Originally published as JCO Early Release 10.1200/JCO.2006.07.1514 on February 20 2007
Journal of Clinical Oncology, Vol 25, No 9 (March 20), 2007: pp. 1027-1032
© 2007 American Society of Clinical Oncology.
Randomized, Double-Blind, Placebo-Controlled Trial of Erythropoietin in Non–Small-Cell Lung Cancer With Disease-Related Anemia
James R. Wright,
Yee C. Ung,
Jim A. Julian,
Kathleen I. Pritchard,
Timothy J. Whelan,
Column Smith,
Barbara Szechtman,
Wilson Roa,
Liam Mulroy,
Leona Rudinskas,
Bruno Gagnon,
Gord S. Okawara,
Mark N. Levine
From the Juravinski Cancer Centre at Hamilton Health Sciences; Department of Medicine, McMaster University; Department of Clinical Epidemiology, McMaster University; Ontario Clinical Oncology Group, Hamilton; Toronto-Sunnybrook Regional Cancer Centre; University of Toronto; Humber River Regional Hospital, Toronto, Ontario; Tom Baker Cancer Centre, Calgary; Cross Cancer Institute, Edmonton, Alberta; Nova Scotia Cancer Centre, Halifax, Nova Scotia; and McGill University, Montreal, Quebec, Canada
Address reprint requests to James R. Wright, MD, FRCP(C), MSc, Juravinski Cancer Center at Hamilton Health Sciences, 699 Concession St, Hamilton, Ontario, L8V 5C2, Canada; e-mail: jim.wright{at}hrcc.on.ca
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ABSTRACT
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Purpose Previous trials have suggested a quality-of-life (QOL) improvement for anemic cancer patients treated with erythropoietin, but few used QOL as the primary outcome. We designed a trial to investigate the effects of epoetin alfa therapy on the QOL of anemic patients with advanced non–small-cell carcinoma of the lung (NSCLC).
Patients and Methods A multicenter, randomized, double-blind, placebo-controlled trial was conducted. The proposed sample size was 300 patients. Eligible patients were required to have NSCLC unsuitable for curative therapy and baseline hemoglobin (Hgb) levels less than 121 g/L. Patients were assigned to 12 weekly injections of subcutaneous epoetin alpha or placebo, targeting Hgb levels between 120 and 140 g/L. The primary outcome was the difference in the change in Functional Assessment of Cancer Therapy–Anemia scores between baseline and 12 weeks.
Results Reports of thrombotic events in other epoetin trials prompted an unplanned safety analysis after 70 patients had been randomly assigned (33 to the active arm and 37 to the placebo arm). This revealed a significant difference in the median survival in favor of the patients on the placebo arm of the trial (63 v 129 days; hazard ratio, 1.84; P = .04). The Steering Committee closed the trial. Patient numbers compromised the interpretation of the QOL analysis, but a positive Hgb response was noted with epoetin alfa treatment.
Conclusion An unplanned safety analysis suggested decreased overall survival in patients with advanced NSCLC treated with epoetin alfa. Although infrequent, other similar reports highlight the need for ongoing trials evaluating erythropoietin receptor agonists to ensure that overall survival is monitored closely.
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INTRODUCTION
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Cancer patients commonly experience anemia.1,2 Although treatments such as systemic chemotherapy are an obvious cause, many cancer patients are anemic at presentation. Up to 34% of patients with lung cancer may present with hemoglobin (Hgb) levels  125 g/L.3 The most common clinical manifestation of anemia is fatigue, but vertigo, loss of appetite, poor concentration, and dyspnea can occur. Anemia often leads to impairment of physical capacity, lowers patients’ subjective sense of well-being, and diminishes their overall quality of life (QOL).4-6
A number of previous trials involving cancer patients have found improved QOL measures with the use of recombinant human erythropoietin (epoetin alfa), but none were designed as placebo-controlled trials with QOL as the primary end point.7-10 Therefore, we investigated whether epoetin alfa could improve the QOL of anemic patients with locally advanced or metastatic non–small-cell carcinoma of the lung (NSCLC).
