Japanese Journal of Clinical Oncology Advance Access originally published online on September 20, 2006
Japanese Journal of Clinical Oncology 2006 36(10):655-661; doi:10.1093/jjco/hyl097
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© 2006 Foundation for Promotion of Cancer Research
Once-Weekly Epoetin-Beta Improves Hemoglobin Levels in Cancer Patients with Chemotherapy-Induced Anemia: A Randomized, Double-Blind, Dose-Finding Study
1 Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, Nagoya, 2 Department of Pulmonary Medicine, Saitama Cancer Center, Saitama, 3 Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, Nagoya, 4 Thoracic Oncology Division, National Cancer Center Hospital East, Kashiwa, Chiba, 5 Division of Oncology/Hematology, Department of Medicine, National Cancer Center Hospital East, Kashiwa, Chiba, 6 Division of Hematology and Oncology, Department of Medicine, Tokai University School of Medicine, Isehara, Kanagawa, 7 Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, 8 Division of Internal Medicine and Thoracic Oncology, National Cancer Center Hospital, Tokyo, 9 Department of Internal Medicine, Niigata Cancer Center Hospital, Niigata, 10 Department of General Thoracic and Thyroid Surgery, Tokyo Medical University Hospital, Tokyo, 11 Department of Thoracic Diseases, Tochigi Cancer Center, Utsunomiya, 12 Department of Respiratory Medicine, Yokohama Municipal Citizen's Hospital, Yokohama, 13 Department of Biostatistics/Epidemiology and Preventive Health Sciences, School of Health Sciences and Nursing, University of Tokyo, Tokyo, 14 Saitama Medical School, Iruma-gun, Saitama and 15 National Cancer Center Hospital East, Kashiwa, Chiba, Japan
For reprints and all correspondence: Yasuo Morishima, Department of Hematology and Cell Therapy, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan. E-mail: ymorisim{at}aichi-cc.jp
Received February 4, 2006; accepted June 16, 2006
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Abstract |
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Objective: To determine a recommended dose of once-weekly epoetin-beta administration for anemic cancer patients receiving myelosuppressive chemotherapy, we conducted a multicenter, randomized, double-blind trial.
Methods: A total of 86 patients with malignant lymphoma or lung cancer who received chemotherapy containing platinum, taxanes or anthracyclines were enrolled in the study. Patients were randomly assigned into groups that received three dose levels of epoetin-beta (9000, 18 000 or 36 000 IU) administered subcutaneously once a week for 12 weeks. The primary endpoint was change in hemoglobin, while the secondary endpoints were quality of life (QOL) assessed by Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire and transfusion requirements.
Results: Among the 69 patients (per protocol set population) assessable for efficacy, hemoglobin level change in the 36 000 IU group was significantly greater than that in the 9000 IU group (1.75 ± 2.15 versus 0.04 ± 1.98 g/dl; P = 0.009), and a significant dose–response relationship was observed for the change in hemoglobin level (P = 0.003). Although changes in FACT-An Total Fatigue subscale (Fatigue subscale) scores were similar for the three dosage groups, there was a statistically significant correlation (r = 0.435, P < 0.001) between the change in hemoglobin levels and the change in Fatigue subscale scores. The proportion of transfused patients was significantly smaller in the 36 000 IU group compared with that in the 9000 IU group (P = 0.022, not adjusted for pre-study transfusions). The incidence of adverse events was similar in the three dosage groups.
Conclusions: Once-weekly epoetin-beta 36 000 IU for 12 weeks was well tolerated and significantly increased hemoglobin levels in anemic cancer patients receiving chemotherapy.
Key Words: chemotherapy-induced anemia • erythropoietin • lung cancer • malignant lymphoma • quality of life
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Introduction |
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Erythropoietin (EPO) is a glycoprotein (MW 30 000) which is the hematologic growth factor produced primarily in the kidney. EPO interacts with erythroid progenitor cells in the bone marrow to increase the peripheral red blood cells (1). Epoetin-beta is recombinant human erythropoietin (rhEPO) (2), which was introduced clinically in the 1990s for the treatment of anemia associated with chronic renal failure, especially in patients receiving hemodialysis.
