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Symptom Management and Supportive Care |
aPacific Cancer Medical Center, Anaheim, California, USA; bUniversity of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania, USA; cCarolina Cancer Center, Aiken, South Carolina; dMedina General Hospital, Medina, Ohio, USA; eAmgen Inc., Thousand Oaks, California, USA; fCache Valley Cancer Treatment and Research Center, Logan, Utah
Key Words. Randomized controlled trial • Darbepoetin alfa • Anemia of cancer
Correspondence: Ali Ben-Jacob, M.D., Cache Valley Cancer Treatment and Research Center, 550 East 1400 North Ste. W, Logan, Utah 84341, USA. Telephone: 435-752-5999; Fax: 714-999-1701; e-mail: aliben{at}comcast.net
Received October 31, 2005; accepted for publication January 17, 2007.
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ABSTRACT |
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11 g/dl) due to cancer, 
18 years old, and had not received chemotherapy or radiotherapy within 4 weeks of study screening. Patients were randomized 4:1 to receive darbepoetin alfa, 3.0 µg/kg every 2 weeks (Q2W) (n = 226), or observation only for 12 weeks (n = 59), followed by an optional 9 weeks of darbepoetin alfa, 3.0 µg/kg Q2W. Endpoints were compared between the two treatment arms at week 13. A planned interim analysis indicated that assumptions regarding hospitalization in the study design were incorrect, so the study was terminated early. Therefore, results for the primary endpoint should be interpreted cautiously. The hospitalization rate was similar (0.5 days) for both the darbepoetin alfa and observation groups (p = .73). Transfusion incidence (weeks 5–12) was significantly lower for darbepoetin alfa patients (8%) than for observation patients (22%) (p = .0092). By week 13, hemoglobin increased by 2.1 g/dl in patients receiving darbepoetin alfa, compared with 0.1 g/dl in the observation group p < .0001. Hemoglobin improvements were paralleled by an increase in Functional Assessment of Cancer Therapy–Fatigue score (mean change in score at week 13: darbepoetin alfa, 6.0; observation, 2.2; p < .05). Darbepoetin alfa Q2W can significantly improve hemoglobin levels and reduce transfusion requirements in patients with AOC, resulting in significant improvements in health-related quality of life. Disclosure of potential conflicts of interest is found at the end of this article.
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INTRODUCTION |
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Treatment with an erythropoietic agent during chemotherapy increases hemoglobin values, thereby reducing transfusion incidence and improving HRQoL [9–18]. For anemic cancer patients who are not currently receiving chemotherapy, however, there are few data on the efficacy of erythropoietic agents. Currently, there is no approved erythropoietic agent for the treatment of AOC. Little is known regarding the relative effect of erythropoietic therapy (i.e., compared with no treatment) and, indeed, whether these patients would require any transfusions or suffer from impaired HRQoL in the absence of therapy.
The largest randomized, placebo-controlled trial conducted in this patient population failed to demonstrate a statistically significant reduction in transfusions with epoetin alfa treatment (100 U/kg three times per week [TIW]), although hematocrit values significantly increased by 6% in 32% of patients (p < .008 versus placebo) [19]. However, the relatively low dose of epoetin alfa (100 U/kg TIW) and short treatment period (8 weeks) may have impacted the ability to observe a treatment effect.
More recently, a single-arm study of epoetin alfa (150 U/kg TIW) for up to 16 weeks reported a significant reduction in transfusions and improvements in HRQoL from baseline [20]. Hemoglobin response (defined as a 2-g/dl hemoglobin increase) was 48% in the nonchemotherapy cohort and 63% in patients receiving chemotherapy, although the dose was doubled to 300 U/kg in 39% of patients in each cohort. The exact magnitude of the treatment effect could not be determined, because the study was uncontrolled.
