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All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/jnccn; (4) view/print certificate.
Release date: May 7, 2012; Expiration date: May 7, 2013.
Learning Objectives
Upon completion of this activity, participants will be able to:
Assess the pathogenesis of anemia in cancer
Analyze the quality of trials of ESAs among patients with cancer
Distinguish the benefits of ESAs among patients with cancer
Evaluate when to use ESAs among patients with cancer
Anemia is frequently encountered in patients with cancer and is often multifactorial, with potential contributing factors, including blood loss from surgery, tumor-associated bleeding, hemolysis or repeated phlebotomy, nutritional deficiencies (iron, B12, or folic acid), hepcidin-mediated disturbances in access to storage iron associated with underlying inflammation (socalled anemia of chronic illness), relative endogenous erythropoietin deficiency, hemolysis, and the myelosuppressive effects of cytotoxic chemotherapy (Figure 1). Cancer-induced anemia can be associated with symptoms and a need for red blood cell transfusions, and it is logical to avoid or minimize it, if possible, through addressing ongoing bleeding, reducing unnecessary blood loss in phlebotomy, and evaluating and treating nutritional deficiencies. Although many patients will remain anemic despite these simple but sometimes overlooked measures, this approach frequently reduces the degree of anemia to a point at which symptoms and/or transfusion requirements diminish.
The recent elucidation of the mechanism underlying anemia frequently observed in patients with chronic illnesses, including cancer,1–5 coupled with the development of parenteral iron preparations that have a more favorable safety profile than the early iron dextran products,6–8 has increased interest in the role of parenteral iron in managing anemia in patients with cancer. In some patients with inflammatory illnesses, interleukin-6 induces the liver to produce hepcidin,9,10 a peptide that induces degradation of the iron transport molecule ferroportin,11 which is required for both the absorption of dietary iron in the gastrointestinal tract and mobilization of storage iron in the reticuloendothelial system. This has raised the question of how frequently iron-restricted erythropoiesis is contributing to the anemia in some patients with cancer, even when sufficient storage iron exists to adequately support red cell production in the absence of inflammation. It also suggests that parenteral iron may be more effective than oral iron in addressing absolute or functional iron deficiency in conditions in which increases in hepcidin levels are suspected.12–17 Clinical trials are needed that are designed to determine whether parenteral iron has a role in the management of anemia in patients with cancer and, if so, what predictors of response, such as iron saturation, hepcidin levels, or red cell cytometry, can be identified.
The pathogenesis of anemia in patients with cancer. Multiple factors result in 3 mechanisms of anemia: a reduced response of the erythron to erythropoietin, a relative deficiency of endogenous erythropoietin, and a decrease in red cell survival. Iron-restricted erythropoiesis, from either reduced iron stores or a diminished access to storage pools mediated by hepcidin, is frequently present in patients with cancer.
Abbreviations: eEPO, endogenous erythropoietin; ESA, erythropoiesis-stimulating agent; IFN, interferon; IL, interleukin; RE, reticuloendothelial; TNF, tumor necrosis factor.
From Glaspy JA. Erythropoietin in cancer patients. Annu Rev Med 2009;60:187; with permission.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 5; 10.6004/jnccn.2012.0065
Long before the discovery of hepcidin and explication of the disturbances in iron metabolism that can occur in patients with chronic illness, chronic inflammatory conditions, including cancer, were shown to be associated with a blunting of the normal erythropoietin response to a given level of anemia.18 This suppression of erythropoietin production is mediated by inflammatory cytokines (e.g., tumor necrosis factor, interleukin-1, interferon-gamma) other than interleukin-6, and it is now understood that the pathophysiology of the hypoproliferative anemia of chronic illness includes both iron-restricted erythropoiesis and inappropriately low endogenous erythropoietin levels.
The advent of biotechnology was associated with the cloning and therapeutic application of several human proteins, including erythropoietin. After recombinant human erythropoietin (rEPO) completed its development for the treatment of patients with renal failure, it was logical, given the previously identified blunting of the endogenous erythropoietin response to anemia, to test it for the treatment of anemia in patients with cancer. These early trials showed that rEPO therapy was associated with an increase in hemoglobin levels in patients with cancer-related anemia and, in those who were also receiving chemotherapy, treatment with erythropoiesis-stimulating agents (ESAs) was associated with a reduction in red cell transfusions. In 1989, the FDA approved epoetin alfa, the rEPO used in clinical trials in the United States, for the treatment of patients with cancer-related anemia undergoing chemotherapy based on the reported reduction in red cell transfusions. Subsequently, another cloned erythropoietic protein, darbepoetin alfa, was approved for this indication. For purposes of this update, epoetin alfa, darbepoetin alfa, and an rEPO developed outside the United States—epoetin beta—will be considered together as ESAs.
