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Early Intervention with Epoetin Alfa During Platinum-Based Chemotherapy: An Analysis of Quality-of-Life Results of a Multicenter, Randomized, Controlled Trial Compared with Population Normative Data

^a VU Medisch Centrum, Amsterdam, The Netherlands; ^b Ortho Biotech, a division of Janssen-Cilag B.V., Tilburg, The Netherlands

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

Guiseppe Giaccone, VU Medisch Centrum, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands. Telephone: 31-20-4444321; Fax: 31-20-4444079; e-mail: g.giaccone{at}vumc.nl

Received August 15, 2005; accepted for publication November 29, 2005.

	LEARNING OBJECTIVES

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After completing this course, the reader will be able to:

1. Discuss the benefit of anemia correction with epoetin alfa therapy on improving quality of life in patients with cancer receiving chemotherapy.
   
2. Relative to population norms, describe the quality-of-life results of a prospective, randomized study in which cancer patients with baseline Hb levels 12.1 g/dl received epoetin alfa or best supportive care.
   
3. Explain how patients with cancer and mild-to-moderate anemia have impaired quality of life relative to the normal population and experience significant and clinically meaningful quality-of-life improvements with earlier epoetin alfa treatment.
   

	ABSTRACT

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Objective. To evaluate the effect of epoetin alfa on quality of life (QOL) in patients with solid tumors and mild-to-moderate anemia receiving platinum-based chemotherapy relative to population norms.

Methods. In the original study, patients (n = 316) with hemoglobin (Hb) levels 12.1 g/dl were randomized 2:1 to receive either epoetin alfa at a dose of 10,000 U thrice weekly s.c. or best supportive care (BSC) to compare the effects on transfusion use, hematologic response, and QOL (measured by the Functional Assessment of Cancer Therapy-Anemia [FACT-An]and Cancer Linear Analogue Scale [CLAS]). The QOL data from this previously reported trial were reanalyzed here relative to population norms.

Results. Mean baseline QOL scores were similar between groups. At study completion, mean CLAS, FACT-An, FACT-An Anemia subscale, and FACT-An Fatigue subscale scores were significantly higher for patients given epoetin alfa than for those treated with BSC. Compared with population norms, both groups had impaired QOL at baseline. Differences in mean QOL change scores from baseline to study end for epoetin alfa versus BSC were 3.17 points for the FACT-General Total, 9.90 for the FACT-An Fatigue subscale, and 7.30 for the FACT-An Anemia subscale. This was equivalent to corrections in QOL deficits attributable to epoetin alfa of 97.3%, 40.7%, and 38.0% for the FACT-General Total, FACT-An Fatigue, and FACT-An Anemia subscale scores, respectively, versus BSC. A somewhat greater QOL benefit was observed for the FACT-An Fatigue and FACT-An Anemia subscales in the subset of patients with baseline Hb levels >10.5 g/dl.

Conclusion. Patients in this study had impaired QOL compared with population norms. Early treatment with epoetin alfa to correct anemia improved QOL in a statistically significant and clinically meaningful way, and improvements were greater in patients with baseline Hb levels >10.5 g/dl.

	INTRODUCTION

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The adverse effects of low hemoglobin (Hb) levels on the energy and activity levels of patients are well known [1, 2], and fatigue associated with anemia has been identified as a major contributor to impaired quality of life (QOL) in patients with cancer- and chemotherapy-related anemia [3]. Recent data have indicated that patients with chemotherapy-related anemia have impaired QOL relative to population norms in people without cancer [1]. Treatment with recombinant human erythropoietin (rHuEPO, epoetin alfa) in this population elicits significant improvements in QOL [4–8], and these QOL improvements have been significantly and positively correlated with increases in Hb levels [4–6, 8, 9].

Guidelines issued jointly by the American Society of Hematology and the American Society of Clinical Oncology recommend erythropoietic therapy in patients with chemotherapy-associated anemia with Hb levels 10.0 g/dl, and state that treatment of Hb >10.0 g/dl to <12.0 g/dl should be determined by clinical circumstances [10]. Guidelines issued by the U.S. National Comprehensive Cancer Network (NCCN) state that erythropoietic therapy should be considered for patients with Hb levels <11.0 g/dl [11]. However, recent data from patients with cancer and chemotherapy-related anemia have shown that there is a direct but nonlinear relationship between QOL and Hb level, with the greatest incremental improvement in QOL during epoetin alfa therapy occurring at an Hb level of 12.0 g/dl [12, 13]. Moreover, findings from recent studies in patients with cancer have suggested that earlier erythropoietic therapy (i.e., in patients with baseline Hb levels 12.0 g/dl) may maintain Hb levels and ameliorate QOL impairment during chemotherapy [14–17].