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PATIENTS AND METHODS
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Patient Population
Eligible patients were required to have histologic evidence of unresectable locally advanced (stage IIIa or IIIb), metastatic or recurrent NSCLC, and an Hgb level 120 g/L. Patients with stage III disease whose status was suitable for high-dose thoracic radiation were not eligible. In an attempt to measure changes in disease-related anemia, and not systemic treatment–related anemia, patients with any recent (2 months) or planned systemic therapy were excluded initially. However, the routine use of palliative systemic therapy increased significantly at the participating centers during the course of the trial. Consequently, when accrual was found to be influenced particularly by this exclusion criterion, it was relaxed to exclude only platinum-based therapy. Patients with less than 3 months expected survival, poor performance status (Eastern Cooperative Oncology Group [ECOG] 3 or 4), multiple brain metastases, recent (2 weeks) blood transfusions, or who had received erythropoietin receptor agonists (ERAs) previously were not eligible. The protocol and informed consent forms were approved by each center's research ethics board before activation.
Intervention
The study was a multicenter, randomized, double-blind, placebo-controlled trial. After written informed consent was received, all baseline QOL assessments were completed before random assignment. Randomly assigned patients were stratified by center and by two factors believed to influence QOL during the 12-week period: baseline Hgb level (< 100 or 100 to 120) and the concurrent planned use/nonuse of palliative radiation. Computer-generated randomization lists were prepared and centrally controlled by the Ontario Clinical Oncology Group (OCOG) located at Hamilton Health Sciences.
Randomly assigned patients were to receive 12 weekly subcutaneous injections of study drug, the initial dose of which was 1.0 mL, which represented 40,000 U of epoetin alfa (Eprex; Ortho Biotech, Bridgewater, NJ) for those patients in the active arm, or an identical-looking placebo for those patients in the control arm. If the Hgb level increased less than 10 g/L from baseline to the 4-week assessment point, the dose of study drug was increased to 1.5 mL or 60,000 U of epoetin alfa in those patients in the active arm. If the Hgb level increased by 20 g/L or more during any 4-week period, the dose of study drug was reduced by 25%. If the Hgb exceeded 140 g/L at any time, study drug was withheld until the Hgb level decreased below 120 g/L, and was then resumed with a 25% dose reduction. Iron supplementation was at the discretion of the attending physician.
Outcomes
The primary outcome of the trial was the change in QOL from baseline to 12 weeks as assessed using the Functional Assessment of Cancer Therapy–Anemia (FACT-An) score.11 Secondary outcomes included the change in the FACT-An total score, the change in Hgb, and the need for transfusions. QOL assessments were completed at baseline and at 4, 8, 12, and 16 weeks after random assignment. Patients were blinded to their Hgb levels before completing their QOL assessments. Hgb levels were also assessed at 26 weeks after random assignment. Only survival status was collected beyond the 26-week assessment.
Statistical Considerations
Sample size calculations assumed a difference of 6 units in the FACT-An score (7.5% of the maximum score of 80) would be clinically significant. Using an estimate of standard deviation for change of 16, and accepting a two-sided type I error of 5%, we would achieve 80% power to detect a 6-unit difference in improvement (effect size, 0.375) with 112 patients per arm. Assuming 25% of randomly assigned patients may not have primary outcome data available, the sample size was adjusted to 150 patients per arm, or a total of 300 patients.
The primary efficacy analysis was to compare the change in the FACT-An score from baseline to 12 weeks in the active and placebo groups using a two-sample t test, and adhering to the intention-to-treat principle. A similar approach was used to analyze the change in Hgb. The proportions of patients undergoing transfusions in the two arms were compared using the Fisher's exact test. All study data were collected and reviewed centrally at OCOG, with statistical analysis performed by the OCOG statisticians using SAS version 9.1 (SAS Institute, Cary, NC).
