Affiliations of authors: J. Seidenfeld, M. Piper, C. Flamm, N. Aronson, Technology Evaluation Center, Blue Cross and Blue Shield Association, Chicago, IL; V. Hasselblad, Duke University, Durham, NC; J. O. Armitage, University of Nebraska Medical Center, Omaha; C. L. Bennett, Department of Veterans Affairs Chicago Healthcare System/Lakeside Division and Northwestern University, Chicago, IL; M. S. Gordon, University of Arizona College of Medicine, Phoenix Campus; A. E. Lichtin, Cleveland Clinic Foundation, OH; J. L. Wade III, Cancer Care Specialists, Decatur, IL; S. Woolf, Medical College of Virginia, Richmond.
Correspondence to: Jerome Seidenfeld, Ph.D., Technology Evaluation Center, Blue Cross and Blue Shield Association, 225 North Michigan Ave., Chicago, IL 606017680 (e-mail: jerome.seidenfeld{at}bcbsa.com).
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ABSTRACT |
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INTRODUCTION |
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RBC transfusion has long been the primary treatment of severe or life-threatening anemia, operationally defined by the National Cancer Institute-sponsored Cooperative Oncology Groups as hemoglobin concentrations of less than 8.0 g/dL (11). Transfusion, however, is used cautiously in the treatment of moderate (8.010.0 g/dL) and mild (10.0 g/dL to just below normal limits) anemia, because of the risks associated with exposure to allogeneic blood products (7,1214) and the concern with conserving the blood supply. With the availability of epoetin, moderate anemia can be treated and severe anemia can be prevented. Epoetin also affords the opportunity to treat mild anemia, but it is uncertain whether there is clinical benefit in doing so. Given the cost of epoetin treatment, estimated at $3700$6600 per chemotherapy cycle (1517), evidence on benefit is needed to make efficient use of epoetin in clinical care.
This systematic review and meta-analysis has two primary objectives. The first objective is to quantify the effects of epoetin on transfusions and quality of life in patients with anemia primarily due to chemotherapy or radiation therapy. The outcomes of epoetin treatment (plus transfusion if needed) are compared with the outcomes of transfusion alone. Combined results of studies are reported for odds of transfusion, the only outcome where sufficient data were available, with sensitivity analysis for parameters of study quality. The second objective is to determine whether outcomes are superior when epoetin is initiated at higher thresholds of baseline hemoglobin concentration, i.e., as prophylaxis or when anemia is mild. This study is part of a comprehensive systematic review on the outcomes of epoetin use in cancer-related anemia, which includes anemia primarily due to treatment of malignancy, anemia primarily due to the underlying disease, and anemia due to myeloablative therapy before stem cell transplantation (18).
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METHODS |
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MEDLINE®, CANCERLIT®, and EMBASE® databases were searched for all articles published from January 1985 through December 1998 that included one of the following textwords (tw) or Medical Subject Headings (MeSH®) in their titles, abstracts, or 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®; all subheadings), anemia/therapy (MeSH®; all subheadings), or anemia/diet therapy (MeSH®; all subheadings). Search results were limited to articles on human subjects indexed under the MeSH® terms "neoplasms" or "myelodysplastic syndromes" (all subheadings). There were no language restrictions.
We also searched issues of Current Contents on Diskette and Medscape Oncology through October 30, 1999. Finally, we sought relevant abstracts presented at the 1999 and 2000 meetings of the American Society of Clinical Oncology. A total of 2943 references were identified.
Study Selection
Study inclusion and exclusion criteria for this systematic review were identified prospectively. Eligibility was limited to controlled trials because many characteristics of cancer patients (e.g., disease stage, tumor progression, and concurrent treatments) could affect the outcomes of interest and confound interpretation of the effects of epoetin. Studies with nonrandomized concurrent or historical controls were included if the reviewers could verify comparability of patients in the treatment and control groups for age, malignancies, and baseline hemoglobin concentration.
