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Journal of Clinical Oncology, Vol 24, No 7 (March 1), 2006: pp. 1079-1089 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.7276 Phase III Study of Two Different Dosing Schedules of Erythropoietin in Anemic Patients With CancerFrom the Mayo Clinic and Mayo Foundation, Rochester; Duluth Community Clinical Oncology Program (CCOP), Duluth, MN; Iowa Oncology Research Association CCOP, Des Moines, IA; Toledo Community Hospital Oncology Program CCOP, Toledo, OH; Carle Cancer Center CCOP, Urbana, IL; Altru Health System, Grand Forks, ND; Sioux Community Cancer Consortium, Sioux Falls, SD; Scottsdale CCOP, Scottsdale AZ; and Geisinger Clinic and Medical Center CCOP, Danville, PA. Address reprint requests to David P. Steensma, MD, Mayo Clinic, 200 First St, SW, Rochester, MN 55905; e-mail: steensma.david{at}mayo.edu
PURPOSE: To compare maintenance epoetin alfa administered once every 3 weeks with continued weekly epoetin alfa for patients with cancer-associated anemia. PATIENTS AND METHODS: Eligible patients were randomly assigned at enrollment to receive three weekly doses of epoetin alfa 40,000 U subcutaneously (SC), followed by either standard weekly epoetin alfa (40K arm) or 120,000 U of epoetin alfa (120K arm) SC every 3 weeks for 18 additional weeks.
RESULTS: Three hundred sixty-five patients were enrolled. One hundred eighty-three patients were assigned to the 40K arm, and 182 were assigned to the 120K arm. There was no difference in the proportion of patients requiring transfusions during the study (23% in 40K arm and 18% in 120K arm, P = .22) or specifically during the maintenance phase (13% in 40K arm v 15% in 120K arm, P = .58). Patients randomly assigned to the 40K arm were more likely to have a CONCLUSION: After three weekly doses of epoetin alfa 40,000 U, a dose of 120,000 U can be administered safely once every 3 weeks without increasing transfusion needs or sacrificing QOL. The Hb increment is somewhat greater with continued weekly epoetin alfa. Lack of blinding as a result of different treatment schedules may have confounded results.
Anemia is a common complication of cancer and antineoplastic therapy, and anemia-associated symptoms can seriously impair patients' quality of life (QOL).1-4 RBC transfusions reliably increase hemoglobin (Hb) levels and ameliorate symptoms of anemia, but transfusions are associated with adverse reactions, processing and administration costs, inconvenience, patient fears, and a small risk of infection.5 Renally secreted erythropoietin is the major endogenous hormonal regulator of marrow erythrocyte production. Recombinant human erythropoietin (epoetin alfa) has been used for more than a decade for treatment of renal failure–associated and cancer-associated anemia,1,6-8 which is a clinical practice supported by evidence-based guidelines published jointly by the American Society of Hematology and the American Society of Clinical Oncology,9 by the National Comprehensive Cancer Network,10 and by other groups. Although the initial epoetin alfa administration schedule approved by the US Food and Drug Administration for chemotherapy-associated anemia was 150 U/kg (approximately 10,000 U) three times per week, several studies have supported the utility of a more convenient weekly epoetin administration, and the drug is now approved by the US Food and Drug Administration for use at an initial fixed dose of 40,000 U on a once-weekly schedule.11 Most anemic cancer patients receiving epoetin alfa are currently treated with a weekly fixed dose. The North Central Cancer Treatment Group (NCCTG) recently reported the results from a multicenter, randomized, double-blind, placebo-controlled trial of weekly epoetin alfa (40,000 U administered subcutaneously [SC]) in patients with chemotherapy-associated anemia.12 Compared with placebo, the active agent significantly improved Hb and reduced transfusion needs, but an overall QOL improvement was not demonstrated. A weekly epoetin schedule is more convenient for patients than a thrice-weekly schedule, but it is still imperfect.13 Many common cancer treatments (eg, cyclophosphamide, doxorubicin, vincristine, and prednisone for lymphoma and the standard doublet regimens for lung cancer) are administered once every 3 weeks, and some patients receiving epoetin do not receive concurrent antineoplastic therapy.14 For these patients, as well as for Medicare beneficiaries who cannot be reimbursed for self-administered medications, epoetin treatment can require weekly physician's office visits that might not otherwise be required. One potential solution to this problem is to alter the glycosylation pattern of recombinant erythropoietin to slow the hormone's metabolism and prolong its active half-life. Darbepoetin alfa, a newer erythropoietic agent with increased sialic acid content compared with epoetin alfa, has a longer terminal half-life than epoetin alfa and is currently approved by the US Food and Drug Administration for once-weekly dosing in chemotherapy-related anemia. Experience with this compound in less frequent dosing schedules is increasing; it is now commonly used once every 2 weeks in clinical practice. However, at