Survival Analysis
After the Data Safety Monitoring Committee (DSMC) report suggesting higher mortality in the active arm (see Results), the overall survival of patients became the primary concern. Given that the trial was not designed to capture detailed information on previous cancer treatment or other potentially confounding variables that may have influenced survival, supplementary data on all patients were obtained while maintaining the blinded status. Overall survival (ie, all-cause mortality) was summarized using the Kaplan-Meier method,12 and the groups were compared using the log-rank test. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and associated 95% CIs, and to adjust the observed treatment effects for the influence of baseline variables considered to be related to survival: age; sex; cell type; disease stage; ECOG status; Hgb; previous radiation, chemotherapy, or surgery; and previous history of a thrombotic event.13 Survival analyses are reported from both the initial DSMC report and the final study data set.
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RESULTS
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The first patient was randomly assigned in February 2001, and the study was suspended to accrual in November 2003. Eleven centers throughout Canada screened 238 potentially eligible patients, of which 114 patients met at least one exclusion criterion, including the planned-use chemotherapy (initially any chemotherapy, but subsequently only platinum-based chemotherapy; 48 patients); ECOG performance status of 3 or 4 (19 patients); brain metastasis (10 patients); and expected survival of less than 3 months (seven patients). Therefore, 124 patients were eligible, 54 declined participation, and 70 patients were randomly assigned (Fig 1).
DSMC Results
In the autumn of 2003, as other trials evaluating ERAs were being suspended or terminated because of unexpected rates of thrombotic events, Ortho Biotech requested a review of the accumulated data by the independent DSMC of the trial. This was an unplanned analysis. The DSMC was aware of the EPO-INT-76 breast cancer trial as initially reported by Leyland-Jones et al,14 as well as the results of a head and neck trial reported by Henke et al.15 The trials suggested a negative impact on survival for epoetin alfa and epoetin beta, respectively. Although the primary intent of the safety review was to examine rates of thrombotic events, the difficulty assigning causality of death prompted a review of overall mortality. The report of the DSMC was based on 66 patients.
The DSMC reported their findings to the steering committee of the trial. Rates of thrombosis were low in both groups: one patient in the active arm, and two patients in the placebo arm. An analysis of overall survival revealed a median time to death of 63 days in the active arm, and 129 days in the placebo arm (HR, 1.84; 95% CI, 1.01 to 3.35; P = .04). The HR adjusted for stratum, sex, Hgb, ECOG status, and disease stage, using the data of 58 patients with available baseline data, was 2.17 (95% CI, 1.07 to 4.41; P = .03). The DSMC noted the low proportion of patients, approximately 50%, with a week-12 QOL assessment, which represented the planned primary outcome of the trial. The DSMC did not make a formal recommendation regarding study closure to the steering committee, but did express a strong concern about the increased mortality in the active treatment arm.
The steering committee reviewed this data and the negative overall survival results of the two studies noted previously. In addition, the steering committee was aware of Radiation Therapy Oncology Group's decision to close the 99-03 study, which involved epoetin alfa in head and neck cancer patients.16 The steering committee decided to suspend the trial to further accrual in December 2003 and immediately discontinue all use of study drug.
Final Results
With updated patient outcomes, and complete details of previous treatments, the database was frozen to additional clinical updates on March 19, 2005. The following results include all available data for the 70 patients entered onto the trial. The characteristics of patients at baseline are summarized in Table 1. The groups were well balanced for known prognostic factors and previous treatments. Approximately half of the patients in the study had evidence of distant disease at the time of random assignment; the involved sites were most commonly bone, followed by adrenal glands and liver in both groups of patients. The baseline FACT-An scores and the proportion of patients with ECOG scores of 0 to 1 versus 2 were both higher in the placebo arm, suggesting better baseline QOL, but these differences were not statistically significant (P = .07 and P = .35, respectively).