Cancer patients treated with chemotherapy often suffer from anemia, which is a major contributing factor to fatigue leading to compromised quality of life (QOL) (3,4). In addition, the presence of anemia is associated with shorter survival of patients with malignancies (5). Red blood cell transfusion is the traditional and quickest method of alleviating symptoms of cancer-related anemia. However, the side effects of transfusion such as viral infections have not been completely resolved. Patients tend to decline transfusions, and physicians do not prescribe them in most cases until the hemoglobin levels become <8.0 g/dl. The administration of rhEPO is another choice for the treatment of chemotherapy-inducted anemia. Numerous studies on anemic cancer patients receiving chemotherapy have demonstrated that rhEPO increased hemoglobin levels and reduced the need for transfusions, and some studies reported improvements in QOL as well (6–11). The schedule of rhEPO administration in most trials was three-times per week. This schedule is inconvenient for outpatients receiving chemotherapy. Gabrilove et al. (10) studied a weekly fixed-dose schedule using 40 000–60 000 IU of epoetin-alfa in cancer patients with anemia. The efficacy was comparable with data on the historical regimen of 10 000 IU three-times weekly. Cazzola et al. (12) compared the efficacy and tolerability of epoetin-beta 30 000 IU once-weekly with that of a 10 000 IU three-times weekly regimen in patients with lymphoproliferative malignancies. Their study showed that the once-weekly regimen was as effective as the three-times weekly one in increasing hemoglobin levels and reducing transfusion requirements.
We therefore conducted a multicenter, randomized, double-blind, dose-finding trial of once-weekly epoetin-beta treatment of malignant lymphoma and lung cancer patients receiving platinum-, taxane- or anthracycline-containing chemotherapy. These chemotherapy regimens are the most active and frequently used for the treatment of these malignancies and also produce relatively high incidences of anemia (4). According to the results of this trial, a recommended dose of epoetin-beta was determined for the subsequent randomized placebo-controlled phase III trial in Japan.
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PATIENT ELIGIBILITY
Patients with histologically or cytologically confirmed malignant lymphoma or lung cancer fulfilling the following criteria were enrolled in the study. (i) Age 20–79 years; (ii) Either platinum-, taxane- or anthracycline-based chemotherapy was administered, and more than 2 courses of chemotherapy were scheduled during the study (radiotherapy during the study period was permitted); (iii) Hemoglobin
11 g/dl after chemotherapy administered within 6 weeks before the study, without iron-deficiencies; (iv) Adequate hepatic and renal function (serum total bilirubin 2.0 mg/dl; serum AST 80 IU/l; serum ALT 80 IU/l; serum creatinine < 2.0 mg/dl); (v) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2; (vi) Life expectancy of at least 12 weeks. Exclusion criteria included uncontrolled hypertension, gastrointestinal bleeding, and a known history of myocardial infarction, cerebral infarction or pulmonary embolism. Patients with known hypersensitivity to rhEPO and previous treatment with rhEPO within 4 weeks before the study were also excluded. Female patients who were pregnant were not eligible. Written informed consent was obtained from all patients before entry into the study.
STUDY DESIGN AND TREATMENT SCHEDULE
This study was a multicenter, randomized, double-blind, parallel-group comparative trial. The study protocol was approved by the institutional review board for each of the 11 participating centers in Japan. Epoetin-beta was supplied by Chugai Pharmaceutical Co., LTD (Tokyo, Japan).
Enrolled patients were randomly assigned to receive one of the three dose levels of epoetin-beta (9000, 18 000, or 36 000 IU). Randomization was prospectively stratified according to age, PS, disease (lung cancer or malignant lymphoma) and institution. Subcutaneous injection of epoetin-beta was started at the beginning of the subsequent chemotherapy course and continued, thereafter, once a week for 12 weeks. If the hemoglobin level increased to more than 14 g/dl, epoetin-beta was discontinued until the hemoglobin level decreased to <12 g/dl, and then re-administered at the same dose. An oral iron supplementation (200 mg/day) was taken daily during the study period. No specific guidelines for transfusion use were defined.