present, neither epoetin alfa nor darbepoetin alfa are approved by the US Food and Drug Administration for longer interval dosing, and it is also unclear whether erythropoietic agents' tissue half-life or cycles of erythropoietin receptor activation are more critical in determining efficacy. Further study is needed for both agents to determine what the most effective doses and schedules might be.15-17 Administering weekly epoetin alfa for a few doses to induce an initial Hb increment (induction) and then switching to a more infrequent maintenance dosing schedule is another attractive approach. The potential efficacy of this strategy is supported by preclinical data18 and by a preliminary human trial.19 The goal of the present study was to compare 120,000 U of epoetin alfa administered every 3 weeks with standard weekly maintenance epoetin alfa treatment (40,000 U) in patients with cancer-associated anemia who had all received a short (three-dose) weekly epoetin induction regimen. Efficacy was measured in terms of RBC transfusion needs, QOL, and various Hb end points. These end points were studied in the context of a randomized, unblended, cooperative group trial.
Patient Eligibility The NCCTG conducted this trial. All participants provided written informed consent. The NCCTG, the National Cancer Institute, and an institutional review board at each participating site approved the study. Eligible patients were at least 18 years old and had anemia (males: Hb < 12.0 g/dL; females: Hb < 11.0 g/dL) believed to be related to a nonmyeloid cancer or antineoplastic therapy, a life expectancy of more than 6 months, a Zubrod performance status of 0 to 2, and a normal or elevated serum ferritin (  20 ng/mL). Patients did not have to be receiving antineoplastic therapy to enroll. Patients with anemia secondary to vitamin deficiency, bleeding, or hemolysis were excluded, as were pregnant or nursing women and patients undergoing stem-cell transplantation. Additional exclusions included uncontrolled hypertension or cardiac arrhythmia, recent thromboembolism (unless receiving anticoagulation), untreated brain metastases or seizures, and previous treatment with an erythropoietic agent within 6 months. Patients who had undergone surgery or erythrocyte transfusion were required to wait at least 14 days before enrollment. All patients had a CBC less than 7 days before study registration (baseline). Endogenous erythropoietin level, creatinine, and ferritin were measured less than 30 days before enrollment.
Study Treatment
If the Hb exceeded 13.0 g/dL during the study, epoetin alfa was held, and Hb was monitored weekly until Hb was
Assessment of End Points QOL instruments included the anemia subscale of the Functional Assessment of Cancer Therapy (13 items),20 the Symptom Distress Scale (13 items),21 the Brief Fatigue Inventory (BFI; nine items),22 and 12 linear analog self-assessment (LASA) items.23 These instruments were incorporated into a booklet designed to be completed by patients in 10 to 15 minutes. Patients completed QOL assessments every 3 to 4 weeks at office visits before they were told their current Hb level or the status of their cancer to avoid confounding. All QOL scores were transformed to a 100-point scale (100 being optimal) to simplify comparisons.24
Statistical Methods
There were five stratification variables, as follows: (1) actively receiving chemotherapy or radiotherapy or both versus not; (2) actively receiving platinum-based therapy (ie, carboplatin or cisplatin, which are agents that are especially toxic to renal cells) versus not; (3) degree of anemia (baseline Hb Fisher's exact test was used for comparing binary events across treatments, including efficacy and toxicity rates and categoric QOL variables. Independent sample t test procedures assessed QOL changes over time. Further analysis was carried out using repeated-measures analysis of variance/generalized estimating equation modeling to assess the relative contributions of variables such as baseline demographics, Hb, ferritin, and endogenous erythropoietin.
With 150 patients planned per arm, there was
Patient Characteristics Three hundred sixty-five patients at 16 NCCTG sites were registered between study activation in June 2003 and closure in March 2004. There were three early cancellations (before an epoetin alfa dose was administered) and two ineligible patients (one had myelodysplasia and the other received epoetin within 6 months of random assignment). Therefore, 360 patients were assessable for efficacy and toxicity. During the 3-week induction phase, 16 patients (4%) died or dropped out and did not reach the maintenance phase. These patients (six in the 40K arm and 10 in the 120K arm) were included with their assignment arm in the intent-to-treat analysis. Results of the analysis were unchanged when data were reanalyzed with these patients excluded. Overall, 67% of the patients randomly assigned to the 40K arm and 69% of the patients assigned to the 120K arm completed at least 18 of the 21 weeks of the study. The majority of patients (63%) completed all protocol therapy. Baseline characteristics were comparable (Table 1); 89% of patients were receiving chemotherapy.
