This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Österborg, A. Articles by Messinger, D. Search for Related Content PubMed PubMed Citation Articles by Österborg, A. Articles by Messinger, D. Social Bookmarking                            What's this?

Randomized, Double-Blind, Placebo-Controlled Trial of Recombinant Human Erythropoietin, Epoetin Beta, in Hematologic Malignancies

From the Departments of Oncology and Hematology, Karolinska Hospital, Stockholm, Sweden; Far-East Medical Center, Khabarovsk, and Research Institute of Hematology and Transfusiology, St Petersburg, Russia; Institute for Hematology and Transfusiology, Tblisi, Georgia; Sundsvall Hospital, Sundsvall, and Sweden; and F. Hoffmann-La Roche Ltd, Mannheim, Germany.

Address reprint requests to A. Österborg, MD, PhD, Department of Oncology (Radiumhemmet), Karolinska Hospital, S-17176 Stockholm, Sweden; email: anders.osterborg{at}ks.se

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To investigate the effect of recombinant human erythropoietin (epoetin beta) on anemia, transfusion need, and quality of life (QOL) in severely anemic patients with low-grade non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CLL), or multiple myeloma (MM).

PATIENTS AND METHODS: Transfusion-dependent patients with NHL (n = 106), CLL (n = 126), or MM (n = 117) and a low serum erythropoietin concentration were randomized to receive epoetin beta 150 IU/kg or placebo subcutaneously three times a week for 16 weeks. Primary efficacy criteria were transfusion-free and transfusion- and severe anemia–free survival (hemoglobin [Hb] > 8.5 g/dL) between weeks 5 to 16. Response was defined as an increase in Hb 2 g/dL with elimination of transfusion need. QOL was assessed by the Functional Assessment of Cancer Therapy scale.

RESULTS: Transfusion-free (P = .0012) survival and transfusion- and severe anemia–free survival (P = .0001) were significantly greater in the epoetin beta group versus placebo (Wald ² test), giving a relative risk reduction of 43% and 51%, respectively. The response rate was 67% and 27% in the epoetin beta versus the placebo group, respectively (P < .0001). After 12 and 16 weeks of treatment, QOL significantly improved in the epoetin beta group compared with placebo (P < .05); this improvement correlated with an increase in Hb concentration ( 2 g/dL). A target Hb that could be generally recommended could not be identified.

CONCLUSION: Many severely anemic and transfusion-dependent patients with advanced MM, NHL, and CLL and a low performance status benefited from epoetin therapy, with elimination of severe anemia and transfusion need, and improvement in QOL.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
ANEMIA IS A COMMON complication of cancer, particularly for patients with hematologic malignancies. For example, nearly all multiple myeloma (MM) patients are, or will become, anemic.^1,2 Further, an estimated 30% to 40% of non-Hodgkin’s lymphoma (NHL) patients are anemic at the time of diagnosis, with the incidence rising to 70% during chemotherapy or progression.³ Anemia may significantly negatively affect the quality of life (QOL) of cancer patients, producing symptoms such as depression, fatigue, weakness, nausea, and vertigo, leaving them unable to work or fulfill family and social roles.^4,5 Effective treatment of anemia is therefore an important goal in the management of patients with hematologic malignancies—not only to ensure an optimal response to chemotherapy, but also to maintain an acceptable QOL.

On the basis of the pilot study conducted by Ludwig et al⁶ in 1990, two randomized studies have demonstrated that recombinant human erythropoietin (epoetin) is effective in increasing hemoglobin (Hb) levels and eliminating transfusion need in patients with hematologic malignancies.^7,8 To our knowledge, however, no randomized study has been published to date on the effect of epoetin therapy on anemia and concomitant QOL benefits in patients with hematologic malignancies by use of a comprehensive, internationally recognized QOL instrument. The present placebo-controlled study was therefore performed to investigate the efficacy of epoetin beta (NeoRecormon; F. Hoffmann-La Roche, Basel, Switzerland) in eliminating severe anemia and transfusion dependency, and concomitant effects on QOL, with the Functional Assessment of Cancer Therapy (FACT) scale,^9,10 in patients with advanced MM, low-grade NHL, and chronic lymphocytic leukemia (CLL). The study also evaluated differences in efficacy parameters and QOL between responders and nonresponders to treatment with epoetin beta.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The present study was a randomized, double-blind, placebo-controlled, multicenter clinical trial conducted between June 1997 and July 1999 at 63 centers in 12 countries. The design and conduct of the study complied with the ethical principles of good clinical practice, in accordance with the Declaration of Helsinki and local legal requirements. The study was approved by an independent ethics committee at each center; all patients provided written informed consent before enrollment.

