemia can typically cause signs and symptoms such as headache, palpitations, tachycardia and shortness of breath. Chronic anemia can result in severe organ damage affecting the cardiovascular system, immune system, lungs, kidneys, and the central nervous system.7 In addition to physical symptoms, the subjective impact of cancer-related anemia on quality of life (QOL), mental health and social activities may be substantial. Clinical studies have reported correlations between Hb levels and QOL.8, 9, 10 A common anemia-related problem is fatigue, which impairs the patient's ability to perform normal daily activities.7, 11 As fatigue is a multifactorial syndrome not only caused by anemia, trying to correlate the relative contribution of anemia to fatigue is complex. Even when anemia is improved, the full symptoms of fatigue might not be relieved, because fatigue can be present independent of anemia.12, 13

Tumor hypoxia and survival

Another aspect of anemia in patients with malignant disease is the effect on the tumor itself. For several cancers, including cervical carcinoma, head and neck, prostate, bladder and lung cancer, as well as lymphoma, anemia is known to be associated with a poor prognosis.14 This association is partly the result of confounding factors, because advanced cancers usually present with lower Hb levels at diagnosis compared with early-stage cancers, and also have poorer survival outcomes. An additional, causal, explanation might be the reduced oxygenation of tumor tissue at lower Hb levels. Tumor cells can become resistant to radiotherapy and chemotherapy because of hypoxia; this is because the decreased oxygen transport capacity as a result of tumor-associated anemia can contribute to the development of hypoxia. Because of an abnormal microenvironment, solid tumor tissue is often hypoxic. Hypoxia might be more prevalent in anemic patients than in patients with normal Hb levels.15 Tumor hypoxia can impair the effectiveness of radiotherapy and oxygen-dependent chemotherapies.15, 16 For example, a study in cervical cancer demonstrated that increased hypoxia (defined as partial pressure of oxygen below 10 mm Hg) was associated with decreased local tumor control and lower rates of disease-free survival and overall survival.17 These observations generated the hypothesis that strategies to diminish cancer-related anemia might not only alleviate anemia-related symptoms but also improve tumor response and overall survival. Such an effect was partly demonstrated in animal models, where the augmentation of Hb levels with erythropoietin led to better tumor control following treatment with either radiotherapy or chemotherapy with cisplatin or cyclophosphamide.18, 19, 20, 21, 22

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Treatment options

Red blood cell transfusions

Before erythropoietin was available, blood transfusion was the only treatment option for severe cancer-related anemia. Homologous blood transfusion is the fastest method by which to alleviate symptoms; however, short-term and long-term risks exist with this procedure.23 Potential complications associated with blood transfusion are transmission of infectious diseases, transfusion reactions, alloimmunization, lung injury, over-transfusion and immune modulation with possible adverse effects on tumor growth.23, 24, 25 In the US, the risks of transfusion-related transmissions are 1:180,000 per unit of blood transfused for hepatitis B virus, 1:1,600,000 for hepatitis C virus, and 1:1,900,000 for HIV.23, 26

Optimal transfusion thresholds have been discussed in the literature. Results from clinical trials in critical care patients indicate that a restrictive transfusion strategy is at least as effective and possibly superior to a liberal transfusion strategy.27, 28 In one study, 838 critically ill patients were randomized to transfusion if Hb dropped below 7 g/dl and remained between 7 and 9 g/dl, or to a more liberal strategy where patients received RBC transfusions if Hb dropped below 10 g/dl and was maintained at between 10 and 12 g/dl.29 With the possible exception of patients with acute myocardial infarction and unstable angina, patients in the restrictive group had a reduced mortality during hospitalization. The British Society for Haematology recommends that mild anemia (grade 1) be left untreated.30 By contrast, RBC transfusions are indicated for patients with Hb of less than 7 g/dl. For patients who might not tolerate anemia well (e.g. patients over the age of 65 years or with cardiovascular or respiratory disease), transfusions might be indicated if Hb levels are less than 8 g/dl. A clear recommendation for Hb levels between 7 and 10 g/dl was not given.30 The recommendations of the College of American Pathologists are similar.31 Following these guidelines, RBC transfusions are rarely needed in patients with Hb levels of greater than 10 g/dl, but are usually required if Hb levels fall below 6 g/dl. For Hb levels between 6 and 10 g/dl the need for a transfusion depends on other factors including vital signs and tissue oxygenation.

