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Original Paper Symptom Management and Supportive Care

Increased Hemoglobin Levels and Improved Quality-of-Life Assessments During Epoetin Alfa Treatment in Anemic Cancer Patients: Results of a Prospective, Multicenter German Trial

^a Medizinische Klinik I, Klinikum Bayreuth, Bayreuth, Germany; ^b Frauenklinik, Klinikum Bayreuth, Bayreuth, Germany; ^c Ortho Biotech, Neuss, Germany

Correspondence: Uwe Reinhardt, M.D., Medizinische Klinik I, Hämatologie and Onkologie, Klinikum Bayreuth, Preuschwitzer Str. 101, 95445 Bayreuth, Germany. Telephone: 49-921-400-6411; Fax: 49-921-400-6409; e-mail: UUReinhardt{at}t-online.de

	ABSTRACT

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This prospective, open-label, multicenter study was undertaken to determine the safety and efficacy of epoetin alfa in increasing hemoglobin levels and improving quality of life (QOL), specifically fatigue, in cancer patients receiving chemotherapy with or without radiotherapy (n = 702). Epoetin alfa, 10,000 IU three times a week s.c. for 8–18 weeks, increased the mean hemoglobin level relative to baseline (1.0 ± 1.5 g/dl by week 4 and 1.7 g/dl from week 10 through the end of the trial), with 63.4% of patients experiencing 2 g/dl increases in hemoglobin above baseline at some time during the study. Fatigue is an important component of QOL. Physicians, nurses, and patients independently assessed patient fatigue level on a linear-analogue scale. Although all three groups reported improvements in patient fatigue over the course of the study (p < .0001), the magnitude of fatigue ratings and their relationship to tumor response and to hemoglobin level varied by group. Overall, epoetin alfa was well tolerated and effective in improving hemoglobin levels and decreasing fatigue in patients undergoing chemotherapy.

Key Words. Anemia • Cancer • Epoetin alfa • Fatigue • Hemoglobin • Quality of life

	INTRODUCTION

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Anemia, a frequent complication of cancer and its treatment [1], results in both a need for transfusions and a decreased functional capacity and quality of life (QOL) [2–4]. In addition, hemoglobin level has been shown to be a prognostic factor for disease and treatment outcomes for a variety of different types of cancer [5]. The growth factor erythropoietin regulates maturation, proliferation, and differentiation of red blood cells. Epoetin alfa is a recombinant form of human erythropoietin. Numerous clinical studies have demonstrated the efficacy and safety of epoetin alfa, in doses of 10,000 IU three times a week or 40,000 IU once a week, in significantly increasing hemoglobin levels and decreasing transfusion requirements in anemic cancer patients undergoing platinum- or nonplatinum-based chemotherapy [6–9].

Recently, investigators have become particularly concerned with the importance of addressing QOL issues involving patients with cancer, regardless of prognosis [10]. The QOL of cancer patients is a complex phenomenon involving many diverse components, including—but not limited to—fatigue, pain, side effects of cancer therapies, and the inability to complete activities of daily living. Of these, fatigue is the most commonly reported symptom of cancer and cancer therapy, and it appears to be a major factor in reduced QOL [1, 11–13]. Cancer patients report that fatigue limits their ability to work, decreases their ability to finish projects, reduces their social activities, and lowers their feelings of physical and emotional well-being [11]. In addition, patients indicate that fatigue has a greater adverse impact on their daily life than cancer-related pain, a situation largely unrecognized by oncologists [11, 12].

A large body of evidence demonstrates that treatment of anemia in cancer patients improves fatigue and overall QOL [6, 8, 9, 14, 15]. The QOL data in these studies were obtained by patient-completed questionnaires, such as the 100-mm Cancer Linear Analog Scale (CLAS, also known as the Linear Analog Scale Assessment [LASA]); the Functional Assessment of Cancer Therapy-Anemia subscale (FACT-An), which comprises a general questionnaire, the FACT-General (FACT-G), and a 20-item Anemia subscale, 13 items of which make up a separate Fatigue subscale; and the physical and mental summary scales of the Medical Outcomes Study Short Form (SF-36). Previous studies have demonstrated differences in patient and physician perceptions of cancer-related fatigue. To explore the relationships between these differences and disease and treatment outcomes, we chose to have physicians, nurses, and patients independently assess patient fatigue. For this purpose, 10-point linear analog rating scales for patients’, physicians’, and nurses’ assessments of fatigue and related QOL parameters were designed and used in this study. (It should be noted that "exhaustion" was the term specified in the study protocol; however, in the context of the study, the terms fatigue and exhaustion were synonymous, and thus, "fatigue" is used throughout this report.)

