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Japanese Journal of Clinical Oncology Advance Access published online on February 21, 2008
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hyn002
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© The Author (2008). Published by Oxford University Press. All rights reserved

Weekly Epoetin Beta Maintains Haemoglobin Levels and Improves Quality of Life in Patients with Non-Myeloid Malignancies Receiving Chemotherapy

Yasuhiro Suzuki1, Yutaka Tokuda1,, Yasuhiro Fujiwara2, Hironobu Minami3, Yasuo Ohashi4 and Nagahiro Saijo5

1 Department of Breast and Endocrine Surgery, Tokai University School of Medicine, Kanagawa, Japan
2 Division of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
3 Division of Oncology/Hematology, Department of Medicine, National Cancer Center Hospital East, Chiba, Japan
4 Department of Biostatistics/Epidemiology and Preventive Health Sciences, School of Health Sciences and Nursing, University of Tokyo, Tokyo, Japan
5 National Cancer Center Hospital East, Chiba, Japan

For reprints and all correspondence: Yutaka Tokuda, Department of Breast and Endocrine Surgery, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan. E-mail: tokuda{at}is.icc.u-tokai.ac.jp

Received July 23, 2007; accepted December 28, 2007


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Acknowledgements
 References
 
Objective: This study was aimed at investigating the effectiveness and safety of once-weekly epoetin beta for anaemic cancer patients receiving chemotherapy.

Methods: A total of 104 patients with a haemoglobin level of ≤11.0 g/dL were enrolled. Patients received a once-weekly subcutaneous dose of 36 000 IU epoetin beta for 12 weeks. If the increase in the haemoglobin level was <1.0 g/dL after 6 weeks, or a red blood cell transfusion was required between days 15 and 42, the dose of epoetin beta was increased to 54 000 IU from the subsequent week. The primary endpoint was the percentage of patients who achieved a haemoglobin increase of ≥2.0 g/dL; the haemoglobin response rate. Quality of life (QOL) was assessed using the Functional Assessment of Cancer Therapy-Anaemia (FACT-An) questionnaire.

Results: The haemoglobin response rate was 66.3% among the 98 patients (breast cancer: n = 25; malignant lymphoma: n = 21; ovarian cancer: n = 20; lung cancer: n = 15; other cancers: n = 17) assessable for a haemoglobin response. Thirty-nine patients (39.8%) required a dose escalation to 54 000 IU. At the end of the study, QOL assessable patients (n = 96) showed a mean improvement in the FACT-An total fatigue subscale score (FSS) of 0.3 points from baseline. Patients with a haemoglobin response had a mean change in the total FSS of +3.2, compared with –3.4 for patients without a haemoglobin response. No serious adverse event of epoetin beta was observed.

Conclusions: Epoetin beta administered at an initial dose of 36 000 IU once-weekly was well tolerated, with increased haemoglobin levels and improved QOL in anaemic cancer patients receiving myelosuppressive chemotherapy.

Key Words: anaemia • erythropoietin • cancer • chemotherapy • quality of life


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Acknowledgements
 References
 
Anaemia is a common complication of cancer patients undergoing chemotherapy. Symptoms of anaemia, including fatigue, palpitations, dizziness and dyspnea markedly reduce patient activity, resulting in impaired quality of life (QOL). In most cases, however, physicians hesitate to prescribe red blood cell (RBC) transfusions until the haemoglobin level is <8.0 g/dL, even if the patient has symptoms related to anaemia, such as fatigue. Although the safety of blood transfusion has improved in recent years, risks still remain, such as viral infections, graft versus host disease and haemolytic reactions.

In Europe and the United States, erythropoietin (EPO) agents have widely been used since the 1990s for the treatment of chemotherapy-induced anaemia. Although a three-times weekly dosing schedule was initially introduced (1–3), this schedule was inconvenient for outpatients. Several studies reported that once-weekly dosing of EPO increased the haemoglobin level and improved QOL in a manner comparable with those obtained by three-times weekly dosing (4,5).