We recently reported the results of a prospective, multi-center, randomized trial of early intervention with epoetin alfa versus best supportive care (BSC) during platinum-based chemotherapy in patients with mild-to-moderate anemia (i.e., Hb 12.1 g/dl) [14]. Significantly fewer patients in the epoetin alfa group than in the BSC group were transfused during the study (36% vs. 65%; p < .001) (primary efficacy parameter). Results were similar when transfusions within 4 weeks after randomization were excluded from the analysis (23% vs. 52%; p < .001). Mean Hb increased by 1.6 g/dl in the epoetin alfa group (p < .001 vs. baseline) and decreased by 0.4 g/dl in the BSC group (p < .001 vs. baseline). Patients in the epoetin alfa group had significantly (p < .005) higher Hb levels than those in the BSC group throughout the study, independent of transfusions. From baseline to the final QOL assessment, scores in the epoetin alfa group increased for all QOL parameters, whereas scores in the BSC group decreased. Final scores for several QOL parameters were significantly higher in the epoetin alfa group than in the BSC group. There were no significant differences between the epoetin alfa and BSC groups with respect to adverse events, thromboembolic events, or survival [14]. These primary results demonstrate the benefit of early intervention with epoetin alfa in preventing anemia and QOL deterioration in patients receiving chemotherapy, with a safety profile similar to that of BSC.

To help clinicians put into perspective and understand the clinical relevance and applicability of statistically significant changes in QOL scores in patients with cancer receiving chemotherapy, Cella et al. [1] determined population QOL normative scores to provide a frame of reference. The objective of the current analysis was to evaluate QOL results from our aforementioned study relative to the population norms reported by Cella et al. [1].

	METHODS

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Study Design and Patients
This prospective, open-label, randomized, multicenter study enrolled patients from November 1999 to December 2002 at 15 hospitals in The Netherlands. Randomization was performed centrally. 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 centralized ethics committee, Medisch-Ethische Toetsing Onderzoek Patiënten en Proefpersonen (METOPP, Tilburg, The Netherlands), and by the independent local ethics committee in each participating hospital.

Complete eligibility criteria have been published previously [14]. In brief, patients were eligible for inclusion if they were 18 years of age, had an Eastern Cooperative Oncology Group (ECOG) performance status score of 0–3, had a confirmed diagnosis of solid malignancy for which they were receiving platinum-based chemotherapy, and had an Hb level 12.1 g/dl. Patients were excluded if they had any clinically significant dysfunction of any organ system not attributable to the malignancy or chemotherapy that would likely result in early withdrawal from the study; known hypersensitivity to epoetin alfa; or acute or chronic bleeding and evidence of untreated iron, folic acid, or vitamin B₁₂ deficiencies.

Treatment
Patients were randomized 2:1 to receive epoetin alfa (Eprex^®; Ortho Biotech/Janssen-Cilag, High Wycombe, United Kingdom; [also marketed in the U.S. as Procrit^®; Ortho Biotech Products, L.P., Bridgewater, NJ]) or BSC. Patients with baseline transferrin saturation < 20% or serum ferritin <100 µg/l received oral iron supplementation (200 mg elemental iron per day). To account for possible differences in transfusion policy among study sites, the protocol specified that transfusions should only be administered to patients with significant complaints of anemia; every effort was to be made to avoid transfusion unless Hb was <9.7 g/dl.