Patients
Adult patients eligible for inclusion were aged 18 years with a confirmed diagnosis of low-grade NHL, MM, or CLL and a Hb level less than 10 g/dL with a transfusion requirement of 2 U of packed RBCs in the 3 months before the study. Patients with NHL or CLL were classified according to the Revised European American Lymphoma classification.¹¹ For patients with MM, the immunoglobulin class was recorded, and staging was carried out according to Durie and Salmon.¹² NHL was staged according to the Ann Arbor staging system and CLL according to the Rai staging system.¹³ All patients were required to have an inadequately low endogenous serum erythropoietin concentration (relative erythropoietin deficiency), defined as a serum erythropoietin level 100 IU/L (if Hb level was > 9 to < 10 g/dL), 180 IU/L (if Hb level was > 8 to 9 g/dL) or 300 IU/L (if Hb level was 8 g/dL). Serum erythropoietin concentration was measured at least 7 days after the last blood transfusion or chemotherapy course. To be eligible for inclusion, patients must have been scheduled to receive antitumor therapy for the next 4 months, with a life expectancy of more than 4 months and a World Health Organization (WHO) performance score of 0 to 3.

Exclusion criteria were therapy-resistant hypertension, relevant acute or chronic bleeding in the 3 months before study commencement, thrombocytopenia or thrombocytosis (platelets < 20 and > 450 x 10⁹/L, respectively), vitamin B₁₂ or folic acid deficiencies, creatinine levels more than 2.5 mg/dL, hemolysis (haptoglobin level < 50 mg/dL), epilepsy, or known hypersensitivity to preservatives used in the study medication injection formulation. Patients with evidence of functional iron deficiency (ie, transferrin saturation < 25%) for which prerandomization intravenous iron supplementation was not possible were also excluded.

Study Procedures
After a run-in period of approximately 2 weeks, patients suitable for inclusion were randomized (stratified according to malignancy type and study center) to receive epoetin beta 150 IU/kg body weight or placebo. Epoetin beta or placebo were administered subcutaneously three times a week for 16 weeks. The dose was increased to 300 IU/kg (ie, 900 IU/kg per week) if no early signs of response were observed after 4 weeks of treatment. Lack of early response was defined as a requirement for a blood transfusion in the previous week, an Hb level of less than 8.5 g/dL, or an increase in Hb of less than 0.5 g/dL compared with baseline. Conversely, if Hb increased by more than 2 g/dL within this period, the dose of study medication was reduced by 50%. If Hb exceeded 14 g/dL, the study medication was suspended until Hb declined to 13 g/dL, when therapy was reinstated at 50% of the previous dose. Blood transfusions were recommended when Hb was less than 8.5 g/dL or at higher levels if medically indicated—that is, the presence of marked anemic symptoms such as angina pectoris.

Enrolled patients with a baseline transferrin saturation of less than 25% received intravenous iron substitution (100 mg elemental iron) before the start of study treatment. Where transferrin saturation levels decreased to below 25% during the course of the study, intravenous iron substitution therapy was administered at a dose of 100 mg elemental iron per week until transferrin saturation reached 25%. Orally administered iron substitution therapy (200 to 300 mg elemental iron per day) was administered to those in whom intravenous iron supplementation was precluded. Adverse events, hematologic parameters, concomitant medications, blood transfusions, and antitumor therapy were documented throughout the course of the study.

Efficacy Assessments
The primary efficacy variable was transfusion-free survival during weeks 5 to 16 of the study. To account for possible differences in transfusion policy between study sites, the study protocol also specified consideration of the transfusion threshold of 8.5 g/dL by analyzing the transfusion- and severe anemia–free survival (Hb 8.5 g/dL) during weeks 5 to 16. For both end points, death without previous event was counted as failure. In case of premature withdrawal from study treatment, patients were observed and Hb level, blood transfusions, and vital status were recorded whenever possible until study week 16. Secondary parameters included the response rate (defined as an increase in Hb level of 2 g/dL above baseline and without the need for a blood transfusion in the previous 6 weeks), the Hb nadir (measured at 4-week long intervals) and changes in QOL from baseline.

Subjective QOL was assessed at baseline and every 4 weeks during the study with an internationally validated QOL instrument, the FACT-An questionnaire.^9,10 The FACT questionnaire was translated into various languages by the Center on Outcomes, Research, and Education (Evanston, IL) according to current standards.¹⁴ Questionnaires were completed before any examination or treatment so that patients’ assessment could not be influenced by references to current Hb level. The FACT-An questionnaire consists of the FACT-G questionnaire and the FACT-F and FACT-An subscales. FACT-G measures general aspects of QOL among cancer patients. It comprises 29 items assessing five dimensions (physical well-being, social and family well-being, relationship with doctor, emotional well-being, and functional well-being). In addition, 20 items measure anemia symptoms (the FACT-An subscale), 13 of which assess fatigue symptoms (the FACT-F subscale) and 7 of which assess nonfatigue-related symptoms. Although the anemia and fatigue subscales were part of the original study plan, the FACT-G questionnaire was introduced by an amendment to the study protocol in January 1998.

Statistical Analysis
We planned to enroll 150 patients with low-grade NHL, CLL, or MM to detect an improvement in the primary variable from 25% to 50% with a power of 85% via a Cox proportional hazard model (two-sided Wald ² test, = 0.05). In an amendment to the study protocol, the sample size was increased to at least 100 patients per stratum (MM, NHL, CLL; 50 patients per treatment group) to achieve a power of 80% for the three corresponding subgroup analyses. Subgroup analyses with a one-sided Wald ² test ( = 0.05) should be performed if the difference in the total study population was significant and no significant interaction between study treatment and strata were present (P > .1). A lost-to-follow-up rate of 10% in weeks 5 to 16 was assumed.