Since EPO agents have not been approved for the treatment of chemotherapy-induced anaemia in Japan, we previously conducted a dose-finding study of weekly epoetin beta in patients with malignant lymphoma or lung cancer, resulting in a recommended weekly dose of 36 000 IU (6). In this prospective study, we investigated the haemoglobin response, the effects on QOL and the safety of once-weekly epoetin beta in anaemic patients with non-myeloid malignancies. We also investigated the effects of dose escalation to 54 000 IU in patients showing insufficient haemoglobin increase.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Funding
 Acknowledgements
 References
 
Patient Eligibility
Inclusion criteria were as follows: (a) histological or cytological confirmation of non-myeloid malignancy diagnosis, (b) treatment with cyclic chemotherapy, (c) anaemia (haemoglobin level ≤11.0 g/dL) considered to be primarily chemotherapy-induced, (d) life expectancy of at least 4 months, (e) aged between 20 and 79 years, (f) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, (g) eligibility for the QOL questionnaire and (h) adequate hepatic and renal function.

Exclusion criteria included: (a) iron deficiency (mean corpuscular volume <80 µm3 or iron saturation [{Fe/(Fe+ unsaturated iron-binding capacity)} x 100] <15.0%); (b) surgery scheduled during the study period; (c) EPO therapy within 4 weeks prior to the study; (d) documented haemorrhagic lesions; (e) pregnancy, breastfeeding or non-use of adequate birth control measures; (f) history of myocardial, pulmonary, cerebral infarction, serious drug allergy, uncontrolled hypertension, hypersensitivity to any EPO agent or any serious complication; and (g) tumor in the central nervous system.

Study Design and Treatment Schedule
This multicentre, open-label study was conducted at 14 sites in Japan.

The protocol was approved by the institutional review board of the respective hospitals, and written informed consent was obtained from all patients who participated in the study.

The initial dose of epoetin beta (Chugai Pharmaceutical Co., Ltd, Tokyo, Japan) was 36 000 IU, and a once-weekly treatment was administered subcutaneously for 12 weeks. If the patient's haemoglobin level did not increase by ≥1.0 g/dL from baseline after 6 weeks of treatment, or an RBC transfusion was required between days 15 and 42, the dose of epoetin beta was increased to 54 000 IU weekly from the subsequent week. If the haemoglobin level increased to ≥14.0 g/dL, epoetin beta was discontinued until the haemoglobin level decreased to ≤12.0 g/dL, and was then restarted at two-thirds (24 000 IU or 36 000 IU) of the previous dose (36 000 IU or 54 000 IU). RBC transfusion was allowed at the discretion of the investigator during the study. An oral daily dose of 100–200 mg elemental iron was recommended if the mean corpuscular volume was <80 µm3 or the iron saturation was <15.0%.

QOL was evaluated at baseline and week 12 using the Japanese Functional Assessment of Cancer Therapy-Anaemia (FACT-An) questionnaire (7,8), a well-validated instrument. In this study, the FACT-An total fatigue subscale, which consists of 13 fatigue related questions, was mainly analysed. The FACT-An total fatigue subscale scores (FSS) range from 0 to 52, with higher scores indicating less fatigue.

Evaluation of Efficacy and Safety
The American Society of Clinical Oncology/The American Society of Hematology guidelines (9) stipulate that the criteria for the haemopoietic effect should be an increase in haemoglobin level ≥1.0–2.0 g/dL in 6–8 weeks. Furthermore, there are reports (2,6), which showed that QOL is improved in patients with an increase in haemoglobin level of ≥2.0 g/dL.

The primary endpoint of the study was the percentage of patients achieving an increase in the haemoglobin level of ≥2.0 g/dL from the baseline between weeks 4 and 12, the haemoglobin response rate, excluding the data within 28 days after an RBC transfusion. The secondary endpoint was the change in FSS after 12 weeks of treatment. The percentage of patients receiving RBC transfusions between day 28 and the end of the study was also assessed. It was not expected that treatment with an EPO agent could influence transfusion requirements before day 28.

Adverse events (AEs) were assessed during the 12-week treatment period and during a 1-week observation period after the last dosing. Anti-erythropoietin antibodies were measured by the enzyme-linked immunosorbent assay and radio-immunoprecipitation (RIP) assay, and detection by either was judged as positive.