Epoetin alfa was initiated at 10,000 U s.c. three times weekly (TIW) for 4 weeks. If after 4 weeks of therapy, Hb had increased by 1.0 g/dl above baseline or the Hb level was 12.1 g/dl, epoetin alfa was continued at the original dose. If Hb had increased <1.0 g/dl and the Hb level was <12.1 g/dl, the dose was increased to 20,000 U s.c. TIW. If after another 4 weeks at the higher dose, Hb had increased <1.0 g/dl above baseline and the Hb level was still <12.1 g/dl, epoetin alfa was discontinued, but these patients remained on study and were eligible for analysis. Patients with Hb levels >14.0 g/dl at any time during the study period did not receive further epoetin alfa until their Hb decreased to <13.0 g/dl, at which point epoetin alfa was restarted at a reduced dose of 10,000 U s.c. twice weekly. The dose was also reduced to 10,000 U s.c. twice weekly if Hb increased by >2.0 g/dl in any 4-week period. Patients who weighed >100 kg received alternating doses of 10,000 U and 20,000 U of epoetin alfa TIW, and dose adjustments were made accordingly. Unless discontinued because of inadequate hematologic response, epoetin alfa was administered until 4 weeks after the last cycle of platinum-containing chemotherapy. Patients who withdrew from the study early received epoetin alfa until the day of early withdrawal.

QOL Assessments
QOL was a secondary efficacy parameter measured using the Functional Assessment of Cancer Therapy-Anemia (FACT-An) scale and the Cancer Linear Analogue Scale (CLAS), also known as the Linear Analogue Scale Assessment (LASA). The FACT-An questionnaire consists of a general questionnaire (FACT-G), measuring domains of physical well-being, social/family well-being, emotional well-being, and functional well-being, and an anemia-specific questionnaire (FACT-An Anemia subscale), measuring 13 fatigue-associated items (FACT-An Fatigue subscale) and seven nonfatigue-associated items (FACT-An NonFatigue subscale) [18, 19]. The CLAS consists of three 100-mm linear analogue scales that measure level of energy, ability to do daily activities, and overall QOL related to cancer symptoms. Patients completed QOL assessments at the start of the study (QOL-1), before the third chemotherapy cycle after randomization (QOL-2), and 4 weeks after the last cycle of platinum-containing chemotherapy or at early withdrawal (QOL-end). All patients who completed the QOL questionnaires at baseline and had at least one postbaseline QOL assessment were included in the analyses.

Statistical Analysis
Target accrual was a sample size of 300 patients (200 in the epoetin alfa group and 100 in the BSC group). This sample size was determined to provide an 80% power to detect a 15% reduction in the proportion of patients with at least one transfusion during the study period at a significance level of 5%. With this sample size it was anticipated that approximately 30% of the patients would withdraw from the study early. The intent-to-treat (ITT) population comprised patients for whom efficacy data were available from at least one time point after randomization. Shifts in continuous or ordinal parameters were analyzed using the Wilcoxon signed rank test. For all analyses, p < .05 was considered statistically significant.

To assess the clinical relevance of QOL improvements, results from the QOL analyses in the current study were compared with previously published population normative data from Cella et al. [1]. To simplify the comparison of FACT scores in our study with the population norms reported by Cella et al. [1], which were described using rescaled scores, all FACT-An Total and FACT-An sub-scale results in our study were also rescaled using a simple linear transformation from 0 to 100, and baseline deficits were calculated between patients in the current study relative to population norms. The differences in mean QOL change scores (from baseline to study completion) between the epoetin alfa and BSC groups were also calculated and rescaled using a linear transformation from 0 to 100. The percentages of the baseline deficits relative to the normal population corrected with epoetin alfa relative to BSC was calculated. Calculations were performed on all patients with QOL data available and also for the subgroup of these patients with baseline Hb levels >10.5 g/dl.

	RESULTS

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Patient Disposition and Baseline Characteristics
A total of 316 patients was enrolled, but one patient (BSC group) withdrew informed consent immediately after randomization and was excluded from both safety and efficacy analyses. Two other patients (BSC group) were excluded from the efficacy analysis. One patient died, and one patient withdrew informed consent, both before any efficacy data had been obtained. Thus, the ITT safety population consisted of 315 patients, and the ITT efficacy population consisted of 313 patients. Demographic and baseline characteristics for the safety population have been published previously [14] and are presented in Table 1. Mean Hb levels at baseline were 10.7 g/dl and 10.8 g/dl for the epoetin alfa and BSC groups, respectively. The most frequently administered chemotherapy regimens are listed in Table 2. The most commonly administered chemotherapy regimen in both groups was gemcitabine (Gemzar^®; Eli Lilly and Company, Indianapolis) plus cisplatin (Platinol^®; Bristol-Myers Squibb, Princeton, NJ). Sixteen (8%) patients in the epoetin alfa group and two (2%) patients in the BSC group received concomitant radiation therapy. Patients were on study for a mean of 13.9 weeks in the epoetin alfa group and a mean of 14.5 weeks in the BSC group (p = .330).