Only a relatively small proportion of patients (23% overall) had received any previous systemic therapy before study entry, and no patients went on to receive additional systemic therapy, although that was not strictly stipulated in the trial design.
Reported adverse events were similar in both arms of the trial. From the time of the initial DSMC report outlining thrombotic events, one additional patient in each arm of the trial experienced such an event.
The differences in the mean change of scores of the FACT-An scale between baseline and weeks 4, 8, and 12 are summarized in Table 2, along with mean Hgb levels and changes. Of the 70 randomly assigned patients, only 34 (49%) had a week-12 QOL assessment available—14 (42%) patients from the active arm and 20 (54%) patients from the placebo arm. The mean increase from baseline was 6.5 for patients from the active arm, and 2.6 for the patients receiving placebo, resulting in a statistically nonsignificant difference of 3.9. Additional modeling, using the 8-week scores for those patients without 12-week assessments, was consistent with the initial findings.
From baseline to the week-12 assessments, mean Hgb levels increased by 20.6 g/L in the 14 patients in the active arm, and by 2.1 g/L in the 20 patients in the placebo arm (Table 2). This difference was statistically significant (P = .003).
Five of the patients in the active arm of the trial each received a single transfusion, two within the first 4 weeks, one between 4 and 12 weeks, and two after 12 weeks. In the placebo arm, 10 patients underwent a total of 13 transfusions (one patient had four transfusions), two in the first 4 weeks, seven between 4 and 12 weeks, and four after 12 weeks. The odds ratio for any transfusion in the epoetin alfa arm relative to placebo was 0.48 (95% CI, 0.15 to 1.60; P = .26).
In the final analysis, death had occurred in 32 of 33 patients on the active arm of the trial, and in 34 of the 37 patients receiving placebo. The majority of deaths were reported as disease progression (Table 3). The Kaplan-Meier curves of overall survival (Fig 2) confirmed a difference in the median time to death favoring the patients receiving placebo (68 v 131 days; P = .04).
However, the shape of the survival curves did not appear to be consistent with the proportional hazards assumption of the Cox regression model. Although a number of formal statistical tests17 were not significant, an inspection of the Schoenfeld residuals for treatment against time was suggestive of nonproportional hazards.18 Therefore, we fit separate models for survival up to the end of 12, 16, and 26 weeks from randomization. These time points represented the duration of study drug delivery, the active phase of the trial, and the last scheduled assessment of the trial, respectively. The HRs, unadjusted and adjusted for baseline variables, are shown in Table 4. The shape of the survival curve shows that the greatest separation occurred after 12 weeks, corresponding to the planned discontinuation of the study drug. The small sample of patients limited the ability to draw insightful conclusions from extensive modeling of the data, but there did not appear to be an imbalance of known baseline prognostic factors that could explain the negative survival effect of active treatment, regardless of the time point selected. Sequential Cox models carrying forward only significant confounding baseline variables (ECOG status and nodal burden) produced HRs similar to those in the initial unadjusted models (data not shown).
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DISCUSSION
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At the time this trial was initiated, the use of epoetin alfa was uncommon in the Canadian setting. We believed that a randomized, double-blind trial with QOL as the primary end point in a specific population of cancer patients was justified.
This trial reaffirms the role of epoetin alfa in increasing Hgb levels in patients with advanced-stage NSCLC. The early termination of the trial, and the low proportion of patients providing QOL data at the 12-week assessment, left the trial insufficiently powered to find significant differences in the QOL measures. Regardless, at no time did the difference between QOL changes in the two arms reach the a priori clinically significant difference of 6 units. In large part, a difference of this magnitude was not reached because of the unusual improvements recorded for the patients in the placebo arm of the trial. At 8 weeks, the patients receiving placebo had a mean increase of over 8 units in the primary QOL life score. This improvement highlights recent concerns raised in the interpretation of unblinded erythropoietin QOL trials.19,20
The survival difference initially reported by the DSMC, and subsequently in the final analysis, was unexpected. This finding may be a chance occurrence, detected only as a result of the timing of the unplanned safety analysis. When various models and adjusted HRs were calculated, the most consistent predictor of patient survival was treatment with epoetin alfa or placebo. Although the CIs for most of these estimates were wide, concern for the routine use of epoetin alfa for disease-related anemia in patients with advanced NSCLC remains.