Robust hemoglobin responses have also been reported in patients with AOC treated with darbepoetin alfa weekly (QW), every 3 weeks (Q3W), and every 4 weeks (Q4W) [21]. In a dose-escalation study of darbepoetin alfa (0.5–4.5 µg/kg QW), most patients achieved a 2.0 g/dl hemoglobin increase, accompanied by a reduction in transfusion requirements. In a subsequent part of the study, Q3W (6.75 µg/kg) and Q4W (6.75 µg/kg or 10.0 µg/kg) schedules were examined using a randomized, double-blind, placebo-controlled design. Up to 70% of patients receiving darbepoetin alfa achieved a hemoglobin response, compared with only 5% of placebo patients. These data provided initial evidence that darbepoetin alfa may effectively treat AOC, even when administered at extended intervals. Furthermore, it appears that without treatment, patients with AOC do not spontaneously recover.
Hospitalization represents the largest component of direct costs in oncology, accounting for approximately 50% of all cancer-related expenditures [22]. The potential impact of anemia (erythropoietic) therapy on the incidence and duration of hospitalization has previously not been examined. We conducted a randomized, controlled, open-label, phase II study to evaluate the efficacy, safety, and impact on hospitalization of every-2-week (Q2W) darbepoetin alfa (3.0 µg/kg) in patients with AOC. The primary objective of this study was to evaluate the difference in hospitalization days over 12 weeks between patients treated with darbepoetin alfa and patients who received no erythropoietic therapy. Secondary objectives were to estimate differences in HRQoL, hemoglobin parameters, transfusions, and safety between the two treatment groups.
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PATIENTS AND METHODS |
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18 years of age with a history of, or currently diagnosed with, a nonmyeloid malignancy were eligible for this study if they had cancer-related anemia (hemoglobin 11.0 g/dl), an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–2, and had previously received chemotherapy and/or radiotherapy. Patients were excluded from the study if they had a history of anemia related to hematologic disorders such as iron deficiency, nutritional deficiency, or a history of red cell aplasia, a history of positive antibody response to any erythropoietic protein, cytotoxic chemotherapy, erythropoietic therapy, and/or >30 Gy of radiotherapy to the whole pelvis within 4 weeks before screening or planned during the study. The study protocol was approved by the institutional review board and all patients provided written informed consent before any study-specified procedures were performed.
Study Design
The study comprised two distinct treatment periods.
Randomized Comparative Phase (Test Period): Weeks 1–12
The first part of the study was a 12-week "test period" (Fig. 1). Patients were randomized in a 4:1 ratio to either darbepoetin alfa (3.0 µg/kg Q2W) or observation. For the darbepoetin alfa arm, if hemoglobin increased by <1.0 g/dl from baseline by week 7, the dose was increased to 5.0 µg/kg Q2W. Patients randomized to the observation arm did not receive darbepoetin alfa during the test period.
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Optional Treatment Phase: Weeks 13–21
The second part of the study, beginning at week 13, was characterized by darbepoetin alfa Q2W therapy in both arms. Patients randomized to the observation arm during the test period received darbepoetin alfa (3.0 µg/kg Q2W) for up to 9 weeks if their hemoglobin concentration was 11 g/dl. Dose increases to 5.0 µg/kg Q2W were allowed after 6 weeks of therapy, if hemoglobin increased by <1.0 g/dl from the start of the optional treatment period (week 13).
Patients randomized to receive darbepoetin alfa during the test period were offered continued therapy until week 21. The dose of darbepoetin alfa was increased to 9.0 µg/kg Q2W if hemoglobin increased by <1.0 g/dl from baseline in those patients who had a dose increase during the treatment period. In both arms, the darbepoetin alfa dose was withheld if hemoglobin concentrations exceeded 14.0 g/dl for women or 15.0 g/dl for men. Once hemoglobin concentration decreased to 13.0 g/dl, darbepoetin alfa was reinstated at the same dose used prior to its withholding.
The end of the study was 4 weeks after the last dose of study drug (i.e., week 25).
Patient-Reported Outcomes
The Functional Assessment of Cancer Therapy (FACT)-Fatigue questionnaires were administered at baseline (week 1) and every 4 weeks through the end of the study.