ASSESSMENT OF EFFICACY AND SAFETY
The primary end point was change in hemoglobin level, and the secondary end points were QOL and red blood cell transfusion requirements. The change in hemoglobin between the baseline and 12 weeks of administration or the last observation was evaluated. If chemotherapy was discontinued within the 12-week period, the change in hemoglobin was evaluated at the last observation; 4 weeks after the beginning of a final-course of chemotherapy. The QOL instrument used in the study was the Functional Assessment of Cancer Therapy-Anemia (FACT-An) questionnaire (13). The Total Fatigue subscale (Fatigue subscale), which consists of 13 items from FACT-An, was mainly analyzed (scores range from 0 to 52). QOL was measured at the baseline, at 7–11 weeks; at the beginning of a chemotherapy course and at 12 weeks after the initiation of epoetin-beta administration. Adverse events were graded according to the NCI-Common Toxicity Criteria version 2.0 (Japanese edition; Japan Clinical Oncology Group version 1).
STATISTICAL ANALYSIS
Of the enrolled patients, those who received epoetin-beta at least once were included in the safety analysis. For efficacy analysis, the per protocol set (PPS) population was defined as eligible patients who received epoetin-beta without protocol violation. Differences in mean changes in hemoglobin between the groups were assessed by Dunnett's multivariate comparison test (14). Changes in the Fatigue subscale scores were compared by using a t-test. Pearson's correlation coefficient was calculated to assess the relationship between change in hemoglobin and change in the Fatigue subscale scores. The potential factors influencing the change in the Fatigue subscale scores were examined by multiple regression analysis.
To determine the required number of patients, Dunnett's multiple comparison test was conducted with the 9000 IU group as the control arm. At 2.0 g/dl of the change in hemoglobin from baseline and with a 1.8 g/dl standard deviation between the 9000 and 36 000 IU groups, the required number of patients was calculated to be 21 per group; this means that 63 in total (two-tailed significance level: 5.0%; power: 90%). In the study, it was planned to use the PPS as the main analysis for efficacy; therefore, the target number of subjects was established as 84 to allow for patient dropout.
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PATIENT CHARACTERISTICS
A total of 86 patients were enrolled between April 2002 and January 2003, and 83 patients were administered epoetin-beta. All of these 83 patients were eligible for the assessment of safety. For efficacy analysis, 14 patients were then excluded; 13 patients received <7 doses of epoetin-beta with or without <2 courses of chemotherapy mainly due to progression of the disease; and one patient lacked the baseline hemoglobin data. So 69 patients comprised the PPS population evaluated for efficacy. Baseline characteristics of the patients in the PPS population were generally well balanced among the three dosage groups (Table 1), except for transfusion requirements within 4 weeks before the study; in the 9000 IU group, more patients had required transfusions (P = 0.130). Table 2 shows the distribution of chemotherapy regimens used during the study.
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HEMOGLOBIN RESPONSE
Figure 1 shows the mean weekly hemoglobin levels over the 12 weeks of the study for the patients in the PPS population. In the 36 000 IU group, the mean hemoglobin level increased significantly starting from 6 weeks. In contrast, in the 9000 IU group, the mean hemoglobin levels changed little during the study period, despite a higher transfusion rate. The mean changes in hemoglobin level from baseline to last observation for the three dosage groups were summarized in Fig. 2. In 36 000 IU group, a significantly greater increase in the hemoglobin level was observed compared with that in 9000 IU group (P = 0.009); however, there was no significant difference between the 18 000 and 9000 IU groups (P = 0.154). A significant dose–response relationship for the change in hemoglobin level was observed (P = 0.003). As an additional evaluation of efficacy, the proportion of patients who achieved a
2 g/dl increase in hemoglobin level during the study was determined. The results were 40.9% (9/22), 66.7% (16/24) and 78.3% (18/23) in the 9000 IU group, 18 000 IU group and 36 000 IU group, respectively. Epoetin-beta was withheld from 16 patients (one patient in 9000 IU, 8 in 18 000 IU and 7 in 36 000 IU) during the study period, whose hemoglobin levels exceeded 14 g/dl.