Studies were included if they enrolled patients with existing anemia due to cancer chemotherapy and/or radiotherapy or nonanemic patients beginning a course of cancer therapy, if they enrolled 10 or more similarly treated evaluable patients in each arm, and if they compared epoetin treatment (plus RBC transfusion when necessary) with RBC transfusion alone. In addition, included studies reported at least one of the following outcomes: change in hemoglobin concentration from baseline to final value after epoetin treatment, percentage of patients responding to epoetin, percentage of patients transfused, number of RBC units transfused per patient, or quality of life. We also sought data on anemia-associated symptoms (e.g., shortness of breath, dyspnea on exertion, and angina) or hospital utilization.
Two reviewers (J. Seidenfeld and M. Piper) independently assessed study eligibility and resolved disagreements by consensus. The comprehensive evidence report includes a list of all studies assessed for eligibility (18). A thorough search identified no additional controlled trials published in a language other than English.
Data Abstraction and Analysis
Two reviewers (M. Piper and C. Flamm) independently abstracted data from each included study to separate copies of an electronic database (Microsoft® Access 97). The completed databases were compared electronically, and disagreements were generally resolved by reconciliation of an oversight. Reviewers estimated numerical values from figures for data reported only in graphs. Disagreements were always less than 5%, and the consensus estimate was the midpoint.
Abstracted data were analyzed to compare the outcomes of epoetin therapy with the outcomes of transfusion alone and to compare the relative effects of epoetin treatment when different hemoglobin thresholds were used for initiating treatment. Included studies were categorized by mean (if available) or median (six studies) hemoglobin concentration at enrollment: below normal limits but 12 g/dL or higher, more than 10 g/dL but less than 12 g/dL, or 10 g/dL or less. For each baseline hemoglobin range, we summarized hemoglobin changes [not shown here; see (18)], transfusions, and health-related quality-of-life outcomes and qualitatively compared results. For each trial, we also calculated the absolute differences between the treatment and control arms for each reported outcome.
We evaluated the possibility that differences in the route, dose, dosing regimen, and duration with which epoetin was administered might confound interpretation of the evidence. Limited space prevents inclusion of the analysis that convinced us that this possibility was unlikely. We also looked for but did not find sufficient evidence to identify reliable predictors of hematologic responses to epoetin. Interested readers are referred to the comprehensive evidence report (18) for detailed information on these issues.
Study Quality
Our study selection criteria served as an initial quality screen and were designed to incorporate generally accepted quality criteria (19). In addition, we identified a subset of studies with a lower potential for biased results, using quality domains that have been tested in empirical studies (2022). Those in the subset, referred to as "higher quality studies" for the remainder of this review, were used for sensitivity analysis, comparing their results with those from remaining studies, hereinafter referred to as "lower quality studies." For sensitivity analysis, we selected as higher quality those randomized, controlled trials that were double-blinded (23) and also minimized exclusion bias. Double-blinding was emphasized, since knowledge of assigned treatment might alter investigators' transfusion orders. We considered exclusion bias to be minimized when a study 1) reported intent-to-treat analysis or 2) excluded fewer than 10% of subjects from analysis, and the ratio of subjects excluded from each arm was less than 2 : 1. We also assessed studies for concealment of allocation to treatment arms, but we found this to be prone to reporting bias because most included studies were published before the CONSORT (i.e., Consolidated Standards of Reporting Trials) statement (24).
Special Issues for Quality of Studies Reporting Quality-of-Life Outcomes
Rigorous control of other factors that may also affect quality of life (e.g., tumor stage and progression, effects of cancer therapy, and changes in cancer therapy regimen) is necessary to demonstrate that epoetin treatment changes quality of life (25). Uncontrolled studies (2628) and comparisons to historical or prospective but nonrandomized control groups have examined quality of life; however, they may suffer from selection bias and the inability to disentangle the effects of such confounding variables. Quality-of-life results also can be affected by the validity of the quality-of-life instrument, how it is administered, and the interaction between the physician and patient.
We examined trials that assessed quality of life for design features related to the administration of quality-of-life instruments and the analysis and interpretation of results. An extensive literature over the past decade has identified key methodologic features needed in studies that measure quality of life (2931). On the basis of this literature, the U.S. Food and Drug Administration has outlined guidelines for conducting randomized, controlled trials that assess quality-of-life end points for oncology drugs (32,33). These features include the following: use of validated instruments; double-blinding or blinding of personnel administering the quality-of-life questionnaires; prospective identification of the key outcomes, critical time points, and minimum differences in scores to be considered clinically significant; and a detailed plan for preventing missing data, investigating the pattern of missing data, and addressing missing data in the analysis.