Erythropoietin

Human erythropoietin is an acidic glycoprotein hormone and the primary regulator of human erythropoiesis. This hormone is synthesized mainly in the kidney, and to a minor degree in the liver.32, 33, 34 Tissue hypoxia triggers the synthesis and release of erythropoietin into the blood plasma. The effects of erythropoietin in the bone marrow are mediated by a specific surface erythropoietin receptor located mainly on RBC precursor cells.4, 35 Erythropoietin has two major functions: stimulating proliferation of erythroid progenitor cells and maintaining their viability.36

Recombinant human erythropoietin was first approved for the treatment of anemia in patients with chronic renal disease. In 1993, the use of erythropoetin was approved by the FDA for the treatment of anemia in cancer patients. Three different recombinant erythropoietins are available to date: epoetin alfa (Procrit®, Johnson & Johnson, Brunswick, NJ; Epogen®, Amgen Inc, Thousand Oaks, CA), epoetin beta (NeoRecormon®, Roche, Basel, Switzerland) and darbepoetin alfa (Aranesp®, Amgen Inc). Another substance called CERA (Continuous Erythropoietin Receptor Activator, Roche) is currently being investigated in phase I and II clinical trials. Epoetin alfa and epoetin beta both consist of 165 amino acids, but differ in their carbohydrate content. Because of this carbohydrate component, recombinant erythropoietins have a longer half-life after subcutaneous injection than the 8.5 hours of natural erythropoietin, with values ranging from 20.5 hours for epoetin beta to 24 hours for epoetin alfa.37, 38, 39, 40 Darbepoetin alfa has an even longer half-life after subcutaneous injection (approx49 hours).41 The frequency of dosing might not be related to a drug's half-life, however, because it might be possible that erythropoietin receptor cycle activation on erythroid precursors is more relevant than the terminal half-life.42 All three erythropoetins have similar clinical efficacy.43, 44, 45 Epoetin alfa and darbepoetin alfa are licensed for patients with solid tumors and nonmyeloid malignancies undergoing chemotherapy. The standard regimen for epoetin alfa and epoetin beta is 10,000 IU or 150 IU/kg thrice weekly, but these erythropoetins can also be administered once weekly.38, 39, 46 The recommended dose for darbepoetin alfa is 2.25 microg/kg per week;40 however, a commonly used regimen for the drug is a fixed dose of 200 microg every 2 weeks.47 Data from clinical studies suggest that the latter regimen might be slightly less effective than once-weekly 40,000 IU epoetin alfa. In two randomized controlled clinical studies, the once-weekly 40,000 IU epoetin alfa dosage achieved higher Hb response rates and a decreased rate of RBC transfusions than did the darbepoetin alfa arm (200 microg every 2 weeks).45, 48 Currently there are no randomized controlled studies that compare the recommended regimen of once-weekly 2.25 mg/kg darbepoetin alfa with once-weekly 40,000 IU epoetin alfa, or that directly compare the recommended weekly darbepoetin alfa dosage with the commonly used 2-weekly regimen.