Efficacy of Epoetin Alfa on Transfusion Requirements and Hb End Points In terms of the primary end point, which was the proportion of patients in each arm requiring transfusions, the treatment groups were similar; overall, 41 patients (23%) in the 40K arm received transfusion compared with 32 patients (18%) in the 120K arm (+5% difference; 95% CI for the difference, –4% to +13%; P = .22). The total number of RBC units transfused during the study was 135 in the 40K arm and 109 in the 120K arm. Dividing these figures by the total number of days that patients in each arm were alive and on study yielded a transfusion units per patient per day alive on study measure of 0.0063 on the 40K arm and 0.0053 for the 120K arm (P < .0001 favoring 120K). The proportion of patients who received transfusion during or after week 4 (ie, during the maintenance phase) was 13% (n = 24) in the 40K arm and 15% (n = 28) in the 120K arm (P = .58; Fig 1).
Hb data are listed in Table 2 and shown in Figure 2. Patients enrolled onto the 40K arm had a slightly higher mean end-of-study Hb than patients enrolled onto the 120K arm (12.0 v 11.5 g/dL, respectively; P = .0006; 95% CI for the difference in means, 0.2 to 0.8 g/dL) and a greater mean increase in Hb from baseline to last measured value (1.8 v 1.4 g/dL, respectively; P = .01; 95% CI for the difference in means, 0.1 to 0.8 g/dL). In addition, patients on the 40K arm, compared with patients on the 120K arm, were more likely to have a 2 g/dL or 3 g/dL increase in Hb from baseline to last value (77% v 67%, respectively, for 2 g/dL; P = .05; 95% CI for the difference in proportions, 0% to 18%; and 55% v 40%, respectively, for 3 g/dL; P = .006; 95% CI for the difference in proportions, 4% to 25%) and were more likely to have an Hb value of 13 g/dL at some point (65% v 43%, respectively; P < .0001; 95% CI for the difference in proportions, 12% to 32%).
Because patients on the 40K schedule were seen more frequently for epoetin injections, they potentially had a chance to be assessed more frequently by a treating physician and have a CBC drawn, because although CBCs were mandated at least every 3 weeks for both treatment groups, they could be performed at any time at physician discretion. The mean number of Hb measurements per patient during the course of the study was 13.3 in the 40K arm and 9.8 in the 120K arm (P < .0001). However, if the comparison points are restricted to every-3-week intervals during the maintenance period (when patients on both arms had a CBC, except for the small group of patients who got off schedule as the result of the need to delay a dose of epoetin for high Hb), the Hb is still greater at each assessment in the 40K arm (Fig 2).
Changes in QOL
Adverse Events Adverse events were monitored and graded using the National Cancer Institute Common Toxicity Criteria version 2.0. The incidence of adverse effects was similar between the two arms. An epoetin alfa dose was held as a result of high Hb (> 13.0 g/dL) more frequently in the 40K arm than in the 120K arm (61% v 36%, respectively; P < .0001). The incidence of ischemic and thrombotic events of any type (eight patients in 40K arm v nine patients in 120K arm; P = .80) was low and comparable between arms. The rate of Hb increase at every time point was lower for patients who had thrombotic events than for the whole study population (eg, week 4, P = .0001).