Study Drug
Darbepoetin alfa (Aranesp®; Amgen Inc., Thousand Oaks, CA) was administered s.c. at a starting dose of 3.0 µg/kg Q2W. Darbepoetin alfa was provided in human serum albumin-free, polysorbate-containing solution at concentrations of 200, 325, and 500 µg/ml in 1.0-ml vials.
Study Endpoints
Endpoints in this study included the number of hospitalization days during weeks 1–12, the incidence of transfusions (weeks 5–12; the first 4 weeks of treatment were excluded due to the lag time required for de novo erythropoiesis), the change in hemoglobin levels from baseline, hematopoietic response (increase of 2.0 g/dl over baseline or a hemoglobin value 12.0 g/dl in the absence of a transfusion), hemoglobin response (a 2-g/dl increase in hemoglobin from baseline in the absence of a transfusion during the previous 28 days), and change in FACT-Fatigue scores from baseline to week 13.
Safety was assessed by the incidence of adverse events, the clinical sequelae associated with exceeding hemoglobin thresholds, and the rate of rise in hemoglobin (maximum hemoglobin increase in any 4-week period).
Statistical Analysis
The study was designed to enroll approximately 1,000 patients to detect a 23%–35% reduction in the mean number of days hospitalized in the darbepoetin alfa group compared with the observation group [13, 18]. Because there were few AOC studies on which to base our estimations, we based our calculations on data available from patients with chemotherapy-induced anemia [13, 18]. In previous phase II studies in this population, approximately 20% of the darbepoetin alfa–treated patients were hospitalized in each study, with a mean duration of stay across studies of approximately 2 days, and with a standard deviation of 5–6 days. Among 22 patients who received placebo in one of the studies, the mean duration of hospital stay was 2.8 days, with a standard deviation of 10 days. Using the assumption that the standard deviation for days of hospitalization was 5.8 days for the 21-week treatment group, then the two-sided 95% confidence interval (CI) would extend 0.4 days from the mean (i.e., if the mean was 2.0 days, then the 95% CI would extend from 1.6 to 2.4 days). Using the assumption that the standard deviation for days of hospitalization in a 12-week period is 10.0 days for the control group (as previously observed), then the two-sided 95% CI would extend approximately 1.4 days from the mean (i.e., if the mean was 2.8 days, the 95% CI would extend from 1.4 to 4.2 days for the control group). For the difference between the treatment groups, using the assumption that the common standard deviation was 6.6 days, then the two-sided 95% CI would extend 1.0 days from the observed difference in the means.
One interim analysis was planned to compare treatment groups after approximately 150 patients had had the opportunity to complete treatment through week 9. The primary goal of this interim analysis was to determine if there was an excessive rate of adverse events associated with a rapid rise in hemoglobin concentration. Also, the number of hospital days in the two treatment groups were estimated to determine if the assumptions used to simulate the sample size were met. If the distribution of the data or variability was substantially different from that assumed, then the sample size could have been re-evaluated. Resource utilization data were reviewed to check cost variability assumptions.
Efficacy and safety analyses were conducted on all patients randomized who received at least one dose of darbepoetin alfa (for the treatment group) or who completed all study-day-1 assessments (for the observation group). The HRQoL analysis set included the patients who completed both a baseline and at least one postbaseline assessment.
The last value carried forward (LVCF) method was used to impute missing hemoglobin values and FACT-Fatigue scores. Hemoglobin values within 28 days following a transfusion were excluded and replaced with the last reported pretransfusion hemoglobin value. Kaplan–Meier estimates of percentages with 95% CIs are provided for efficacy endpoints. An unpaired t-test or the Wilcoxon rank-sum test was used for continuous endpoints; the continuity-corrected 
2 test was used for categorical endpoints. p-values were provided to describe the magnitude of the effect sizes.