The primary efficacy variable was analyzed on an intention-to-treat basis via a Cox proportional hazard model adjusted for the type of underlying malignant disease at a significance level of 5%. Corresponding hazard ratios were calculated to estimate the relative risk of failure, and event-free curves were displayed that were based on Kaplan-Meier estimates. Multivariate Cox proportional hazard methods were subsequently used to assess the contribution of other baseline characteristics on event-free rates. Cumulative response rates were analyzed by the stratified log-rank test and displayed as Kaplan-Meier curves. Analysis of covariance techniques were used to analyze the changes from baseline in QOL and Hb data, where baseline values were considered as covariates.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Patients
A total of 349 patients were randomized onto the study. Three patients in each treatment group were subsequently withdrawn before receiving study medication because of withdrawal of consent (n = 5) or protocol violation (n = 1). The remaining 343 patients receiving study treatment (epoetin beta, n = 170; placebo, n = 173) formed the intention-to-treat and safety populations. There were no major differences in the demographics and clinical characteristics of the two treatment groups (Table 1). Most patients had advanced disease, and 59% had WHO performance status grade 2 or 3.

Elimination of Severe Anemia and Transfusion Need
As expected, the percentage of patients with blood transfusions in the first 4 weeks of study treatment was similar in both groups (29.0% v 27.2% for epoetin beta and placebo patients, P = .707). The proportion of patients who were alive and who had not received transfusions between weeks 5 and 16 (primary end point) is indicated in Fig 1. The difference in the transfusion-free survival rate between the epoetin beta group and the placebo group was statistically significant (P = .0012), as it was for transfusion- and severe anemia–free survival (P = .0001). Patients receiving epoetin beta had a risk reduction of 43% and 51% in these parameters relative to placebo, respectively. No significant interaction between underlying malignant disease and treatment on primary end points was found (P > .1). The difference in transfusion- and severe anemia–free survival was statistically significant across all malignancy subtypes and was particularly apparent in patients with MM (P = .0001), with a risk reduction of 66% in those receiving epoetin beta compared with placebo. In those with NHL and CLL, the risk was reduced by approximately 40% in both groups (P = .02 and P = .03, respectively).

View larger version (13K): [in this window] [in a new window]   Fig 1. Kaplan-Meier plots of transfusion-free survival during 16 weeks’ treatment with either epoetin beta or placebo in anemic, transfusion-dependent patients with MM, NHL, or CLL. Circles indicate censored patients. P = .0012, Wald 2 test.

View larger version (13K): [in this window] [in a new window]   Fig 2. Time to response for patients allocated to epoetin beta and placebo arms of study. Circles indicate censored patients. P < .0001, log-rank test.

QOL
The FACT-An and FACT-F subscales were answered by 97%, 95%, 94%, 95%, and 92% of the patients, respectively, in the study at baseline, 4, 8, 12, and 16 weeks after start of study treatment. The FACT-G questionnaire was introduced into the study by an amendment to the study protocol in January 1998, after which 265 patients (90% of those included) responded to the baseline questionnaire. Of these, 23 patients completed the questionnaire after 8 weeks, 218 after 12 weeks, and 209 at the last (16 weeks) assessment, which is a completion rate of 95%, 96%, and 94%, respectively, taking into account the number of patients still in the study at each assessment point. There were no relevant differences in the baseline characteristics, transfusion-free survival, and transfusion- and severe anemia–free survival between patients included before and patients included after the introduction of FACT-G. Baseline scores for the total FACT-An (49 items) were comparable for the two treatment groups (Table 1). For the total FACT-An questionnaire, an increase in score (consistent with improved QOL) was apparent for both groups during the course of the study, the magnitude of which was greater for epoetin beta recipients (Table 5).

The differences in QOL between responders to epoetin beta treatment (increase in Hb level of 2 g/dL after elimination of transfusion need) and nonresponders were analyzed (Table 6). A statistically significant greater improvement in the total FACT-An questionnaire was observed after 8, 12, and 16 weeks of therapy among responders compared with nonresponders (P < .05; Table 6). Similar results were obtained for most dimensions and subscales, physical well-being (P < .05), emotional well-being (P < .05), FACT-F (P < .01), and FACT-An subscales (P < .01) from week 8 to 12 onward. Improvement in functional well-being was only significant in responders versus nonresponders at week 8 (P < .05). There were no differences between responders and nonresponders in the social and family well-being dimensions.

Safety
Treatment with epoetin beta was well tolerated. The proportion of patients reporting at least one adverse event was comparable for the two treatment groups (epoetin beta, n = 122, 72%; placebo, n = 132, 76%). Most adverse events were attributed to the underlying malignancy or concomitant antitumor therapy with similar frequency in each treatment group, and they were therefore not considered to be epoetin related. As expected, adverse events previously reported during epoetin therapy, such as hypertension, were slightly more common for epoetin beta recipients than for those treated with placebo (9% v 5%, respectively). Two patients (1%) experienced a local, transient reaction after subcutaneous injection of epoetin beta.