The decision to suspend this trial was complex. The DSMC was created to monitor treatment-related toxicity but no stopping rules were written into the protocol. Although the results of the DSMC's interim analysis may appear to provide sufficient justification to suspend the trial, the members of the DSMC and the steering committee of the trial were aware and influenced by external developments. If no other trials had documented a negative impact on survival, how might the present data have been interpreted? The DSMC reported a survival analysis with a statistically significant difference, but even a less convincing statistical outcome may have justified trial closure based on safety concerns. How much confidence does one require that an investigational agent is contributing to poorer survival? Conversely, this was a well-studied drug with numerous trials involving thousands of patients, conducted in multiple disease sites without previous evidence of a negative impact on survival. Its role in patients with chemotherapy-induced anemia was well supported with many trials, systematic reviews, and evidence-based guidelines.21,22
Since the initial report of the INT-76 trial, many theories of an underlying mechanism with a detrimental impact on survival have been suggested23; the obvious theory was that ERAs can act as growth factors to accelerate cancer growth. The survival curve in our study would support this hypothesis, given that the slope of the curve clearly changes once the 12 weeks of drug therapy are complete. Thus far, the reported populations of patients who have experienced a negative outcome have shared a higher disease burden, and the patients entered onto this trial had particularly poor survival. The differences in survival may relate to aggressive targets for Hgb support. Higher Hgb targets may have contributed to higher rates of thrombotic disease. Although the rates of thrombotic disease in this trial are low, it is not clear how often fatal thrombotic events are undetected or uninvestigated in patients with end-stage cancer.14,24 Both entry and target levels of Hgb for this trial, 120 and 140 g/L, respectively, would be considered high relative to contemporary prescribing information, suggesting initiation of therapy at the 110 g/L level and suspension at 130 g/L.
The controversy of these findings has not gone unnoticed. In May 2004, the US Food and Drug Administration requested a review of all ERA products. Data from multiple trials, including this trial, have been summarized and are available to the public.25 No trends that caused concern were identified. A recent meta-analysis also failed to demonstrate any survival concerns,26 and although the negative overall survival results from the two previously noted trials were not included, other reviews,27 guidelines,28 and primary publications continue to support the overall safety of epoetin alfa therapy for cancer patients.20,29,30 As future meta-analyses are conducted to further enlighten the issue of a survival effect, adjuvant and palliative populations of patients should be considered separately. In addition, time to death, not simple proportions of patients dead or alive with or without ERA support, may be a more revealing outcome in patients with advanced disease. This trial will provide data for those required meta-analyses. However, as suggested by the US Food and Drug Administration panel reviewing the use of ERAs at currently recommended doses, it is clear that ongoing and future trials must continue to collect data on the survival outcomes of patients.
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Authors’ Disclosures of Potential Conflicts of Interest
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The authors indicated no potential conflicts of interest.