Statistical Analysis
We expected that 90 patients would need to be enrolled in the study to obtain a haemoglobin response rate of 70 ± 10% (95% confidence interval [CI]), as the primary endpoint.

Patients who received at least one dose of the study drug comprised the safety population. For efficacy analysis, the full analysis set (FAS) population was defined as eligible patients who received at least one dose of the study drug.

The changes in the haemoglobin level and FACT-An scores were calculated by subtracting each patient's baseline values from the last values. The rates of increase in haemoglobin before and after dose escalation were compared using a linear mixed-effects model. The potential factors influencing the change in FSS were examined by multiple regression analysis. Pearson correlation coefficients were calculated to assess the association between changes in the haemoglobin level and FACT-An scores.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Funding
 Acknowledgements
 References
 
Demographics and Baseline Characteristics
A total of 104 patients were enrolled in the study between February and November 2004. Five patients discontinued the study before the first dosing for the following reasons: patient eligibility criteria violation, n = 3; patient denial, n = 1; and disease progression, n = 1. Thus, 99 patients were administered epoetin beta. One patient was excluded because of non-compliance with the eligibility criteria, leaving 98 patients as the FAS population. Eighty-seven patients (88.8%) completed all 12 weeks of the study. Eleven patients (11.2%) withdrew from the study. The primary reasons for withdrawal were progressive disease and AEs.

The demographics and baseline characteristics of the FAS population are listed in Table 1. Common types of cancer were breast (n = 25), malignant lymphoma (n = 21), ovarian (n = 20) and lung (n = 15). The mean age was 58.4 years (range: 23–78), and the mean body weight was 50.7 kg (range: 31.7–74.0). Most of the patients had an ECOG PS of 0 or 1 and a tumour stage of III or IV. The main chemotherapeutic agents used during the study were platinum for lung and other types of cancer, anthracycline for malignant lymphoma, taxane for breast cancer and platinum plus taxane for ovarian cancer. All patients met the criterion that they should not be iron-deficient at the time of enrollment.


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  		Table 1. Characteristics of the full analysis set population

 
Haemoglobin Response
The mean change in the haemoglobin level from baseline to the end of the study was 2.47 g/dL (standard deviation [SD]: 2.09; range: –2.8 to 6.0), as shown in Fig. 1. Figure 1 shows the mean changes in haemoglobin levels by tumour type. The pattern of changes in haemoglobin level was similar for the different tumour types. The mean increase in the haemoglobin level in patients with and without an initial EPO level of ≥100 mIU/mL were 1.76 g/dL (SD: 2.60) and 2.50 g/dL (SD: 1.85), respectively.


Figure 1
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  		Figure 1. Change in haemoglobin level by tumor type. Mean weekly haemoglobin levels for the FAS population. Haemoglobin values within 28 days after RBC transfusion were excluded. FAS, full analysis set; RBC, red blood cell.

 
The haemoglobin response rates, defined as the percentage of patients achieving an increase in haemoglobin level of ≥2.0 g/dL from the baseline between weeks 4 and 12, are listed in Table 2. The overall haemoglobin response rate was 66.3% (65 of 98 patients). The median time to the haemoglobin response was 56 days from the first dosing, analysed by the Kaplan–Meier method. The percentage of patients with a haemoglobin level of ≥12.0 g/dL between weeks 4 and 12 was 59.2% (58 of 98 patients).


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  		Table 2. Haemoglobin response rate by baseline haemoglobin, tumour type and dose escalation

 
The percentage of patients who required dose escalation to 54 000 IU was 39.8% (39 of 98 patients). In these patients, the haemoglobin level increased after dose escalation, and the change in the haemoglobin level was 1.23 g/dL (SD: 2.19) at the end of the study. The haemoglobin response rate was 33.3% (13 of 39 patients) in patients who required dose escalation. The rate of haemoglobin increase before and after dose escalation was 0.023 g/dL/week (Weeks 0–6) and 0.266 g/dL/week (Weeks 7–12), respectively (P = 0.0055).

