Evidence Report/Technology Assessment: Number 30

Uses of Epoetin for Anemia in Oncology

Summary


Under its Evidence-based Practice Program, the Agency for Healthcare Research and Quality (AHRQ) is developing scientific information for other agencies and organizations on which to base clinical guidelines, performance measures, and other quality improvement tools. Contractor institutions review all relevant scientific literature on assigned clinical care topics and produce evidence reports and technology assessments, conduct research on methodologies and the effectiveness of their implementation, and participate in technical assistance activities.

Overview / Reporting the Evidence / Methodology / Findings / Future Research / Availability of Full Report


Overview

Erythropoietin is an endogenous hormone, produced primarily in the kidney, which participates in regulating production of red blood cells (erythropoiesis). "Epoetin" is the term used for recombinant human erythropoietin. It was developed in the 1980s as a treatment for anemia. Epoetin replicates the biologic activity of the endogenous hormone and increases the number of red blood cells and thus the blood concentration of hemoglobin when given to persons with functioning erythropoiesis. The initial clinical use of epoetin was to treat patients with anemia of chronic renal failure, especially patients on dialysis (i.e., end-stage renal disease).

Anemia is a deficiency in the concentration of hemoglobin-containing red blood cells (RBCs) that occurs when the equilibrium between red cell loss and production is disturbed. Anemia is relatively common among patients with either hematologic or solid tissue malignancies. It may be caused by effects of treatment, the underlying disease, or both on production of or responses to erythropoietin (or it can be caused by other mechanisms).

Anemia caused by occult bleeding, hemolysis, marrow replacement, or a nutritional deficiency is unlikely to respond to epoetin treatment but may be corrected using other therapies. When cancer treatment or the disease itself decreases production of or impairs response to endogenous erythropoietin, epoetin treatment may correct the resulting anemia. However, some patients in whom other causes of anemia have been ruled out nonetheless fail to respond to epoetin.

The severity of anemia can range from mild to life threatening. The National Cancer Institute and Cooperative Oncology Groups use a grading system for anemia. Within normal limits (WNL) hemoglobin (Hb) values are 12.0-16.0 g/dL for women and 14.0-18.0 g/dL for men. There are four grades of anemia, indicating increasing severity:

A recent review cataloged the incidence and severity of anemia for various malignancies and treatment regimens and found substantial variation. Because hematopoiesis is temporarily discontinued until after engraftment in patients undergoing myeloablation prior to transplant, nearly all would experience life-threatening anemia without RBC transfusion.

Data are unavailable to correlate the frequencies of anemia-related symptoms with Hb levels in cancer patients. However, the spectrum of symptoms associated with mild compared to severe anemia has been well described. Mild anemia is often asymptomatic or may manifest as tachycardia, palpitations and dyspnea on exertion, and mild fatigue. Severe anemia is characterized by palpitations and dyspnea at rest, severe fatigue, and exercise intolerance. Other signs and symptoms include cardiac enlargement and impaired cognition.

Red blood cell (RBC) transfusion has long been the primary treatment of severe or life-threatening anemia. But transfusion is used cautiously in the treatment of moderate and mild anemia because of the risks associated with exposure to allogeneic blood products and concern to conserve the blood supply. With the availability of epoetin, severe anemia may be prevented; however, it is not useful for the acute treatment of severe or life-threatening anemia because adequate hematologic response does not occur until after 4 or more weeks of treatment. Epoetin is also used to treat or prevent mild anemia.

This evidence report/technology assessment was developed under contract by a team of reviewers/investigators from the Blue Cross and Blue Shield Association's Technology Evaluation Center (TEC).

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Reporting the Evidence

This systematic review compares outcomes of managing anemia with and without the use of epoetin. Epoetin (with red blood cell transfusion used as necessary) was compared to red blood cell transfusion alone.

Four groups of patients with malignancy are included in this systematic review:

  1. Patients with anemia or at risk of anemia due primarily to cancer therapy. These are patients being treated for malignancy with chemotherapy, radiation, or chemotherapy and radiation.
  2. Patients with anemia due primarily to their malignant disease who may also be receiving cancer therapy. All patients in these studies had nonmyeloid hematologic malignancies or myelodysplastic syndrome (MDS).
  3. Patients who are anemic as a result of bone marrow ablation prior to allogeneic stem-cell transplantation.
  4. Patients who are anemic as a result of bone marrow ablation prior to autologous stem-cell transplantation.

This systematic review does not address use of epoetin to reduce the need for transfusion or to facilitate collection of autologous blood in patients undergoing surgery for cancer.