The primary purpose of this study was to determine the effects on fatigue of three-times-a-week administration of epoetin alfa, 10,000 IU s.c., to cancer patients receiving chemotherapy and experiencing a high level of fatigue.

	PATIENTS AND METHODS

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Study Design
The study was a prospective, open-label, phase III trial of epoetin alfa in anemic, fatigued, adult cancer patients receiving chemotherapy or chemotherapy and radiotherapy. The study was conducted at 212 centers in Germany between November 1998 and April 2001 (see supplementary online data). Epoetin alfa was supplied in prefilled syringes ready for s.c. injection. (Outside the U.S., epoetin alfa is manufactured by Ortho Biologics, LLC; Manati, Puerto Rico and distributed and marketed as Eprex^® or Erypo^® by Ortho Biotech, a division of Janssen-Cilag; Neuss, Germany.) Study medication could be administered for a minimum of 8 weeks and up to a maximum of 18 weeks. Patients with hemoglobin levels of 9–12 g/dl received 10,000 IU epoetin alfa three times a week; if their hemoglobin levels increased to >12 g/dl, the frequency of dosing was reduced to twice weekly. For patients whose hemoglobin levels rose to >14 g/dl, the study medication was stopped completely until their hemoglobin values fell to 12 g/dl, after which twice-weekly dosing with 10,000 IU epoetin alfa was resumed. If hemoglobin values increased by 2 g/dl per month, epoetin alfa dosing was reduced to twice weekly.

Physicians made individual decisions pertaining to a patient’s need for iron supplementation. If required, patients were to take oral iron capsules (ferrosanol duodenal, 100 mg) throughout the study duration to maintain transferrin saturation at >20% and/or a ferritin level of 30 mg/l. Red blood cell transfusions were given at the physician’s discretion.

Inclusion and Exclusion Criteria
Male or female patients aged 18 years or older with solid tumors or hematologic malignancies undergoing or about to undergo chemotherapy or combination chemotherapy and radiotherapy were enrolled. Additional inclusion criteria were: high level of overall fatigue, with a physician-determined score of >7 on the linear analog scale developed for this study (range, 0–10; 10 indicates highest level of fatigue); Eastern Cooperative Oncology Group (ECOG) performance score of 0–3; planned duration of oncologic therapy of at least 8 weeks; hemoglobin level of 9.0–11.5 g/dl and/or a hemoglobin decrease of 2.5 g/dl during the current cycle of chemotherapy. Female patients had to be postmenopausal, sterilized, or using a reliable method of birth control. Patients were excluded from enrollment if they had any of the following: clinically significant disease unrelated to the malignancy; uncontrolled hypertension (diastolic >100 mmHg); suspected untreated vitamin B12 or folic acid deficiency; hormone therapy with androgens in the 2 months prior to study initiation; myeloablative chemotherapy; acute leukemia; clinically significant acute disease within 7 days and/or acute infection within 1 month before study initiation; known hypersensitivity to epoetin alfa or its excipients; or terminal disease with a life expectancy of <6 months.

End Points
The primary end point was the course of fatigue during treatment with epoetin alfa, 10,000 IU three times weekly, as assessed by the physician. Secondary end points included effects of epoetin alfa on fatigue rated by the patients and nurses, and effects of epoetin alfa on other QOL parameters (lethargy, mood, interest, social activity, problems of daily living, performance of various tasks) rated by physicians, nurses, and patients. As an additional end point, changes from baseline in hemoglobin level over the study were determined.