Meta-analysis
Reduction in the risk of RBC transfusion was the only outcome for which adequate data were available for meta-analysis. Because epoetin affects anemia rather than malignancy, we combined data from epoetin trials on patients affected with different malignancies and receiving different therapies. We limited inclusion in the meta-analysis to randomized, controlled studies in which epoetin was administered subcutaneously and numbers or percentages of patients transfused were reported. Results from each study were summarized as a ratio of the odds of transfusion for epoetin-treated patients to the odds for control patients.
Protocols of the randomized trials included in the meta-analysis varied with respect to epoetin dose, baseline hemoglobin concentration, duration of follow-up, and study quality. Therefore, we used a random-effects model [the Empirical Bayes estimator (34), calculated with FAST*PRO software (35)]. We tested for heterogeneity according to the procedure of DerSimonian and Laird (36).
To adjust for other variables (e.g., epoetin dose) that might influence the effect of treatment, we fitted a multiple logistic regression model with a random- effects term using Egret software (37). The model can be written as
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where pik(x) is the probability of a transfusion event for the kth arm of the ith study, j is a term for the log-odds of transfusion in the control group of the ith study, xij = 1 if i equals j and xij equals 0 otherwise (i.e., xij matches the correct value of
for each study).
is the logistic regression coefficient for the effect of the epoetin dose in the ith study, xi,m+1 is the actual epoetin dose for the kth arm of the ith study,
is a standard normal random variable, and
2 is the random-effects variation. The terms are estimated with the use of maximum likelihood methods.
In the analysis, each study was treated exactly as it was designeda three-arm study contributed three records. Each study had its own dummy variables to allow for study differences, and the effects of different doses were modeled with the use of appropriate regression terms. Thus, the assumption of independence was not violated. This analysis is described in detail by Hasselblad (38).
The number of patients who would need to be treated with epoetin to spare one patient from receiving a transfusion (NNT) was derived from the reciprocal of the absolute risk reduction (39). Absolute risk for the controls was determined by the estimation of the odds of transfusion for the combined control study arms (from studies with a known follow-up duration) with the use of a logistic normal model and the point estimate for a 12-week follow-up duration (38). The estimate of the odds was converted to the corresponding probability. From this and the summary odds ratio, the probability of odds of transfusion for the combined epoetin-treated study arms was calculated.
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RESULTS |
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Twenty-two controlled trials (4061) met the study selection criteria of this systematic review. The total enrollment was 1927 patients, of whom 1838 (95%) were evaluable. Unless otherwise specified, data on patient numbers refer to enrollment. The mean hemoglobin concentration at enrollment ranged from 8.6 to 13.0 g/dL in these studies. Of the 22 studies, 17 (4047,4953,55, 57,60,61) reported at least one transfusion outcome (n = 1703), of which 12 [n = 1390 evaluable; (4044,5153,55,57,60,61)] met selection criteria for the meta-analysis. Six [n = 829; (4045)] of the 17 trials met our definition of higher quality, but one [n = 30; (45)] was excluded from the meta-analysis because epoetin was administered intravenously.
Table 1 lists the number of trials (and their combined enrollment) that used different study designs, studied different patient populations, and reported the outcomes of interest. One trial [Quirt et al. (51); n = 56] was published only as an abstract. A second trial [Littlewood et al. (44); n = 375)1] was available only as an abstract when the systematic review was conducted, but it was published in full as this review went to press.
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No trials reported on symptoms of anemia (including shortness of breath, dyspnea on exertion, or angina) or number of days in hospital. The only trial that reported changes in performance status (49) used the Karnofsky performance scale as a surrogate for quality of life.
Study quality. Study selection criteria eliminated single-arm trials and ensured a basic level of study quality for all included studies. Only five trials (4043,55) reported all four hematologic and transfusion outcomes of interest for each study arm. Furthermore, trials did not consistently report tests of statistical significance for differences in baseline characteristics or outcomes between epoetin and control arms. Although 10 trials prospectively specified a transfusion trigger (42,43,45,46, 47,49,50,53,57,60), only four (40,41,55,61) reported the mean hemoglobin concentration at transfusion for each arm, leaving open the possibility that transfusion practices may have differed between arms in the other 18 studies.