The incidence of adverse events in each treatment group was provided as a crude percentage with 95% CI. Crude percentages (95% CI) of patients with a 2.0-g/dl rise in hemoglobin concentration within a 28-day window during the treatment period were calculated. The percentage of patients with confirmed neutralizing antibody formation to darbepoetin alfa was summarized.
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RESULTS |
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By the close of enrollment, 287 patients were randomized into the study, 228 to the darbepoetin alfa group and 59 to observation (Fig. 2). Two patients were excluded from the analysis because they did not receive study drug. A total of 230 patients completed the 12-week randomized comparative period (193 [85%] darbepoetin alfa, 37 [63%] observation). The reasons for early withdrawal from the randomized, comparative period were similar between groups and included withdrawal of consent, initiation of chemotherapy, adverse event, and death. %Patient demographics and baseline clinical characteristics were well balanced between groups (Table 1
). Consistent with prior studies of AOC, the endogenous serum EPO (eEPO) level was increased over the normal range (15–19 mU/ml): median eEPO levels were 45.3 mU/ml for the darbepoetin alfa group and 54.6 mU/ml for the observation group (Table 1). Also consistent with a diagnosis of AOC, median serum ferritin concentrations were normal to high, and serum iron concentrations were low.
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Randomized Comparative Phase (Test Period)
The percentages of patients hospitalized for at least one overnight stay were similar in the two groups: 11% (95% CI, 7%–16%) for the darbepoetin alfa group versus 13% (95% CI, 5%–27%) for the observation group (Table 2). The average lengths of stay were also similar (0.5 days for each group; p = .73). There was no significant difference in mean number of hospitalizations between the darbepoetin alfa group (0.1; 95% CI, 0.1–0.2) and the observation group (0.2; 95% CI, 0–0.3), but this was expected because the study was closed prematurely.
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Optional Treatment Phase
As patients entered this period of the study (week 13), the mean hemoglobin was 10.7 (SD, 0.9) g/dl (n = 33). By the end of study (week 25), the mean hemoglobin for these patients was 11.7 (SD, 1.8) g/dl (Fig. 7).
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Safety Results
The overall safety profiles were similar in both the darbepoetin alfa and observation groups. In the darbepoetin alfa group, 72% of patients had at least one adverse event, but only 1% were attributed to the study drug. Serious adverse events were reported for 29% of patients. Four (2%) patients had deep venous thrombosis and three (1%) had a pulmonary embolism. In the control group, 64% of patients had at least one adverse event; 14% of patients experienced a serious adverse event.
The percentage of patients with a hemoglobin rise of >2 g/dl in 28 days, excluding the effect of a transfusion during the 28-day window, was 14% (95% CI, 9%–19%) for the darbepoetin alfa group and 3% (95% CI, 0%–16%) for the 33 patients randomized to observation who subsequently received darbepoetin alfa treatment after week 12. No rapid rise in hemoglobin was observed for observation patients who did not receive darbepoetin alfa.
Twenty-seven patients (9.5%) died while on study. During the randomized comparative phase (weeks 1 to 12), 19 patients died (16 [7.1%] darbepoetin alfa, 3 [5.1%] observation; relative risk, 1.4 [95% CI, 0.4–4.6]). Of the patients who entered the optional treatment phase (all patients with darbepoetin alfa after week 12), 8 patients died. None of the deaths were considered to be related to the study drug. There was no evidence of neutralizing antibodies to darbepoetin alfa reported in patients with serum samples.
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DISCUSSION |
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To our knowledge, this is the largest randomized, controlled trial that directly compares the effects of erythropoietic therapy in patients with AOC with patients receiving no treatment. There were a number of important findings, including the insight that AOC does not improve without treatment: between weeks 5 and 12, 22% of patients not receiving erythropoietic therapy became so severely anemic that transfusions were required. Darbepoetin alfa treatment at 3 µg/kg Q2W improved hemoglobin, with a clinically meaningful and statistically significant reduction in transfusion requirements and improvement in patient-reported symptoms of fatigue. The effect size observed for transfusion and FACT-Fatigue parameters was comparable with that observed in studies of patients with CIA, and may be greater, especially for improvement in self-reported fatigue. The hematopoietic response rates observed in the present study were generally comparable with those previously reported in a similar patient population treated with TIW epoetin alfa [19, 26]. Additionally, the current results are consistent with those from a phase II double-blind, placebo-controlled study of Q3W and Q4W darbepoetin alfa in patients with AOC [21], emphasizing the effectiveness of darbepoetin alfa in this patient population.