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RED BLOOD CELL TRANSFUSION REQUIREMENTS
Five of 22 patients (22.7%) were transfused in the 9000 IU group, 4 of 24 patients (16.7%) in the 18 000 IU group and none of 23 patients in the 36 000 IU group. The proportion of transfused patients was significantly smaller in the 36 000 IU group compared with that in the 9000 IU group (P = 0.022). When patients who had received transfusions within 4 weeks before the study were excluded from the analysis; however, there was no significant difference between the three dosage groups.
QOL
Of the PPS population, 69 patients (100%) at baseline, 62 (89.9%) at 7–11 weeks and 61 (88.4%) at 12 weeks were evaluated for QOL scores. No significant mean change in Fatigue subscale scores was observed in any group at 7–11 weeks and 12 weeks. The relationship between change in hemoglobin level and change in the Fatigue subscale score was examined by correlation analysis. There was a statistically significant correlation (r = 0.435, P < 0.001) between change in hemoglobin levels and change in the Fatigue subscale scores at 7–11 weeks (Fig. 3). Multiple regression analysis was then performed to assess the potential factors contributing to the change in the Fatigue subscale score at 7–11 weeks. The Fatigue subscale score at baseline and change in hemoglobin level were significantly associated with the change in the Fatigue subscale score (P = 0.001). Association with other factors such as the weekly dose of epoetin-beta and chemotherapy regimens were not significantly associated. Patients who achieved an increase in hemoglobin of 2 g/dl at 7–11 weeks had significant improvements in their Fatigue subscale scores (P = 0.012) (Fig. 4).
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SAFETY
The incidence of adverse events was generally similar between the three dosage groups (Table 3). As hematological adverse events, most common were leukocytopenia, neutropenia and thrombocytopenia. As non-hematological adverse events, nausea and appetite loss were commonly observed. One patient in the 36 000 IU group experienced deep vein thrombosis, which was evaluated as unrelated to epoetin-beta. When the thrombosis was found, anemia had not improved (baseline hemoglobin level was 9.9 g/dl and that at the onset of thrombosis was 9.2 g/dl); therefore, deep vein thrombosis was considered to be due to prolonged immobility brought on by aggravated malignant lymphoma and PS.
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Severe adverse events were reported for 12 patients and were judged by the investigators as unrelated to the administration of epoetin-beta. Of the adverse events, 65 events in 23 patients (27.7%) were considered related to epoetin-beta. The incidence of these events was similar between the three dosage groups (Table 3). An increase of serum ALT was observed in one patient (3.6%) in the 9000 IU group, two (7.4%) in the 18 000 IU group and two (7.1%) in the 36 000 IU group. Hypertension or an increase of blood pressure was observed in one patient (3.6%) in the 9000 IU group, three (11.1%) in the 18 000 IU group and one (3.6%) in the 36 000 IU group. Drug administration was discontinued in one of these patients due to hypertension. No tendency was found in the onset time of hypertension, nor in changes of hemoglobin from baseline at the time hypertension occurred.
Anti-erythropoietin antibody was not detected in any patient, but pure red cell aplasia (PRCA) was reported in one malignant lymphoma (Angioimmunoblastic T-cell Lymphoma) patient over a year after this trial. In this patient, neutralizing anti-erythropoietin antibody was not detected even after PRCA was diagnosed.
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Recently, results of several clinical studies have demonstrated the efficacy and safety of weekly rhEPO for the treatment of cancer-related anemia (10,12,15,16). In a large, nonrandomized, community-based study reported by Gabrilove et al. (10), once-weekly dosing of epoetin-alfa was as effective as three-times weekly dosing in increasing hemoglobin levels and improving QOL. Cazzola et al. (12) reported a randomized study of epoetin-beta that compared the efficacy and tolerability of 30 000 IU once-weekly with the conventional 10 000 IU three-times weekly regimen in patients with lymphoproliferative malignancies. Between these two dosing regimens, there was no significant difference in time-adjusted area under the hemoglobin curve and increase in hemoglobin. Two randomized phase III studies using 40 000 IU once-weekly epoetin-alfa also support the use of epoetin-alfa as an ameliorative agent for cancer-related anemia (15,16).