One hundred fifty patients in the epoetin alfa group and 63 patients in the BSC group were included in the three CLAS subscale analyses. Mean CLAS scores at study completion in the epoetin alfa group were significantly higher than those in the BSC group for all three subscales: energy level (6.2 vs. –6.9; p = .005), ability to do daily activities (4.4 vs. –5.3; p = .023), and overall QOL (5.3 vs. –7.3; p = .001).

Clinical Relevance of QOL Improvements
Rescaled baseline FACT-An Total and subscale scores in the epoetin alfa and BSC groups indicated that both groups had impaired QOL relative to the normal population (Fig. 1). Baseline deficits for the epoetin alfa group and BSC group from the normal population for the FACT-G Total, FACT-An Anemia subscale, and FACT-An Fatigue subscale were 3.26 and 3.83, 19.21 and 17.05, and 24.33 and 22.04, respectively. Differences in mean change scores from baseline to QOL-end for epoetin alfa compared with BSC were 3.17 points for the FACT-G Total, 7.30 for the FACT-An Anemia subscale, and 9.90 for the FACT-An Fatigue subscale. This benefit of epoetin alfa therapy over BSC represented corrections from the original QOL deficits of 97.3%, 38.0%, and 40.7%, respectively.

View larger version (13K): [in this window] [in a new window]   Figure 1. Rescaled (0–100) scores at baseline and the final assessment for all patients on the FACT-G Total scale (A), FACT-An Anemia subscale (B), and FACT-An Fatigue sub-scale (C). Abbreviations: An, anemia; BSC, best supportive care; FACT, Functional Assessment of Cancer Therapy; QOL, quality of life. To convert to raw scores, divide rescaled scores by the following conversion factors: FACT-G, 1.08; FACT-An Anemia subscale, 0.80; FACT-An Fatigue subscale, 0.52.

View larger version (13K): [in this window] [in a new window]   Figure 2. Rescaled (0–100) scores at baseline and final assessment for patients with baseline hemoglobin (Hb) levels >10.5 g/dl on the FACT-G Total scale(A), FACT-An Anemia subscale(B), and FACT-An Fatigue subscale(C). Abbreviations: An, anemia; BSC, best supportive care; FACT, Functional Assessment of Cancer Therapy; QOL, quality of life. To convert to raw scores, divide rescaled scores by the following conversion factors: FACT-G, 1.08; FACT-An Anemia sub-scale, 0.80; FACT-An Fatigue subscale, 0.52.

	DISCUSSION

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Cella et al. [1] collected FACT-An data from a normal population of 1,078 individuals and compared those data with FACT-An data from a randomized, double-blind, placebo-controlled trial of epoetin alfa in patients with solid tumors or nonmyeloid hematologic malignancies receiving nonplatinum chemotherapy with mean baseline Hb levels of 9.9 g/dl (epoetin alfa) and 9.7 g/dl (placebo) [8]. The use of population normative data to interpret differences in QOL allows clinicians to evaluate the effect of anemia on QOL and the effects of anemia therapy. Comparing QOL data from a clinical trial with a perfect scale may overestimate the amount of change that should be considered clinically important. Comparison against the normal population provides a more realistic approach to assessing the effects of epoetin alfa treatment on patients with cancer and anemia.

In their analysis, Cella et al. [1] rescaled the QOL data from the earlier clinical trial using a simple linear transformation from 0 to 100 and calculated baseline deficits between patients in the clinical trial relative to the data from the surveyed normal population. Baseline deficits in the epoetin alfa group compared with the population norm were 5.9 for the FACT-G Total, 20.0 for the FACT-An Fatigue subscale, and 17.1 for the FACT-An Anemia subscale. Rescaled differences in mean change scores between the epoetin alfa and placebo groups at study completion were 5.6, 10.1, and 8.3, respectively, representing 95%, 51%, and 49% of the original QOL deficits, and attributable to epoetin alfa therapy [1]. In the study reported here, the rescaled percentage corrections of the original QOL deficits with epoetin alfa were 97%, 41%, and 38%, respectively. Thus, in the current study, correction of the original QOL deficits with epoetin alfa therapy was somewhat smaller than that observed in the Littlewood et al. [8] study with respect to the FACT-An Fatigue and FACT-An Anemia subscales. The slight differences between the percentage QOL corrections in the two studies could be related to several factors, including differences between studies with regard to baseline Hb levels, chemotherapy regimens, magnitudes of baseline QOL deficits, and magnitudes of QOL corrections.