Our analysis suggests that darbepoetin alfa does not affect the rate of hospitalization, although because of the decision to halt enrollment, it should be noted that the target sample size was not reached. The hospitalization rate for this patient population was lower than had been estimated during the design of the study, at only 0.5 days. With such a low incidence of overall hospitalization, it is difficult to evaluate any potential treatment effect for this endpoint.
Recently, concerns were raised by two clinical trial reports of epoetin alfa and epoetin beta that suggested a shorter survival time among recombinant human erythropoietin–treated patients with CIA, in part as a result of a higher incidence of thromboembolic events [27, 28]. It has been suggested that these adverse outcomes may have occurred as a result of initiating treatment in nonanemic patients (hemoglobin >12 g/dl) [27] and allowing hemoglobin levels to rise to 15 g/dl during the study period [28]. While these outcomes should not be disregarded, insufficient data collection while these studies were ongoing has precluded definitive conclusions regarding the potential adverse effects of erythropoietic agents in this patient population. Additional randomized, controlled trials are under way to determine if there is an association between thromboembolic events and erythropoietic agents. In the current study, all patients were anemic, and although the dose-withholding levels were relatively high (14 g/dl for women or 15 g/dl for men), and a higher percentage of patients in the treated group experienced a rapid rise in hemoglobin (14%, versus 3% in the observation group), the thrombotic adverse event rates were comparable between the two groups (8% in each). This trial was initiated before darbepoetin alfa was approved by the U.S. Food and Drug Administration, that is, before any prescribing information had been published. The registrational trials for darbepoetin alfa in CIA used the same target hemoglobin thresholds as used here. Subsequently, the prescribing information for darbepoetin alfa and evidence-based guidelines for the treatment of anemia in cancer patients in the presence or absence of chemotherapy have indicated lower target thresholds [29–32]. However, in the absence of significant safety and efficacy data, it is prudent to adopt hemoglobin targets/thresholds in keeping with those now recommended for cancer patients receiving chemotherapy, that is, target hemoglobin not to exceed 12 g/dl and dose withholding at 13 g/dl.
The current study has some limitations. As a result of the unequal 4:1 randomization of darbepoetin alfa to observation and the lack of blinding, it is difficult to assess safety. However, the observed risk to patients left untreated, combined with the dramatic effect observed for both clinical endpoints (transfusions and HRQoL) and surrogate hemoglobin outcomes, creates a clinical imperative to confirm these results in a placebo-controlled study, thereby confirming safety and efficacy. Although currently not indicated for use in AOC, the results of this clinical study suggest broader use for erythropoiesis-stimulating proteins for this indication.
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NOTE ADDED IN PROOF |
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Recently, the results of a phase III, randomized, double-blind, placebo-controlled trial (Amgen Study 20010103) and its accompanying roll-over study (20020149) in anemic patients (n = 989) neither receiving nor planning to receive chemotherapy or radiation therapy have been reported. The patients in this study represented a subset of anemia of cancer patients with active malignant disease.
Based on these findings, the label for Aranesp® was recently updated to include a boxed warning (the U.S. Food and Drug Administration includes boxed warnings on certain drugs to communicate serious safety information to physicians and patients) to include the following statement:
"Increased the risk of death when administered to target a hemoglobin of 12 g/dL in patients with active malignant disease receiving neither chemotherapy nor radiation therapy. ESAs are not indicated for this population."
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DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST |
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ACKNOWLEDGMENTS |
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REFERENCES |
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