Although there are many points of contention regarding the efficacy and safety of ESAs in the treatment of patients with cancer, the observation that ESA therapy is associated with a reduction in the rate of red cell transfusions in patients with cancer-related anemia who are receiving chemotherapy has stood the test of time. Although some investigators have reported that these patients also have reduced symptoms or improved functional status or quality of life,19,20 this has not been a consistent observation and has not been accepted by regulatory authorities as a proven benefit of ESA therapy in this setting. Much of the current controversy and uncertainty regarding ESAs in oncology surrounds their safety in patients with cancer, specifically their effect on tumor progression and survival. The remainder of this update addresses this safety issue. For the sake of brevity, it will focus most on the limited data that have become available since the time of the previous, more-extensive reviews of this topic.
Limitations of the Available Safety Data
Because ESAs are cloned human proteins being administered to supplement an already present endogenous hormone with the same mechanism of action, for more than a decade after FDA approval of an ESA for the treatment of anemia in patients with cancer receiving chemotherapy, the primary safety concerns were hypertension, the potential to “overshoot” and induce polycythemia, and the formation of cross-reacting antibodies causing pure red cell aplasia, which had been observed in a small number of dialysis patients.21 During those years, despite increasing application of ESAs in oncology practice, no well-designed and adequately powered randomized clinical trials were performed to document the safety of ESAs with respect to survival when used to treat patients with cancer-related anemia and raise hemoglobin levels sufficiently to either address symptoms or eliminate transfusion risk. The attributes of such a trial would include:
Focus on a particular tumor type
Use of stratification to balance the ESA and control groups at baseline for prognostic factors relevant to survival and tumor progression
A randomized control arm not receiving ESAs
Standardization of cancer treatments in the 2 arms
Adherence to ESA treatment in the active treatment arm that mimics the use of the drug in current oncology practice in terms of hemoglobin level at initiation, ESA dosing, and target hemoglobin level
Sufficient sample size to ensure the power to detect a clinically meaningful effect on survival
Efforts to follow all patients indefinitely, despite whether they remain on the study drug or cancer treatment, for survival outcomes
Systematic collection of tumor response data until progression is documented
Efforts to minimize cross-over between study groups
Although it may be understandable that this bank of trials was not at least attempted, given the extreme difficulty and high cost of performing this type of trial in each of the common tumor types in which anemia is frequently observed and treated, it is, in retrospect, regrettable. Two such trials are ongoing, and the results will be critically important, but none have been reported to date. The randomized trials that have been performed and reported fall short on one or more of the criteria. The most common problems have been lack of balance of the study arms at baseline for key prognostic factors (usually, but not always, because tumor outcomes were not primary study end points), use of ESAs to increase hemoglobin concentration to levels higher than those targeted in oncology practice (in some cases significantly higher than normal), initiation of treatment in patients who were not anemic, inclusion of multiple tumor types in both arms, and lack of standardization of anticancer treatments in the 2 arms. In the absence of high-quality, well-powered, randomized trials with survival as the primary end point, attempts have been made to address the issue through meta-analysis. Except for increasing sample size and power, this approach cannot overcome the shortcomings of the studies included and, unsurprisingly, it has led to very different results depending on which studies are included and whether the analysis is restricted to mortality during the brief period of ESA treatment or includes longer-term survival data. The safety of ESAs in patients with cancer remains an area of controversy because the inadequate data available regarding survival impacts are subject to varying interpretations.
Anemia, Tumor Cell Hypoxia, ESAs, and Survival in Patients With Cancer
Given that ESAs supplement an already present endogenous hormone, and seemed to have manageable side effects, including hypertension, in randomized trials designed to study their effects on transfusions, they were initially assumed to have a neutral effect on cancer outcomes, such as survival and tumor progression.22 However, an interest was shown in the potential of ESAs to improve tumor outcomes based on preclinical data that suggested that tumor cell hypoxia would be associated with the development of a more aggressive phenotype and with resistance to treatments, such as radiation or chemotherapy, and on clinical data that suggested that anemia was associated with tumor cell hypoxia and with poorer outcomes.23 Several studies were conducted to test the hypothesis that optimization of tumor oxygenation using ESAs would be associated with improved tumor response or enhanced survival.24–28 One serious flaw with these hemoglobin optimization trials is that none of them set hemoglobin targets that had been validated to enhance tumor oxygenation.