Survival
Despite the potential benefits of erythropoietic agents in cancer-associated anemia, less than one half of eligible persons currently receive therapy with these drugs.26 Many factors may contribute to this putative underuse, including inconvenience of the administration route (injection) and of US Food and Drug Administration–approved schedules (once weekly or three times per week). The results of this study suggest that, after three weekly doses of epoetin alfa, patients can safely receive 120,000 U (three times the fixed weekly dose) once every 3 weeks to consolidate and maintain erythropoietic gains, with similar efficacy in terms of transfusion end points and QOL compared with continuing weekly epoetin. Toxicity is also comparable between these two approaches. However, although the every-3-week epoetin alfa regimen may be more convenient than weekly dosing, there may be a trade-off; Hb end points were not equivalent between the two schedules, even when we accounted for the more frequent discretionary blood count measurements in the weekly therapy group. The greater frequency with which blood counts were obtained in the 40K arm must be considered when analyzing this study's results. Because a health care provider assessed such patients more frequently (ie, while patients received the weekly injection), there were more opportunities for obtaining blood counts, considering transfusion, or documentation of potential drug toxicity. When this trial was being designed, blinding with placebo controls and mandating weekly Hb and toxicity assessments in both arms was considered. These ideas were ultimately rejected because doing so might have altered QOL assessment in the 120K group if the convenience of less frequent travel and office visits contributed to QOL. Indeed, global QOL improvement during the study was greater in the 120K group, although it is not possible to assign causation. Lack of blinding and assessment bias may also have confounded assessments of some transfusion and Hb end points. However, the mean Hb increase from baseline to end of study was superior in the 40K group, and this difference is unlikely to be a result of bias. Additionally, at each point during the maintenance phase when scheduled measurements were taken from patients in both groups, the mean Hb value favored the 40K arm (Fig 2). There is growing concern about a possible increased risk of thrombosis in patients treated with erythropoietic agents to a goal Hb level of more than 12 g/dL.2 Several erythropoietin treatment trials in which Hb normalization was attempted were stopped prematurely because of excess adverse events in the treatment arm, and other studies raised the specter of inferior overall or progression-free survival, although all published trials have had methodologic limitations.27-32 When this study opened in 2003, maintenance epoetin alfa doses were to be withheld only for an Hb level of more than 15.0 g/dL, but new adverse event data prompted revision to an Hb level of more than 13.0 g/dL (at that time, only a few patients had been enrolled, and none had reached Hb > 15.0 g/dL). The epoetin alfa product labels were voluntarily changed in 2004 by the manufacturers to recommend holding epoetin alfa treatment if the Hb is more than 13.0 g/dL and reinitiating with a 25% dose reduction when Hb decreases to less than 12.0 g/dL. Therefore, although the Hb increment in the weekly 40K arm was greater in this study, this is not necessarily salutary; the 40K arm also had epoetin alfa doses held more often for Hb levels of more than 13.0 g/dL. We do not know whether 120K therapy is associated with a similar time with Hb more than 13.0 g/dL because we did not mandate weekly Hb assessment between doses, but no immediate dosing decision could have been made if that information were available. Although there was no difference between treatment groups in the proportion of patients receiving transfusions during the maintenance phase, the overall number of transfusion events in both arms was relatively low. This may be because this study enrolled patients with a higher mean Hb (10.1 g/dL) than some other trials of erythropoietic agents and because a transfusion rule was specified. Many patients were enrolled and started on epoetin therapy at Hb levels where transfusion would not ordinarily be contemplated. This reflects typical clinical practice, but specification of transfusions as the primary end point (chosen because of predicted Hb ascertainment bias) must be considered a study limitation. Differences in Hb assessment frequency could also affect transfusion frequency, resulting in more transfusions in the 40K arm, potentially equalizing the primary end point when the 120K arm would otherwise be inferior. The total planned dose of epoetin alfa administered in this study was equivalent between arms to evaluate the specific effect of treatment schedule. It may actually be possible to administer epoetin alfa doses of less than 120K on an every-3-week schedule with similar efficacy, which would have an overall cost benefit. It might also be possible to administer epoetin alfa less frequently right from the start of therapy (ie, no induction phase), although a nonhuman primate model suggested that doing this might result in slower Hb improvement.18 Such questions could be addressed in a future study, perhaps also comparing darbepoetin alfa and including formal economic analysis. This study was a comparative trial. Demonstrating strict equivalence between two therapies can require a much larger treatment group than what was enrolled onto this study.33 Several previously published studies described improvement in various measurements of QOL in anemic cancer patients treated with epoetin alfa.34-36 However, the most recent placebo-controlled NCCTG epoetin study by Witzig et al,12 although demonstrating Hb improvement and transfusion reduction with active therapy, showed no QOL difference despite apparently adequate power to detect a difference. In this study, we compared QOL changes between two active therapy arms, so the power to detect relevant differences is less than in a placebo-controlled trial. There was an increased QOL improvement in the 120K arm relative to the standard 40K arm, but patients started treatment at different QOL levels. The reasons for baseline differences in QOL between study groups are unknown and were observed only with the global QOL measurement tool. In conclusion, a more convenient every-3-week epoetin alfa maintenance regimen is comparable to standard weekly epoetin alfa in terms of QOL and transfusion needs in patients with cancer-associated anemia. Clinicians must decide whether the possibly slightly inferior Hb measurements outweigh the added convenience of this dosing schedule and whether these inferior Hb measurements are clinically meaningful.