Six trials (4045) were identified as higher quality for sensitivity analysis. The seventh randomized, placebo-controlled, double-blinded trial (46) did not meet the criterion for percentage of patients excluded from analysis. Five of the higher quality studies (4044) enrolled groups with a mean baseline hemoglobin concentration of 10 g/dL or less. In the remaining higher quality trial (45), the mean baseline hemoglobin concentration was greater than 10 g/dL but less than 12 g/dL; however, this trial was excluded from the meta-analysis because epoetin was administered intravenously.
Study quality for quality-of-life outcomes. Nine studies (40,41,43,44,49,54,55,60,61) reported quality-of-life outcomes (n = 851 evaluable), but two of these studies [n = 216 evaluable; (40,55)] reported only within-arm changes and did not compare differences between arms. None of the studies reported the features considered important for minimizing bias in measuring quality of life (25,2933). Linear Analogue Self-Assessment (LASA) scales were the most frequently used quality-of-life instruments, reported in seven trials overall (40,41,43,44,54,55,61) and in five (41,43,44,54,61) of seven that compared differences between treatment arms. The LASA scale questionnaire items reported most frequently in these studies were overall quality of life, energy level, and daily activities. Note that the overall quality-of-life score is not a summary score, and it is only one of three or more separate dimensions. Furthermore, results with different LASA scales cannot be combined, since each is a unidimensional instrument. Only one trial (44) used the Functional Assessment of Cancer Therapyanemia (FACT-An) instrument (62,63) and LASA scales. Of the two remaining trials, one (49) used Karnofsky performance scales and one (60) used the Psychological Distress Inventory.
Four (40,41,43,44) of nine studies that reported quality-of-life outcomes were selected as higher quality for sensitivity analysis of transfusion outcomes. But three (40,41,44) of the four exceeded our threshold for excluding patients from quality-of-life outcomes, with 10%40% of enrolled patients not evaluable. Such missing data may not be distributed randomly and may be independently associated with quality of life. For example, patients who are severely ill may be more likely to have missing quality-of-life data after baseline, potentially biasing results.
Epoetin Compared With Transfusion
Table 2 summarizes the ranges of results reported for transfusion outcomes: the percentage of patients transfused and the number of RBC units transfused per patient (normalized to 4 weeks whenever possible). For results reported by each included study, see the comprehensive evidence report (18). Table 3
and Figs. 1 and 2
present combined results for percentage of patients transfused. Table 4
summarizes results from studies reporting quality-of-life outcomes.
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Of three pediatric trials (n = 108), two trials (46,57) reported that one transfusion outcome statistically significantly favored the epoetin arm and one trial (49) reported that the difference was statistically significant for both outcomes. The range of differences between epoetin and control arms for percentage of patients transfused was 10%80%. The differences for RBC units transfused per patient per 4 weeks were 1.1 and 2.2 units.
Combined odds of transfusion. To provide a quantitative summary estimate of the effects of epoetin, we conducted a meta-analysis of the odds of transfusion. All randomized trials in which epoetin was administered subcutaneously and the number or the percentage of patients transfused was reported were eligible for meta-analysis. Twelve trials reporting on 1390 evaluable patients are included in the meta-analysis; this number constitutes 72% of all patients enrolled in the 22 studies included in this systematic review. Two otherwise eligible trials [n = 49 evaluable; (45,46)] were excluded because epoetin was administered intravenously; a preliminary analysis showed that the intravenous studies had little effect on the summary estimate.
A test for homogeneity (36) among the 12 randomized trials with subcutaneous administration (4044,5153,55,57,60,61) indicated some degree of heterogeneity (chi-square of 17.3 for 11 df; P = .099). Meta-analysis using an empirical Bayesian random-effects model (34,35) resulted in a combined odds ratio of 0.38 (95% confidence interval [CI] = 0.28 to 0.51; Table 3; Fig. 1
).