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Author Contributions
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Conception and design: James R. Wright, Yee C. Ung, Jim A. Julian, Kathleen I. Pritchard, Timothy J. Whelan, Mark N. Levine
Administrative support: Kathleen I. Pritchard, Mark N. Levine
Provision of study materials or patients: Yee C. Ung, Column Smith, Barbara Szechtman, Wilson Roa, Liam Mulroy, Leona Rudinskas, Bruno Gagnon, Gord S. Okawara
Collection and assembly of data: James R. Wright, Jim A. Julian, Column Smith, Barbara Szechtman, Wilson Roa, Liam Mulroy, Leona Rudinskas, Bruno Gagnon, Gord S. Okawara
Data analysis and interpretation: James R. Wright, Jim A. Julian, Kathleen I. Pritchard, Timothy J. Whelan, Mark N. Levine
Manuscript writing: James R. Wright, Yee C. Ung, Jim A. Julian, Kathleen I. Pritchard, Timothy J. Whelan, Mark N. Levine
Final approval of manuscript: James R. Wright, Yee C. Ung, Jim A. Julian, Kathleen I. Pritchard, Timothy J. Whelan, Column Smith, Barbara Szechtman, Wilson Roa, Liam Mulroy, Leona Rudinskas, Bruno Gagnon, Gord S. Okawara, Mark N. Levine
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NOTES
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published online ahead of print at www.jco.org on February 20, 2007.
Supported by a grant-in-aid from Ortho Biotech to the Ontario Clinical Oncology Group.
Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Submitted May 4, 2006;
accepted August 1, 2006.
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N. L. Metzger, K. E. Francis, and S. A. Voils
A Comparative Review of Erythropoiesis Stimulating Agents
Journal of Pharmacy Practice,
December 1, 2008;
21(6):
424 - 430.
[Abstract]
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M. Saltiel
The Erythropoietic Receptors Agonists: FDA Warnings, Changing Guidelines, and Other Responses to Negative Data
Journal of Pharmacy Practice,
December 1, 2008;
21(6):
402 - 404.
[Abstract]
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A. M Newland and C. D Black
Tumor Progression Associated with Erythropoiesis-Stimulating Agents
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December 1, 2008;
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[Abstract]
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M. H. DAVIDSON
IN REPLY
Cleveland Clinic Journal of Medicine,
November 1, 2008;
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[Full Text]
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K. S. Courneya, L. W. Jones, C. J. Peddle, C. M. Sellar, T. Reiman, A. A. Joy, N. Chua, L. Tkachuk, and J. R. Mackey
Effects of Aerobic Exercise Training in Anemic Cancer Patients Receiving Darbepoetin Alfa: A Randomized Controlled Trial
Oncologist,
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[Abstract]
[Full Text]
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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,
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[Abstract]
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R. Zarychanski MD and D. S. Houston MD PhD
Anemia of chronic disease: A harmful disorder or an adaptive, beneficial response?
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August 12, 2008;
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[Full Text]
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M. O. Arcasoy
Erythropoiesis-Stimulating Agent Use in Cancer: Preclinical and Clinical Perspectives
Clin. Cancer Res.,
August 1, 2008;
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[Abstract]
[Full Text]
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M. Jadersten, L. Malcovati, I. Dybedal, M. Giovanni Della Porta, R. Invernizzi, S. M. Montgomery, C. Pascutto, A. Porwit, M. Cazzola, and E. Hellstrom-Lindberg
Erythropoietin and Granulocyte-Colony Stimulating Factor Treatment Associated With Improved Survival in Myelodysplastic Syndrome
J. Clin. Oncol.,
July 20, 2008;
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[Abstract]
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M. O. Arcasoy
Erythropoiesis-Stimulating Agents in Cancer
J. Clin. Oncol.,
June 20, 2008;
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[Full Text]
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K. A. May and F. R. Khuri
Unraveling the Mystery of Erythropoietin-Stimulating Agents in Cancer Promotion
Cancer Res.,
June 1, 2008;
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[Abstract]
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V. Juneja, P. Keegan, J. E. Gootenberg, M. D. Rothmann, Y. L. Shen, K. Y. Lee, K. D. Weiss, and R. Pazdur
Continuing Reassessment of the Risks of Erythropoiesis-Stimulating Agents in Patients with Cancer
Clin. Cancer Res.,
June 1, 2008;
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[Abstract]
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W. H. Geerts, D. Bergqvist, G. F. Pineo, J. A. Heit, C. M. Samama, M. R. Lassen, and C. W. Colwell
Prevention of Venous Thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)
Chest,
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133(6_suppl):
381S - 453S.
