Phase III, Randomized, Double-Blind Study of Epoetin Alfa Compared With Placebo in Anemic Patients Receiving Chemotherapy
http://www.100md.com
▲還散笫雖悝◎
the Department of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN
ABSTRACT
PURPOSE: To determine whether weekly epoetin alfa could improve hemoglobin (HgB) levels, reduce RBC transfusions, and improve quality of life (QOL) in patients with advanced cancer and with anemia after receiving myelosuppressive chemotherapy.
PATIENTS AND METHODS: This double-blind, placebo-controlled study randomly assigned patients to placebo or epoetin alfa (Ortho Biotech, Bridgewater, NJ) 40,000 U subcutaneous weekly for 16 weeks. QOL, HgB, and RBC transfusions were measured pretreatment and monthly.
RESULTS: The study accrued 344 patients; 330 were assessable for efficacy and 305 were assessable for QOL. Placebo-treated patients had a mean increase in HgB of 0.9 g/dL (range, 每3.8 to +5.3) compared with 2.8 g/dL (range, 每2.2 to +7.5) for epoetin-treated patients (P < .0001). During the study, 31.7% of placebo-treated patients achieved a 2 g/dL HgB increase compared with 72.7% of epoetin-treated patients (P < .0001). The incidence of RBC transfusion for placebo and epoetin treatment arms was 39.6% and 25.3% (P = .005), respectively. The placebo group received 256 units of RBCs compared with 127 units in the epoetin group (P < .0001). The incidence of toxicity in the groups was similar. Changes in the average QOL scores from baseline to the end of the study were similar in the two groups (P = not significant). The HgB responders (irrespective of treatment arm) had a mean change in Functional Assessment of Cancer Therapy (FACT) fatigue score from a baseline of +5.1 compared with 每2.1 for the nonresponders (P = .006).
CONCLUSION: Epoetin alfa significantly improved HgB and reduced transfusions in this patient population. These results support the use of weekly epoetin alfa as an ameliorative agent for cancer-related anemia.
INTRODUCTION
Erythropoietin (EPO), a naturally occurring hormone produced in the kidney, stimulates red cell production in the bone marrow. Since its introduction in the 1980s, recombinant human erythropoietin (epoetin alfa) has become an important agent for treatment of the anemia associated with renal failure. The typical schedule is subcutaneous (SC) or intravenous epoetin alfa three times weekly timed with hemodialysis. Anemia is a major problem in the treatment of patients with cancer undergoing chemotherapy1 and has many causes. Cancer patients have lower than expected serum EPO concentrations for their corresponding levels of hemoglobin (HgB) compared with patients with other forms of anemia.2,3 Myelosuppressive chemotherapy, cytokines produced by tumor cells, and infectious complications can decrease the number of erythroid precursors in the marrow and decrease their proliferative rate.4 Other potential contributors to cancer-related anemia are gastrointestinal blood loss, poor nutritional status, and frequent phlebotomies.
Anemia is a major contributing factor to fatigue and decreased quality of life (QOL).5-7 Fatigue lowers the performance status of the cancer patient and impairs his or her ability to perform daily activities and work. RBC transfusions are often prescribed to correct cancer-related anemia. Most physicians do not prescribe transfusions until the HgB is in the range of 8.0 g/dL, a level associated with significant fatigue; therefore, patients tend to spend a significant amount of time with HgB values between 8 and 10 g/dL.
Randomized, placebo-controlled trials have consistently demonstrated that EPO, when delivered in a variety of schedules, produces a statistically significant increase in HgB, a reduction in transfusions, and an improvement in QOL scores compared with placebo.8-18 The typical schedule used in these trials was 150 to 300 U/kg SC three times per week, a schedule that is inconvenient for outpatients with cancer, who typically receive treatment every 3 to 4 weeks. A recent study19 administered two doses of EPO at 600 U/kg (approximately 40,000 U for a 70-kg patient) 10 days apart to normal volunteers and showed a significant increase in HgB levels and reticulocyte counts. A second trial demonstrated comparable hematologic and transfusion responses in patients undergoing major orthopedic procedures given either weekly or daily EPO.20 Subsequently, Gabrilove et al21 studied the weekly, fixed-dose (rather than weight based) schedule using 40,000 to 60,000 U of epoetin alfa SC in patients with cancer-related anemia. The HgB and QOL responses were similar to those found for the three times per week schedule in other studies.
The goals of this study were to determine whether weekly epoetin alfa treatment increases HgB levels and decreases transfusion requirements in anemic patients with advanced cancer who are undergoing myelosuppressive chemotherapy for malignancy; to determine if this increase in HgB translated into an improvement in the QOL of this patient population; and to test the Ludwig algorithm22 to predict response to epoetin alfa. This algorithm uses EPO, ferritin, and HgB concentrations at baseline and after 2 weeks to predict HgB response to epoetin alfa at 12 weeks. These goals were studied in the context of a randomized, double-blind, placebo-controlled trial in patients with advanced cancer who were receiving myelosuppressive chemotherapy.
PATIENTS AND METHODS
Patient Eligibility
This study was conducted through the North Central Cancer Treatment Group. Patients were at least 18 years of age and had active, incurable cancer that required treatment with myelosuppressive chemotherapy; patients receiving adjuvant therapy were not eligible. The patients were required to have anemia (males < 11.5 g/dL; females < 10.5 g/dL), an Eastern Cooperative Oncology Group performance status of 0 or 1, a life expectancy 6 months, and a normal or elevated ferritin; patients could not have received any RBC transfusions within 2 weeks of study entry. Patients with uncontrolled hypertension or anemia secondary to vitamin deficiency (B12, folic acid, or iron), gastrointestinal blood loss, or hemolysis were not eligible. Patients with a primary or chemotherapy-induced myelodysplastic syndrome, acute leukemia, previous treatment with EPO within 1 year of study entry, or who were undergoing high-dose therapy with stem-cell rescue were not eligible. All patients provided written, informed consent for this study. The study was approved by the respective institutional review board at each North Central Cancer Treatment Group treatment site.
In addition to a CBC and serum ferritin tests, all patients had routine blood chemistries (alkaline phosphatase, creatinine, total bilirubin, and AST) and a serum EPO performed before study entry. The ferritin and EPO levels were tested again after 1 month of treatment with EPO.
Study Treatment
Patients were randomly assigned to receive either placebo or epoetin alfa 40,000 U SC weekly for 16 weeks. Study drug (epoetin alfa and placebo) was supplied by Ortho Biotech Products LP (Bridgewater, NJ). Patients were instructed to take oral ferrous sulfate 324 mg each day. After the first month, the dose of epoetin alfa was increased to 60,000 U weekly if the HgB had not increased by more than 1.0 g/dL or the patient had required an RBC transfusion. Patients were transfused RBCs at the discretion of the treating physician and a CBC was obtained before the transfusion. If the HgB increased to more than 15 g/dL, CBC was to be repeated 1 week later. If the HgB remained more than 15 g/dL, epoetin alfa was discontinued until the HgB was less than 13.0 g/dL, and then restarted at 75% of the prior dose.