The overall frequency of serious adverse events was similar for the two treatment groups (epoetin beta, n = 57, 33%; placebo, n = 55, 32%). Fifty deaths were reported (epoetin beta, n = 28, 16%; placebo, n = 22, 13%), of which 40 (epoetin beta, n = 21, 12%; placebo, n = 19, 11%) occurred during the 16-week study period and the remaining 10 thereafter. All deaths were generally attributed to the underlying disease, cardiovascular events (eg, myocardial infarction), or respiratory infection. With the exception of one patient in the epoetin beta group who died as a result of pulmonary embolus 90 days after the commencement of study treatment (considered to be possibly drug related), no deaths were regarded as attributable to the study medication. No antibodies to erythropoietin were detected in any patient.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The results of this randomized, placebo-controlled trial demonstrate that a large proportion of severely anemic, transfusion-dependent patients with advanced MM, NHL, or CLL and a low performance status benefited from epoetin therapy, with elimination of severe anemia and transfusion need and improvement of QOL. The risk of requiring a blood transfusion or suffering from severe anemia (Hb < 8.5 g/dL) was halved after the first 4 weeks of treatment. The proportion of patients who achieved an increase of 2 g/dL in Hb concentration (without need for further transfusions) was 2.5 times higher in the epoetin beta group. Further, Hb nadirs were significantly increased compared with placebo. This effect was attributable to epoetin beta because the intensity of chemotherapy and the proportion of patients responding to chemotherapy was similar in the epoetin beta and placebo groups during the study period. These findings are in accordance with an earlier study with epoetin in transfusion-dependent MM, NHL, and CLL patients.⁸ The study duration was 16 weeks, which limited the treatment with placebo to the minimum necessary to fully investigate the efficacy of epoetin beta. An earlier study designed with a longer treatment period in a corresponding group of patients did not indicate reduced efficacy with ongoing treatment.⁸

Whether MM, NHL, and CLL respond equally well to epoetin therapy has been a matter of debate.⁸ In this trial, which is the first powered to analyze the effect in each malignancy, the effect seemed to be more pronounced in MM than in NHL or CLL patients with regard to elimination of severe anemia (Hb < 8.5 g/dL) and transfusion dependence. In contrast, the proportion of patients who responded with a 2 g/dL increase in Hb after elimination of transfusion need was similar in all three subgroups (Table 2). Thus, all three subgroups seem to benefit significantly from epoetin therapy, although with a possibly slight additional benefit for patients with MM.

The decision to include only patients who had a relative erythropoietin deficiency and who were receiving ongoing chemotherapy was based on the previous finding in two different studies that an inappropriately low serum level of erythropoietin for the degree of anemia was the most important predictor of response to epoetin beta in patients with MM, NHL, and CLL^7,8 In contrast, endogenous erythropoietin concentration does not predict response in patients with solid tumors. Furthermore, patients with an intact residual bone marrow function responded more frequently in those studies. This was also confirmed by the present study, in which patients who had a platelet count of 100 x 10⁹/L had a high probability of benefiting from epoetin therapy. Approximately 75% of patients with MM, NHL, and CLL have a relative erythropoietin deficiency; 115 of 511 patients who were screened for enrollment onto this study were ineligible because of they did not have a deficiency of endogenous erythropoietin. Thus, targeting anemic MM, NHL, and CLL patients with ongoing chemotherapy, a relative erythropoietin deficiency, and a relatively normal platelet count may be important in identifying those patients most likely to respond to epoetin therapy. Such easily available predictors of response may be more likely to enter widespread use in routine health care or clinical practice than the more complicated (although efficient) algorithms that have been proposed.^16-18 After response to epoetin therapy, it is often possible to reduce the maintenance dose in a stepwise fashion, to low weekly doses.¹⁹ All these aspects may contribute to further improve the cost-benefit relationship of epoetin.

The improvement in QOL associated with a close-to-normal Hb concentration,¹⁵ and the potential of epoetin to stabilize the Hb concentration at a level usually not reached with transfusion, further emphasizes that epoetin may be an important agent to treat cancer-related anemia. Whether this may change with the advent of synthetic blood is currently unknown.

A further cost reduction can be achieved by the use of iron supplementation, which may be important in compensating for epoetin-induced functional iron deficiency. Intravenous iron supplementation has been found to reduce the weekly epoetin requirement by 30% to 70% in patients with renal anemia²⁰ and has also been recommended during epoetin therapy of cancer-associated anemia.²¹ Therefore, all patients in the present study who had a transferrin saturation less than 25% at any time during the study period received iron intravenously or orally. The design of the study did not allow us to decide whether iron supplementation contributed to the clinical effects obtained with epoetin. However, the similar incidence of a low transferrin saturation and level of exposure to intravenously or orally administered iron supplementation in the epoetin beta and placebo groups suggests that functional iron deficiency may be a less important problem in cancer-related anemia than in renal anemia, and therefore, the importance of iron supplementation is uncertain. Randomized trials are required to answer this question.