A sensitivity analysis was performed with the use of only the five higher quality studies that administered epoetin subcutaneously and that reported the number of patients transfused (Table 3; Fig. 2
). We estimated the epoetin effect on transfusion for the five higher quality studies [n = 771 evaluable; (4044)] and separately for the seven remaining studies [n = 619 evaluable; (5153,55,57,60,61)]. The results of this analysis are shown in Table 3
and Fig. 2
. Higher quality studies showed a statistically significantly smaller effect of epoetin on the risk of transfusion (odds ratio = 0.45; 95% CI = 0.33 to 0.62) than lower quality studies (odds ratio = 0.14; 95% CI = 0.060 to 0.31); 95% CIs for the odds ratios do not overlap.
To express the absolute effectiveness of epoetin, we also calculated the number of patients who would need to be treated to prevent one patient from being transfused (NNT). The overall NNT for all studies in the meta-analysis was 4.4 (95% CI = 3.6 to 6.1; Table 3). Therefore, four to five patients would need to receive epoetin for one patient to avoid transfusion. The NNT for higher quality and lower quality studies is 5.2 (95% CI = 3.8 to 8.4) and 2.6 (95% CI = 2.1 to 3.8), respectively. Thus, the higher quality studies predict that one patient would avoid transfusion for every five to six patients treated with epoetin, whereas the lower quality studies predict one for every two to three treated.
Quality-of-life outcomes.
The strongest evidence is currently a randomized, controlled trial that enrolled patient populations with mean baseline hemoglobin concentrations of 10 g/dL or less (44). This trial (n = 375, with 359 evaluable for transfusion outcomes but 290335 evaluable for quality-of-life outcomes) compared the change in quality-of-life scores between control and epoetin-treated study arms from visual analog scales and from the FACT-An and found positive, statistically significant differences (Table 4). Results from the Medical Outcomes Study Short Form-36 (SF-36) were in the same direction but not statistically significant. However, key methodologic features for administering the quality-of-life instruments (see the "Methods" section) were not described. In addition, the minimum changes in quality-of-life scores considered to be clinically significant were not defined prospectively or in the discussion of results.
Of the eight other studies reporting quality-of-life outcomes (40,41,43,49,54,55,60,61), six (41,43,49,54,60,61) reported statistical comparisons between control and epoetin-treated study arms [Table 4; see the comprehensive evidence report (18) for within-arm comparisons of baseline to final results]. Of these six, only one (41) reported a statistically significant between-arm difference on a quality-of-life measure favoring epoetin. This study reported statistically significantly improved results on an item that asked about overall quality of life with the use of a visual analog scale but not on items that asked about energy level or daily activities (Table 4
). Another study (49) reported a statistically significant difference favoring epoetin with the use of the Karnofsky scale as a surrogate for quality of life. Meta-analysis on quality-of-life outcomes was not possible, since the available studies used different instruments.
Relative Effects of Initiating Epoetin at Different Thresholds of Baseline Hemoglobin
No trials directly compared the outcomes of initiating epoetin treatment at alternative hemoglobin thresholds. In addition, no trials associated the outcomes of epoetin therapy with patients' baseline hemoglobin concentration. Thus, only inferences based on indirect comparison are possible as to whether initiating epoetin at one or another hemoglobin threshold results in superior outcomes.
Transfusion outcomes at different baseline hemoglobin ranges. Data included in the comprehensive evidence report (18), but not shown here, demonstrate that epoetin increased the percentage of patients with a hematologic response and increased hemoglobin concentrations by approximately the same amount for groups in each range of mean baseline hemoglobin concentrations. Here we report only on transfusion outcomes.
Of six trials [n = 1026; (4044,52)] on adults with mean baseline hemoglobin concentrations of 10 g/dL or less and reporting the percentage of patients transfused, four (4244,52), including three of the five higher quality studies, reported statistically significantly fewer patients transfused. Four (40,42,43, 52) of five reporting trials, including three (40,42,43) of the higher quality studies, also found that patients required fewer RBC units, although the differences were statistically significant in only two of the trials (42,52).
In five trials [n = 347; (45,47,50,51,53)] with a mean baseline hemoglobin concentration greater than 10 g/dL but less than 12 g/dL and reporting the percentage of patients transfused, the difference between subjects treated with epoetin and control subjects was statistically significant in one study (53). Three trials (45,51,53) also reported fewer RBC units transfused per patient among epoetin-treated patients, but the difference was statistically significant only in one trial (45).