Assessment of Study End Points
The study end points were HgB response, the percentage of patients receiving RBC transfusions, and changes in QOL. Patients completed QOL forms at the beginning of the study and then monthly during the 16-week trial. The QOL instruments used in this study were the Uniscale, the anemia subscale of the Functional Assessment of Cancer Therapy (FACT每An), and a symptom distress scale (SDS). The Uniscale is a simple, single-item, well-validated instrument for measuring global QOL.23 Patients rate their QOL in the last week on a scale of 0 to 100 by placing a mark within a horizontal bar where lowest quality is indicated on the left (0) and the highest quality is indicated on the right (100). The FACT每An instrument assesses the five major domains of QOL and also provides some disease-specific information on cancer patients with anemia.24 For the FACT每An, the patient is asked to rate his or her health-related QOL during the last 7 days. The FACT每An fatigue subscale consists of 13 items from the FACT每An and was the primary QOL assessment used in this study. The FACT-General (FACT每G) subscale uses 27 items from the FACT每An and was also evaluated. The SDS is a 13-item, well-validated instrument specifically for cancer patients that has been used in numerous oncology clinical trials and found to be prognostic for survival in cancer patients.25-28 Patients are asked to score (1 [most favorable] to 5 [least favorable]) the following occurrences in the past 7 days: nausea frequency, nausea severity, appetite, insomnia, pain frequency, pain severity, fatigue, bowel pattern, concentration, appearance, breathing, outlook, and cough.
The 67 different items in the QOL assessment were collected into booklets and administered to the patient before the visit with the physician so that the QOL data were obtained before the patient knew the current status of his or her cancer. The booklet was designed to take 10 to 15 minutes to complete. All QOL scores were transformed to a 0 to 100 scale (a higher score translates to a better QOL) to make results comparable and easier to interpret.
To assess the impact of epoetin alfa or placebo on HgB and RBC transfusions, a CBC was performed every 4 weeks and before any transfusion. HgB values obtained subsequent to RBC transfusions were not excluded. The number of RBC transfusions given during the previous 4 weeks was also recorded. Information on the patient's chemotherapy regimen while participating in the study and the dose of chemotherapy delivered was also collected, as well as a global estimate of tumor response to the regimen (complete response, partial response, stable, regression, or progressive disease). Formal response assessment (with tumor imaging) to the chemotherapy regimens was not required as part of this protocol. After completing 16 weeks of the study, the patient was observed for 1 year for survival.
Statistical Methods
The intent-to-treat patient population was defined as all patients who registered for the study (Fig 1). Patients who received at least one dose of study drug comprised the safety population. The efficacy population was defined as eligible patients who received drug and did not have a protocol violation. The QOL patient population was defined as treated patients who had baseline and at least one subsequent QOL assessment. Patients who died while participating in the study were classified as having completed the study.
Patients were stratified by their type of malignant disease (lung v breast v other), planned concurrent radiation therapy (yes v no), the degree of anemia (mild [ 9.0 g/dL] v more severe [< 9.0 g/dL]), and treatment site. The primary end points were the scores for the following measures of QOL obtained at random assignment and monthly during treatment (Uniscale, SDS, and FACT每An). Secondary end points were the proportion of patients who required transfusions, the average change in HgB levels from baseline, and the incidence of HgB levels less than 9.0 g/dL. Hemoglobin response was defined as a 2 g/dL increase from baseline. All information on transfusions was gathered from the date of study entry until the patient discontinued the study. Because epoetin alfa typically requires several weeks to exert its stimulatory effect on erythropoiesis, we specifically examined the relationship between epoetin alfa versus placebo treatment in transfusions given after the first 28 days. We also carried out a sensitivity analysis using only the subset of patients who survived at least 8 weeks post-treatment initiation. This was done because the HgB response to epoetin alfa usually occurs within 8 weeks.
The QOL scales were standardized by transforming them to a range of 0 to 100 so that comparative changes across scales could be examined. Differences in the transformed QOL scores were tested via the Wilcoxon rank sum test or t test, depending on the veracity of normality assumptions as determined by Shapiro-Wilk testing. The differences between the QOL tests, as measured by the two-sided t test with a 5% type I error rate, were predicted to have an 80% power to detect the difference of 0.33 standard deviations between the epoetin alfa and placebo groups. Average scores had a sample size of 150 assessable patients per group. The study was overaccrued by approximately 10% to account for drop out.
RESULTS
Patient Characteristics
A total of 344 patients were registered and randomly assigned onto the study between December 1998 and September 2001 (Fig 1). Seventy-two percent of patients receiving placebo completed the study compared with 70% of patients treated with epoetin alfa (P = not significant). The percentages of patient withdrawal were also similar at 28% and 30% for the placebo and epoetin alfa groups, respectively. The percentage of patients who refused additional treatment was 12% in the placebo group compared with 8% in the epoetin alfa group (P = .27). Thirteen patients in each group withdrew because of disease progression.
The two treatment groups were similar with respect to baseline characteristics (Table 1). There was no significant difference between the two arms for the type of chemotherapy that was being administered or the chemotherapy dose-intensity for each myelosuppressive chemotherapy agent (P > .05 for each comparison; data not shown). The treating physician provided an assessment of the tumor response obtained from the chemotherapy the patient received during the study period. The overall response rate, percentage with stable disease, and the percentage who experienced disease progression while receiving chemotherapy in the placebo versus epoetin alfa treatment arms was 29% v 25%, 42% v 43%, and 29% v 33%, respectively (P = .86).
The dose of drug was to be increased to 60,000 U if the HgB did not increase by more than 1 g/dL or if an RBC transfusion had been given. Over the course of the study, 72.0% of patients receiving placebo had a dose escalation to 60,000 U/wk, whereas only 42.8% of patients receiving epoetin alfa had the dose escalated (P < .001); these results are indicative of the effectiveness of epoetin alfa at stimulating hematopoiesis and preventing the need for a dose increase.
Efficacy of Epoetin Alfa on Hemoglobin and Transfusion Requirements
The mean HgB at baseline in placebo-treated patients was 9.4 g/dL (median, 9.5; range, 6.9 to 11.4) compared with 9.5 g/dL (median, 9.6; range, 6.0 to 11.4) for patients treated with epoetin alfa (P = .47). Patients randomly assigned to receive epoetin alfa had a significant (P < .001) increase in HgB starting at week 4 and continuing throughout the 16 weeks of the study (Fig 2). The mean change in HgB from baseline to the last reported value was 0.9 g/dL (median, 0.9; range, 每3.8 to +5.3) in the placebo group and 2.8 g/dL (median, 2.8; range, 每2.2 to +7.5) in the epoetin alfa group (P < .0001). The rate of HgB increase was 0.064 g/dL/wk in the placebo group compared with 0.201 g/dL/wk in the epoetin alfa group (P < .0001).
Over the course of the study, 32% of placebo-treated patients achieved a 2 g/dL HgB increase compared with 73% of patients treated with epoetin alfa (P < .0001); the results for a 3 g/dL increase were 10% and 56%, respectively (P < .0001). Because patients receiving RBC transfusions remained in the study and because the transfusion rate was greater in the placebo group than in the epoetin alfa group (vide infra), these differences in HgB increase between the arms are even more significant. Epoetin alfa treatment also prevented the development of severe anemia. After cycle 1, 30% of placebo-treated patients had an HgB less than 9 g/dL compared with only 11% of patients treated with epoetin alfa (P = .0001).
Epoetin alfa was highly effective at prolonging the time to first RBC transfusion (Fig 3) and reducing the need for transfusions. Of the patients receiving placebo, 40% (65 of 164) received RBC transfusions compared with 25% of patients (42 of 166) treated with epoetin alfa (P = .005). Twenty-nine percent of patients (48 of 164) receiving placebo and 15% of patients (24 of 166) receiving epoetin alfa required transfusions after day 28 (P = .001). During the entire study, the placebo group received 256 units of RBC (0.0156 units/d alive) compared with only 127 units (0.0076 units/d alive) in the epoetin alfa group (P < .0001), representing a 50% reduction in transfusion requirement for patients receiving epoetin alfa. The pretransfusion HgB for the first RBC transfusion was a mean of 7.8 g/dL (median, 7.8; range, 4.8 to 10.2) for patients receiving placebo and a mean of 7.9 g/dL (median, 7.7; range, 6.5 to 10.7) for those receiving epoetin alfa.