Several studies on solid tumors have demonstrated a positive correlation between increase in Hb and QOL, especially for variables such as levels of energy and activity and overall QOL.²² The present investigation was the first randomized study on the effect of epoetin on anemia and QOL among patients with hematologic malignancies that used a comprehensive QOL instrument, demonstrating a larger improvement in the epoetin group than in the placebo group for the total FACT-An. The time needed to establish a significant difference was 12 weeks, indicating that patients with a shorter life expectancy will most likely not benefit. Differences between groups were found primarily in social and family functioning and in emotional and physical well-being. The emotional dimension consists primarily of questions concerning anxiety, depression, despair, and loss of self-esteem, whereas the physical well-being dimension encompasses physical symptoms such as energy, nausea, pain, and unwanted side effects. The social and family dimension investigates the impact of cancer on the patients’ ability to relate to the world around them. All of these concerns are obviously of importance to cancer patients and might be influenced by an increase in Hb concentration.

When the analysis was refined by looking at responders versus nonresponders in the epoetin group, most QOL dimensions, particularly those addressing anemia-related symptoms and fatigue, were markedly improved in those who responded to epoetin therapy with a 2 g/dL increase in Hb concentration. This is in agreement with earlier findings.²³ In this trial, the magnitude of the increase in QOL in patients receiving epoetin was comparable to that observed in the study of Littlewood et al.²⁴ However, in contrast to the study by Littlewood et al,²⁴ where the QOL of the placebo group decreased, the QOL of the placebo group in the present study improved modestly. The reason for this is not clear but may reflect differences between the studies in tumor type, phases (newly diagnosed v end-stage disease), and chemotherapy used. Whether the difference in the magnitude of the QOL improvement between groups in this and other studies is clinically important is a matter of intensive debate and research. At the moment, no consensus exists on the magnitude of change that represents a clinically significant improvement in the various FACT subscales.²⁵

A previous report suggested that an increase in the Hb level from 11 to 12 g/dL leads to the greatest improvements in QOL and that 12 g/dL should be the goal during epoetin therapy.¹⁴ In the present study, a considerable variability between patients was observed when the final Hb concentration and change in QOL score were compared. Our data suggest that in addition to one target Hb level being important, an increase in Hb of at least 2 g/dL (without need of blood transfusions) may be important for the improvement in QOL for the individual patient. This finding is in agreement with the work of Demetri et al²³ and Glimelius et al,²⁶ who found a correlation between increase in Hb and QOL, with those achieving a mean Hb increase of 1 to 2 g/dL or greater having the most significant improvement in QOL.

In conclusion, this randomized, placebo-controlled study has demonstrated that epoetin beta treatment is effective in relieving anemia and improving QOL in severely anemic, transfusion-dependent patients with advanced-phase NHL, CLL, and MM. Overall, the improvement in QOL was particularly apparent in patients with Hb increases of 2 g/dL. This suggests that the minimum increase in Hb may be a more important determinant of improved QOL than a uniform, and close to normal, target Hb level.

APPENDIX
The appendix listing Epoetin Beta Hematology Study Group members is available online at www.jco.org.

	ACKNOWLEDGMENTS

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Kyle RA: Multiple myeloma: Review of 869 cases. Mayo Clin Proc 50: 29-40, 1975[Medline]

2. Mittleman M, Zeidman A, Fradin Z, et al: Recombinant human erythropoietin in the treatment of multiple myeloma–associated anemia. Acta Haematol 98: 204-210, 1997[Medline]

3. Coiffier B: Anemia associated with non-platinum chemotherapy for Hodgkin’s lymphoma or non-Hodgkin’s lymphoma. European Cancer Conference (ECCO 10), Vienna, Austria, September 12-16, 1999 (abstr)

4. Thomas ML: Impact of anemia and fatigue on quality of life in cancer patients: A brief review. Med Oncol 15: S3-S7, 1998 (suppl)

5. Cella D: Factors influencing quality of life in cancer patients: Anemia and fatigue. Semin Oncol 25: 43-46, 1998 (3 suppl 7)[Medline]

6. Ludwig H, Fritz E, Kotzmann H, et al: Erythropoietin treatment of anemia associated with multiple myeloma. N Engl J Med 322: 1693-1699, 1990[Abstract]

7. Cazzola M, Messinger D, Battistel V, et al: Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin’s lymphoma: Dose finding and identification of predictors of response. Blood 86: 4446-4453, 1995[Abstract/Free Full Text]

8. Österborg A, Boogaerts MA, Cimino R, et al: Recombinant human erythropoietin in transfusion-dependent anemic patients with multiple myeloma and non-Hodgkin’s lymphoma: A randomized multicenter study—The European Study Group of Erythropoietin (Epoetin Beta) Treatment in Multiple Myeloma and Non-Hodgkin’s Lymphoma. Blood 87: 2675-2682, 1996[Abstract/Free Full Text]

9. Cella DF, Tulsky DS, Gray G, et al: The Functional Assessment of Cancer Therapy scale: Development and validation of the general measure. J Clin Oncol 11: 570-579, 1993[Abstract/Free Full Text]

10. Yellen SB, Cella DF, Webster K, et al: Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 13: 63-74, 1997[CrossRef][Medline]

11. Harris NL, Jaffe ES, Stein H, et al: A revised European-American classification of lymphoid neoplasms: A proposal from the International Lymphoma Study Group. Blood 84: 1361-1392, 1994[Free Full Text]