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Evidence-based guidelines for erythropoietin treatment

In order to provide a framework for erythropoietin therapy, several evidence-based guidelines have been developed, differing in scope and methodological rigor.49 The most authoritative guideline to date was developed by the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH).50 The main recommendations of these groups are summarized in Box 1. The guidelines are based on the results of trials published between 1985 and 1999. Since studies on the use of darbepoetin alfa were not available during this period, the guidelines only recommend the use of epoetin. Guidance on the use of darbepoetin alfa was given in the more-recently published guidelines of the European Organization for Research and Treatment of Cancer (EORTC),51 the National Comprehensive Cancer Network47 and Cancer Care Ontario.52 Comparing the different guidelines, erythropoetin treatment is generally recommended in anemic nonmyeloid cancer patients undergoing chemotherapy who have Hb of less than 10 g/dl. Erythropoetin can also be given in patients with Hb levels of 10–12 g/dl, depending on clinical circumstances such as anemia-related symptoms51, 52 or risk factors for developing anemia.47 The recommended target is usually Hb of at least 12 g/dl,47, 50, 52 although the EORTC guidelines recommended slightly higher targets of Hb 12–13 g/dl.51

Box 1 American Society of Clinical Oncology/American Society of Hematology guidelines for the use of epoetin.a

  1. The use of epoetin is recommended as a treatment option for patients with chemotherapy-associated anemia with a Hb concentration of less than or equal to10 g/dl. Red blood cell transfusion is also an option depending upon the severity of anemia or the clinical circumstances. (Level of evidence and grade of recommendation: IIB.)
  2. Patients with Hb levels declining to <12 g/dl might also receive epoetin depending on the clinical circumstances. Red blood cell transfusions are also a therapeutic option in case of severe clinical conditions. (Level of evidence and grade of recommendation: IIC.)
  3. The recommendations are based on evidence from trials in which epoetin was administered t.i.w. subcutaneously. The recommended starting dose is therefore 150 IU/kg t.i.w. for a minimum of 4 weeks, with consideration given to dose escalation to 300 IU/kg t.i.w. for an additional 4–8 weeks in those who do not respond to the initial dose. An alternative weekly dosing regimen (40,000 IU) can also be considered. (Level of evidence and grade of recommendation: IIB.)
  4. Continuing epoetin treatment beyond 6–8 weeks in the absence of response (e.g. <1–2 g/dl rise in Hb) does not appear beneficial. Where iron deficiency can be ruled out, epoetin therapy should be discontinued. (Level of evidence: not applicable; expert opinion based on indirect evidence and biologic inference. The recommendation is based on a panel consensus.)
  5. Hb levels can be raised to a concentration of 12 g/dl, at which time the dosage of epoetin should be titrated to maintain that level or restarted when the level falls to near 10 g/dl. (Level of evidence: not applicable; expert opinion based on indirect evidence and biologic inference. The recommendation is based on a panel consensus.)
  6. Baseline and periodic monitoring of iron, total iron-binding capacity, transferrin saturation or ferritin levels and instituting iron repletion when indicated may be valuable in limiting the need for epoetin, maximizing symptomatic improvement for patients and determining the reason for failure to respond adequately to epoetin. (Level of evidence: not applicable; expert opinion based on indirect evidence and biologic inference. The recommendation is based on a panel consensus.)
  7. Treatment with epoetin for myeloma, non-Hodgkin's lymphoma, or chronic lymphocytic leukemia patients experiencing chemotherapy–associated anemia should follow the recommendations outlined above. (Level of evidence and grade of recommendation: IIB.)
  8. If in these patients a rise in Hb cannot be achieved after treatment with chemotherapy corticosteroids or both, epoetin should be used in accordance with the criteria outlined. (Level of evidence and grade of recommendation: IVB.)

aModified with permission from reference 50 © (2002) American Society of Clinical Oncology. t.i.w., three times a week.