Epoetin alfa was effective at reducing transfusions in patients with mild anemia ( 9 g/dL) as well as in those with severe anemia (< 9 g/dL) at random assignment. In those with mild anemia, the incidence of transfusion was 29% v 19% in the placebo and epoetin alfa groups, respectively; in the severe anemia group the incidence of transfusion was 62% v 40%. The average change in HgB showed equivalent response to epoetin alfa among the main primary malignant disease types (lung, breast, and other).
Prediction of Response to Epoetin Alfa
A modified algorithm was tested in this study on the patients receiving active drug using data from baseline and after 4 weeks (Table 2). Eighty-four percent of patients (43 of 51) with a serum EPO level less than 100 and an increase in hemoglobin of 0.5 g/dL after 4 weeks of treatment showed an HgB response at 16 weeks. This is somewhat lower than the more than 95% predicted in the previous study.22 In contrast, only 50% of patients (six of 12) with an EPO level more than 100 and a change in HgB of less than 0.5 g/dL at week 4 had an HgB response at 16 weeks.
The mean ferritin concentration at baseline was similar in the two groups: 507 ng/mL (median, 391; range, 11 to 2,216 ng/mL) for patients receiving placebo and 564 ng/mL (median, 405; range, 37 to 2,463 ng/mL) for patients receiving epoetin alfa (P = .35). If hematopoiesis is being stimulated by exogenous EPO, then there should be use of ferritin and a reduction in serum ferritin levels after epoetin alfa treatment. Indeed, after 1 month of treatment, the ferritin level increased by 45 ng/mL for patients treated with placebo and decreased by 63 ng/mL for patients treated with epoetin alfa (P < .0001), indicative of effective hematopoiesis being stimulated by epoetin alfa. The response rate in patients with a ferritin level less than 400 ng/mL at 4 weeks was 77% (50 of 65), which was similar to the 72% found in the study by Ludwig et al22; however, the HgB response for those with a ferritin 400 ng/mL was 39% (16 of 41), compared with only 12% by Ludwig et al.
Given that EPO and ferritin value analyses are not typically repeated for patients undergoing chemotherapy or epoetin alfa treatment, we evaluated the ability of the HgB change at 1 month in the 114 patients treated with epoetin alfa compared with baseline and week 16 HgB values to predict overall epoetin alfa response ( 2 g HgB increase). In the 52 patients (46%) with less than 1 g increase in HgB at 1 month, 62% responded; in the 62 patients (54%) with 1 g increase in HgB at 1 month, 77% eventually responded (P = .10). If the analysis was further restricted to only those patients receiving epoetin alfa and not transfused during the study (to remove the effect of any RBC transfusions on HgB), then the eventual responses were 66% v 84% (P = .077) for the patients with less than 1 g and 1g HgB increase at 1 month, respectively.
Serum EPO levels at baseline were similar in the two treatment groups, with a mean of 102 U/mL (median, 55.8; range, 1.4 to 1,576 U/mL) in the placebo-treated patients compared with 101 U/mL (median, 65; range, 7 to 1,181 U/mL) in the patients treated with epoetin alfa. The baseline EPO concentration was related to subsequent transfusion use (Table 3). When all patients were considered, those with the highest tertile of EPO level were most likely to receive a transfusion (P = .04). However, when the analysis was restricted to the patients who were randomly assigned to epoetin alfa, there was a trend in the same direction but it was not statistically significant (P = .15). Performing the analysis using other EPO level cut points did not alter the overall results. There was no difference in HgB response or improvement in QOL after epoetin alfa treatment with respect to baseline EPO level (Table 3).
Changes in QOL
The baseline median scores for patients receiving placebo were modestly higher (indicative of a higher QOL) than were those for the patients treated with epoetin alfa (Table 4). After treatment, patients treated with epoetin alfa had a mean improvement in the FACT每An fatigue QOL score of +3 compared with +0.6 in the placebo arm (P = .18). Patients treated with epoetin alfa were more likely (34%) than those treated with placebo (28%) to achieve a 10-point improvement in the QOL score, but this difference was not statistically significant (P = .27). When the QOL analysis for FACT每An fatigue was confined to the patients who responded to epoetin alfa (n = 115), there was a mean improvement of 5.4 compared with 0.8 for the 147 patients receiving placebo (P = .05) and to 4.3 for the 48 patients who responded to placebo (P = .62). There was no difference between patients who responded to epoetin alfa and placebo on the Uniscale (P = .99).
To explore the relationship of HgB response (irrespective of treatment arm) and improvement in QOL, the 52 HgB responders from the placebo arm were included. The HgB responders (n = 163) had a mean change in FACT每An fatigue score from baseline of +5.1 compared with 每2.1 for the HgB nonresponders (P = .006). When the analysis was restricted to the patients treated with epoetin alfa, HgB responders had a mean change in FACT每An fatigue score of +5.4 from baseline compared with 每5.7 for nonresponders (P = .02).
Adverse Events
Adverse events are summarized in Table 5. Deaths as a result of disease progression were not reported as adverse events. The incidence of each of these events was similar in the two treatment groups. This suggests that the symptoms were not caused by the study agents. Serious adverse events of grades 3 to 4 were reported for 73 patients (44%) treated with placebo and 81 patients (48%) treated with epoetin alfa (P = NS). Within the grade 3 to 4 adverse events, 11 in the placebo group and nine in the epoetin alfa group were considered possibly, probably, or definitely related to study drug. In the epoetin alfa group, the serious adverse events that were evaluated as possibly or probably drug related were constipation, dizziness, hyponatremia, thrombosis, dyspnea, infection, increased alkaline phosphatase, hemolysis, abdominal pain, and myalgia. No events in the patients treated with epoetin alfa were considered definitely drug related. Except for HgB, data summaries for other laboratory tests measured specifically for the study revealed no treatment-related effects. Occasional laboratory abnormalities were reported as adverse events, but no treatment-related trends were apparent in these data except for anemia. No patient was reported to have pure RBC aplasia.
Thirteen patients (4%) had thrombotic vascular events (TVEs)〞five (3%) in the placebo arm and eight (5%) in the epoetin alfa arm (P = NS). All TVE occurrences were grade 3 to 4 except for one patient receiving placebo who had a myocardial infarction resulting in death (grade 5). One patient in the epoetin alfa group had a nonfatal episode of cerebral ischemia. The other 11 TVEs were cases of thrombosis. One case of thrombosis in each treatment group was evaluated as possibly drug related, whereas the other seven TVEs were evaluated as unrelated or unlikely to be related to study drug. No case of TVE was evaluated as probably or definitely related to study drug. To determine if the patients with TVEs had a rapid increase in HgB values in the cycle preceding the TVE, the mean changes in HgB values from the cycle preceding a TVE to the cycle in which the TVE occurred were evaluated. There was no consistent pattern of HgB change; thus, there is no evidence that a rapid increase in HgB occurred in association with any of the TVEs.
Over the course of the study, drug was withheld for 79 of the 330 patients (15% receiving placebo, 33% receiving epoetin alfa). In the epoetin alfa group the most frequent (16%) single reason for withholding drug was an HgB more than 15 g/dL. The study drug dose was not withheld or reduced for any patients in the placebo group because of elevation of the hemoglobin above 15 g/dL. Fifty-three of the patients (22 receiving placebo, 31 receiving epoetin alfa; P = .23) died within 30 days after the last dose of study medication. Twenty-one of the deaths (eight receiving placebo, 13 receiving epoetin alfa) occurred while the patients were enrolled onto the study; 32 deaths occurred after the patients had completed or been withdrawn from the study.