When evaluating only those patients with baseline Hb levels >10.5 g/dl in the current study, the corrections of the original deficits in the FACT-An Fatigue and FACT-An Anemia subscales were greater than those observed for all patients. Consequently, the percentages of the original deficits that were corrected with epoetin alfa therapy were 10%–12% larger for the FACT-An Fatigue and FACT-An Anemia subscales in patients who started epoetin alfa therapy at higher baseline Hb levels. This is in agreement with an analysis by Crawford et al. [12] that demonstrated a direct significant correlation (p < .01) between Hb level and LASA/FACT-An scores, and demonstrated that the greatest incremental increase in QOL score occurred when Hb levels increased from 11.0 g/dl to 12.0 g/dl [12].

Fatigue and impaired QOL continue to be frequent complaints of patients with cancer and anemia [20]. Despite evidence from randomized clinical trials [8, 21] and large community-based studies [4–6] indicating that epoetin alfa therapy decreases transfusion requirements, increases Hb levels, and improves QOL, cancer- and chemotherapy-related anemia remains undertreated. Moreover, a significant correlation has been found between Hb increase and improved QOL in studies of once-weekly (QW) and TIW epoetin alfa administered to patients with cancer and moderate anemia [5, 8, 9, 12, 22]. In addition, in recent open-label studies in patients with breast cancer [23, 24] or hematologic malignancies [17], QW epoetin alfa administered to patients with cancer and mild anemia (mean baseline Hb level >11.0 g/dl) has been shown to maintain Hb level and prevent QOL deterioration during chemotherapy. The results of the current subanalysis provide additional support for the QOL benefits of epoetin alfa therapy, indicating that improvements in QOL are both statistically significant and clinically meaningful. Moreover, patients in this study had higher baseline Hb levels than those of patients in the study by Littlewood et al. [8], yet they had impaired QOL at baseline relative to the normal population and were able to experience meaningful improvements in QOL at study completion. Finally, the QOL improvements were actually greater in patients with baseline Hb levels >10.5 g/dl. These data suggest that early treatment with epoetin alfa to correct anemia can improve QOL in a clinically significant and meaningful way.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

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Lars W. Wormhoudt is an employee of Ortho Biotech and indicates a financial interest.

	ACKNOWLEDGMENT

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This study was supported by a grant from Ortho Biotech, a division of Janssen-Cilag B.V., Tilburg, The Netherlands.