Of three reporting studies (n = 222; (55,60,61)] with a mean baseline hemoglobin concentration of 12 g/dL or higher, the difference in the percentage of patients transfused was statistically significant in one trial (55). Fewer RBC units were transfused per patient in the two reporting studies (55,61), and the difference was statistically significant in one study (55).
As summarized in Table 2, the reported difference between epoetin and control arms in the proportion of patients transfused was similar across the three groups of trials on adults: 9%45% for those with a mean baseline hemoglobin concentration of 10 g/dL or less, 7%47% for those with a mean baseline hemoglobin concentration more than 10 g/dL but less than 12 g/dL, and 7%39% for those with a mean baseline hemoglobin concentration of 12 g/dL or higher. For RBC units per patient per 4 weeks, the differences for the three groups of studies were 00.7, 0.11.3, and 0.30.6, respectively. Thus, the available data do not show an improvement in the transfusion-sparing effects of epoetin by initiating treatment when anemia is less severe. The range of reduction in the percentage of patients transfused and the number of RBC units transfused per patient was similar whether epoetin treatment was initiated when the mean hemoglobin concentration was greater than 10 g/dL or was 10 g/dL or less.
Effects of baseline hemoglobin on odds of transfusion. We explored whether the effect of epoetin on the odds of transfusion depended on the groups' mean baseline hemoglobin concentration. However, the association between baseline hemoglobin and odds of transfusion could be confounded by differences in study quality. We could not restrict the analysis to higher quality studies because all higher quality studies that used the subcutaneous route enrolled groups with a mean baseline hemoglobin concentration of 10 g/dL or less. Therefore, the evidence does not allow us to test for an effect of baseline hemoglobin concentration on the odds of transfusion or to determine by meta-analysis whether there is greater benefit from initiating epoetin treatment at higher hemoglobin concentrations.
Quality-of-life outcomes.
The only studies (41,44) that reported a statistically significant improvement in quality-of-life outcomes attributable to epoetin treatment enrolled patient groups with mean baseline hemoglobin concentrations of 10 g/dL or less (Tables 2 and 4). No studies that enrolled groups with mean concentrations of more than 10 g/dL but less than 12 g/dL reported quality-of-life outcomes. Of four studies (54,55,60,61) that enrolled groups with mean baseline hemoglobin concentrations of 12 g/dL or more and reported quality-of-life outcomes, none reported a statistically significant improvement in quality of life.
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DISCUSSION |
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Evidence is insufficient to determine whether initiating epoetin earlier spares more patients from transfusion than waiting until the hemoglobin concentration declines to nearly 10 g/dL. No studies examined this issue directly. The most robust evidence that epoetin reduces the risk of transfusion comes from trials on groups with a mean baseline hemoglobin concentration of 10 g/dL or less. The quantitative decrease in transfusion use did not appear to be greater in trials where epoetin treatment was initiated in groups with a mean hemoglobin concentration of greater than 10 g/dL compared with trials in which the mean hemoglobin concentration was 10 g/dL or less. Among trials on adult patients with a baseline hemoglobin concentration of 10 g/dL or less, the range of differences between the epoetin and control arms for percentage of patients transfused was 9%45%. For a baseline hemoglobin concentration greater than 10 g/dL, the range was 7%47%. This similarity in transfusion-sparing effect cannot be explained by lower responsiveness to epoetin at higher hemoglobin levels, since the magnitude of the increase in hematologic outcome was approximately the same, regardless of the mean baseline hemoglobin concentration.