Outcomes of interest include:

This systematic review also sought evidence on:

The team also sought to compare the costs of epoetin to transfusion alone, but no controlled trials reported such data. As a result, its review of evidence on cost is limited to a discussion of secondary cost analyses summarized in the introductory section of the full evidence report. What follows are the specific objectives and key questions for each of these patient groups.

Anemia Due Primarily to Cancer Therapy and Anemia Due Primarily to Malignant Disease

For patients with anemia primarily of cancer therapy and patients with anemia primarily of malignant disease, the objective of this systematic review is to compare the outcomes of the following alternatives for managing anemia:

  1. Initiating epoetin when the level of hemoglobin decreases to a specified threshold:
  2. Managing anemia without epoetin, using transfusion (usually initiated when hemoglobin decreases to a threshold between 7 and 9 g/dL).
  3. Initiating prophylactic epoetin treatment concurrent with cancer therapy even if hemoglobin levels are above the anemic range. (Note that this alternative is not applicable to patients with anemia due primarily to malignancy, who are by definition already anemic and who may not be undergoing cancer therapy.)

In this area, four key questions were addressed:

  1. What are the outcomes of managing anemia with epoetin compared to transfusion alone? What are the relative effects of epoetin treatment according to the alternative hemoglobin thresholds for initiating treatment?
  2. In the studies included in this review, does varying the characteristics of the administration of epoetin affect the outcomes of treatment? The characteristics of epoetin administration are dose, route, dosing regimen (fixed, increasing, or decreasing dose) and treatment duration. Are the characteristics of epoetin administration likely to confound interpretation of the evidence on relative effects of alternative hemoglobin thresholds for initiating epoetin?
  3. Are there populations or subgroups of patients that are more or less likely to benefit from epoetin treatment? Are there laboratory measurements that can either predict or permit early identification of patients whose anemia will respond to epoetin?
  4. What are the incidence and severity of adverse effects associated with the use of epoetin, and how do these compare with the adverse affects of transfusion?

Anemia Resulting from Bone-Marrow Ablation Prior to Stem-Cell Transplantation

For patients with anemia resulting from bone-marrow ablation prior to allogeneic or autologous stem-cell transplantation, the objective is to compare the outcomes of the following alternatives for managing anemia:

  1. Managing anemia after bone-marrow ablation with transfusion initiated at a predefined Hb threshold (usually 7-10 g/dL) supplemented with epoetin treatment, beginning at the time of stem-cell infusion and continuing for a period of 4 to 8 weeks.
  2. Managing anemia after bone-marrow ablation with transfusion initiated at a predefined Hb threshold.

In this area, four key questions were addressed:

  1. Does managing anemia after high-dose chemotherapy and stem-cell support using epoetin (with RBC transfusion support initiated at a predefined Hb threshold) improve outcomes compared to managing anemia with RBC transfusion alone?
  2. Are any characteristics of epoetin administration associated with superior outcomes? The characteristics of epoetin administration are dose, route, dosing regimen, and treatment duration.
  3. Are there populations or subgroups of patients that are more or less likely to benefit from epoetin treatment?
  4. What are the incidence and severity of adverse effects associated with the use of epoetin compared with the adverse affects of the transfusion alone?

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Methodology

The protocol for this review was prospectively designed to define:

Two independent reviewers completed each step in this protocol. Data were abstracted directly into two separate electronic databases and the databases were compared electronically. Disagreements were infrequent and generally resolved by consensus of the two reviewers; resolution by a third reviewer was seldom required.

A technical advisory group of six members provided ongoing guidance on all phases of this project. Four of the six technical advisors were appointed by the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH), which each appointed two members to the technical advisory group.

A comprehensive literature search was performed that attempted to identify all publications of relevant controlled trials. The search process began with the MEDLINE, Cancerlit, and Embase databases. These online sources were searched for all articles published since 1985 that included at least one of the following text words (tw) or Medical Subject Headings (MeSH®) terms in their titles, their abstracts, or their keyword lists: erythropoietin (MeSH®); epoetin alfa (MeSH®); erythropoietin (tw); epoetin (tw); Epogen (tw); Procrit (tw); Eprex (tw); Marogen (tw); Recormon (tw); epo (tw); Anemia/drug therapy (MeSH®; included all subheadings); Anemia/therapy (MeSH®; included all subheadings); Anemia/diet therapy (MeSH®; included all subheadings).

The search results were then limited to include only those articles that were indexed under the MeSH® terms "neoplasms" or "myelodysplastic syndromes" (including all subheadings), and that addressed studies on human subjects. The MEDLINE, Cancerlit, and Embase databases were last searched in December 1998; total retrieval through this date was 2,915 references.