12. Durie BGM, Salmon SE: A clinical staging system for multiple myeloma. Cancer 36: 842-854, 1975[CrossRef][Medline]

13. Rai KR, Sawitsky A, Cronkite EP, et al: Clinical staging of chronic lymphocytic leukemia. Blood 46: 219-234, 1975[Abstract/Free Full Text]

14. Bonomi AE, Cella DF, Hahn EA, et al: Multilingual translation of the Functional Assessment of Cancer Therapy (FACT) quality of life measurement system. Qual Life Res 5: 309-320, 1996[CrossRef][Medline]

15. Cleeland CS, Demetri GD, Glaspy J, et al: Identifying hemoglobin level for optimal quality of life: Results of an incremental analysis. Proc Am Soc Clin Oncol 18: 574a, 1999 (abstr)

16. Henry D, Abels R, Larholt K: Prediction of response to recombinant human erythropoietin (r-HuEPO/epoetin alpha) therapy in cancer patients. Blood 85: 1676-1678, 1995[Free Full Text]

17. Cazzola M, Ponchio L, Pedrotti C, et al: Prediction of response to recombinant human erythropoietin (rHuEpo) in anemia of malignancy. Haematologica 81: 434-441, 1996[Abstract/Free Full Text]

18. Ludwig H, Fritz E, Leitgeb C, et al: Prediction of response to erythropoietin treatment in chronic anemia of cancer. Blood 84: 1056-1063, 1994[Abstract/Free Full Text]

19. Österborg A: Recombinant human erythropoietin (rHuEPO) therapy in patients with cancer-related anemia: What have we learned? Med Oncol 15: S47-S49, 1998 (suppl 1)

20. Sunder-Plassmann G, Horl WH: Importance of iron supply for erythropoietin therapy. Nephrol Dial Transplant 10: 2070-2076, 1995[Abstract/Free Full Text]

21. Glaspy J, Cavill I: Role of iron in optimizing responses of anemic cancer patients to erythropoietin. Oncology 13: 461-473, 1999[Medline]

22. Brandberg Y: Assessing the impact of cancer-related anaemia on quality of life and the role of rHuEPO. Med Oncol 17: S23-S31, 2000 (suppl 1)

23. Demetri GD, Kris M, Wade J, et al: Quality of life benefit in chemotherapy patients treated with epoetin alfa is independent of disease response or tumor type: Results from a prospective community oncology study—Procrit Study Group. J Clin Oncol 16: 3412-3425, 1998[Abstract]

24. Littlewood TJ, Bajetta E, Nortier JWR, et al: Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: Results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 19: 2865-2874, 2001[Abstract/Free Full Text]

25. Osoba D, Rodriques G, Myles J, et al: Interpreting the significance of changes in health-related quality of life scores. J Clin Oncol 16: 139-144, 1998[Abstract/Free Full Text]

26. Glimelius B, Linne T, Hoffman K, et al: Epoetin beta in the treatment of anemia in patients with advanced gastrointestinal cancer. J Clin Oncol 16: 434-440, 1998[Abstract]

Submitted February 26, 2001; accepted February 26, 2002.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

				H. Ludwig, J. Crawford, A. Osterborg, J. Vansteenkiste, D. H. Henry, A. Fleishman, K. Bridges, and J. A. Glaspy Pooled Analysis of Individual Patient-Level Data From All Randomized, Double-Blind, Placebo-Controlled Trials of Darbepoetin Alfa in the Treatment of Patients With Chemotherapy-Induced Anemia J. Clin. Oncol., June 10, 2009; 27(17): 2838 - 2847. [Abstract] [Full Text] [PDF]

				M. Tonelli, B. Hemmelgarn, T. Reiman, B. Manns, M. N. Reaume, A. Lloyd, N. Wiebe, and S. Klarenbach Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a meta-analysis Can. Med. Assoc. J., May 26, 2009; 180(11): E62 - E71. [Abstract] [Full Text] [PDF]

				M. Tsuboi, K. Ezaki, K. Tobinai, Y. Ohashi, and N. Saijo Weekly Administration of Epoetin Beta for Chemotherapy-induced Anemia in Cancer Patients: Results of a Multicenter, Phase III, Randomized, Double-blind, Placebo-controlled Study Jpn. J. Clin. Oncol., March 1, 2009; 39(3): 163 - 168. [Abstract] [Full Text] [PDF]

				O. Minton, A. Richardson, M. Sharpe, M. Hotopf, and P. Stone A Systematic Review and Meta-Analysis of the Pharmacological Treatment of Cancer-Related Fatigue J Natl Cancer Inst, August 20, 2008; 100(16): 1155 - 1166. [Abstract] [Full Text] [PDF]

				M. Dicato Venous Thromboembolic Events and Erythropoiesis-Stimulating Agents: An Update Oncologist, May 1, 2008; 13(suppl_3): 11 - 15. [Abstract] [Full Text] [PDF]

				J.-P. Spano and D. Khayat Treatment Options for Anemia, Taking Risks into Consideration: Erythropoiesis-Stimulating Agents Versus Transfusions Oncologist, May 1, 2008; 13(suppl_3): 27 - 32. [Abstract] [Full Text] [PDF]