Effectiveness: transfusion, hemoglobin response and quality of life

The ability of erythropoietin to increase Hb levels and reduce the risk for blood transfusions in cancer patients has been demonstrated in several randomized, controlled trials and subsequent meta-analyses.53, 54, 55 The results of the licensing indication studies and large randomized controlled trials are presented in Tables 2 and 3. The data are exemplified in a study by Littlewood et al., who investigated the efficacy of epoetin alfa on transfusion needs and QOL in 375 patients suffering from solid or nonmyeloid hematologic tumors treated with a non-platinum-based chemotherapy.56 Patients with an initial Hb level of up to 10.5 g/dl or with a decrease in Hb of at least 1.5 g/dl per chemotherapy cycle received subcutaneous epoetin alfa (150 IU/kg three times weekly) or placebo given for 12–24 weeks during chemotherapy and then for an additional 4 weeks. While the mean Hb level in the epoetin alfa group showed an increase of 2.2 g/dl (SD 2.18), the average increase for the placebo group was 0.5 g/dl (SD 1.79; P <0.001). Hematologic response (defined as an Hb increase of >2 g/dl unrelated to transfusion) was achieved in 172 out of 244 (70.5%) patients in the erythropoietin arm compared with 22 out of 115 (19.1%) in the control group (P <0.001). Transfusion needs were significantly reduced in those receiving epoetin alfa compared with those receiving placebo (25% versus 40%, P = 0.006). Transfusions occurring during the first 4 weeks of treatment were excluded from this analysis. Median survival in the epoetin alfa group was 17 months, compared with 11 months for patients receiving placebo, but statistical significance was not reached (P = 0.13). Since this study was not adequately designed to evaluate survival, however, these results are not readily interpretable. Patients in this study receiving epoetin alfa also showed statistically significantly higher energy levels, daily activity and overall QOL, while fatigue-related symptoms were reduced.

Table 2 Effect of recombinant human erythropoietin on hemoglobin response and transfusion rates: FDA license indication studies.
Table 2 - Effect of recombinant human erythropoietin on hemoglobin response and transfusion rates: FDA license indication studies
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Table 3 Effect of recombinant human erythropoietin on hemoglobin response and transfusion rates in randomized controlled trials including published data on >200 patients.
Table 3 - Effect of recombinant human erythropoietin on hemoglobin response and transfusion rates in randomized controlled trials including published data on >200 patients
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Results for both transfusion rates and hematologic response were confirmed in systematic reviews and meta-analyses.52, 53, 55, 57, 58 A meta-analysis based on 25 randomized controlled trials including 3,069 patients showed that the use of erythropoietin significantly reduced the relative risk (RR) of RBC transfusion (RR 0.67, 95% CI 0.62–0.73; Figure 2).55, 57 The reduction in RR was more pronounced in patients with solid tumors than in patients with hematologic malignancies or myelodysplastic syndrome. One possible explanation for this pattern is that the bone marrow of patients with hematologic malignancies is more compromised by the cancer than that in patients with solid cancers, and is therefore less responsive to erythropoietin. Applied to an estimated risk of 50% to receive RBC transfusions, the number needed to treat is 6.06 (95% CI 5.26–7.41).55, 57 Thus, about six patients would need to receive erythropoietin to spare one patient from receiving RBC transfusion. Similar numbers needed to treat were reported in previous meta-analyses.53, 58

Figure 2 Meta-analysis of the relative risk to receive red blood cell transfusions for cancer patients receiving erythropoietin or standard care.
Figure 2 : Meta-analysis of the relative risk to receive red blood cell transfusions for cancer patients receiving erythropoietin or standard care Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

Solid squares represent risk estimates for the single studies. The size of the squares are proportional to the sample size and the number of events. Horizontal lines denote 95% CIs. The diamond shows the CI for the pooled relative risks. Values below 1 indicate a relative risk reduction for red blood cell transfusions favoring the erythropoietin group; a–d denotes different treatment arms. Test for overall effect: z = -9.73 (P <0.001), test for heterogeneity chi-square = 57.76, degrees of freedom = 29 (P = 0.0012). Figure modified with permission from reference 50 © (2005) Oxford University Press.