To supplement this strategy, issues of Current Contents on Diskette and issues of Medscape Oncology, an electronic medical journal, were searched through October 30, 1999, to identify recently published articles that had not yet been indexed by the online databases. The team also searched abstracts presented at the 1999 meeting of the American Society of Clinical Oncology. An additional source of bibliographic information was provided by Ortho Biotech, Inc., the pharmaceutical company that markets epoetin for use in oncology patients. Finally, all relevant review articles, editorials, and letters published in 1995 or later were retrieved. Reference lists from these articles were searched for studies not identified by these methods. A total of 28 additional published reports were identified by supplementary searches for a total retrieval of 2,943 references considered for this review.

The primary study selection criterion required that studies be designed as controlled trials comparing the outcomes of managing anemia with and without the use of epoetin in one of the four patient populations of interest. Uncontrolled trials were excluded from this systematic review.

Abstraction of data on adverse events was also limited to controlled trials because the objective was to estimate the frequency of occurrence in the oncology setting of the common adverse effects of epoetin. This precluded analysis of uncontrolled series, because adverse events related to disease progression and cancer therapy could not be distinguished from those related to epoetin. Hypertension and thromboembolic events are known adverse effects of epoetin (but are generally manageable).

All controlled trials were published in English; no controlled trials published only in languages other than English were identified.

To supplement this systematic review, the team conducted a meta-analysis of the effect of epoetin on the odds of transfusion in patients with anemia or at risk of anemia due primarily to cancer therapy. A random effects model was used to combine results of the 14 randomized controlled trials that reported numbers of patients transfused. The odds ratio expresses the relative likelihood that epoetin-treated patients will be transfused compared to the likelihood for control patients.

Sensitivity analysis was performed to compare results of higher quality trials to lesser quality trials. A trial was classified as higher quality when it was randomized and double-blinded and met the team's criteria to limit subjects excluded from the analysis of results. It required that less than 10 percent of subjects within each study arm were excluded from the analysis, and that the ratio of exclusions between arms was less than a 2:1 ratio; or, alternatively, that results were reported as an intention to treat analysis.

This report has undergone extensive expert review. A preliminary analysis of the evidence base for this report was reviewed by the Blue Cross and Blue Shield Association Medical Advisory Panel, which includes nationally recognized experts in technology assessment and hematology/oncology.

In addition, 20 external reviewers reviewed the study protocol and draft report, and revisions were made based on their comments. Eight reviewers were invited by the Technology Evaluation Center under the auspices of this task order for their expertise in medical oncology, hematology, transfusion medicine, quality of life, and systematic review methodology. One reviewer directs another AHRQ Evidence-based Practice Center and is a medical oncologist/hematologist. Ten of the external reviewers were appointed by professional organizations other than ASCO or ASH and by patient advocacy groups. These reviewers included clinical and research specialists involved in the treatment of cancer and/or management of cancer-related anemia and patient advocacy representatives. The final external reviewer was from the technical staff of Ortho Biotech, Inc., which markets epoetin alfa for the treatment of cancer patients.

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Findings

Anemia Due Primarily to Cancer Therapy

The conclusions are based on data abstraction and analysis of 22 controlled trials with a total enrollment of 1,927 patients. All trials compared the outcomes of managing anemia with epoetin treatment or with red blood cell transfusion alone in patients undergoing therapy for a malignancy. Eighteen trials with a total 1,698 enrolled patients (88 percent) were randomized, and 7 randomized trials with a total of 853 patients were placebo-controlled and double-blinded (44 percent). The number of patients reported as evaluable is 1,838, which is 95 percent of all enrolled patients. The team classified the 22 trials into 3 categories defined by the study patients' mean Hb at enrollment:

No trial directly compared the outcomes of initiating epoetin treatment at different Hb thresholds.

1. What are the relative effects on outcomes of managing anemia with epoetin compared to transfusion alone? What are the relative effects of epoetin treatment when different Hb thresholds are used to initiate treatment?

2. In the studies included in this review, does varying the characteristics of the administration of epoetin affect the outcomes of treatment? Are the characteristics of epoetin administration likely to confound the interpretation of the evidence on the relative effects of epoetin treatment according to the alternative Hb thresholds for initiating treatment?

3. Are there populations or subgroups of patients that are more or less likely to benefit from epoetin treatment? Are there laboratory measurements that can either predict or permit early identification of patients whose anemia responds to epoetin?

4. What are the incidence and severity of adverse effects associated with the use of epoetin and how do these compare with the adverse affects of transfusion?