The following institutions and investigators also participated in this study: Iowa Oncology Research Association Community Clinical Oncology Program (CCOP), Des Moines, IA (Roscoe F. Morton, MD); Rapid City Regional Oncology Group, Rapid City, SD (Larry P. Ebbert, MD); Mayo Clinic Scottsdale CCOP, Scottsdale, AZ (Robert F. Marschke Jr, MD); CentraCare Clinic, St Cloud, MN (Harold E. Windschitl, MD); Geisinger Clinical Oncology Program, Danville, PA (Suresh Nair, MD); Grand Forks Clinic, Ltd, Grand Forks, ND (John A. Laurie, MD); Metro-Minnesota CCOP, St Louis Park, MN (Patrick J. Flynn, MD); Quain and Ramstad Clinic, Bismarck, ND (Ferdinand Addo, MD); Meritcare Hospital CCOP, Fargo, ND (Ralph Levitt, MD); and Saskatchewan Cancer Foundation, Saskatoon, Saskatchewan, Canada (Maria Tria Tirona, MD).
The authors indicated no potential conflicts of interest.
Supported in part by Public Health Service Grant Nos. CA-25224, CA-37404, CA-35103, CA-63849, CA-63848, CA-35195, CA-35272, CA-35269, CA-35101, CA-60276, CA-52352, CA-37417, CA-35448, and CA-35415. D.P.S. is supported by the Paul Calabresi Award for Clinical Oncology No. K12 CA-90628-04G from the National Cancer Institute. This was an investigator-initiated study. Ortho Biotech provided study drug and unrestricted administrative funds to the North Central Cancer Treatment Group. National Cancer Institute Cooperative Group–Industry Relationship Guidelines were strictly observed. In accordance with these guidelines, the industry collaborator was provided with the manuscript from the trial for advisory review and comment before initial submission for publication. The study collaborator otherwise had no role in the analysis or reporting of the study data or in revising the manuscript. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. Spivak JL: Cancer-related anemia: Its causes and characteristics. Semin Oncol 21:3-8, 1994[Medline] 2. Steensma DP: Management of anemia in patients with cancer. Curr Oncol Rep 6:297-304, 2004[Medline] 3. Cella D: Factors influencing quality of life in cancer patients: Anemia and fatigue. Semin Oncol 25:43-46, 1998[Medline] 4. Ludwig H, Strasser K: Symptomatology of anemia. Semin Oncol 28:7-14, 2001[Medline] 5. Goodnough LT: Erythropoietin therapy versus red cell transfusion. Curr Opin Hematol 8:405-410, 2001[CrossRef][Medline] 6. Oster W, Herrmann F, Gamm H, et al: Erythropoietin for the treatment of anemia of malignancy associated with neoplastic bone marrow infiltration. J Clin Oncol 8:956-962, 1990[Abstract] 7. Eschbach JW, Egrie JC, Downing MR, et al: Correction of the anemia of end-stage renal disease with recombinant human erythropoietin: Results of a combined phase I and II clinical trial. N Engl J Med 316:73-78, 1987[Abstract] 8. 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] 9. Rizzo JD, Lichtin AE, Woolf SH, 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 100:2303-2320, 2002 10. National Comprehensive Cancer Network: Cancer and treatment-related anemia, in Clinical Practice Guidelines in Oncology (version 2.2004), 2004. http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf 11. Gabrilove JL, Cleeland CS, Livingston RB, et al: Clinical evaluation of once-weekly dosing of epoetin alfa in chemotherapy patients: Improvements in hemoglobin and quality of life are similar to three-times-weekly dosing. J Clin Oncol 19:2875-2882, 2001 12. Witzig TE, Silberstein PT, Loprinzi CL, et al: Phase III, randomized, double-blind study of epoetin alfa compared with placebo in anemic patients receiving chemotherapy. J Clin Oncol 23:2606-2617, 2005 13. Meehan K, Tchekmedyian S, Ciesla G, et al: The burden of weekly epoetin alfa injections to patients and their caregivers. Proc Am Soc Clin Oncol 22:543, 2003 (abstr 2186) 14. Abels RI: Use of recombinant human erythropoietin in the treatment of anemia in patients who have cancer. Semin Oncol 19:29-35, 1992[Medline] 15. Vansteenkiste J, Pirker R, Massuti B, et al: Double-blind, placebo-controlled, randomized phase III trial