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With hematologic response defined as an increase in Hb of at least 2 g/dl unrelated to transfusion, response rates of 9–70% were reported in 14 randomized controlled trials (n = 2,347) published before May 2002 and systematically evaluated by Bohlius et al.55, 57 The corresponding RR for hematologic response in the erythropoietin group was 3.60 (95% CI 3.07–4.23). Thus, patients receiving erythropoietin are three to four times more likely to achieve Hb response defined as an Hb increase of 2 g/dl than are patients not receiving erythropoietin. The Hb response depends on several factors, including underlying disease and type of treatment, but also methodological aspects such as the definition for Hb response chosen and the time point of assessment. For example, less restrictive Hb response criteria such as Hb change of 1 g/dl are easier to achieve, and therefore response rates following this definition would most likely be higher than under conservative Hb response definitions.

Ludwig et al. conducted the most influential study to investigate possible predictive factors for Hb response.61 According to their multivariate logistic regression analysis of 80 patients, a combination of endogenous erythropoietin level at baseline and changes of Hb after 2 weeks of treatment seemed to be the most promising criteria by which to discriminate between responders and nonresponders. A recent study by Witzig et al.62 evaluated a slightly modified version of the algorithm proposed by Ludwig et al.61 that also discriminated between responders and nonresponders. The discriminative power of the modified algorithm, however, seems to be of limited clinical value. Given the lack of data on possible predictive factors and the low reporting quality in such studies, no conclusions and recommendations for clinical use can be made.

Darbepoetin alfa

Darbepoetin alfa was introduced in 2003, and fewer data on this drug are available than on other erythropoietins. Two large trials in patients with lung cancer and malignant lymphoma have been reported.59, 60 In a double-blind, placebo-controlled, phase III study in 320 small-cell lung cancer patients undergoing platinum-containing chemotherapy, darbepoetin alfa was given at a dose of 2.25 microg/kg per week for 12 weeks.59 At baseline, patients had a median Hb level of 10 g/dl (range 6.6–13.6 g/dl). Significantly fewer patients in the darbepoetin alfa arm received transfusions than in the placebo arm (27% versus 52%). The first 4 weeks of transfusion were excluded from analysis. The hematopoietic response in patients receiving darbepoetin alfa was superior to those receiving placebo (66% versus 24 %); response was defined as an increase in Hb level of more than 2 g/dl or achievement of an Hb level of 12 g/dl. By contrast, when the response definition was limited to an Hb increase of 2 g/dl or more (i.e. hematologic response), only 51% of patients achieved a response. This example highlights how different Hb response definitions influence the effect estimates. In this study, improvement in fatigue symptoms (measured using the Functional Assessment of Cancer Therapy—Fatigue [FACT-F] scale) was greater in the darbepoetin alfa arm (56% versus 44%), with borderline statistical significance (P = 0.052).

Similar results were achieved in patients with hematologic malignancies.60 In a double-blind, placebo-controlled study, patients with lymphoma and myeloma undergoing chemotherapy received weekly 2.25 microg/kg darbepoetin alfa or placebo for a period of 12 weeks. At baseline the mean Hb in the erythropoietin group was 9.59 g/dl (SD 1.22), which was comparable to that in the placebo group. Based on intention-to-treat analysis, the average Hb change from baseline to the end of the study was 2.66 g/dl (SE 0.17) in the erythropoietin group and 0.19 g/dl (SE 0.10) in the control group (P <0.001). Response rates (defined as a change in Hb greater than or equal to2 g/dl) were significantly higher in the darbepoetin alfa arm than in the control group (60% versus 18%; P <0.001). Transfusion rates in patients receiving darbepoetin alfa were significantly lower than in controls (P <0.001). Fatigue symptoms were also significantly improved in the darbepoetin alfa arm (P = 0.032). Overall, the data demonstrate that darbepoetin alfa is effective in increasing Hb response and decreasing transfusion rates. These data also suggest that patients receiving darbepoetin alfa have improved QOL compared with controls.