[Abstract]
[Full Text]
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R. Pirker, R. A. Ramlau, W. Schuette, P. Zatloukal, I. Ferreira, T. Lillie, and J. F. Vansteenkiste
Safety and Efficacy of Darbepoetin Alfa in Previously Untreated Extensive-Stage Small-Cell Lung Cancer Treated With Platinum Plus Etoposide
J. Clin. Oncol.,
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[Abstract]
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H. Kitamura, Y. Isaka, Y. Takabatake, R. Imamura, C. Suzuki, S. Takahara, and E. Imai
Nonerythropoietic derivative of erythropoietin protects against tubulointerstitial injury in a unilateral ureteral obstruction model
Nephrol. Dial. Transplant.,
May 1, 2008;
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[Abstract]
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M. S. Aapro
Editorial: Anemia Management with Erythropoiesis-Stimulating Agents: A Risk-Benefit Update
Oncologist,
May 1, 2008;
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P. Gascon
Safety Update on Erythropoiesis-Stimulating Agents: Trials Within and Outside the Accepted Indications
Oncologist,
May 1, 2008;
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[Abstract]
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M. de Perrot, K. McRae, M. Anraku, K. Karkouti, T. K. Waddell, A. F. Pierre, G. Darling, S. Keshavjee, and M. R. Johnston
Risk Factors for Major Complications After Extrapleural Pneumonectomy for Malignant Pleural Mesothelioma
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[Abstract]
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J. W. Polli, J. E. Humphreys, K. A. Harmon, S. Castellino, M. J. O'Mara, K. L. Olson, L. St. John-Williams, K. M. Koch, and C. J. Serabjit-Singh
The Role of Efflux and Uptake Transporters in N-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methylsulfonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine (GW572016, Lapatinib) Disposition and Drug Interactions
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April 1, 2008;
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[Abstract]
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P. Saintigny, B. Besse, J.-C. Soria, J.-F. Bernaudin, and P. Callard
Does Erythropoietin Promote Tumor Growth?
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S. S Shord, J.M. Hamilton Jr, and S. Cuellar
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[Abstract]
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C. L. Bennett, S. M. Silver, B. Djulbegovic, A. T. Samaras, C. A. Blau, K. J. Gleason, S. E. Barnato, K. M. Elverman, D. M. Courtney, J. M. McKoy, et al.
Venous Thromboembolism and Mortality Associated With Recombinant Erythropoietin and Darbepoetin Administration for the Treatment of Cancer-Associated Anemia
JAMA,
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[Abstract]
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W. C. Levy
Anemia in heart failure: marker or mediator of adverse prognosis?
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J. M. Hoffman, N. D. Shah, L. C. Vermeulen, F. Doloresco, P. Grim, R. J. Hunkler, K. M. Hontz, and G. T. Schumock
Projecting future drug expenditures--2008
Am. J. Health Syst. Pharm.,
February 1, 2008;
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[Abstract]
[Full Text]
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A. G. Shankar
The Role of Recombinant Erythropoietin in Childhood Cancer
Oncologist,
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[Abstract]
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J. D. Rizzo, M. R. Somerfield, K. L. Hagerty, J. Seidenfeld, J. Bohlius, C. L. Bennett, D. F. Cella, B. Djulbegovic, M. J. Goode, A. A. Jakubowski, et al.
Use of Epoetin and Darbepoetin in Patients With Cancer: 2007 American Society of Clinical Oncology/American Society of Hematology Clinical Practice Guideline Update
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[Abstract]
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J. W. Adamson
The Anemia of Inflammation/Malignancy: Mechanisms and Management
Hematology,
January 1, 2008;
2008(1):
159 - 165.
