Treatment of chemotherapy-related anemia with erythropoietic agents: Current approaches and new paradigms

Treatment of Chemotherapy-Related Anemia With Erythropoietic Agents: Current Approaches and New Paradigms Roger J. Waltzman Anemia is common among patients with cancer receiving chemotherapy (CT) and/or radiotherapy (RT) and may limit cancer treatment, clinical outcomes, and overall patient quality of life (QOL). In the United States, epoetin alfa and darbepoetin alfa are approved for the treatment of CT-induced anemia in patients with nonmyeloid malignancies. Goals of treatment are to reduce transfusions, increase hemoglobin (Hb) levels, and improve overall QOL. Results from ongoing head-to-head trials comparing these agents will allow for direct comparisons of Hb response profiles and overall QOL effects. To optimize patient benefits from erythropoietic therapy, new doses and schedules of these agents are being studied. Data from investigations of the use of a higher weekly starting dose (“front-loading”) followed by maintenance dosing on a less frequent schedule (when Hb has increased to a specified level or by a specified amount after the higher initial starting dose) suggest that both agents can increase and subsequently maintain Hb levels on such schedules. This approach may lead to benefits for patients and healthcare providers, such as earlier increases in Hb and earlier identification of nonresponders. Consequently, evolving strategies with erythropoietic agents should ultimately improve overall QOL in anemic cancer patients receiving CT. Semin Hematol 41(suppl 7):9-16 © 2004 Elsevier Inc. All rights reserved.

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nemia is a common and serious problem in oncology. In patients with hematologic malignancies, the prevalence of anemia (hemoglobin [Hb] ⱕ12 g/dL) is high, estimated in one report to be 72%.28 The causes of anemia in cancer patients are multifactorial. Prior to receiving chemotherapy (CT) and/or radiotherapy (RT), patients may be anemic due to anemia of chronic disease (ACD), occult bleeding, or nutritional deficiencies, and anemic patients typically experience a worsening of anemia during cancer treatment.25,28,43,47 In addition, CT alone or in combination with RT often induces anemia in patients whose pretreatment Hb levels are normal.20,25,43,47 Anemia has a negative impact on patient quality of life (QOL), and in some types of cancer, anemia is a negative prognostic factor for locoregional tumor control and survival.4,5,19,29 St. Vincent’s Comprehensive Cancer Center and St. Vincent’s Hospital, New York, NY. Dr Waltzman has received grants and/or research support from Ortho Biotech Products, L.P. and is a member of the Speakers Bureaus of Ortho Biotech Products, L.P. and Amgen Inc. Address correspondence to Roger J. Waltzman, MD, St. Vincent’s Comprehensive Cancer Center and St. Vincent’s Hospital, 325 W 15th St, New York, NY 10011. E-mail: [email protected]

0037-1963/04/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1053/j.seminhematol.2004.09.003

Fatigue, a major consequence of anemia, frequently affects a patient’s ability to perform daily functions and may extend to negatively impact cognitive function in some patients who are undergoing or have undergone CT.13,31 Consequently, anemia management has become an important component of patient care in oncology. Prior to the availability of erythropoietic agents, anemia was managed primarily by blood transfusion; however, the associated risks of transfusion have made this strategy undesirable in all but severe circumstances in which immediate correction of anemia is required.30,38 The National Comprehensive Cancer Network (NCCN) has developed clinical practice guidelines for cancer and treatment-related anemia, classifying normal Hb levels as 12 to 16 g/dL for women and 14 to 18 g/dL for men.30 Both the NCCN guidelines and guidelines developed jointly by the American Society of Clinical Oncology (ASCO) and the American Society of Hematology (ASH)38 contain recommendations for the use of erythropoietic agents to treat cancerrelated anemia. Common to both sets of guidelines are the following anemia management goals: (1) increase Hb levels, (2) improve overall QOL, and (3) reduce transfusion requirements. 9

R.J. Waltzman

10 Table 1 Structural and Pharmacokinetic Differences Between Available Erythropoietic Agents12 Characteristic

Epoetin Alfa

Darbepoetin Alfa

N-linked suger chains Sialic acid residues Carbohydrate (%) Molecular weight (kd) Subcutaneous half-life (h) Relative binding affinity

3 <14* ⬃40* 30.4 ⬃16–19 4X

5 <22 51 37.1 33–48 1X

*Identical to endogenous erythropoietin.