There were 55 patients (31 receiving placebo, 24 receiving epoetin alfa) who received cisplatin chemotherapy, and the incidence of nephrotoxicity was 29% (nine of 31) in the group receiving placebo and 25% (six of 24) in group receiving epoetin alfa (P = .77). There were no differences in the grades 1 or 2 creatinine toxicities between the two groups.
Analysis of Overall Survival
When the entire group of 330 patients was analyzed, the median overall survival (OS) was 11.2 months for placebo-treated patients compared with 10.4 months for the epoetin alfa group (P = not significant; Fig 4). The OS was also analyzed by HgB response, irrespective of treatment arm, in patients who survived for at least 8 weeks. This time point was chosen because as seen in Fig. 2 and 3, the HgB response to epoetin alfa usually occurs within 8 weeks; therefore, the effect of early deaths on the OS analysis is removed. Hgb responders had a median OS of 11.8 months compared with 10.5 months for HgB nonresponders (P = .05 by Wilcoxon). When the analysis was confined to the patients treated with epoetin alfa, HgB responders had a median survival of 11.7 v 8.8 months for nonresponders (P = .05 by Wilcoxon).
DISCUSSION
Anemia is a frequent complication of cancer and is an important factor contributing to cancer-related fatigue.5-7 The optimal treatment for the anemia is the treatment of the underlying cancer. Unfortunately, treatment for advanced, metastatic cancer usually is not effective or the drugs themselves suppress the marrow and RBC transfusions are required. RBC transfusions are readily available and provide an immediate increment in the HgB but they are not without adverse effects. These include transfusion reactions, volume overload, infection, and expense to the health care system to recruit donors and to administer the transfusions. The attractiveness of EPO is that it is a physiologic stimulant of autologous RBC production and thus has few adverse effects. In fact, the major adverse effect of EPO is economic and thus it is important to demonstrate its efficacy definitively. Current guidelines for use of EPO in patients with cancer-related anemia have been reported recently.29,30
The initial trials of EPO for cancer-related anemia were single-arm studies that administered EPO three times weekly,22,31-39 a schedule developed to fit the dialysis schedule for patients with chronic renal failure. Subsequent randomized studies of EPO daily or three times weekly versus placebo have clearly demonstrated the superiority of EPO over placebo for improving HgB and reducing transfusions.8-16 The daily or even three times weekly practices are inconvenient for cancer patients because they do not synchronize with typical chemotherapy schedules. A recent single-arm study of weekly epoetin alfa demonstrated similar efficacy as the three times weekly schedule using historical controls.21 Our study is the first to evaluate the weekly dose in a randomized, double-blind, placebo-controlled manner, and the results demonstrate that weekly epoetin alfa is superior to placebo in improving HgB and reducing transfusions. The number of RBC transfusions in the epoetin alfa group were half of that received by the patients treated with placebo. These results are similar to other trials that used three times weekly dosing and the single-arm study of weekly epoetin alfa,21 and provide additional rationale for the current medical practice of administering epoetin alfa weekly. In fact, weekly epoetin alfa at 40,000 to 60,000 U SC is already used in current oncology practice.
It is likely that this is the last placebo-controlled trial of EPO for cancer-related anemia. By the time this trial was initiated in 1998, EPO was beginning to be widely used in community oncology practice. Although one could envision a formal randomized trial of the weekly versus three times weekly schedule, the results would not likely change the current clinical practice and thus this study would appear to be of low priority.
To better predict which patients would respond to epoetin alfa, we modified the algorithm22 to use EPO, ferritin, and CBC values at baseline and 4 weeks, and confirmed the findings of Ludwig et al.22 However, we found that simply a 1-g increase in HgB at 1 month also predicted a high rate of epoetin alfa response. The problem with any of the algorithms is that they fail to identify a group with such a low rate of predicted response to epoetin alfa that makes it futile to continue epoetin alfa past 1 month. Thus, at present, the current algorithms to predict response cannot be recommended routinely for clinical practice. It is reasonable to base the decision to continue epoetin alfa treatment or increase the dose simply on HgB response.
This study provides another view of the current transfusion practices of hematology and oncology physicians. Although patients could be entered onto the study with mild anemia (males < 11.5 g/dL; females < 10.5 g/dL), the mean HgB of the enrolled patients was approximately 9.5 g/dL and the HgB value at the time of RBC transfusion was approximately 8 g/dL. Given that epoetin alfa requires several weeks to produce a noticeable increase in HgB, and because physicians wait until the HgB is quite low before transfusions or EPO, cancer patients usually spend weeks with a low HgB and consequently experience fatigue and a low QOL. Whether strategies to treat patients with EPO earlier40 will result in better QOL over time need to be tested along with a pharmacoeconomic analysis to determine whether QOL is improved by a clinically significant amount to warrant the cost.
A primary goal of this study was to determine if the improvement in HgB was associated with an improvement in QOL. Indeed, this hypothesis was proven in that patients who had an HgB response had an improved QOL detected on the FACT每An fatigue subscale. This is in agreement with the findings of others.7,41 However, we were unable to demonstrate a statistically significant increase in global QOL as measured by the Uniscale in the patients treated with epoetin alfa. There are several potential reasons for this lack of effect. First, the Uniscale results at baseline indicated that the placebo-treated patients had a slightly higher median QOL score than the patients treated with epoetin alfa (Table 4). Second, the increase in QOL relates to an increase in HgB, and because RBC transfusions were permitted at physician discretion, the increased transfusion rate in the patients receiving placebo may have masked the true difference in QOL effects between the two arms. Third, the QOL of the patient with cancer is determined by the HgB and a complex mix of factors that includes the activity of the cancer, the type of treatment being received, the level of pain produced by the cancer, and the psychologic state of the patient. In this study, the patients enrolled had advanced incurable cancer, anemia, and were currently receiving chemotherapy. Given that EPO corrects only one of the factors that influence QOL, the global QOL changes were not dramatic. This provides an important caveat to QOL studies in cancer patients: merely correcting one factor in the QOL equation without effective treatment of the underlying cancer is unlikely to produce meaningful changes in global QOL. A similar finding has been observed repeatedly in studies evaluating megestrol acetate as treatment for cancer anorexia and cachexia.42 Although this drug clearly improves appetite and produces weight gain, it generally does not seem to improve QOL measurements.
Epoetin alfa was well tolerated and the adverse events were similar to those experienced by patients who received placebo. Pure RBC aplasia, a rare complication of epoetin alfa found in patients with chronic renal failure,43 was not observed in any patients in this study. Previous studies have suggested a potential survival benefit in patients treated with EPO compared with the placebo group.37,44,45 One recent study showed inferior survival in the EPO-treated patients.17 In our study, when all patients were analyzed there was no difference in OS between the two groups.