Quality of life

Apart from improving physiologic parameters such as Hb and hematocrit, erythropoietin was also hypothesized to improve QOL and alleviate fatigue; improved QOL after erythropoietin therapy was previously reported in community-based, single-arm studies,63, 64, 65, 66 but these data were inconclusive because the studies lacked controls. Later, several randomized controlled studies were conducted to investigate this hypothesis.56, 62, 67, 68 One difficulty in the assessment of QOL is that trials require specific methodological standards, such as the use of validated instruments, double blinding, and a detailed plan to minimize missing data, investigate the pattern of missing data, and address data not present in the analysis.69

Littlewood et al. prospectively investigated the effects of epoetin alfa on QOL in a placebo controlled study (see above).56 Measurement of QOL included validated instruments for general QOL, such as the Medical Outcomes Study Short Form-36 and cancer-specific QOL, such as the Functional Assessment of Cancer Therapy—General (FACT-G), Functional Assessment of Cancer Therapy—Anemia (FACT-An) and a fatigue subscale (FACT-An Fatigue). Statistically significant improvements measured by the QOL scales were found in all three cancer-specific QOL scales for patients receiving epoetin alfa compared with placebo (FACT-G P = 0.004, FACT-An P = 0.0007 and FACT-An Fatigue P = 0.004). Similarly, the overall QOL was significantly improved in patients receiving epoetin alfa compared with controls (P = 0.0048). A strong correlation between Hb change and QOL was demonstrated; however, the QOL results are limited by the fact that about 20% of the patients initially randomized were not included in the analysis. Whether and how the missing data were evaluated was not reported.

In contrast to this notion are the results reported by Witzig et al.62 QOL was the primary endpoint of this randomized, double-blind and placebo-controlled study investigating the effects of weekly 40,000 IU epoetin alfa in 344 patients with advanced breast and lung cancer undergoing chemotherapy. Mean baseline Hb was 9.45 g/dl (range 6.0–11.4 g/dl) and all patients had an ECOG performance score of 0 (23.9%) or 1 (76.1%) at study entry. Both global (Uniscale®; seca corporation, Columbia, MD) and cancer-specific instruments were used, including FACT-G and FACT-An. Importantly, patients had to complete their QOL questionnaires every 4 weeks before visiting the physician, meaning that they had no information on their current Hb values or the cancer status—information that might have affected the QOL assessment. About 12% of the randomized patients were excluded from the QOL analysis. There was an improvement in FACT-An Fatigue scores in those treated with epoetin alfa (+3 versus +0.6, P = 0.18) and more patients in the epoetin alfa arm achieved an at least 10-point improvement in the QOL score (34% versus 28%), but the differences were not statistically significant (P = 0.27). When the analysis was restricted to patients in the epoetin arm who achieved an Hb response (defined as increase of 2 g/dl from baseline), the responders had a mean FACT-An Fatigue score of 5.4, compared with -5.7 for nonresponders (P = 0.02). There was no difference, however, for overall QOL (measured with Uniscale®) between patients who responded to epoetin alfa and those receiving placebo (P = 0.99). The authors concluded that QOL is influenced by Hb levels, but also by other factors such as the cancer activity, treatment received, pain and psychologic state of the patient. Correcting anemia may reduce anemia-related symptoms such as fatigue; however, such correction will not necessarily dramatically affect the overall QOL. Overall, although single clinical trials suggest improved QOL through correction of anemia with epoetin alfa, the data have to be judged with care, and new or updated systematic reviews are required.