[Abstract]
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T. B. Gernsheimer
The Pathophysiology of ITP Revisited: Ineffective Thrombopoiesis and the Emerging Role of Thrombopoietin Receptor Agonists in the Management of Chronic Immune Thrombocytopenic Purpura
Hematology,
January 1, 2008;
2008(1):
219 - 226.
[Abstract]
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H. Sikand, A. Decter, T. Greco, S. H Watson, Y. J. Kang, S. H Mody, C. T. Piech, M. S. Duh, and A. Naeem
Cost Analytic Model to Determine the Least Costly Inpatient Erythropoiesis Stimulating Therapy Regimen
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January 1, 2008;
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[Abstract]
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K. A. May and F. R. Khuri
Role of Erythropoietin-stimulating Agents in the Outcomes of Patients with Cancer
ASCO Educational Book,
January 1, 2008;
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140 - 144.
[Abstract]
[Full Text]
[PDF]
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J. D. Rizzo, M. R. Somerfield, K. L. Hagerty, J. Seidenfeld, J. Bohlius, C. L. Bennett, D. F. Cella, B. Djulbegovic, M. J. Goode, A. A. Jakubowski, et al.
Use of epoetin and darbepoetin in patients with cancer: 2007 American Society of Hematology/American Society of Clinical Oncology clinical practice guideline update
Blood,
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[Abstract]
[Full Text]
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A. Tefferi
Pharmaceutical Erythropoietin Use in Patients With Cancer: Is It Time to Abandon Ship or Just Drop Anchor?
Mayo Clin. Proc.,
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V. Charu, B. Saidman, A. Ben-Jacob, G. R. Justice, A. S. Maniam, D. Tomita, G. Rossi, T. Rearden, and J. Glaspy
A Randomized, Open-Label, Multicenter Trial of Immediate Versus Delayed Intervention with Darbepoetin Alfa for Chemotherapy-Induced Anemia
Oncologist,
October 1, 2007;
12(10):
1253 - 1263.
[Abstract]
[Full Text]
[PDF]
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Erythropoiesis- Stimulating Agents: Continued Challenges
J. Oncol. Pract,
September 1, 2007;
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R. K. Spence
Medical and economic impact of anemia in hospitalized patients
Am. J. Health Syst. Pharm.,
August 15, 2007;
64(16_Supplement_11):
S3 - S10.
[Abstract]
[Full Text]
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J. Thomas and A. Martinez
Blood conservation in the critically ill
Am. J. Health Syst. Pharm.,
August 15, 2007;
64(16_Supplement_11):
S11 - S18.
[Abstract]
[Full Text]
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D. Jaspan
Erythropoietic therapy: Cost efficiency and reimbursement
Am. J. Health Syst. Pharm.,
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64(16_Supplement_11):
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[Abstract]
[Full Text]
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C. A. Blau
Erythropoietin in Cancer: Presumption of Innocence?
Stem Cells,
August 1, 2007;
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2094 - 2097.
[Abstract]
[Full Text]
[PDF]
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T. J. Littlewood
Response to "Warning Flags for Erythropoiesis-Stimulating Agents and Cancer-Associated Anemia"
Oncologist,
August 1, 2007;
12(8):
1031 - 1032.
[Abstract]
[Full Text]
[PDF]
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F. R. Khuri
Weighing the Hazards of Erythropoiesis Stimulation in Patients with Cancer
N. Engl. J. Med.,
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Erythropoietin for Cancer Patients -- Adverse Effect on Survival?
Journal Watch (General),
April 17, 2007;
2007(417):
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[Full Text]
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T. R. Lappin, A. P. Maxwell, and P. G. Johnston
Warning Flags for Erythropoiesis-Stimulating Agents and Cancer-Associated Anemia
Oncologist,
April 1, 2007;
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362 - 365.
[Full Text]
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J. Crawford
Erythropoietin: High Profile, High Scrutiny
J. Clin. Oncol.,
March 20, 2007;
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[Full Text]
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TOP
ABSTRACT
INTRODUCTION