For three patients, the drug treatment was discontinued when the haemoglobin level exceeded 14.0 g/dL, and was restarted at a dose of 24 000 IU when the haemoglobin level decreased to ≤12.0 g/dL.

Quality of Life
Overall compliance in terms of the percentage of patients who completed the FACT-An was 100% at baseline and 97% (95 of 98 patients) at the end of the study. For three patients who dropped out due to progressive disease and were regarded as missing not at random, the scores at the end of the study were substituted with the minimum scores for all patients. Two patients were excluded from the evaluation of the change in the FSS because the responses to some items were missing.

The mean baseline FSS was 31.8 (SD: 11.4, n = 98) points. At the end of the study, the mean change from baseline was 0.3 (SD: 11.8, n = 96) points. The mean FSS change in the patients with progressive disease, as judged by each investigator, was –3.8 (SD: 16.7, n = 15) points (haemoglobin change: 2.4 g/dL). On the other hand, the mean change in patients without progressive disease was 1.9 (SD: 9.6, n = 78) points (haemoglobin change: 2.3 g/dL). These data indicated that progressive disease may be one of the independent variables affecting the change in FSS.

Relationship Between Haemoglobin Response and QOL Score
The results of a multiple regression analysis suggested that the change in the haemoglobin level (P = 0.014), the FSS at the initiation of dosing (P < 0.0001) and the PS at the end of the study (P < 0.0001) largely contributed to the change in the FSS. The correlation coefficient between the change in the FSS and the changes in the haemoglobin level was 0.280, indicating a significant correlation (P = 0.006, n = 96).

Patients who achieved an increase in the haemoglobin level of ≥2.0 g/dL experienced a 3.2-point mean change in FSS. On the other hand, patients who did not achieve an increase in haemoglobin level of ≥2.0 g/dL experienced a –3.4-point change (Fig. 2). There were no differences in the FSS at the initiation of dosing between patients with and without a change in haemoglobin level of ≥2.0 g/dL (32.0 versus 31.6). These data indicate that the change in FSS is dependent on the change in the haemoglobin level.


Figure 2
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  		Figure 2. Changes in the FACT-An total fatigue subscale score by change in haemoglobin level. FACT-An, Functional Assessment of Cancer Therapy-Anaemia.

 
Concerning the relationship between the FSS at the initiation of dosing and the change in the FSS, patients with a baseline FSS of ≤36.0 reported greater improvement (mean ± SD: 1.6 ± 13.0) in the FSS at the end of the study (Table 3).


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  		Table 3. Changes in the FACT-An total fatigue subscale score by baseline FSS and final PS

 
RBC Transfusion Requirement
The percentage of patients who received RBC transfusions between day 28 and the end of the study was only 6.1% (6 of 98 patients). The mean pretransfusion haemoglobin level at the time of the first transfusion was 6.2 g/dL (range: 5.4–7.3 g/dL). The percentage of patients whose haemoglobin level had decreased to <8.0 g/dL or who received an RBC transfusion between day 28 and the end of the study was 20.4% (20 of 98 patients).

Safety
AEs reported by at least 20% of the patients are summarised in Table 4. Death as a result of disease progression was not reported as an AE. Adverse drug reactions reported by at least 5% of patients are listed in Table 5. Among the 133 events in 48 patients (48.5%) that were considered related to the study drug, Grade III events were headache, hypertension, diarrhea, decreased serum potassium, impaired consciousness, anorexia and decreased serum phosphate. Three events (3.0%) of hypertension were reported as possibly related to epoetin beta treatment. An antihypertensive drug was administered after the onset of hypertension in one patient, who had hypertension as a comorbidity before the study. One patient (65-year-old female with malignant lymphoma) experienced a thrombovascular event, a lacunar infarction, at week 6. This event was evaluated as being unrelated to epoetin beta and was attributed to aging.


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  		Table 4. Frequencies of adverse events (n = 99)

 

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  		Table 5. Frequencies of adverse drug reactions (n = 99)

 
The incidence and type of AEs in patients who required dose escalation did not differ from those in patients who did not.