On the apparent assumption that more is always better, hemoglobin levels were increased above normal in the ESA arm in several trials. What little information exists suggests that the optimal hemoglobin for tumor oxygenation is in the 12 to 13 g/dL range and that hypoxia increases when hemoglobin levels fall below or rise above these levels.29 Hence, the hypothesis that tumor outcomes can be improved through optimization of hemoglobin levels has not been tested. The results of 2 hemoglobin optimization trials in which reduced tumor response or decreased survival was observed in the ESA arm became available in 2003.24,25 These unexpected results, and similar results subsequently reported in additional trials, which were summarized previously in JNCCN,30 began a process of reassessing the safety of ESAs in patients with cancer and appropriate attempts to fully understand the relationship of ESA therapy to cancer outcomes and to provide for optimal safety and balancing of risk and benefit for patients while that process is occurring.
Since the authors’ last review of this subject in 2008, the FDA and manufacturers of ESAs have established a detailed risk management plan and education program for patients and physicians to help manage ESA use in patients with cancer. However, only one trial of hemoglobin optimization, in patients with esophageal cancer,28 showed improved tumor response or enhanced survival using ESAs to achieve this goal, with the remainder of studies showing either no effect or a deleterious outcome. Hence, ESAs have no role in enhancing the response to radiation therapy or chemotherapy, or improving survival in current oncology practice.
Mechanisms Through Which ESAs Could Impact Cancer Outcomes
If ESAs can impact tumor progression and/or survival in patients with cancer, the mechanisms of action remain unknown and intensely debated (Figure 2). The authors previously reviewed this in more detail, but possibilities raised have included changes in hemoglobin that adversely affect tumor oxygenation, the presence of erythropoietin receptors (EPO-R) on tumor cells, and effects of rEPO on thrombosis and/or angiogenesis.31
Since the authors’ last review, no important progress has been made showing adverse effects of ESA-induced changes in hemoglobin level or the existence of functional EPO-R on human cancers. It seems to be becoming increasingly likely that if ESAs have an adverse effect on tumor outcomes, this will prove to be from their effects on hemostasis. One consistent finding of all the meta-analyses and randomized ESA trials is an increase in the incidence of venous thrombosis associated with ESA use.32,33 Mounting data suggest that hemostasis can play a role in tumor progression,34,35 and even provocative indications that anticoagulation may improve survival in patients with cancer.36,37
Theoretical framework for the multiple postulated effects of ESA therapy on tumor progression or survival in patients with cancer. Although this figure illustrates the complexity of potential factors involved, none of the hypothesized mechanisms have been shown to occur in patients with cancer treated with ESAs.
Abbreviations: eEPO, endogenous erythropoietin; EPO-R, erythropoietin receptors; ESA, erythropoiesis-stimulating agent; Hb, hemoglobin.
From Glaspy JA. Erythropoietin in cancer patients. Annu Rev Med 2009;60:183; with permission.
Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 10, 5; 10.6004/jnccn.2012.0065
Anemia in Patients With Cancer Not Undergoing Chemotherapy
Although ESAs have been shown to increase hemoglobin levels in patients with anemia of cancer (AOC), researchers have not been able to show that this translates into a reduction in transfusions in this population of patients. In this author’s opinion, the randomized trial of ESAs in patients with cancer that raised the greatest concern regarding safety was the one performed in this population of patients, because it was a large trial (N = 985) and involved the treatment, rather than prevention, of anemia with a reasonable, subnormal target hemoglobin level.38 The trial is not definitive; it was designed with transfusions as an outcome, all of the stratification was devoted to equalizing transfusion risks in the 2 arms, and it included many different tumor types. Nevertheless, for patients with AOC, no benefit has been seen and a concerning safety signal has been noted. Accordingly, ESAs currently have no role in addressing AOC.