Eythropoietin, tumor growth and survival

As discussed above, it was hypothesized that increasing Hb levels using erythropoietin might improve tumor oxygenation and thus improve the effectiveness of radiation and chemotherapy and subsequently improve survival, a theory that was supported by data from the study by Littlewood et al.56 and a subsequent meta-analysis.57 In this meta-analysis, the data from 19 randomized controlled trials published before May 2002, including 2,865 patients, were assessed; results indicated a survival benefit for patients receiving erythropoietin (adjusted data: hazard ratio 0.81, 95% CI 0.67–0.99; unadjusted data: hazard ratio 0.84, 95% CI 0.69–1.02).55, 57 None of the studies included were designed to detect differences in survival. These promising results were contradicted by two large randomized controlled trials published in 2003, which were specifically designed to assess survival.70, 71

In the first study, published by Henke and co-workers, 351 patients undergoing radiotherapy for head and neck cancer were randomized to receive epoetin beta or placebo, given in parallel with radiotherapy.70 The primary endpoint was locoregional progression-free survival. Reported Hb targets were Hb of 14 g/dl or more in women and 15 g/dl or more in men. Patients received a relatively high dose of epoetin beta (300 IU/kg three times a week). Survival in patients receiving epoetin beta was significantly lower than in patients receiving placebo (RR of death 1.39, 95% CI 1.05–1.84, P = 0.02). There were more episodes of hypertension, hemorrhage, thrombosis and pulmonary embolism in patients receiving epoetin beta than in those receiving placebo (11% versus 5%), and more patients died of cardiac disorders in the treatment group (5.5% versus 3%). The rate of locoregional tumor progression was also higher in patients receiving epoetin beta, with an RR of 1.69 (95% CI 1.16–2.47, P = 0.007).

The second study (BEST), reported by Leyland-Jones et al., was a multinational, multicenter study including 939 women with metastatic breast cancer. Women were prospectively randomized to receive epoetin alfa 40,000 IU once weekly or placebo.71, 72 This study was terminated prematurely by an independent data monitoring committee based on the first 4 months of safety data. There was a significant survival difference between patients receiving epoetin alfa (70%) and those in the placebo group (76%) at 12 months (P = 0.01). This difference was because of an increased mortality in the treatment arm in the first 4 months (41 deaths versus 16 deaths). In particular, mortality rates due to fatal thrombovascular events (1.1% versus 0.2%) and disease progression (6% versus 2.8%) were both higher with epoetin alfa than with placebo. At 19 months there was a convergence of survival curves. Both the Leyland-Jones et al. and Henke et al. studies had methodological limitations, such as baseline imbalances, suboptimal cancer treatment70 and lack of prospective documentation of prognostic factors.71 In the study published by Henke et al., patients with stage III and IV head and neck cancer underwent surgery and received radiotherapy, as this was the standard treatment at the time of protocol development for this study.70 Treatment for this patient group, however, has evolved over time and would nowadays include chemotherapy as well. Some causes of death still remain unclear, despite intensive re-evaluation.

The unexpected results of these and three other studies, which had to be closed prematurely because of increased rates of thromboembolic events, prompted an Oncologic Drugs Advisory Committee hearing at the FDA in May 2004.73 At this meeting, hypotheses to explain these results were discussed, including both methodological and biological factors relating to thromboembolic complications and tumor growth stimulation by erythropoietin.

Opposing mechanisms on the effects of erythropoietin on tumor growth have been proposed. As discussed earlier, tumor tissue is often hypoxic, and increasing Hb levels with erythropoietin might improve tumor oxygenation, and subsequently tumor control and survival. By contrast, it has been hypothesized that erythropoietin might directly stimulate tumor cell growth. Preclinical studies have reported high levels of erythropoietin and erythropoietin receptors in breast cancer cells and other malignancies.74, 75, 76, 77 Either endogenously produced or exogenously administered erythropoietin could theoretically promote the proliferation and survival of erythropoietin-receptor-expressing cancer cells. Preclinical studies used non-physiologic pharmacologic doses to trigger tumor proliferation.76 It remains unclear whether the increased rates of deaths due to tumor progress in both the BEST study and the study by Henke et al. can be explained by tumor growth stimulation, since this observation has not been seen consistently across trials.70, 71, 72