In two patients with ovarian and gastric cancer, anti-erythropoietin antibodies were detected only by RIP assay. Neutralisation of EPO activity was detected in neither patient, and the haemoglobin level was elevated after dosing with the study drug. The investigators judged that the antibody did not cause pure red cell aplasia.

When re-examined six months after the last observation, one of these patients (ovarian cancer) was antibody negative, whereas the other (gastric cancer) could not be re-examined, having died of the underlying disease.


   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Funding
 Acknowledgements
 References
 
Several studies have been conducted to assess the effects of EPO agents in anaemic cancer patients, and increased haemoglobin levels and improvement in QOL that correlated with the increased haemoglobin level were reported (1,10).

The objectives of our study were to investigate the effects of an initial once-weekly 36 000 IU dose of epoetin beta on haemoglobin levels and QOL in patients with non-myeloid malignancy undergoing chemotherapy. The criterion for a haemoglobin response, an increase in the haemoglobin level of ≥2.0 g/dL, was based on a report that symptoms of anaemia assessed by the FACT-An are improved in patients with a change in the haemoglobin level of ≥2.0 g/dL (2,6). According to this index, the haemoglobin response rate in the present study was 66.3% (65 of 98 patients). The increases in haemoglobin levels that were observed were independent of the tumour type or the baseline haemoglobin level. None of the investigators performed a randomised comparison of a dose increase versus an unchanged dose in EPO low responders. In the present study, there was an increase in the rate of haemoglobin increase after dose escalation to 54 000 IU, and the haemoglobin response rate for patients who required a dose escalation was 33.3% (13 of 39 patients).

The secondary endpoint, the change in the FSS, showed an increase of 0.3 points; however, in patients who showed an increase in the haemoglobin level of ≥2.0 g/dL, the FSS was increased by 3.2 points, which was significantly higher than the –3.4-point change in patients whose haemoglobin level increased by <2.0 g/dL. A 3.2-point increase is comparable with the 3 points considered to be a clinically significant change in FSS (11). In addition, the mean change in FSS for patients with progressive diseases (PD) was –3.8 points (median: –6.5 points, range: –37 to 35 points) even though correction of anaemia was observed. In total, excluding PD cases, a 1.9- point improvement was observed.

Investigating the relationship between the FSS at the initiation of dosing and the change in the FSS showed that greater improvements in FSS were observed in patients with lower FSS. The FSS before treatment with epoetin beta was 31.8 ± 11.4 points, which is higher than the scores (FSS: 22.1–29.7 points, change in FSS: 1.6–5.2 points) in cancer patients with anaemia reported in several randomised trials (1,10,12–14). Nevertheless, the mean initial haemoglobin level (9.3 g/dL) in the present study was equal to the levels in the other trials (9.2–10.1 g/dL). Since it has been reported that the FSS after treatment with an EPO agent is aggravated in patients with an FSS exceeding 36.0 at the initiation of dosing (15), the scores were analysed after stratification at 36.0. This resulted in improved scores (1.6 ± 13.0 points) for those patients with a baseline score of ≤36.0, when compared with patients with a score >36.0 (–2.2 ± 8.8 points). The results of a multiple regression analysis of the change in the FSS demonstrated that the change in the haemoglobin level, the FSS at the initiation of dosing and the PS at the end of the study were factors that largely contributed to the change in the FSS. A positive and significant association was observed between the degree of increase in the haemoglobin level and the degree of improvement in the FSS (r = 0.280, P = 0.006). It was comparable with the results (r = 0.2879, P = 0.0002; r = 0.35, P = 0.001 and r = 0.2893, P < 0.0001) of three other studies (1,10,16).

The RBC transfusion rate was only 6.1% (6 of 98 patients) between day 28 and the end of the study. As reported for once-weekly epoetin alfa administered to patients with various types of cancer (14), the transfusion rates between week 5 and the end of treatment were 14.5% (24 of 166 patients) for epoetin alfa and 29.3% (48 of 164 patients) for placebo. Furthermore, the mean pretransfusion haemoglobin levels for the first transfusion reported in the previous trial in the United States (7.9 and 7.8 g/dL, respectively) were higher than those (6.2 g/dL) in the present study in Japan. To evaluate the effect of EPO agents, the percentage of patients whose haemoglobin level had decreased to <8.0 g/dL or who received an RBC transfusion was considered to be a more objective index than the RBC transfusion rate in Japan, because RBC transfusion itself is prescribed at the discretion of the investigator and when the haemoglobin level is low.