This placebo-controlled study clearly demonstrates that epoetin alfa can increase HgB and reduce transfusions in patients with cancer-related anemia. The challenge that remains is improving the other factors that cause fatigue so that patients with cancer will have a significantly improved QOL.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Garton J, Gertz M, Witzig T, et al: Epoetin alfa for the treatment of the anemia of multiple myeloma. Arch Intern Med 155:2069-2074, 1995
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Osterborg A, Boogaerts M, Cimino R, et al: Recombinant human erythropoietin in transfusion-dependent anemic patients with multiple myeloma and non-Hodgkin's lymphoma: A randomized multicenter study〞The European Study Group of Erythropoietin (Epoetin Beta) Treatment in Multiple Myeloma and Non-Hodgkin's Lymphoma. Blood 87:2675-2682, 1996
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Rutherford CJ, Schneider TJ, Dempsey H, et al: Efficacy of different dosing regimens for recombinant human erythropoietin in a simulated perisurgical setting: The importance of iron availability in optimizing response. Am J Med 96:139-145, 1994
Goldberg M, McCutchen J, Jove M, et al: A safety and efficacy comparison study of two dosing regimens of epoetin alfa in patients undergoing major orthopedic surgery. Am J Orthop 25:544-552, 1996
Gabrilove JL, Cleeland CS, Livingston RB, et al: Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: Improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 19:2875-2882, 2001
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ABSTRACT
PURPOSE: To determine whether weekly epoetin alfa could improve hemoglobin (HgB) levels, reduce RBC transfusions, and improve quality of life (QOL) in patients with advanced cancer and with anemia after receiving myelosuppressive chemotherapy.
PATIENTS AND METHODS: This double-blind, placebo-controlled study randomly assigned patients to placebo or epoetin alfa (Ortho Biotech, Bridgewater, NJ) 40,000 U subcutaneous weekly for 16 weeks. QOL, HgB, and RBC transfusions were measured pretreatment and monthly.
RESULTS: The study accrued 344 patients; 330 were assessable for efficacy and 305 were assessable for QOL. Placebo-treated patients had a mean increase in HgB of 0.9 g/dL (range, 每3.8 to +5.3) compared with 2.8 g/dL (range, 每2.2 to +7.5) for epoetin-treated patients (P < .0001). During the study, 31.7% of placebo-treated patients achieved a 2 g/dL HgB increase compared with 72.7% of epoetin-treated patients (P < .0001). The incidence of RBC transfusion for placebo and epoetin treatment arms was 39.6% and 25.3% (P = .005), respectively. The placebo group received 256 units of RBCs compared with 127 units in the epoetin group (P < .0001). The incidence of toxicity in the groups was similar. Changes in the average QOL scores from baseline to the end of the study were similar in the two groups (P = not significant). The HgB responders (irrespective of treatment arm) had a mean change in Functional Assessment of Cancer Therapy (FACT) fatigue score from a baseline of +5.1 compared with 每2.1 for the nonresponders (P = .006).
CONCLUSION: Epoetin alfa significantly improved HgB and reduced transfusions in this patient population. These results support the use of weekly epoetin alfa as an ameliorative agent for cancer-related anemia.
INTRODUCTION
Erythropoietin (EPO), a naturally occurring hormone produced in the kidney, stimulates red cell production in the bone marrow. Since its introduction in the 1980s, recombinant human erythropoietin (epoetin alfa) has become an important agent for treatment of the anemia associated with renal failure. The typical schedule is subcutaneous (SC) or intravenous epoetin alfa three times weekly timed with hemodialysis. Anemia is a major problem in the treatment of patients with cancer undergoing chemotherapy1 and has many causes. Cancer patients have lower than expected serum EPO concentrations for their corresponding levels of hemoglobin (HgB) compared with patients with other forms of anemia.2,3 Myelosuppressive chemotherapy, cytokines produced by tumor cells, and infectious complications can decrease the number of erythroid precursors in the marrow and decrease their proliferative rate.4 Other potential contributors to cancer-related anemia are gastrointestinal blood loss, poor nutritional status, and frequent phlebotomies.
Anemia is a major contributing factor to fatigue and decreased quality of life (QOL).5-7 Fatigue lowers the performance status of the cancer patient and impairs his or her ability to perform daily activities and work. RBC transfusions are often prescribed to correct cancer-related anemia. Most physicians do not prescribe transfusions until the HgB is in the range of 8.0 g/dL, a level associated with significant fatigue; therefore, patients tend to spend a significant amount of time with HgB values between 8 and 10 g/dL.
Randomized, placebo-controlled trials have consistently demonstrated that EPO, when delivered in a variety of schedules, produces a statistically significant increase in HgB, a reduction in transfusions, and an improvement in QOL scores compared with placebo.8-18 The typical schedule used in these trials was 150 to 300 U/kg SC three times per week, a schedule that is inconvenient for outpatients with cancer, who typically receive treatment every 3 to 4 weeks. A recent study19 administered two doses of EPO at 600 U/kg (approximately 40,000 U for a 70-kg patient) 10 days apart to normal volunteers and showed a significant increase in HgB levels and reticulocyte counts. A second trial demonstrated comparable hematologic and transfusion responses in patients undergoing major orthopedic procedures given either weekly or daily EPO.20 Subsequently, Gabrilove et al21 studied the weekly, fixed-dose (rather than weight based) schedule using 40,000 to 60,000 U of epoetin alfa SC in patients with cancer-related anemia. The HgB and QOL responses were similar to those found for the three times per week schedule in other studies.
The goals of this study were to determine whether weekly epoetin alfa treatment increases HgB levels and decreases transfusion requirements in anemic patients with advanced cancer who are undergoing myelosuppressive chemotherapy for malignancy; to determine if this increase in HgB translated into an improvement in the QOL of this patient population; and to test the Ludwig algorithm22 to predict response to epoetin alfa. This algorithm uses EPO, ferritin, and HgB concentrations at baseline and after 2 weeks to predict HgB response to epoetin alfa at 12 weeks. These goals were studied in the context of a randomized, double-blind, placebo-controlled trial in patients with advanced cancer who were receiving myelosuppressive chemotherapy.
PATIENTS AND METHODS
Patient Eligibility
This study was conducted through the North Central Cancer Treatment Group. Patients were at least 18 years of age and had active, incurable cancer that required treatment with myelosuppressive chemotherapy; patients receiving adjuvant therapy were not eligible. The patients were required to have anemia (males < 11.5 g/dL; females < 10.5 g/dL), an Eastern Cooperative Oncology Group performance status of 0 or 1, a life expectancy 6 months, and a normal or elevated ferritin; patients could not have received any RBC transfusions within 2 weeks of study entry. Patients with uncontrolled hypertension or anemia secondary to vitamin deficiency (B12, folic acid, or iron), gastrointestinal blood loss, or hemolysis were not eligible. Patients with a primary or chemotherapy-induced myelodysplastic syndrome, acute leukemia, previous treatment with EPO within 1 year of study entry, or who were undergoing high-dose therapy with stem-cell rescue were not eligible. All patients provided written, informed consent for this study. The study was approved by the respective institutional review board at each North Central Cancer Treatment Group treatment site.
In addition to a CBC and serum ferritin tests, all patients had routine blood chemistries (alkaline phosphatase, creatinine, total bilirubin, and AST) and a serum EPO performed before study entry. The ferritin and EPO levels were tested again after 1 month of treatment with EPO.
Study Treatment
Patients were randomly assigned to receive either placebo or epoetin alfa 40,000 U SC weekly for 16 weeks. Study drug (epoetin alfa and placebo) was supplied by Ortho Biotech Products LP (Bridgewater, NJ). Patients were instructed to take oral ferrous sulfate 324 mg each day. After the first month, the dose of epoetin alfa was increased to 60,000 U weekly if the HgB had not increased by more than 1.0 g/dL or the patient had required an RBC transfusion. Patients were transfused RBCs at the discretion of the treating physician and a CBC was obtained before the transfusion. If the HgB increased to more than 15 g/dL, CBC was to be repeated 1 week later. If the HgB remained more than 15 g/dL, epoetin alfa was discontinued until the HgB was less than 13.0 g/dL, and then restarted at 75% of the prior dose.