Evidence also was insufficient to conclude that starting epoetin treatment at hemoglobin concentrations much above 10 g/dL results in better quality of life than starting treatment when the hemoglobin concentration declines to nearly 10 g/dL. The most frequently cited data on quality-of-life outcomes after epoetin treatment are derived from uncontrolled community-based studies (2628) that report on a population with a mean baseline hemoglobin concentration less than 10 g/dL. However, these uncontrolled studies did not meet the selection criteria for this systematic review and also lack key methodologic features recommended to control for bias in quality-of-life measurements (25,2933). The strongest evidence for an effect of epoetin on quality of life is a randomized, double-blinded trial in a patient population with a mean baseline hemoglobin concentration of 10 g/dL or less (44). That study (44) also reported statistically significant positive correlations between changes in hemoglobin concentration and changes in quality-of-life scores. However, the trial did not actually compare the quality-of-life effects of initiating epoetin treatment at alternative hemoglobin thresholds, and the analysis did not stratify patients by different hemoglobin levels at entry. Trials that enrolled groups with mean baseline hemoglobin concentrations greater than 10 g/dL did not report statistically significant effects of epoetin on quality-of-life outcomes.
The cost of epoetin treatment has been estimated at $3700$6600 per patient per chemotherapy cycle (1517). These costs justify efforts to maximize the efficiency of epoetin use. The available evidence is insufficient to demonstrate that initiating treatment when hemoglobin levels are still well above 10 g/dL either spares more patients from transfusion or improves their quality of life.
A limitation of our findings is the absence of data to permit direct analysis of the likelihood of transfusion as a function of baseline hemoglobin concentration. We classified studies by mean (or, in a few instances, by median) baseline hemoglobin concentrations, which might have obscured clinically important variance around that mean within studies in each category. A particular concern is whether, in the group of studies for which the mean baseline hemoglobin concentration was 10 g/dL or less, this classification might underestimate the benefit of epoetin to subgroups from those studies with a mean baseline hemoglobin concentration of greater than 10 g/dL.
Although it is possible that adequately powered comparative trials might demonstrate the superiority of initiating epoetin at hemoglobin concentrations substantially greater than 10 g/dL, the extant evidence suggests two reasons not to assume that earlier intervention must necessarily be better.
First, in epoetin-treated groups with mean baseline hemoglobin concentrations of 10 g/dL or less, patients with values well below the mean may account for a substantial proportion of transfusions. Only six trials with adult patients reported the standard deviation for the mean baseline hemoglobin concentration [data not shown here; see comprehensive evidence report (18)], and the mean baseline hemoglobin concentration was 10 g/dL or less in four of these trials (4144). In two (41,42) of the four studies, patients with hemoglobin at entry greater than or equal to 1 standard deviation (SD) below the mean were already near the transfusion trigger. For example, Henry et al. (41) reported that patients in their trial were transfused at a mean hemoglobin concentration of 8.2 g/dL, while 1 SD below the mean baseline hemoglobin concentration was 8.5 g/dL. Further details of this analysis are included in the complete evidence report (18).
Second, patients who do not respond to epoetin may account for a substantial proportion of transfusions, irrespective of the hemoglobin concentration at which epoetin treatment is initiated. Although patients with other obvious causes of anemia, for which epoetin treatment would be ineffective, are excluded in these studies, not all patients are able to respond to epoetin. An analysis of potential predictors of response, such as baseline serum erythropoietin concentration, failed to identify any statistically significant predictors of response (18). Nine trials (4044,47,49,52,55) reported data that permit comparison of the percentage of nonresponders with the percentage of transfused patients in the epoetin arms [data not shown here; see comprehensive evidence report (18)]. Only two (41,42) of the nine trials reported that the percentage of epoetin-treated patients transfused was greater than the percentage of patients failing to achieve a hematologic response, and the differences were only 1.5% and 2%, respectively. Seven (40,43,44,47,49,52,55) of the nine trials reported that the percentage of nonresponding patients was greater than the percentage of patients transfused in the epoetin-treated arm; the range of differences was 2.4%39.6%.
On the basis of these considerations, it appears that patients who have baseline hemoglobin concentrations well below 10 g/dL and those who do not respond to epoetin could account for nearly all epoetin-treated patients who are transfused. If true, this interpretation implies that the greatest yield for reducing the number of patients transfused would be obtained by preventing the hemoglobin concentration from falling much below 10 g/dL rather than from setting a hemoglobin threshold well above 10 g/dL for initiating epoetin treatment.