Currently Available Erythropoietic Agents In the United States, two erythropoietic agents are approved for the treatment of anemia in patients with nonmyeloid malignancies where anemia is due to the effects of concomitantly administered CT— epoetin alfa (PROCRIT, Ortho Biotech Clinical Affairs, L.L.C., Bridgewater, NJ) and darbepoetin alfa (Aranesp, Amgen, Thousand Oaks, CA). Both are administered via subcutaneous (SC) injection. Epoetin alfa, approved in 1993 for this indication, is identical in structure to endogenous erythropoietin. Darbepoetin alfa, approved in 2002, is a modified form of erythropoietin that differs slightly from epoetin alfa in structure and pharmacokinetics. The five Nlinked carbohydrate chains and additional sialic acid residues on the darbepoetin alfa molecule increase its half-life approximately threefold after intravenous administration compared with epoetin alfa; in contrast, the binding affinity of epoetin alfa for the erythropoietin receptor has been estimated to be four times greater than that of darbepoetin alfa.12 The structural and pharmacokinetic characteristics of each agent are summarized in Table 1. Although these agents are approved for the treatment of CT-related anemia, studies in other clinical oncology settings have revealed further benefits. For example, in anemic patients receiving chemoradiation, epoetin alfa therapy increases Hb levels, improves QOL, and reduces transfusion requirements.42 Further, administration of epoetin alfa to patients with normal Hb levels prior to CT or RT has been shown to protect against the development of anemia during CT in patients with breast or lung cancer,7,10,23,32 and administration of erythropoietic agents to anemic patients who are not undergoing CT or RT can alleviate anemia and improve QOL.36,37,45 While many applications of epoetin alfa and darbepoetin alfa are currently under investigation in cancer patients, the remainder of this review will focus on clinical data obtained from trials evaluating their use for the treatment of CT-related anemia. The Hb level at which to initiate erythropoietic therapy is determined by the physician; no starting Hb level is specified in the current prescribing information for either epoetin alfa or darbepoetin alfa. A recent report of oncologists’ and hematologists’ responses to a questionnaire assessing erythropoietin use in cancer patients in clinical practice and in hypothetical cases stated that most physicians, both US and

international, did not initiate erythropoietic therapy until Hb was ⱕ10 g/dL.1 The NCCN guidelines for patients with symptoms of anemia suggest consideration of erythropoietic therapy when Hb is 10 to 11 g/dL and strong consideration of erythropoietic therapy when Hb ⬍10 g/dL30; the American Society of Clinical Oncology (ASCO)/American Society of Hematology (ASH) guidelines recommend use when Hb is ⱕ10 g/dL.38 Patients with mild anemia (Hb ⬎10 g/dL and ⱕ12 g/dL) experience negative effects on QOL, and in these patients, treatment with erythropoietic agents has been shown to provide clinical benefits. For example, in patients with hematologic malignancies who were receiving CT, epoetin alfa 40,000 U once weekly increased Hb, improved QOL, decreased healthcare resource utilization, and decreased transfusion requirements when initiated at Hb ⱖ10 g/dL and ⱕ12 g/dL compared with patients in whom it was initiated at Hb ⬍9 g/dL.46 In a 16-week study of patients with advanced non-small cell lung cancer who were scheduled to receive CT for ⱖ8 weeks, significantly fewer patients treated with epoetin alfa 40,000 U once weekly at Hb ⱖ11 g/dL to less than 15 g/dL had Hb decrease to less than 10 g/dL compared with patients who did not receive epoetin alfa until Hb ⱕ10 g/L (P ⬍ .0001).10 In patients with breast cancer receiving CT, a comparison of epoetin alfa 40,000 U once weekly (n ⫽ 175) initiated when Hb ⱕ12 g/dL with best supportive care (BSC, transfusion when Hb ⬍8 mg/dL; n ⫽ 175) revealed that after 16 weeks of treatment, 52% of patients in the epoetin alfa group maintained Hb ⱖ12 g/dL, while only 5% in the BSC group were able to do so.7 As mentioned above, the NCCN guidelines suggest consideration of erythropoietic therapy for symptomatic patients with Hb in the 10 to 11 g/dL range.30 The ASCO/ASH guidelines state that, in patients with Hb ⬍12 g/dL but whose Hb has not fallen ⬍10 g/dL, use of erythropoietic therapy should be guided by clinical circumstances.38 An incremental analysis of Hb rise and QOL improvement, which compared improvements in QOL with 1-g/dL increases in Hb, demonstrated that the greatest QOL improvement occurs when the Hb value rises from 11 to 12 g/dL (range, 11 to 13 g/dL).9 Figure 1 illustrates this relationship for QOL measured by the linear analog scale assessment (LASA). Consequently, eryth-