Other randomized controlled trials reported either no differences in tumor control78, 79 or improved tumor control with erythropoietin treatment. Antonadou et al.80 investigated tumor response in 385 participants with pelvic malignancies undergoing radiotherapy with or without erythropoietin. They showed a statistically significant improved disease-free survival at 4 years for participants treated with erythropoietin (85.3%) compared with the control group (67.2%, P <0.001). Blohmer et al.81 investigated the impact of epoetin alfa in patients with high-risk carcinoma of the uterine cervix (n = 257) treated with sequential chemoradiotherapy. The first interim report suggests an improvement in relapse-free survival (17% versus 25%) for patients treated with epoetin alfa (10,000 IU three times weekly); however, this observation is not statistically significant (P = 0.058). Both studies have not been fully published to date.

Whether thromboembolic complications are triggered by higher Hb levels in patients receiving erythropoietin has also been considered. As described above, in the Henke et al. study more patients receiving erythropoietin experienced thrombovascular events and died from cardiac disorders. Very high Hb levels were achieved at the end of the study (15.4 g/dl in men, SD 1.7), which might have substantially contributed to the high number of thrombovascular events and cardiac deaths.70 In three prematurely closed randomized controlled trials, 24 of 34 patients with vascular events treated with epoetin alfa had Hb levels greater than 13 g/dl within 28 days prior to the thromboembolic event.73 Thus, it was concluded that studies targeting Hb levels above 12 g/dl, aiming beyond the mere correction of anemia as suggested in the ASCO/ASH guidelines,50 were associated with a higher risk of thrombovascular events. Similarly, in studies evaluating the effects of erythropoietin on hematocrit in patients with end-stage renal failure who had pronounced cardiovascular risk factors, patients with high hematocrit levels had an increased mortality due to thrombovascular events.82 Erythropoietin might also have a thrombogenic potential independent of Hb levels. A retrospective case–control study in 147 consecutive cervical carcinoma patients undergoing concurrent chemotherapy, radiation and recombinant human erythropoietin found a statistically significant association between erythropoietin treatment and thromboembolic complications (odds ratio compared with women not receiving erythropoietin 10.3, 95% CI 2.3–46.2).83 No association was found between the mean or maximum Hb level and risk of thromboembolic complications, suggesting that erythropoietin might have a genuinely thrombogenic potential. This notion is supported by in vitro studies that demonstrate augmented platelet reactivity in erythropoietin-stimulated RBCs84 and endothelial activation in healthy volunteers.85

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Conclusions and implications for practice

In view of the evidence presently available, erythropoietin should not be used to attempt to increase overall survival outside clinical trials. Erythropoietin may be used routinely outside of clinical trials to increase Hb levels and to reduce the need for transfusion in patients with Hb levels of less than 10 g/dl and in patients with falling Hb levels approaching 10 g/dl. Dosing erythropoietin products to target Hb levels of more than 12 g/dl is potentially unsafe, and studies using such strategies should be conducted only under Investigational New Drug authorization. Clinicians are cautioned to adhere to dose adjustment guidelines incorporated into product package inserts or as exemplified by the ASCO/ASH guidelines.50 Adverse events such as thromboembolic complications should be monitored closely.

Key points

  • The pathophysiology of tumor anemia is multifactorial, and treatment with recombinant human erythropoietins has been shown to reduce transfusion rates and increase hemoglobin (Hb) response

  • For many cancers anemia is known to be a factor associated with a worse prognosis

  • In cancer patients, cytostatic therapy and radiation can aggravate anemia, and platinum-based chemotherapy regimens might diminish endogenous erythropoietin

  • Dose-intensified treatment regimens or shortened treatment intervals are associated with a higher degree of anemia

  • Systematic review analysis showed that patients receiving erythropoietin are three to four times more likely to achieve Hb response (Hb increase of 2 g/dl) than those not treated with this agent

  • Thromboembolic complications can be increased in patients receiving erythropoietin, and is not recommended in patients with Hb levels >12 g/dl

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