Assessment of Study End Points
The study end points were HgB response, the percentage of patients receiving RBC transfusions, and changes in QOL. Patients completed QOL forms at the beginning of the study and then monthly during the 16-week trial. The QOL instruments used in this study were the Uniscale, the anemia subscale of the Functional Assessment of Cancer Therapy (FACT每An), and a symptom distress scale (SDS). The Uniscale is a simple, single-item, well-validated instrument for measuring global QOL.23 Patients rate their QOL in the last week on a scale of 0 to 100 by placing a mark within a horizontal bar where lowest quality is indicated on the left (0) and the highest quality is indicated on the right (100). The FACT每An instrument assesses the five major domains of QOL and also provides some disease-specific information on cancer patients with anemia.24 For the FACT每An, the patient is asked to rate his or her health-related QOL during the last 7 days. The FACT每An fatigue subscale consists of 13 items from the FACT每An and was the primary QOL assessment used in this study. The FACT-General (FACT每G) subscale uses 27 items from the FACT每An and was also evaluated. The SDS is a 13-item, well-validated instrument specifically for cancer patients that has been used in numerous oncology clinical trials and found to be prognostic for survival in cancer patients.25-28 Patients are asked to score (1 [most favorable] to 5 [least favorable]) the following occurrences in the past 7 days: nausea frequency, nausea severity, appetite, insomnia, pain frequency, pain severity, fatigue, bowel pattern, concentration, appearance, breathing, outlook, and cough.
The 67 different items in the QOL assessment were collected into booklets and administered to the patient before the visit with the physician so that the QOL data were obtained before the patient knew the current status of his or her cancer. The booklet was designed to take 10 to 15 minutes to complete. All QOL scores were transformed to a 0 to 100 scale (a higher score translates to a better QOL) to make results comparable and easier to interpret.
To assess the impact of epoetin alfa or placebo on HgB and RBC transfusions, a CBC was performed every 4 weeks and before any transfusion. HgB values obtained subsequent to RBC transfusions were not excluded. The number of RBC transfusions given during the previous 4 weeks was also recorded. Information on the patient's chemotherapy regimen while participating in the study and the dose of chemotherapy delivered was also collected, as well as a global estimate of tumor response to the regimen (complete response, partial response, stable, regression, or progressive disease). Formal response assessment (with tumor imaging) to the chemotherapy regimens was not required as part of this protocol. After completing 16 weeks of the study, the patient was observed for 1 year for survival.
Statistical Methods
The intent-to-treat patient population was defined as all patients who registered for the study (Fig 1). Patients who received at least one dose of study drug comprised the safety population. The efficacy population was defined as eligible patients who received drug and did not have a protocol violation. The QOL patient population was defined as treated patients who had baseline and at least one subsequent QOL assessment. Patients who died while participating in the study were classified as having completed the study.
Patients were stratified by their type of malignant disease (lung v breast v other), planned concurrent radiation therapy (yes v no), the degree of anemia (mild [ 9.0 g/dL] v more severe [< 9.0 g/dL]), and treatment site. The primary end points were the scores for the following measures of QOL obtained at random assignment and monthly during treatment (Uniscale, SDS, and FACT每An). Secondary end points were the proportion of patients who required transfusions, the average change in HgB levels from baseline, and the incidence of HgB levels less than 9.0 g/dL. Hemoglobin response was defined as a 2 g/dL increase from baseline. All information on transfusions was gathered from the date of study entry until the patient discontinued the study. Because epoetin alfa typically requires several weeks to exert its stimulatory effect on erythropoiesis, we specifically examined the relationship between epoetin alfa versus placebo treatment in transfusions given after the first 28 days. We also carried out a sensitivity analysis using only the subset of patients who survived at least 8 weeks post-treatment initiation. This was done because the HgB response to epoetin alfa usually occurs within 8 weeks.
The QOL scales were standardized by transforming them to a range of 0 to 100 so that comparative changes across scales could be examined. Differences in the transformed QOL scores were tested via the Wilcoxon rank sum test or t test, depending on the veracity of normality assumptions as determined by Shapiro-Wilk testing. The differences between the QOL tests, as measured by the two-sided t test with a 5% type I error rate, were predicted to have an 80% power to detect the difference of 0.33 standard deviations between the epoetin alfa and placebo groups. Average scores had a sample size of 150 assessable patients per group. The study was overaccrued by approximately 10% to account for drop out.
RESULTS
Patient Characteristics
A total of 344 patients were registered and randomly assigned onto the study between December 1998 and September 2001 (Fig 1). Seventy-two percent of patients receiving placebo completed the study compared with 70% of patients treated with epoetin alfa (P = not significant). The percentages of patient withdrawal were also similar at 28% and 30% for the placebo and epoetin alfa groups, respectively. The percentage of patients who refused additional treatment was 12% in the placebo group compared with 8% in the epoetin alfa group (P = .27). Thirteen patients in each group withdrew because of disease progression.
The two treatment groups were similar with respect to baseline characteristics (Table 1). There was no significant difference between the two arms for the type of chemotherapy that was being administered or the chemotherapy dose-intensity for each myelosuppressive chemotherapy agent (P > .05 for each comparison; data not shown). The treating physician provided an assessment of the tumor response obtained from the chemotherapy the patient received during the study period. The overall response rate, percentage with stable disease, and the percentage who experienced disease progression while receiving chemotherapy in the placebo versus epoetin alfa treatment arms was 29% v 25%, 42% v 43%, and 29% v 33%, respectively (P = .86).
The dose of drug was to be increased to 60,000 U if the HgB did not increase by more than 1 g/dL or if an RBC transfusion had been given. Over the course of the study, 72.0% of patients receiving placebo had a dose escalation to 60,000 U/wk, whereas only 42.8% of patients receiving epoetin alfa had the dose escalated (P < .001); these results are indicative of the effectiveness of epoetin alfa at stimulating hematopoiesis and preventing the need for a dose increase.
Efficacy of Epoetin Alfa on Hemoglobin and Transfusion Requirements
The mean HgB at baseline in placebo-treated patients was 9.4 g/dL (median, 9.5; range, 6.9 to 11.4) compared with 9.5 g/dL (median, 9.6; range, 6.0 to 11.4) for patients treated with epoetin alfa (P = .47). Patients randomly assigned to receive epoetin alfa had a significant (P < .001) increase in HgB starting at week 4 and continuing throughout the 16 weeks of the study (Fig 2). The mean change in HgB from baseline to the last reported value was 0.9 g/dL (median, 0.9; range, 每3.8 to +5.3) in the placebo group and 2.8 g/dL (median, 2.8; range, 每2.2 to +7.5) in the epoetin alfa group (P < .0001). The rate of HgB increase was 0.064 g/dL/wk in the placebo group compared with 0.201 g/dL/wk in the epoetin alfa group (P < .0001).
Over the course of the study, 32% of placebo-treated patients achieved a 2 g/dL HgB increase compared with 73% of patients treated with epoetin alfa (P < .0001); the results for a 3 g/dL increase were 10% and 56%, respectively (P < .0001). Because patients receiving RBC transfusions remained in the study and because the transfusion rate was greater in the placebo group than in the epoetin alfa group (vide infra), these differences in HgB increase between the arms are even more significant. Epoetin alfa treatment also prevented the development of severe anemia. After cycle 1, 30% of placebo-treated patients had an HgB less than 9 g/dL compared with only 11% of patients treated with epoetin alfa (P = .0001).