Anemia Due Primarily to Malignant Disease

The literature search identified 6 controlled trials, all randomized, with a total enrollment of 693 patients that met inclusion criteria for this systematic review. Three trials were placebo-controlled and double-blinded (n=332; 48 percent). Of the 693 patients enrolled, 648 (93.5 percent) were reported as evaluable. Patients in this evidence base had diagnoses known to have a high occurrence of anemia of malignancy (multiple myeloma, non-Hodgkin's lymphoma, chronic lymphocytic leukemia, and myelodysplastic syndromes). With the exception of one trial on patients with MDS, the preponderance of patients in these trials received concurrent therapy for their malignancy.

1. What are the outcomes of managing anemia with epoetin (plus transfusion when necessary) compared to transfusion alone? What are the relative effects of epoetin treatment according to the alternative hemoglobin thresholds for initiating treatment?

2. In the studies included in this review, does varying the characteristics of the administration of epoetin affect the outcomes of treatment?

3. Are there populations or subgroups of patients that are more or less likely to benefit from epoetin treatment? Are there laboratory measurements that can either predict or permit early identification of patients whose anemia responds to epoetin?

4. What are the incidence and severity of adverse effects associated with the use of epoetin, and how do these compare with the adverse affects of transfusion alone?

Anemia Resulting from Bone-Marrow Ablation Prior to Allogeneic Stem-Cell Transplantation

The evidence concerning the use of epoetin after high-dose chemotherapy and allogeneic stem-cell transplantation is derived from 7 controlled studies (total enrollment: 493) of patients that are representative of those undergoing bone marrow-derived allogeneic stem-cell transplantation in clinical practice. Of the 7 controlled trials, all but 2 were randomized (total enrollment in randomized studies: 400); nonrandomized trials compared epoetin-treated patients to historical controls. The largest study enrolled and evaluated 215 patients; all other studies enrolled less than 100 patients.

These studies compared the outcomes of transfusion of red blood cells (RBC) initiated at a predefined threshold supplemented with epoetin treatment with the outcomes of RBC transfusion alone. One study exclusively enrolled pediatric patients. Enrolled patients had a variety of hematologic tumors. All studies used bone marrow as the stem-cell source, and all studies administered epoetin intravenously.

1. Does managing anemia after high-dose chemotherapy and allogeneic stem-cell support using epoetin (with RBC transfusion support initiated at a predefined Hb threshold) improve outcomes compared to managing anemia with RBC transfusion (initiated at a predefined Hb threshold) alone?

2. Are any characteristics of epoetin administration associated with superior outcomes?

3. Are there populations or subgroups of patients that are more or less likely to benefit from epoetin treatment?

4. What are the incidence and severity of adverse effects associated with the use of epoetin compared with the adverse affects of the transfusion alone?

Anemia Resulting from Bone-Marrow Ablation Prior to Autologous Stem-Cell Transplantation

The literature search and review for studies of epoetin use after autologous transplantation identified 6 controlled trials (total enrollment: 321). Three of the 6 trials were randomized (total enrollment: 169); nonrandomized trials compared epoetin-treated patients to historical controls. Studies ranged in size from 20 to 114 enrolled patients. All of the studies used bone marrow as the exclusive source of stem cells except for one in which patients with Hodgkin's lymphoma were additionally given peripheral blood-derived stem cells.

Although these studies of autologous transplantation do not meet the current standard of care regarding stem-cell source (i.e., peripheral blood stem cells), the results are generalizable to patients undergoing peripheral blood stem-cell transplants.

1. Does managing anemia after high-dose chemotherapy and autologous stem-cell support using epoetin (with RBC transfusion support initiated at a predefined Hb threshold) improve outcomes compared with managing anemia with RBC transfusion alone?

2. Are any characteristics of epoetin administration associated with superior outcomes?

3. Are there populations or subgroups of patients that are more or less likely to benefit from epoetin treatment?

4. What are the incidence and severity of adverse effects associated with the use of epoetin compared with the adverse affects of the transfusion alone?

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Future Research

Future research should include the following:

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Availability of Full Report

The full evidence report from which this summary was derived was prepared for the Agency for Healthcare Research and Quality by the Blue Cross and Blue Shield Association Technology Evaluation Center (TEC) under contract No. 290-97-0015. Print copies of the report may be obtained free of charge from the AHRQ Publications Clearinghouse by calling 800-358-9295. Requestors should ask for Evidence Report/Technology Assessment No. 30, Use of Epoetin for Anemia in Oncology (AHRQ Publication No. 01-E009).

The Evidence Report is also online on the National Library of Medicine Bookshelf, or can be downloaded as a zipped file.

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AHRQ Publication Number 01-E008
Current as of March 2001


Internet Citation:

Uses of Epoetin for Anemia in Oncology. Summary, Evidence Report/Technology Assessment: Number 30. AHRQ Publication Number 01-E008, March 2001. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/epcsums/epoetsum.htm


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