Figure 1 Correlation of Hb level with QOL by incremental analysis. Adapted from Crawford et al9. CANCER Vol. 95, No. 4, 2002, pp 888-895. Copyright © 2002 American Cancer Society. Reprinted by permission of Wiley-Liss, Inc., a subsidiary of John Wiley & Sons.

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Table 2 Efficacy of Epoetin Alfa in CT-Related Anemia

Study Littlewood et al, 2001 (N ⴝ Gabrilove et al, 2001 (N ⴝ 2,964)15 Demetri et al, 1998 (N ⴝ 2,289)11 Glaspy et al, 1997 (N ⴝ 2,030)16 Sloan et al, 2002 (N ⴝ 172)44 Shasha et al, 2003 (N ⴝ 442)42 244)27

Starting Dose

Study Duration (wk)

Mean Hb Change at 4 Weeks (g/dL)

Mean Hb Change at Study End (g/dL)

150-300 U/kg TIW 40,000 U QW 10,000 U TIW 150 U/kg TIW 40,000 U QW 40,000 U QW

28 16 16 16 16 16

0.8* 1.0 1.0 1.1 1.2 1.1

2.2* 1.8 2.0 1.8 3.1 1.7

QOL Assessment Tool LASA, LASA, LASA, LASA, LASA, LASA

SF-36, FACT-An FACT-An FACT-An FACT-An FACT-An

Abbreviations: TIW, 3 times weekly; QW, once weekly; LASA, linear analog scale assessment; SF-36, Short Form-36; FACT-An, Functional Assessment of Cancer Therapy-Anemia. *Estimated values based on graph of mean Hb over time.

ropoietic therapy initiated when Hb is in this range should result in earlier achievement of clinical benefits than therapy initiated when Hb falls below 10 g/dL. Patients who do not respond to initial doses of erythropoietic agents may respond to somewhat higher doses. An early response to erythropoietic therapy is considered to be a Hb increase of at least 1 g/dL after 4 weeks of epoetin alfa administration or after 6 weeks of darbepoetin alfa administration, as defined by the NCCN guidelines.30 For those who do not experience an early response to epoetin alfa, the dose is increased from 40,000 U once weekly to 60,000 U once weekly, and for darbepoetin alfa, the dose is increased from 200 ␮g every 2 weeks to 300 ␮g every 2 weeks.30 If after 6 to 8 weeks at the higher dose, Hb has not increased by at least 1 g/dL, discontinuation of therapy should be considered.38 With epoetin alfa 40,000 U once weekly, the average Hb increase after 4 weeks was 1.0 g/dL.15 Average increases with darbepoetin alfa 3.0 ␮g/kg every 2 weeks after 6 weeks were reported in graphical form only; the average increase reported after 16 weeks was 1.7 g/dL.48 Both NCCN and ASCO/ASH guidelines state that Hb should be maintained at 12 g/dL. This recommendation aligns with the incremental analysis results of Crawford and colleagues (Fig 1) discussed previously,9 and has been validated by results of studies investigating the relationship between Hb and QOL in patients undergoing chemoradiation therapy41 and in patients with breast cancer receiving adjuvant CT.18 In addition, the NCCN guidelines recommend that the dose of either agent should be reduced by 25% if Hb increases ⬎1 g/dL in a 2-week period, should be withheld if Hb is ⬎12 g/dL, and, in those patients who have doses withheld, the dose should be restarted at 25% of the original dose when Hb falls to ⬍12 g/dL.30