				L. Bastit, A. Vandebroek, S. Altintas, B. Gaede, T. Pinter, T. S. Suto, T. W. Mossman, K. E. Smith, and J. F. Vansteenkiste Randomized, Multicenter, Controlled Trial Comparing the Efficacy and Safety of Darbepoetin Alfa Administered Every 3 Weeks With or Without Intravenous Iron in Patients With Chemotherapy-Induced Anemia J. Clin. Oncol., April 1, 2008; 26(10): 1611 - 1618. [Abstract] [Full Text] [PDF]

				Y. Suzuki, Y. Tokuda, Y. Fujiwara, H. Minami, Y. Ohashi, and N. Saijo Weekly Epoetin Beta Maintains Haemoglobin Levels and Improves Quality of Life in Patients with Non-Myeloid Malignancies Receiving Chemotherapy Jpn. J. Clin. Oncol., March 1, 2008; 38(3): 214 - 221. [Abstract] [Full Text] [PDF]

				A. G. Shankar The Role of Recombinant Erythropoietin in Childhood Cancer Oncologist, February 1, 2008; 13(2): 157 - 166. [Abstract] [Full Text] [PDF]

				D. Cella, L. Wagner, J. Cashy, T. A. Hensing, S. Yount, and R. C. Lilenbaum Should Health-Related Quality of Life Be Measured in Cancer Symptom Management Clinical Trials? Lessons Learned Using the Functional Assessment of Cancer Therapy J Natl Cancer Inst Monographs, October 1, 2007; 2007(37): 53 - 60. [Abstract] [Full Text] [PDF]

				P. Kokhaei, A. O. Abdalla, L. Hansson, E. Mikaelsson, M. Kubbies, A. Haselbeck, H. Jernberg-Wiklund, H. Mellstedt, and A. Osterborg Expression of Erythropoietin Receptor and In vitro Functional Effects of Epoetins in B-Cell Malignancies Clin. Cancer Res., June 15, 2007; 13(12): 3536 - 3544. [Abstract] [Full Text] [PDF]

				J. K. Carroll, S. Kohli, K. M. Mustian, J. A. Roscoe, and G. R. Morrow Pharmacologic Treatment of Cancer-Related Fatigue Oncologist, May 1, 2007; 12(suppl_1): 43 - 51. [Abstract] [Full Text] [PDF]

				A. Dmoszynska, J. Kloczko, M. Rokicka, A. Hellmann, I. Spicka, and J. E. Eid A dose exploration, phase I/II study of administration of continuous erythropoietin receptor activator once every 3 weeks in anemic patients with multiple myeloma receiving chemotherapy Haematologica, April 1, 2007; 92(4): 493 - 501. [Abstract] [Full Text] [PDF]

				S. Yennurajalingam and E. Bruera Palliative Management of Fatigue at the Close of Life: "It Feels Like My Body Is Just Worn Out" JAMA, January 17, 2007; 297(3): 295 - 304. [Abstract] [Full Text] [PDF]

				Y. Morishima, M. Ogura, S. Yoneda, H. Sakai, K. Tobinai, Y. Nishiwaki, H. Minami, T. Hotta, K. Ezaki, Y. Ohe, et al. Once-Weekly Epoetin-Beta Improves Hemoglobin Levels in Cancer Patients with Chemotherapy-Induced Anemia: A Randomized, Double-Blind, Dose-Finding Study Jpn. J. Clin. Oncol., October 1, 2006; 36(10): 655 - 661. [Abstract] [Full Text] [PDF]

				J. Glaspy, S. Vadhan-Raj, R. Patel, L. Bosserman, E. Hu, R. E. Lloyd, R. V. Boccia, D. Tomita, and G. Rossi Randomized Comparison of Every-2-Week Darbepoetin Alfa and Weekly Epoetin Alfa for the Treatment of Chemotherapy-Induced Anemia: The 20030125 Study Group Trial J. Clin. Oncol., May 20, 2006; 24(15): 2290 - 2297. [Abstract] [Full Text] [PDF]

				J. Bohlius, J. Wilson, J. Seidenfeld, M. Piper, G. Schwarzer, J. Sandercock, S. Trelle, O. Weingart, S. Bayliss, B. Djulbegovic, et al. Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst, May 17, 2006; 98(10): 708 - 714. [Abstract] [Full Text] [PDF]

				K. R. LaMontagne, J. Butler, D. J. Marshall, J. Tullai, Z. Gechtman, C. Hall, A. Meshaw, and F. X. Farrell Recombinant epoetins do not stimulate tumor growth in erythropoietin receptor-positive breast carcinoma models. Mol. Cancer Ther., February 1, 2006; 5(2): 347 - 355. [Abstract] [Full Text] [PDF]

				B. Coiffier Response to "Effect of Patient Exclusion Criteria on the Efficacy of Erythropoiesis-Stimulating Agents in Patients with Cancer-Related Anemia" Oncologist, October 1, 2005; 10(9): 762 - 763. [Full Text] [PDF]