Epoetin alfa was highly effective at prolonging the time to first RBC transfusion (Fig 3) and reducing the need for transfusions. Of the patients receiving placebo, 40% (65 of 164) received RBC transfusions compared with 25% of patients (42 of 166) treated with epoetin alfa (P = .005). Twenty-nine percent of patients (48 of 164) receiving placebo and 15% of patients (24 of 166) receiving epoetin alfa required transfusions after day 28 (P = .001). During the entire study, the placebo group received 256 units of RBC (0.0156 units/d alive) compared with only 127 units (0.0076 units/d alive) in the epoetin alfa group (P < .0001), representing a 50% reduction in transfusion requirement for patients receiving epoetin alfa. The pretransfusion HgB for the first RBC transfusion was a mean of 7.8 g/dL (median, 7.8; range, 4.8 to 10.2) for patients receiving placebo and a mean of 7.9 g/dL (median, 7.7; range, 6.5 to 10.7) for those receiving epoetin alfa.
Epoetin alfa was effective at reducing transfusions in patients with mild anemia ( 9 g/dL) as well as in those with severe anemia (< 9 g/dL) at random assignment. In those with mild anemia, the incidence of transfusion was 29% v 19% in the placebo and epoetin alfa groups, respectively; in the severe anemia group the incidence of transfusion was 62% v 40%. The average change in HgB showed equivalent response to epoetin alfa among the main primary malignant disease types (lung, breast, and other).
Prediction of Response to Epoetin Alfa
A modified algorithm was tested in this study on the patients receiving active drug using data from baseline and after 4 weeks (Table 2). Eighty-four percent of patients (43 of 51) with a serum EPO level less than 100 and an increase in hemoglobin of 0.5 g/dL after 4 weeks of treatment showed an HgB response at 16 weeks. This is somewhat lower than the more than 95% predicted in the previous study.22 In contrast, only 50% of patients (six of 12) with an EPO level more than 100 and a change in HgB of less than 0.5 g/dL at week 4 had an HgB response at 16 weeks.
The mean ferritin concentration at baseline was similar in the two groups: 507 ng/mL (median, 391; range, 11 to 2,216 ng/mL) for patients receiving placebo and 564 ng/mL (median, 405; range, 37 to 2,463 ng/mL) for patients receiving epoetin alfa (P = .35). If hematopoiesis is being stimulated by exogenous EPO, then there should be use of ferritin and a reduction in serum ferritin levels after epoetin alfa treatment. Indeed, after 1 month of treatment, the ferritin level increased by 45 ng/mL for patients treated with placebo and decreased by 63 ng/mL for patients treated with epoetin alfa (P < .0001), indicative of effective hematopoiesis being stimulated by epoetin alfa. The response rate in patients with a ferritin level less than 400 ng/mL at 4 weeks was 77% (50 of 65), which was similar to the 72% found in the study by Ludwig et al22; however, the HgB response for those with a ferritin 400 ng/mL was 39% (16 of 41), compared with only 12% by Ludwig et al.
Given that EPO and ferritin value analyses are not typically repeated for patients undergoing chemotherapy or epoetin alfa treatment, we evaluated the ability of the HgB change at 1 month in the 114 patients treated with epoetin alfa compared with baseline and week 16 HgB values to predict overall epoetin alfa response ( 2 g HgB increase). In the 52 patients (46%) with less than 1 g increase in HgB at 1 month, 62% responded; in the 62 patients (54%) with 1 g increase in HgB at 1 month, 77% eventually responded (P = .10). If the analysis was further restricted to only those patients receiving epoetin alfa and not transfused during the study (to remove the effect of any RBC transfusions on HgB), then the eventual responses were 66% v 84% (P = .077) for the patients with less than 1 g and 1g HgB increase at 1 month, respectively.
Serum EPO levels at baseline were similar in the two treatment groups, with a mean of 102 U/mL (median, 55.8; range, 1.4 to 1,576 U/mL) in the placebo-treated patients compared with 101 U/mL (median, 65; range, 7 to 1,181 U/mL) in the patients treated with epoetin alfa. The baseline EPO concentration was related to subsequent transfusion use (Table 3). When all patients were considered, those with the highest tertile of EPO level were most likely to receive a transfusion (P = .04). However, when the analysis was restricted to the patients who were randomly assigned to epoetin alfa, there was a trend in the same direction but it was not statistically significant (P = .15). Performing the analysis using other EPO level cut points did not alter the overall results. There was no difference in HgB response or improvement in QOL after epoetin alfa treatment with respect to baseline EPO level (Table 3).
Changes in QOL
The baseline median scores for patients receiving placebo were modestly higher (indicative of a higher QOL) than were those for the patients treated with epoetin alfa (Table 4). After treatment, patients treated with epoetin alfa had a mean improvement in the FACT每An fatigue QOL score of +3 compared with +0.6 in the placebo arm (P = .18). Patients treated with epoetin alfa were more likely (34%) than those treated with placebo (28%) to achieve a 10-point improvement in the QOL score, but this difference was not statistically significant (P = .27). When the QOL analysis for FACT每An fatigue was confined to the patients who responded to epoetin alfa (n = 115), there was a mean improvement of 5.4 compared with 0.8 for the 147 patients receiving placebo (P = .05) and to 4.3 for the 48 patients who responded to placebo (P = .62). There was no difference between patients who responded to epoetin alfa and placebo on the Uniscale (P = .99).
To explore the relationship of HgB response (irrespective of treatment arm) and improvement in QOL, the 52 HgB responders from the placebo arm were included. The HgB responders (n = 163) had a mean change in FACT每An fatigue score from baseline of +5.1 compared with 每2.1 for the HgB nonresponders (P = .006). When the analysis was restricted to the patients treated with epoetin alfa, HgB responders had a mean change in FACT每An fatigue score of +5.4 from baseline compared with 每5.7 for nonresponders (P = .02).
Adverse Events
Adverse events are summarized in Table 5. Deaths as a result of disease progression were not reported as adverse events. The incidence of each of these events was similar in the two treatment groups. This suggests that the symptoms were not caused by the study agents. Serious adverse events of grades 3 to 4 were reported for 73 patients (44%) treated with placebo and 81 patients (48%) treated with epoetin alfa (P = NS). Within the grade 3 to 4 adverse events, 11 in the placebo group and nine in the epoetin alfa group were considered possibly, probably, or definitely related to study drug. In the epoetin alfa group, the serious adverse events that were evaluated as possibly or probably drug related were constipation, dizziness, hyponatremia, thrombosis, dyspnea, infection, increased alkaline phosphatase, hemolysis, abdominal pain, and myalgia. No events in the patients treated with epoetin alfa were considered definitely drug related. Except for HgB, data summaries for other laboratory tests measured specifically for the study revealed no treatment-related effects. Occasional laboratory abnormalities were reported as adverse events, but no treatment-related trends were apparent in these data except for anemia. No patient was reported to have pure RBC aplasia.
Thirteen patients (4%) had thrombotic vascular events (TVEs)〞five (3%) in the placebo arm and eight (5%) in the epoetin alfa arm (P = NS). All TVE occurrences were grade 3 to 4 except for one patient receiving placebo who had a myocardial infarction resulting in death (grade 5). One patient in the epoetin alfa group had a nonfatal episode of cerebral ischemia. The other 11 TVEs were cases of thrombosis. One case of thrombosis in each treatment group was evaluated as possibly drug related, whereas the other seven TVEs were evaluated as unrelated or unlikely to be related to study drug. No case of TVE was evaluated as probably or definitely related to study drug. To determine if the patients with TVEs had a rapid increase in HgB values in the cycle preceding the TVE, the mean changes in HgB values from the cycle preceding a TVE to the cycle in which the TVE occurred were evaluated. There was no consistent pattern of HgB change; thus, there is no evidence that a rapid increase in HgB occurred in association with any of the TVEs.