Update on Safety in Patients With Cancer Receiving Chemotherapy
The benefit of reduced transfusions has been clearly shown with ESA treatment in patients with chemotherapy-induced anemia (CIA).39 Assessment of the risks in terms of tumor progression and survival is problematic, given the serious deficiencies of the available trials and their failure to model appropriate ESA use in oncology practice before 2004, wherein only patients with anemia sufficient to cause symptoms and place them at risk for future transfusion and treatment achieved targeted hemoglobin levels of 12 g/dL or less. The data available through 2007 have been extensively reviewed.30,31 The intervening 4 years have brought the following:
Reassuring safety data for patients with small cell lung cancer: a previous randomized controlled trial showed that patients with extensive-stage small cell lung cancer did not have an inferior response to cytotoxic chemotherapy, even though they were started on treatment when hemoglobin levels were already normal.40 In 2008, the results of a similar 600-patient randomized controlled trial suggested no impact of ESA therapy on survival.26 Similarly, no effect of ESA on survival was observed in a smaller randomized controlled trial in patients with limited-stage small cell lung cancer.41
Additional data for adjuvant treatment of breast cancer: for patients with metastatic breast cancer, a previous randomized controlled trial of ESAs in treatment-naïve nonanemic patients observed increased early, but not late, mortality in the ESA arm.25 In 2011, the results of PREPARE were published, which was a 733-patient trial of dose-intense versus less-intensive chemotherapy that also included randomization to be at risk to receive ESA if hemoglobin levels decreased. Patients at risk to receive an ESA had a lower 3-year disease-free survival. One important issue is that the 3-year disease-free survival was apparently poorest for patients randomized to be at risk for receiving ESA but never received it.42 One of the survival studies launched when the survival signal occurred was in patients with breast cancer; this is one area in which more data are expected in the future. In contrast, the results of the randomized German trial (N = 1170) presented at the 2011 San Antonio Breast Cancer Symposium showed no difference in progression-free or overall survival with ESA use.43
Additional meta-analyses of available randomized controlled trials: 2 additional meta-analyses were published using patient level, rather than study level, data to improve the power to detect an impact. In the first, which included epoetin alfa and darbepoetin, randomized controlled trials enrolling 13,933 subjects (10,441 receiving chemotherapy) chose to focus primarily on on-study mortality.44 This approach has an obvious rationale, but has the significant drawback of causing the 2 studies in which significant on-study mortality occurred to contribute disproportionately to the conclusion. This analysis concluded that ESAs were associated with a reduced survival in patients with cancer overall; they were not able to statistically show or exclude a negative effect on survival for the subset of patients with CIA. In a second patient-level meta-analysis that was limited to darbepoetin trials in 2112 patients with CIA, no difference in rates of tumor progression or survival were observed between the ESA and placebo groups.33 This group sought but could not find any relationship between rates of hemoglobin rise, initiation hemoglobin level, or peak hemoglobin level and adverse cancer outcomes. Interestingly, both red cell transfusions and ESA therapy were associated with an increase in rates of venous thrombosis, and survival outcomes were reduced for the subset of patients who received both ESA therapy and red cell transfusions.
Additional data on patients with B-cell lymphoma and Hodgkin’s disease: some prior randomized controlled trials noted that ESAs had a possible deleterious impact on survival in patients with lymphoma.45 However, 2 large randomized controlled trials have since been completed, with stratification balancing progression risk and survival in the 2 arms. The German Hodgkin Study Group randomized 1379 patients to ESA or no ESA during chemotherapy46 and found no impact on progression or survival. A similar trial completed by the GELA group in large cell lymphoma, which was reported in abstract form and presented as a poster at ASCO,47 also found no difference in progression or survival.
Additional data on patients undergoing radiation therapy for cancer of the head and neck: in some prior randomized controlled trials, patients with head and neck cancer receiving ESAs were observed to experience increased tumor progression or decreased survival.24 A randomized controlled trial enrolling 301 patients showed no effect of ESA on tumor progression or survival.48 ESAs should not be used to enhance radiation response because of the absence of efficacy data and the existence of counterbalancing data suggesting a risk.
Conclusions
Anemia is common and may result in symptoms and/or red cell transfusions. In many patients, the anemia can be addressed through minimization of blood loss and correction of nutritional deficiencies. Recent advances in understanding of the biology of this anemia have raised interest in the use of parenteral iron to reduce the requirement for ESAs and also perhaps the risk of thrombosis.49,50 Until the definitive studies of the effects of ESAs on progression and survival are performed, ESA use should be restricted to patients with CIA who are at risk for transfusions, who have been fully informed of the available safety data, and in whom the benefits outweigh the risks. For patients with cancer- and chemotherapy-induced anemia whose hemoglobin levels are less than 10 g/dL and in whom other causes of anemia have been excluded, ESA use is safe and more often effective than nonuse in raising hemoglobin, reducing transfusion requirement, and perhaps reducing symptoms of anemia. Nevertheless, fewer than 50% of clinicians use ESAs in this fashion and continue to expose their patients to the risk and inconvenience of transfusion.
EDITOR
Kerrin M. Green, MA, Assistant Managing Editor, Journal of the National Comprehensive Cancer Network
Disclosure: Kerrin M. Green, MA, has disclosed no relevant financial relationships.
AUTHORS AND CREDENTIALS
John Glaspy, MD, Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California
Disclosure: John Glaspy, MD, has disclosed the following relevant financial relationships:
The university that employs Dr. Glaspy receives payments to support clinical trials underway from Amgen.
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