of darbepoetin alfa in lung cancer patients receiving chemotherapy. J Natl Cancer Inst 94:1211-1220, 2002 16. Smith RE Jr, Tchekmedyian NS, Chan D, et al: A dose- and schedule-finding study of darbepoetin alpha for the treatment of chronic anaemia of cancer. Br J Cancer 88:1851-1858, 2003[CrossRef][Medline] 17. Kotasek D, Steger G, Faught W, et al: Darbepoetin alfa administered every 3 weeks alleviates anaemia in patients with solid tumours receiving chemotherapy: Results of a double-blind, placebo-controlled, randomised study. Eur J Cancer 39:2026-2034, 2003[CrossRef][Medline] 18. Farrell FX, Jolliffe LK: Administration of epoetin alfa every two weeks is able to sustain target hemoglobin in a nonhuman primate alternate dosing model. Blood 98:297a, 2001 (abstr 1253) 19. Patton J, Kuzur M, Liggett W, et al: Epoetin alfa 60,000 U once weekly followed by 120,000 U every 3 weeks increases and maintains hemoglobin levels in anemic cancer patients undergoing chemotherapy. Oncologist 9:90-96, 2004 20. Cella D: The Functional Assessment of Cancer Therapy–Anemia (FACT-An) Scale: A new tool for the assessment of outcomes in cancer anemia and fatigue. Semin Hematol 34:13-19, 1997[Medline] 21. McCorkle R, Young K: Development of a symptom distress scale. Cancer Nurs 1:373-378, 1978[Medline] 22. Mendoza TR, Wang XS, Cleeland CS, et al: The rapid assessment of fatigue severity in cancer patients: Use of the Brief Fatigue Inventory. Cancer 85:1186-1196, 1999[CrossRef][Medline] 23. Bretscher M, Rummans T, Sloan J, et al: Quality of life in hospice patients: A pilot study. Psychosomatics 40:309-313, 1999 24. Sloan JA, Dueck A: Issues for statisticians in conducting analyses and translating results for quality of life end points in clinical trials. J Biopharm Stat 14:73-96, 2004[CrossRef][Medline] 25. Fairclough DL, Cella DF: Functional Assessment of Cancer Therapy (FACT-G): Non-response to individual questions. Qual Life Res 5:321-329, 1996[Medline] 26. Demetri GD: Anaemia and its functional consequences in cancer patients: Current challenges in management and prospects for improving therapy. Br J Cancer 84:31-37, 2001 (suppl 1) 27. Rosenzweig MQ, Bender CM, Lucke JP, et al: The decision to prematurely terminate a trial of R-HuEPO due to thrombotic events. J Pain Symptom Manage 27:185-190, 2004[CrossRef][Medline] 28. Leyland-Jones B: Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 4:459-460, 2003[CrossRef][Medline] 29. Henke M, Laszig R, Rube C, et al: Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: Randomised, double-blind, placebo-controlled trial. Lancet 362:1255-1260, 2003[CrossRef][Medline] 30. Glaspy J, Dunst J: Can erythropoietin therapy improve survival? Oncology 67:5-11, 2004 (suppl 1)[CrossRef][Medline] 31. Leyland-Jones B, Mahmud S: Erythropoietin to treat anaemia in patients with head and neck cancer. Lancet 363:80, 2004[Medline] 32. Steensma DP, Loprinzi CL: Erythropoietin use in cancer patients: A matter of life and death? J Clin Oncol 23:5865-5868, 2005 33. Julious SA: Sample sizes for clinical trials with normal data. Stat Med 23:1921-1986, 2004[CrossRef][Medline] 34. Patrick DL, Gagnon DD, Zagari MJ, et al: Assessing the clinical significance of health-related quality of life (HrQOL) improvements in anaemic cancer patients receiving epoetin alfa. Eur J Cancer 39:335-345, 2003[CrossRef][Medline] 35. Littlewood TJ, Bajetta E, Nortier JW, 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 36. Crawford J, Cella D, Cleeland CS, et al: Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer 95:888-895, 2002[CrossRef][Medline] Submitted May 17, 2005; accepted November 18, 2005.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
12.0 g/dL; then epoetin was restarted at a reduced dose (30,000 U weekly or 80,000 U every 3 weeks, depending on random assignment). No further dose adjustments were permitted. All patients were administered ferrous sulfate 324 mg orally daily but were permitted to discontinue this if GI adverse effects became intolerable. 