The evidence from this systematic review and meta-analysis also has implications for the design of any future randomized trials that might directly compare different hemoglobin thresholds for initiating epoetin therapy. The meta-analysis found a smaller magnitude of risk reduction for higher quality studies selected for sensitivity analysis, which were double-blinded, than for lower quality, unblinded studies. Thus, the higher quality studies predict that one patient would avoid transfusion for every five to six patients treated with epoetin, whereas the lower quality studies predict one for every two to three treated. Note that a previous meta-analysis (64) on fewer studies (eight studies; n = 813 randomly assigned patients) reported that the magnitude of reduction in transfusion requirements was similar across strata defined by methodologic quality. However, fewer unblinded studies were available for the earlier meta-analysis.
There is some evidence that, in unblinded studies, physicians may be more aggressive in transfusing patients in the control arm, thus overestimating the observed effect of epoetin. The authors of one study (55) noted a tendency for physicians in this unblinded trial to undertransfuse patients in the arm with the higher epoetin dose. Patients in the high-dose arm were transfused at a mean hemoglobin level of 8.0 g/dL, while those in the control and low-dose arms were transfused at mean hemoglobin levels of 8.5 and 8.6 g/dL, respectively. The authors hypothesized that this situation may have inflated the magnitude of effect. This also implies that a patient-level meta-analysis on existing studies to assess whether earlier epoetin intervention results in superior outcomes would be of questionable value, even if feasible. Almost all patients with baseline hemoglobin concentrations greater than 10 g/dL were studied in unblinded trials, which are subject to bias in transfusion orders and thus in measuring the effect of epoetin on transfusions.
The systematic review identified opportunities to improve the standard of study design and reporting for future trials of epoetin and other supportive therapies for oncology patients. We had substantial concern about the impact of subjective judgments regarding the need to transfuse on measurement of treatment outcomes in the available trials. Other deficiencies common to this literature included inadequate statistical power, failure to report on concealment of allocation, failure to consistently report on a common set of clinically relevant outcomes, failure to consistently test and report on statistical significance, failure to account for patients lost to follow-up or excluded from the analysis, failure to use intent-to-treat analyses, and failure to use procedures for minimizing bias in measuring quality of life. In addition, many of these studies suffered from incompleteness of reporting. Future trials should conform to the recommendations of the CONSORT (24). Future trials also should specify a transfusion trigger and should report the mean hemoglobin levels at which transfusion actually occurred in each arm.
Finally, future trials should prospectively stratify patients by characteristics of interest and report outcomes separately for these stratified subgroups. Such characteristics include type of malignancy, prior treatments, therapeutic regimen, and predictors of response. These considerations will produce a more robust body of cumulative evidence by improving the ability to compare results among trials and by increasing the potential for combined analyses.
In conclusion, epoetin reduces the odds of transfusion for cancer patients undergoing therapy, but double-blind studies with less than 10% exclusions reported smaller effects. The number of patients needed to treat to prevent one transfusion is 4.4 for all studies, 5.2 for higher quality studies, and 2.6 for lower quality studies. Only studies with a mean baseline hemoglobin concentration of 10 g/dL or less reported statistically significant effects on quality of life; data were insufficient for a meta-analysis. The available evidence is inadequate to determine whether outcomes are superior if epoetin treatment is initiated when the hemoglobin concentration is substantially higher than 10 g/dL, compared with starting the treatment when the hemoglobin concentration declines to nearly 10 g/dL. Randomized, controlled trials, double-blinded and adequately powered, are needed. Inferences from indirect comparison of the results of the available trials cannot resolve this question.
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NOTES |
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Editor's note: C. L. Bennett has received grants in the past from Amgen (Thousand Oaks, CA) and Ortho-Biotech (Raritan, NJ) and has done consulting work for Amgen. M. S. Gordon has served on a scientific advisory board for Amgen regarding anemia and occasionally speaks on the topic. J. L. Wade III participated as an investigator in an open-cohort study on Procrit for the treatment of anemia secondary to chemotherapy; the study was sponsored by Ortho-Biotech.
This work was developed under contract with the Agency for Healthcare Research and Quality (AHRQ) contract number 290970015. The Blue Cross and Blue Shield Association Technology Evaluation Center is an Evidence-Based Practice Center of the AHRQ.
The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the AHRQ or of the U.S. Department of Health and Human Services.
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Manuscript received December 1, 2000; revised June 7, 2001; accepted June 12, 2001.
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