Efficacy of Erythropoietic Agents in the Treatment of CT-Related Anemia Epoetin Alfa The Food and Drug Administration (FDA)-approved doses of epoetin alfa are 10,000 U three times weekly and 40,000 U

weekly.8,30,35 As summarized in Table 2, results from several clinical trials that represent a total of approximately 8,000 patients indicate that epoetin alfa administered either thrice weekly or once weekly effects a mean Hb increase of 1 g/dL after 4 weeks and approximately 2 g/dL after 8 weeks, which is maintained through to study end point (typically 16 weeks).11,15,16,27,42,44 To determine whether blood transfusion had any influence on these results, within-study comparisons were carried out using data from two of the large, open-label, 16-week studies described in Table 2.15,42 In one analysis, Hb recorded within 28 days of transfusion was imputed with the last value carried forward (LVCF); in the other, Hb measured within 28 days of transfusion was excluded from the analysis. The Hb response curves from each study were superimposable, suggesting that transfusions had a minimal effect on Hb levels in these large studies (data on file, Ortho Biotech Products, L.P.). In addition, epoetin alfa significantly improves overall QOL, as demonstrated in these trials by measures including the LASA and the Functional Assessment of Cancer TherapyAnemia (FACT-An).11,15,16,27,42,44 The FACT-An is a 47-item self-report scale that measures anemia-related and general QOL. It is comprised of (1) the FACT-G, a 27-item general questionnaire, and (2) the FACT-An Anemia subscale, a 20item scale that contains 13 items on cancer-related fatigue (FACT-An Fatigue subscale [FACT-F]) and seven non–fatigue-related items. In the trials by Glaspy,16 Demetri,11 Gabrilove,15 and Shasha,42 a direct and significant correlation was found between the magnitude of increase in Hb and the extent of improvement on QOL as measured by the LASA. Using data from the double-blind, placebo-controlled study by Littlewood et al,27 Patrick and coworkers investigated the minimally important/clinically meaningful difference in QOL.33 On the LASA, the minimally important difference, defined as the QOL difference between patients with a Hb change between ⫺1.0 g/dL and 1 g/dL and those with a change ⱖ1.0 g/dL, was 9.61 on the energy domain, 8.74 on the activity domain, and 9.81 on the overall QOL domain, each of which was achieved with epoetin alfa treatment when analyzing between-group differences.33 In addition, when compared with the QOL of a normative population sample

R.J. Waltzman

12 Table 3 Efficacy of Darbepoetin Alfa in CT-Related Anemia

Study Vansteenkiste et al, 2002 (N ⴝ Hedenus et al, 2002* (N ⴝ 17)21 Glaspy et al, 2002* (N ⴝ 216)17 Kotasek et al, 2003 (N ⴝ 198)26 Vadhan-Raj et al, 2003 (N ⴝ 1,173)48

156)49

Starting Dose

Study Duration (wk)

Mean Hb Change at 4 Weeks (g/dL)

Mean Hb Change at Study End (g/dL)

QOL Assessment Tool

2.25 ␮g/kg QW 2.25 ␮g/kg QW 0.5-0.8 ␮g/kg QW 4.5-15.0 ␮g/kg Q3W 3.0 ␮g/kg Q2W

12 12 12 12 16

Not reported 0.4 0-1.5 Not reported Not reported

Not reported 1.6 1.4–2.75 0.7–2.25 1.7

FACT-F FACT-F FACT-F FACT-F FACT-F, ENRG

Abbreviations: QW, once weekly; Q3W, every 3 weeks; Q2W, every 2 weeks; FACT-F, Functional Assessment of Cancer Therapy-Fatigue subscale; ENRG, Energy Numerical Rating Grade. *Dose-finding study.

(N ⫽ 1,078; QOL assessed with the FACT-An), QOL improvements obtained in this same patient population were shown to be clinically significant.6 Epoetin alfa also reduces transfusion requirements in anemic cancer patients receiving CT, as measured by the percentage of patients requiring transfusions, the number of units of blood transfused per patient, and the time to first transfusion.11,15,16,27,42,44 Decreases in these parameters were observed as early as 4 weeks after initiation of epoetin alfa therapy in some trials, and decreases continued throughout the treatment course.