The usual procedures for QOL assessments were followed for all physician, patient, and nurse evaluations. To assure consistency across centers, assessments were discussed at meetings with the investigators, and study monitors received intensive instruction in assessment procedures. All QOL assessments during the study were made independently, that is, at the time of evaluation, the physician had no knowledge of the assessments made by either the nurse or the patient. Whenever possible, the respective questionnaires were completed by the same physician and the same nurse. QOL assessments were made with the use of a series of newly developed linear analog scales (Appendix 1). Changes in fatigue and performance of various tasks were measured on a linear analog scale (0–10); changes in lethargy, mood, interest, social activity, and problems of daily living also were measured on a linear analog scale (1–10). Changes in QOL parameters were defined as the pretherapy value minus the post-therapy value. For several parameters, for example, appetite in the patient-rated scale, rating scores were inverted to maintain direction of results for the purpose of statistical analyses. All QOL evaluations were performed at the study start, every 4 weeks thereafter through week 20, and at the final visit (study completion or early termination). The fatigue questionnaire developed for this study, the German Exhaustion Scale, was based on the 47-item FACT-An scale (including the 13-item Fatigue subscale) and contains fewer items (eight), with the intent to increase the number of patients willing to participate in the QOL assessment. Also, in contrast to the FACT-An, which is a patient-rated instrument, the German Exhaustion Scale contains additional questionnaires that provide for physicians’ and nurses’ assessments of fatigue. To validate the new fatigue questionnaire, it and the FACT-An were applied in another study of epoetin alfa (EPO-INT-50) at the start of the study (visit 1), at visit 3 (after 8–9 weeks), and at visit 4 (after 12 weeks) (data on file). The following Pearson correlations between the total scores of both instruments were found: visit 1 (n = 155; Pearson’s r = 0.767; p < .0001); visit 3 (n = 111; Pearson’s r = 0.768; p < .0001); visit 4 (n = 90; Pearson’s r = 0.691; p < .0001). These correlations indicate good validity of the fatigue questionnaire.

For assessment of the impact of epoetin alfa therapy on hemoglobin level, a response was defined as an increase in hemoglobin of 2 g/dl compared with baseline at any time during the study, irrespective of transfusion. Hemoglobin was measured at baseline; at weeks 4, 8, 12, 16, and 20; and at the last visit. Additionally, the data were examined to evaluate the possible impact of tumor response on change in fatigue scores categorized by hemoglobin level. To facilitate this, standard definitions for tumor responses specific to each tumor type were provided in the case report forms. Tumor response was evaluated by the treating physician during the study using World Health Organization criteria, and the treating physician documented tumor response to therapy on completion of the study by the patient, using rating sheets provided for this purpose. Thus, the physician had an impression of the therapeutic success during chemotherapy or radiation therapy, but the final classification of tumor response (e.g., complete, partial) took place at the end of the patient’s participation in the study.

Statistics
Of the 702 patients enrolled, 645 who received study medication at least once and for whom at least two hemoglobin values were available (baseline and at least one value obtained during the study) were included in the efficacy analyses. Missing values at any evaluation point were replaced by the last-observation-carried-forward method. Within-group pre- and post-treatment comparisons were performed using the Wilcoxon signed rank test. Pre- and post-treatment changes in hemoglobin values and QOL scores between different groups were compared using the Mann-Whitney test. Spearman rank correlations were used to describe the relationship between pre- and post-treatment hemoglobin levels and QOL scores as assessed by the patient, nurse, and physician. All statistical tests were univariate and evaluated descriptively at p = .05 without adjustment for multiple comparisons.

	RESULTS

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Patients
A total of 702 patients was enrolled at 212 sites in Germany. All enrolled patients were included in the analyses of safety and tolerability (intent-to-treat [ITT] population). Of these patients, 645 were included in the efficacy analysis (efficacy [EFF] population). Fifty-seven patients were excluded from efficacy analyses, mainly because of a lack of a baseline or at least one follow-up hemoglobin value (32 patients, 15 of whom died), invalid data (10 patients), no exact data on study medication (eight patients), or no chemotherapy (eight patients). Patients may have been excluded for more than one reason. Three patients dropped out because of an adverse event (circulatory dysregulation, deep vein thrombosis, and thrombosis), and one patient, who did not receive chemotherapy because of cardiac decompensation, was excluded; in all cases, the adverse event was rated as possibly related to therapy by the investigator. All results are reported for the EFF population. As shown in Table 1, most patients (71.4%) were female, and the mean (± standard deviation [SD]) age was 58.5 ± 11.4 years. On average, patients received 32 ± 14.30 (range, 2–75) doses of epoetin alfa, and the mean treatment duration was 12 ± 5.53 weeks (range, 1–30). All 645 patients were treated with chemotherapy; of these, 222 (34.4%) underwent platinum-based chemotherapy. Radiation therapy was also administered to 98 (15.2%) patients.

View larger version (23K): [in this window] [in a new window]   Figure 1. Tumor response assessed at final visit.

View larger version (13K): [in this window] [in a new window]   Figure 2. Mean hemoglobin (Hb) values for the total sample (n = 645) and for patients without transfusion (n = 481) and with transfusion (n = 164) over the course of the study (last-observation-carried-forward [LOCF] method). p < .0001 for difference between pre- and post-treatment values, all groups.