Epoetin beta was well tolerated in the present study. Most of the AEs were consistent with the underlying disease or with the chemotherapy. Hypertension, which was judged to be related to epoetin beta was observed in three patients. It was alleviated either by no treatment or the administration of hypotensive agents. Lacunar infarction was also observed in one patient. A relationship to epoetin beta was ruled out, however, and this event was judged to be due to aging. Two recently published studies (17,18) targeting higher haemoglobin levels, in which survival was a primary endpoint, have raised concerns that EPO agents may have a negative impact on survival in cancer patients. A meta-analysis of 57 studies, including these two recent studies revealed an overall survival hazard ratio of 1.08 (95%CI: 0.99–1.18) and that uncertainties remain as to whether EPO agents affected survival (19). The FDA has provided new safety information on erythropoiesis-stimulating agents (ESAs), in which the target haemoglobin level is not to exceed 12 g/dL, because analyses of other studies in patients with cancer found a higher chance of serious and life-threatening adverse drug reactions or deaths with the use of ESAs (20). Although, in the present studies, there was no problem with safety when the haemoglobin level at which dosing was withheld was set at 14 g/dL, in consideration of FDA ALERTs, etc., we intend to investigate the use of lower values for target haemoglobin level and haemoglobin level at which dosing should be withheld.

In conclusion, once-weekly epoetin beta treatment increased the haemoglobin level and correspondingly improved the QOL in anaemic patients with non-myeloid malignancies receiving chemotherapy. Additionally, haemoglobin levels could be improved and controlled by once-weekly treatments at an initial dose of 36 000 IU followed by dose adjustment in the range of 24 000–54 000 IU.


   Funding
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
Acknowledgements
 References
 
This study was supported by Chugai Pharmaceutical Co., Ltd, Tokyo, Japan.


   Acknowledgements
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Acknowledgements
References
 
The authors thank all investigators of Japan Erythropoietin Study Group: Tokai University School of Medicine, National Cancer Center Hospital, National Cancer Center Hospital East, Aichi Cancer Center Hospital, Saitama Medical University, Kinki University School of Medicine, Nihon University School of Medicine, Saitama Cancer Center, Tsukuba University Hospital, Niigata Cancer Center Hospital, National Hospital Organization Nagoya Medical Center, Niigata University Medical & Dental Hospital, Tochigi Cancer Center and Osaka City General Hospital.

Conflict of interest statement

One of the authors, Hironobu Minami, receives honoraria from Chugai Pharmaceutical Co., Ltd. and Kirin Pharma Co., Ltd.

One of the authors, Yasuo Ohashi, consults on design and data analysis of clinical trials for Chugai Pharmaceutical Co., Ltd.

One of the authors, Nagahiro Saijo, holds stock option for Takeda Pharmaceutical Co., Ltd.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Acknowledgements
 References
 
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6 Morishima Y, Ogura M, Yoneda S, Sakai H, Tobinai K, Nishiwaki Y, et al. Qnce-weekly epoetin-beta improves hemoglobin levels in cancer patients with chemotherapy-induced anemia: a randomized, double-blind, dose-finding study. Jpn J Clin Oncol (2006) 36(10):655–61.[Abstract/Free Full Text]

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14 Witzig TE, Silberstein PT, Loprinzi CL, Sloan JA, Novotny PJ, Mailliard JA, et al. Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol (2005) 23(12):2606–17.[Abstract/Free Full Text]

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20 FDA ALERT [Updated 2007 Mar 09; cited 2006 Nov 16]. Information on Erythropoiesis Stimulating Agents (ESA). available at http://www.fda.gov/cder/drug/InfoSheets/HCP/RHE2007HCP.htm.


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