	REFERENCES

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1. Cella D, Zagari MJ, Vandoros C et al. Epoetin alfa treatment results in clinically significant improvements in quality of life in anemic cancer patients when referenced to the general population. J Clin Oncol 2003;21:366–373.[Abstract/Free Full Text]
2. Curt GA, Breitbart W, Cella D et al. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition. The Oncologist 2000;5:353–360.[Abstract/Free Full Text]
3. Cella D, Webster KA. Quality of life and treatment value in the management of hematologic malignancies. Semin Oncol 1999;26(suppl 14):34–42.[Medline]
4. 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. J Clin Oncol 1998;16:3412–3425.[Abstract]
5. 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 2001;19:2875–2882.[Abstract/Free Full Text]
6. Glaspy J, Bukowski R, Steinberg D et al. Impact of therapy with epoetin alfa on clinical outcomes in patients with nonmyeloid malignancies during cancer chemotherapy in community oncology practice. J Clin Oncol 1997;15:1218–1234.[Abstract/Free Full Text]
7. Jones M, Schenkel B, Just J et al. Epoetin alfa improves quality of life in patients with cancer: results of metaanalysis. Cancer 2004;101:1720–1732.[CrossRef][Medline]
8. Littlewood TJ, Bajetta E, Nortier JW et al. for the Epoetin Alfa Study Group 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 2001;19:2865–2874.[Abstract/Free Full Text]
9. Fallowfield L, Gagnon D, Zagari M et al. for the Epoetin Alfa Study Group Multivariate regression analyses of data from a randomised, double-blind, placebo-controlled study confirm quality of life benefit of epoetin alfa in patients receiving non-platinum chemotherapy. Br J Cancer 2002;87:1341–1353.[CrossRef][Medline]
10. 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. J Clin Oncol 2002;20:4083–4107.[Abstract/Free Full Text]
11. Rodgers GM, Cella D, Chanan-Khan A et al. Cancer and treatment-related anemia. National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology – v.2.2005. Available at http://www.nccn.org. Accessed July 14, 2005.
12. 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 2002;95:888–895.[CrossRef][Medline]
13. Shasha D, Cremieux P, Harrison L. Relationship between hemoglobin levels and quality of life during radiation therapy plus concomitant or sequential chemotherapy in patients with cancer and anemia treated with epoetin alfa. J Natl Compr Cancer Netw 2004;2:509–517.
14. Savonije JH, van Groeningen CJ, van Bochove A et al. Effects of early intervention with epoetin alfa on transfusion requirement, hemoglobin level and survival during platinum-based chemotherapy: results of a multicenter randomised controlled trial. Eur J Cancer 2005;41:1560–1569.
15. Grote TH, Castillo R, Fishkin E et al. Effects of early intervention with epoetin alfa in patients with small cell lung cancer. Lung Cancer 2003;41: S3–314a.
16. Milroy R, Scagliotti G, van den Berg PM et al. Early intervention with epoetin alfa maintains hemoglobin in advanced non-small-cell lung cancer patients. Lung Cancer 2003;41:S3–314a.
17. Straus DJ, Testa M, Riggs SA et al. Early treatment with epoetin alfa improves anemia, quality of life, and productivity in patients with hematologic malignancies and mild anemia during chemotherapy. Blood 2003;102:497a.
18. 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 1997;34(suppl 2):13–19.[Medline]
19. Yellen SB, Cella DF, Webster K et al. Measuring fatigue and other anemia-related symptoms of cancer with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 1997;13:63–74.[CrossRef][Medline]
20. Groopman JE, Itri LM. Chemotherapy-induced anemia in adults: incidence and treatment. J Natl Cancer Inst 1999;91:1616–1634.[Abstract/Free Full Text]
21. Dammacco F, Castoldi G, Rödjer S. Efficacy of epoetin alfa in the treatment of anaemia of multiple myeloma. Br J Haematol 2001;113:172–179.[CrossRef][Medline]
22. 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 2005;23:2606–2617.[Abstract/Free Full Text]
23. Chang J, Couture F, Young S et al. Weekly epoetin alfa maintains hemoglobin, improves quality of life, and reduces transfusion in breast cancer patients receiving chemotherapy. J Clin Oncol 2005;23:2597–2605.[Abstract/Free Full Text]
24. Hudis CA, Vogel CL, Gralow JR et al. Weekly epoetin alfa during adjuvant chemotherapy for breast cancer: effect on hemoglobin levels and quality of life. Clin Breast Cancer 2005;6:132–142.[Medline]

	ADDITIONAL READING

Top Learning Objectives Abstract Introduction Methods Results Discussion Disclosure of Potential... References Additional Reading

Savonije JH, van Groeningen CJ, van Bochove A et al. Effects of early intervention with epoetin alfa on transfusion requirement, hemoglobin level and survival during platinum-based chemotherapy: results of a multi-center randomised controlled trial. Eur J Cancer 2005;41:1560–1569.

Cella D, Zagari MJ, Vandoros C et al. Epoetin alfa treatment results in clinically significant improvements in quality of life in anemic cancer patients when referenced to the general population. J Clin Oncol 2003;21:366–373.[Abstract/Free Full Text]

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 2002;95:888–895.

Hudis CA, Vogel CL, Gralow JR et al. Weekly epoetin alfa during adjuvant chemotherapy for breast cancer: effect on hemoglobin levels and quality of life. Clin Breast Cancer 2005;6:132–142.

Grote TH, Castillo R, Fishkin E et al. Effects of early intervention with epoetin alfa in patients with small cell lung cancer. Lung Cancer 2003;41: S3–314a.

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This Article Abstract Full Text (PDF) CME: Take the course for this article: Early Intervention With Epoetin Alfa During Platinum-Based Chemotherapy: An... eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Savonije, J. H. Articles by Giaccone, G. Search for Related Content PubMed PubMed Citation Articles by Savonije, J. H. Articles by Giaccone, G.