Over the course of the study, drug was withheld for 79 of the 330 patients (15% receiving placebo, 33% receiving epoetin alfa). In the epoetin alfa group the most frequent (16%) single reason for withholding drug was an HgB more than 15 g/dL. The study drug dose was not withheld or reduced for any patients in the placebo group because of elevation of the hemoglobin above 15 g/dL. Fifty-three of the patients (22 receiving placebo, 31 receiving epoetin alfa; P = .23) died within 30 days after the last dose of study medication. Twenty-one of the deaths (eight receiving placebo, 13 receiving epoetin alfa) occurred while the patients were enrolled onto the study; 32 deaths occurred after the patients had completed or been withdrawn from the study.
There were 55 patients (31 receiving placebo, 24 receiving epoetin alfa) who received cisplatin chemotherapy, and the incidence of nephrotoxicity was 29% (nine of 31) in the group receiving placebo and 25% (six of 24) in group receiving epoetin alfa (P = .77). There were no differences in the grades 1 or 2 creatinine toxicities between the two groups.
Analysis of Overall Survival
When the entire group of 330 patients was analyzed, the median overall survival (OS) was 11.2 months for placebo-treated patients compared with 10.4 months for the epoetin alfa group (P = not significant; Fig 4). The OS was also analyzed by HgB response, irrespective of treatment arm, in patients who survived for at least 8 weeks. This time point was chosen because as seen in Fig. 2 and 3, the HgB response to epoetin alfa usually occurs within 8 weeks; therefore, the effect of early deaths on the OS analysis is removed. Hgb responders had a median OS of 11.8 months compared with 10.5 months for HgB nonresponders (P = .05 by Wilcoxon). When the analysis was confined to the patients treated with epoetin alfa, HgB responders had a median survival of 11.7 v 8.8 months for nonresponders (P = .05 by Wilcoxon).
DISCUSSION
Anemia is a frequent complication of cancer and is an important factor contributing to cancer-related fatigue.5-7 The optimal treatment for the anemia is the treatment of the underlying cancer. Unfortunately, treatment for advanced, metastatic cancer usually is not effective or the drugs themselves suppress the marrow and RBC transfusions are required. RBC transfusions are readily available and provide an immediate increment in the HgB but they are not without adverse effects. These include transfusion reactions, volume overload, infection, and expense to the health care system to recruit donors and to administer the transfusions. The attractiveness of EPO is that it is a physiologic stimulant of autologous RBC production and thus has few adverse effects. In fact, the major adverse effect of EPO is economic and thus it is important to demonstrate its efficacy definitively. Current guidelines for use of EPO in patients with cancer-related anemia have been reported recently.29,30
The initial trials of EPO for cancer-related anemia were single-arm studies that administered EPO three times weekly,22,31-39 a schedule developed to fit the dialysis schedule for patients with chronic renal failure. Subsequent randomized studies of EPO daily or three times weekly versus placebo have clearly demonstrated the superiority of EPO over placebo for improving HgB and reducing transfusions.8-16 The daily or even three times weekly practices are inconvenient for cancer patients because they do not synchronize with typical chemotherapy schedules. A recent single-arm study of weekly epoetin alfa demonstrated similar efficacy as the three times weekly schedule using historical controls.21 Our study is the first to evaluate the weekly dose in a randomized, double-blind, placebo-controlled manner, and the results demonstrate that weekly epoetin alfa is superior to placebo in improving HgB and reducing transfusions. The number of RBC transfusions in the epoetin alfa group were half of that received by the patients treated with placebo. These results are similar to other trials that used three times weekly dosing and the single-arm study of weekly epoetin alfa,21 and provide additional rationale for the current medical practice of administering epoetin alfa weekly. In fact, weekly epoetin alfa at 40,000 to 60,000 U SC is already used in current oncology practice.
It is likely that this is the last placebo-controlled trial of EPO for cancer-related anemia. By the time this trial was initiated in 1998, EPO was beginning to be widely used in community oncology practice. Although one could envision a formal randomized trial of the weekly versus three times weekly schedule, the results would not likely change the current clinical practice and thus this study would appear to be of low priority.
To better predict which patients would respond to epoetin alfa, we modified the algorithm22 to use EPO, ferritin, and CBC values at baseline and 4 weeks, and confirmed the findings of Ludwig et al.22 However, we found that simply a 1-g increase in HgB at 1 month also predicted a high rate of epoetin alfa response. The problem with any of the algorithms is that they fail to identify a group with such a low rate of predicted response to epoetin alfa that makes it futile to continue epoetin alfa past 1 month. Thus, at present, the current algorithms to predict response cannot be recommended routinely for clinical practice. It is reasonable to base the decision to continue epoetin alfa treatment or increase the dose simply on HgB response.
This study provides another view of the current transfusion practices of hematology and oncology physicians. Although patients could be entered onto the study with mild anemia (males < 11.5 g/dL; females < 10.5 g/dL), the mean HgB of the enrolled patients was approximately 9.5 g/dL and the HgB value at the time of RBC transfusion was approximately 8 g/dL. Given that epoetin alfa requires several weeks to produce a noticeable increase in HgB, and because physicians wait until the HgB is quite low before transfusions or EPO, cancer patients usually spend weeks with a low HgB and consequently experience fatigue and a low QOL. Whether strategies to treat patients with EPO earlier40 will result in better QOL over time need to be tested along with a pharmacoeconomic analysis to determine whether QOL is improved by a clinically significant amount to warrant the cost.
A primary goal of this study was to determine if the improvement in HgB was associated with an improvement in QOL. Indeed, this hypothesis was proven in that patients who had an HgB response had an improved QOL detected on the FACT每An fatigue subscale. This is in agreement with the findings of others.7,41 However, we were unable to demonstrate a statistically significant increase in global QOL as measured by the Uniscale in the patients treated with epoetin alfa. There are several potential reasons for this lack of effect. First, the Uniscale results at baseline indicated that the placebo-treated patients had a slightly higher median QOL score than the patients treated with epoetin alfa (Table 4). Second, the increase in QOL relates to an increase in HgB, and because RBC transfusions were permitted at physician discretion, the increased transfusion rate in the patients receiving placebo may have masked the true difference in QOL effects between the two arms. Third, the QOL of the patient with cancer is determined by the HgB and a complex mix of factors that includes the activity of the cancer, the type of treatment being received, the level of pain produced by the cancer, and the psychologic state of the patient. In this study, the patients enrolled had advanced incurable cancer, anemia, and were currently receiving chemotherapy. Given that EPO corrects only one of the factors that influence QOL, the global QOL changes were not dramatic. This provides an important caveat to QOL studies in cancer patients: merely correcting one factor in the QOL equation without effective treatment of the underlying cancer is unlikely to produce meaningful changes in global QOL. A similar finding has been observed repeatedly in studies evaluating megestrol acetate as treatment for cancer anorexia and cachexia.42 Although this drug clearly improves appetite and produces weight gain, it generally does not seem to improve QOL measurements.
Epoetin alfa was well tolerated and the adverse events were similar to those experienced by patients who received placebo. Pure RBC aplasia, a rare complication of epoetin alfa found in patients with chronic renal failure,43 was not observed in any patients in this study. Previous studies have suggested a potential survival benefit in patients treated with EPO compared with the placebo group.37,44,45 One recent study showed inferior survival in the EPO-treated patients.17 In our study, when all patients were analyzed there was no difference in OS between the two groups.
This placebo-controlled study clearly demonstrates that epoetin alfa can increase HgB and reduce transfusions in patients with cancer-related anemia. The challenge that remains is improving the other factors that cause fatigue so that patients with cancer will have a significantly improved QOL.
Authors' Disclosures of Potential Conflicts of Interest
The authors indicated no potential conflicts of interest.
NOTES
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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