Overall, 409 patients (63.4%) met the criterion for hematologic treatment response. The response rate was 63.8% for patients with solid tumors (n = 596) and 59.2% for those with hematologic malignancies (n = 49). Subgroup analysis by tumor type showed that the highest response rate occurred in patients with breast cancer (72.6%), whereas those with lung cancer had the lowest response rate (57.1%) (Table 3).

View larger version (22K): [in this window] [in a new window]   Figure 3. Changes in fatigue, according to tumor response and hemoglobin change, as assessed by physicians, nurses, and patients. Change was defined as pretherapy value minus the post-therapy value (last-observation-carried-forward [LOCF] method). A) Patients with complete tumor responses. B) Patients with partial tumor responses. C) Patients whose disease was unchanged. D) Patients with progressive disease.

For the QOL parameters lethargy, mood, and interest, physicians and nurses generally noted significant (p < .05) improvements for most patients at the study end versus baseline (Table 4). The major exception was patients with progressive disease, who were viewed as having stable or worsening lethargy, mood, and interest. Most patients, again with the exception of those with progressive disease, noted substantial benefits during the course of study in terms of activities of daily living, including walking, concentration, appetite, starting and finishing activities, and engaging in family activities (p < .05).

Safety
All 702 patients were included in the safety analyses. Epoetin alfa was generally well tolerated. The most common adverse events were disease progression, leukopenia, fever, neutropenia, thrombocytopenia, nausea, diarrhea, and vomiting. Hypertension was reported in 12 patients (1.7%). A total of 41 patients (5.8%) experienced a thrombotic or possible thrombotic event during the course of the study. Pure red blood cell aplasia was not observed in any patient during or after the study. There were 120 deaths during and after the end of the study, and of these, three were judged by the study investigators to have a possible causal relationship to the study drug. The associated adverse events and the physicians’ judgments of degree of causality were, respectively, diffuse alveolar injury with decreased pulmonary function (probable), severe headache (very likely), and thrombosis of the subclavian and jugular veins (possible). Attribution of headache as a very likely drug-related adverse event associated with a patient’s death was considered highly questionable by the study monitor as the patient showed an immediate response to treatment with a standard analgesic. A total of 252 (39.1%) patients discontinued the study prematurely. The most common reasons for discontinuation were death (23%), discontinuation or end of chemotherapy (17%), disease progression (15%), withdrawal of informed consent (14%), good therapeutic effect (12%), and insufficient compliance (10%).

	DISCUSSION

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Results of the present study demonstrate that the administration of epoetin alfa, 10,000 IU three times a week, to anemic cancer patients receiving chemotherapy increases hemoglobin levels in a predictable and timely manner. The mean hemoglobin level increased by approximately 1.0 g/dl by 4 weeks and by 1.5 g/dl by 8 weeks and was 1.7 g/dl higher than baseline at the end of the study (maximum 18 weeks). Because hemoglobin was assessed regardless of transfusion status, response at week 4 may have been influenced by transfusion. However, as shown in Figure 2, the mean increase in hemoglobin level at week 4 in patients who received transfusions was approximately 0.55 g/dl, versus a 1.19-g/dl mean increase in patients who did not receive transfusions. These results are in agreement with those of an open-label, single-arm study of epoetin alfa [16] that suggested that any increase in hemoglobin level resulting from transfusion may be minimal. In that study, analyses of mean hemoglobin levels and mean changes in hemoglobin levels were performed to take into account the effect of transfusion on hemoglobin level. In one method, hemoglobin values for patients transfused in the past 28 days were considered missing and were excluded from the analysis; in the second method, a last-value-carried-forward procedure was used, in which missing hemoglobin values were replaced with pretransfusion values. In both analyses, the mean hemoglobin change values at weeks 4, 8, 12, and 16 were consistent with the values calculated in the original analysis, differing at most by 0.1 g/dl at any time point.

In the current study, hemoglobin increases occurred regardless of tumor response, although the magnitude of increase appeared to be positively related to tumor response. Mean (± SD) hemoglobin values (g/dl), based on the prospectively collected data, were 2.4 ± 2.0 in the complete response group, 2.2 ± 2.2 in the partial response group, 1.6 ± 2.0 in the group with stable disease, and 0.9 ± 2.2 in the group with progressive disease (Table 2). These findings are in agreement with those of two large, open-label studies. In one study [16], significant (p < .05) increases in hemoglobin from baseline to last observation were observed regardless of tumor response; however, hemoglobin values categorized by tumor response were not reported. In the second study [15], the magnitudes of the hemoglobin level changes in patients with complete responses, partial responses, stable disease, and disease progression were similar to those observed in the present study; however, the interpretive value of this finding is limited due to the retrospective nature of the tumor response data collected and the fact that response data were unavailable for more than half the study population. The present study thus adds to the information available regarding hemoglobin changes relative to tumor response.