This is the first prospective randomized dose-finding study of once-weekly epoetin-beta in anemic cancer patients treated with chemotherapy. The study demonstrated that the mean increase in hemoglobin level in the 36 000 IU group was significantly higher than that in the 9000 IU group, while the mean increase in hemoglobin level in the 18 000 IU group was not significantly higher than that in the 9000 IU group. In the present study, epoetin-beta 36 000 IU once-weekly administration showed the same efficacy (an increase in hemoglobin level) as a 200 IU/kg thrice-weekly regimen studied in lung cancer patients receiving chemotherapy (6). It is noteworthy to point out that once-weekly epoetin-beta can be conveniently used in an outpatient-based chemotherapy regimen.
FACT-An is one of the widely used QOL assessment tools, which comprises the FACT-General and a 20-item Anemia subscale, 13 items of which make up a Fatigue subscale. Many reports indicated that chemotherapy-induced anemia increased the ease of a patient becoming fatigued and resulted in decreased patient QOL (17–19). The administration of 36 000 IU epoetin-beta did not significantly improve the patients' Fatigue subscale score in spite of increased hemoglobin levels. As a primary goal of the study was to determine a recommended dose of epoetin-beta, the study design was not planned and did not have adequate statistical power to determine whether epoetin-beta would improve the Fatigue subscale scores. According to the results of the study by Hedenus et al. (20), patients with the lowest baseline Fatigue subscale scores (baseline scores of <24) reported the largest improvement in Fatigue subscale scores after the treatment with darbepoetin alfa. In contrast, patients with baseline Fatigue subscale scores of >36 did not show any improvement. In the subset analysis of our study, among the patients with baseline Fatigue subscale scores of 36, a mean improvement in the Fatigue subscale scores at 7–11 weeks were –1.8 for the 9000 IU group, +1.9 for the 18 000 IU group and +4.3 for the 36 000 IU group (36 000 IU versus 9000 IU P = 0.183). Our data also demonstrated a significant correlation between change in Fatigue subscale score and change in hemoglobin level and showed that the patients who responded with a hemoglobin increase of 2 g/dl showed significant improvements in the Fatigue subscale scores. In conjunction with these findings, the administration of epoetin-beta may not be beneficial for the patients with relatively high hemoglobin levels and/or less symptomatic even in an anemic state. Thus, the actual hemoglobin level for initiation of epotein beta will be critical for its optimal use. The ASCO/ASH clinical practice guideline in 2002 recommends the use of rhEPO for chemotherapy-associated anemia patients with the hemoglobin level of 10 g/dl and that the use of rhEPO for patients with the hemoglobin level of 10–12 g/dl should be determined by clinical circumstances (21).
Most of the adverse events in the present study were considered to be related to concomitant chemotherapy, and the incidence of side effects was similar among the three dosage groups. Two large randomized studies (22,23) targeting higher hemoglobin levels raised concerns about the safety of rhEPO, because of the increased thrombovascular events and worsening survival of cancer patients. In our study, one patient in the 36 000 IU group experienced deep vein thrombosis, which was evaluated as unrelated to epoetin-beta. Stimulated tumor growth is another possible mechanism for worsened survival in the rhEPO studies. A meta-analysis of 27 randomized trials of rhEPO showed suggestive but inconclusive evidence for improved overall survival in patients who received rhEPO (8). Further large scale randomized studies are necessary to confirm the effect of rhEPO on tumor outcome and overall survival.
In conclusion, once-weekly epoetin-beta 36 000 IU for 12 weeks was well tolerated and significantly increased hemoglobin levels in anemic cancer patients receiving chemotherapy. Therefore, the weekly dose of 36 000 IU epoetin-beta was determined as a recommended dose for a subsequent randomized, placebo-controlled, phase III study in Japan.
Part of the results in this report was contributed as Abstract No. 8169 at the 2004 American Society of Clinical Oncology Annual Meeting.
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Acknowledgments |
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The authors thank all investigators of Japan Erythropoietin Study Group: Aichi Cancer Center Hospital, Saitama Cancer Center, National Cancer Center Hospital, National Cancer Center Hospital East, Tokai University School of Medicine, Fujita Health University School of Medicine, Niigata Cancer Center Hospital, Tokyo Medical University Hospital, Tochigi Cancer Center and Yokohama Municipal Citizen's Hospital. This study was supported by Chugai Pharmaceutical Co., Ltd., Tokyo, Japan.
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