				R. Stasi, S. Amadori, T. J. Littlewood, E. Terzoli, A. C. Newland, and D. Provan Management of Cancer-Related Anemia with Erythropoietic Agents: Doubts, Certainties, and Concerns Oncologist, August 1, 2005; 10(7): 539 - 554. [Abstract] [Full Text] [PDF]

				T. J. Smith, P. J. Coyne, P. S. Staats, T. Deer, L. J. Stearns, R. L. Rauck, R. L. Boortz-Marx, E. Buchser, E. Catala, D. A. Bryce, et al. An implantable drug delivery system (IDDS) for refractory cancer pain provides sustained pain control, less drug-related toxicity, and possibly better survival compared with comprehensive medical management (CMM) Ann. Onc., May 1, 2005; 16(5): 825 - 833. [Abstract] [Full Text] [PDF]

				R. C. Leonard, M. Untch, and F. Von Koch Management of anaemia in patients with breast cancer: role of epoetin Ann. Onc., May 1, 2005; 16(5): 817 - 824. [Abstract] [Full Text] [PDF]

				T. J. Littlewood, B. Schenkel, and M. Liss Effect of Patient Exclusion Criteria on the Efficacy of Erythropoiesis-Stimulating Agents in Patients with Cancer-Related Anemia Oncologist, May 1, 2005; 10(5): 357 - 360. [Abstract] [Full Text] [PDF]

				T. E. Witzig, P. T. Silberstein, C. L. Loprinzi, J. A. Sloan, P. J. Novotny, J. A. Mailliard, K. M. Rowland, S. R. Alberts, J. E. Krook, R. Levitt, et al. Phase III, Randomized, Double-Blind Study of Epoetin Alfa Compared With Placebo in Anemic Patients Receiving Chemotherapy J. Clin. Oncol., April 20, 2005; 23(12): 2606 - 2617. [Abstract] [Full Text] [PDF]

				J. Chang, F. Couture, S. Young, K.-L. McWatters, and C. Y. Lau Weekly Epoetin Alfa Maintains Hemoglobin, Improves Quality of Life, and Reduces Transfusion in Breast Cancer Patients Receiving Chemotherapy J. Clin. Oncol., April 20, 2005; 23(12): 2597 - 2605. [Abstract] [Full Text] [PDF]

				J. Bohlius, S. Langensiepen, G. Schwarzer, J. Seidenfeld, M. Piper, C. Bennett, and A. Engert Recombinant Human Erythropoietin and Overall Survival in Cancer Patients: Results of a Comprehensive Meta-analysis J Natl Cancer Inst, April 6, 2005; 97(7): 489 - 498. [Abstract] [Full Text] [PDF]

				D. Cella, J. Kallich, A. McDermott, and X. Xu The longitudinal relationship of hemoglobin, fatigue and quality of life in anemic cancer patients: results from five randomized clinical trials Ann. Onc., June 1, 2004; 15(6): 979 - 986. [Abstract] [Full Text] [PDF]

				A. Levis, A. P. Anselmo, A. Ambrosetti, F. Adamo, M. Bertini, E. Cavalieri, P. Gavarotti, A. Genua, M. Liberati, V. Pavone, et al. VEPEMB in elderly Hodgkin's lymphoma patients. Results from an Intergruppo Italiano Linfomi (IIL) study Ann. Onc., January 1, 2004; 15(1): 123 - 128. [Abstract] [Full Text] [PDF]

				B. Barlogie, J. Shaughnessy, G. Tricot, J. Jacobson, M. Zangari, E. Anaissie, R. Walker, and J. Crowley Treatment of multiple myeloma Blood, January 1, 2004; 103(1): 20 - 32. [Abstract] [Full Text] [PDF]

				J. D. Rizzo, D. Cella, and J. Seidenfeld In Reply: J. Clin. Oncol., June 1, 2003; 21(11): 2224 - 2225. [Full Text] [PDF]

				D. Cella, D. Dobrez, and J. Glaspy Control of cancer-related anemia with erythropoietic agents: a review of evidence for improved quality of life and clinical outcomes Ann. Onc., April 1, 2003; 14(4): 511 - 519. [Abstract] [Full Text] [PDF]

				J. D. Rizzo, A. E. Lichtin, S. H. Woolf, J. Seidenfeld, C. L. Bennett, D. Cella, B. Djulbegovic, M. J. Goode, A. A. Jakubowski, S. J. Lee, et al. Use of Epoetin in Patients With Cancer: Evidence-Based Clinical Practice Guidelines of the American Society of Clinical Oncology and the American Society of Hematology J. Clin. Oncol., October 1, 2002; 20(19): 4083 - 4107. [Abstract] [Full Text] [PDF]

				J. D. Rizzo, A. E. Lichtin, S. H. Woolf, J. Seidenfeld, C. L. Bennett, D. Cella, B. Djulbegovic, M. J. Goode, A. A. Jakubowski, S. J. Lee, et al. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology Blood, September 18, 2002; 100(7): 2303 - 2320. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Österborg, A. Articles by Messinger, D. Search for Related Content PubMed PubMed Citation Articles by Österborg, A. Articles by Messinger, D. Social Bookmarking                            What's this?