In this study, patients who did not receive transfusions demonstrated a greater overall mean increase in hemoglobin (2.0 g/dl) than patients who were transfused (1.0 g/dl, p < .0001), possibly reflecting greater responsiveness to epoetin alfa or less chemotherapy-related myelotoxicity than in transfused patients. Additionally, the study showed that epoetin alfa therapy provided substantial benefits with respect to QOL parameters, particularly fatigue.

Overall, the findings of this study are consistent with previously reported results of several open-label and placebo-controlled studies in which a three-times-a-week or a once-a-week regimen of epoetin alfa significantly increased hemoglobin levels, thereby ameliorating anemia and reducing transfusion requirements. Previous studies have also shown improved scores for overall QOL, as well as for specific parameters such as energy, ability to perform activities of daily living, and fatigue [7–9, 15–18]. Improvements in QOL have been consistently correlated with magnitude of hemoglobin increase [8, 9] and, in some cases, considered independent of tumor response [7]. One study [7] prospectively examined both the benefit of epoetin alfa and the influence of tumor response on QOL in anemic cancer patients receiving chemotherapy. QOL measures included the total FACT-An, FACT-An Anemia subscale, and the 100-mm CLAS. Results showed that improvements in QOL occurred in patients who responded to epoetin alfa, regardless of their disease responses to anticancer therapy. For patients with responding or stable disease, the magnitude of the QOL change paralleled the magnitude of the hemoglobin value change with epoetin alfa therapy; patients with progressive disease showed an overall decrease in QOL, but the decrease in those who responded to epoetin alfa was minimal compared with the decrease experienced by patients who did not respond to this agent.

Particularly noteworthy in the present study was the finding that the increase in hemoglobin from baseline to study end correlated with a decrease in fatigue level as judged by physicians, patients, and nurses (p < .05 for all three), although perceptions of the degree of fatigue improvement differed somewhat among the three sets of evaluators. Because fatigue can deleteriously affect patient compliance with treatment and, ultimately, treatment outcome, it is important that physicians and nurses correctly identify the symptom and its impact on patients so patient care can be modified accordingly. However, emerging data suggest physicians’ and nurses’ perceptions of fatigue may differ from those of patients. In 1996, a telephone survey was conducted in the U.S. to characterize cancer-related fatigue from the perspectives of patients (n = 419), caregivers (n = 200), and oncologists (n = 197) [11]. In that survey, 61% of patients who experienced fatigue reported that this symptom had a greater effect on their daily lives than did pain, whereas only 37% of oncologists perceived this to be the case. Consistent with these perceptions, 41% of patients felt it was more important to treat fatigue than pain, while 94% of oncologists indicated that treatment of pain was more important. In 1997, patients (n = 50) and nurses (n = 21) participating in a study conducted in Iran were asked to indicate their perceptions of the seriousness of chemotherapy treatment stressors [19]. According to the patients, the greatest physical stressor was fatigue (66%), whereas nurses rated alopecia as the greatest stressor (62%). More recently, a cross-sectional survey of cancer patients (576 respondents) and randomly selected health care professionals (oncologists, nurses, radiographers, hematologists; 368 respondents) conducted in the United Kingdom found that 56% of patients experienced fatigue and that fatigue had a significant impact on their QOL [20]. The health care professionals also recognized fatigue as a common symptom in their cancer patients, but tended to overestimate its impact on some aspects of the patients’ daily lives. For example, health care professionals thought fatigue greatly affected their patients’ relationships with family/friends (42%), ability to work (72%), and ability to enjoy life (76%), compared with 16%, 37%, and 30%, respectively, of patients reporting this to be the case. Also, in the recently published All Ireland Fatigue Surveys, again conducted to learn more about the nature of cancer patients’ fatigue and physicians’ (n = 109) and nurses’ (n = 160) perceptions of fatigue in cancer patients, the vast majority of physicians and nurses reported they believed nausea to be the side effect of most concern in their cancer patients, whereas 41% of 143 patients surveyed reported that fatigue was the side effect that most affected them [21]. In the current study, which further explored the nature of cancer-related fatigue, physicians, nurses, and patients assessed various patient QOL parameters using linear analog scales, with fatigue being the only parameter assessed by all three groups. The three groups of evaluators generally reported that the level of fatigue decreased during the course of the study, with change in hemoglobin level and disease response to therapy being major factors influencing the amount of decrease. Physicians’ reporting of fatigue appeared to be consistently influenced by disease response to therapy and by increase in hemoglobin level, although disease response appeared to have had a stronger influence. Physicians also tended to overestimate improvements in fatigue relative to nurses and patients. Nurses’ and patients’ ratings of fatigue were generally comparable, although nurses often reported less improvement than patients. Both nurses and patients reported changes in fatigue related to disease response to therapy, although the relationship was less consistent than that seen for doctors. Patients also generally saw greater improvements in fatigue with increases in hemoglobin level, regardless of tumor response. The causes for the different perceptions of estimates of fatigue improvement and of relationships to changes in hemoglobin level and tumor response are unclear, but a number of explanatory factors (including evaluator attitudes and study methodology) merit consideration. It is possible that patient prognosis affects physicians’ assessments of fatigue, that is, physicians may have greater confidence in improvements based on knowledge of the remission status and prognosis of malignant disease. Also, physicians’ assessments of fatigue may reflect the different goals of the evaluators—good patient outcome being paramount for physicians and symptom relief being paramount for patients. Further, some patients may be more reticent about discussing the full extent of their discomfort with their physicians than with nurses. Regarding the nurse/patient evaluations, it has been suggested [20] that a response shift in patient perceptions of symptom severity over the trajectory of the disease may change. Thus, acute symptoms may be ranked higher in severity than persistent symptoms, as patients tend (unconsciously) to reduce their assessments of symptom severity as they learn to live with the symptom and/or lower their expectations for its relief. Also, patients may unconsciously make accommodations in response to the symptom, for example, shifting from active to more sedentary recreational activities, changing daily schedules, and decreasing work productivity, or may base comparisons on the previous evaluation rather than baseline status [22]. In these instances, nurses, as experienced observers, may be more objective, and hence more reliable, raters of fatigue than the patients themselves, but will also produce ratings different from those of the patients. A possible error source regarding assessment of fatigue in this study was the use of slightly different questionnaires for physicians, nurses, and patients. Clearly, further investigation is required regarding the underlying causes of fatigue, their interrelationships, and evaluator perceptions that may influence assessment of fatigue and determine the course of its management.

Regarding safety, epoetin alfa was well tolerated overall, with incidences of individual adverse effects (including thrombotic or possible thrombotic events) generally slightly lower than those reported in a double-blind, placebo-controlled study of epoetin alfa [8]. Recently, there has been concern about the potential for epoetin alfa to increase thrombotic risk. However, the noncontrolled design of the current study, together with the multifactorial etiology of thrombotic events (e.g., venous catheterization, drugs that affect the coagulation system, infections/septic complications), preclude drawing any conclusions regarding occurrence of thrombotic events with epoetin alfa. Also, recent publications have questioned the impact of epoetin alfa and epoetin beta on survival [23, 24]. The current study was neither designed nor powered to address this question, and interpretation of the results of other studies is complicated due to differences in study design (chemotherapy versus radiotherapy), study populations (nonanemic versus anemic), and post-trial analyses, as well as intrastudy design, methodology, and analysis.

In conclusion, epoetin alfa therapy substantially increases hemoglobin levels while reducing fatigue in anemic cancer patients with solid tumors and hematologic malignancies who are undergoing chemotherapy with or without radiation therapy. The efficacy of epoetin alfa in this study, in terms of rapidity, reliability, and magnitude of hemoglobin response, is consistent with that reported in other clinical studies. Improvements in hemoglobin levels are strongly correlated with improvements in fatigue and other QOL parameters. The 10-point linear analog scale used in this study appears to be a simple but effective tool for assessing fatigue in the context of QOL. Physicians’, nurses’, and patients’ assessments of fatigue differ and are related both to disease response to therapy and to change in hemoglobin level. Physicians’ reporting of improvement in patient fatigue is more optimistic than nurses’ and patients’ reporting and tends to be strongly influenced by disease response; it is important for physicians to be cognizant of these differing perceptions when considering therapeutic interventions for fatigue and anemia.

	Appendix 1. Translated questionnaires (1 of 3)

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	Appendix 1. Translated questionnaires (2 of 3)

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	Appendix 1. Translated questionnaires (3 of 3)

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	ACKNOWLEDGMENT

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This study was supported by a research grant from Ortho Biotech Germany.

	REFERENCES

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