Darbepoetin Alfa The FDA-indicated dose of darbepoetin alfa is 2.25 ␮g/kg once weekly2; however, the dose of 3.0 ␮g/kg every 2 weeks has been reported to be the most commonly used.3,40,48 Results of clinical trials with darbepoetin alfa are summarized in Table 3. In the registration trial, Vansteenkiste and colleagues showed that after 12 weeks of treatment, darbepoetin alfa 2.25 ␮g/kg once weekly increased Hb, improved QOL and decreased transfusion requirements compared with placebo in anemic (Hb ⱕ11 g/dL) lung cancer patients receiving CT.49 In this trial, the primary efficacy end point was incidence of transfusions (week 5 to end of treatment phase, N ⫽ 149 patients per group). Hb change from baseline (n ⫽ 156, darbepoetin alfa group; n ⫽ 158, placebo group) was considered an additional indication of efficacy. QOL was assessed using the FACT-F. Both the percentage of patients who received a transfusion and the mean number of units transfused per patient were significantly lower in the darbepoetin alfa group than in the placebo group (P ⬍ .001). Hb was measured weekly in each group, but these values were not reported. However, the percentage of patients with a 2-g/dL increase in Hb or a Hb of 12 g/dL in the absence of a transfusion in the previous 28 days, defined as a hematopoietic response, was significantly higher in the darbepoetin alfa group compared with placebo (P ⬍ .001). The percentage of patients who had at least a 25% improvement from baseline on the FACT-F was higher for the darbepoetin alfa group than for the placebo group (66% v 24%, respectively, P ⫽ .019).49 An ongoing open-label trial investigating the benefits of twice-weekly darbepoetin alfa dosing, the Successful Out-

comes in Anemia Research (SOAR) study, is a multicenter, randomized study of anemic (Hb ⬍11 g/dL) patients with nonmyeloid malignancies receiving CT.3,48 Patients receive a starting dose of darbepoetin alfa 3.0 ␮g/kg every 2 weeks (200 ␮g for the average patient), with dose escalation to 5 ␮g/kg every 2 weeks after 6 weeks if Hb does not increase by ⱖ1 g/dL. Fatigue is measured by the FACT-F and the Energy Numerical Rating Grade (ENRG). The ENRG asks patients to rate their relative energy level over the previous 4 weeks using an 11-point scale (0 to 10), with scores then converted to a 0- to 100-point scale.48 An interim analysis (N ⫽ 1,173) showed that darbepoetin alfa every 2 weeks produced a ⱖ1g/dL mean Hb increase after 8 weeks and a 1.7-g/dL mean Hb increase after 16 weeks.48 Improvements in fatigue and energy levels were reflected by significant changes from baseline on the FACT-F and ENRG, respectively, after 16 weeks, but not after 8 weeks of treatment. The incidence of transfusions decreased by 64% at the end of the study compared with month 1.3 In this study, the primary end point of functional capacity is being measured by a modified version of the Harvard step test14; these results have not been reported to date.

Cumulative Change in Hb: A New Measure of Efficacy? Historically, hematologic end points in clinical trials of erythropoietic agents have measured the change in Hb from baseline to a distant time point. However, evaluating Hb at time points other than end of treatment may provide additional information regarding treatment efficacy and timing of patient benefits related to increased Hb. Based on the findings that incremental gains in QOL occur with incremental gains in Hb,9 it follows logically that earlier increases in Hb during CT may lead to earlier improvements in symptoms and QOL. Thus, a more comprehensive method of analyzing the efficacy of erythropoietic agents may be to measure the time to Hb response (increase of 1 g/dL or 2 g/dL) or the cumulative change in Hb over the course of the study, known as the area under the Hb change curve (Hb AUC). Hb AUC is a single measurement that assesses Hb response over the entire treatment course rather than at a fixed time point. For example,

Erythropoietic agents for anemia

Figure 2 Theoretical Hb response curves of two anemia treatments, illustrating differences in cumulative change in Hb despite similar Hb increases from baseline at end of treatment.

Fig 2 shows the rates of rise of two anemia treatments, both of which achieve the same increase in Hb at study end. Given its greater Hb AUC, which represents a greater cumulative change in Hb and more time spent above a target or threshold Hb, might the treatment illustrated by the curve with the greater initial rate of rise provide an earlier and greater overall QOL benefit, even if the Hb value at the end of the study was the same for both treatments? Ongoing clinical trials are now beginning to assess the effects of erythropoietic agents in this way. This analysis may be particularly relevant for ongoing studies of front-loaded regimens, which are designed to improve early Hb response. In addition, a recent analysis of data sets of two phase IV, 16-week, clinical trials of epoetin alfa 40,000 U once weekly administered to anemic (Hb ⱕ11 g/dL) patients receiving CT or RT showed that a ⱖ1-g/dL rise in Hb after 4 weeks of treatment was associated with better clinical outcomes, including greater improvements in QOL and lower transfusion rates, compared with a less than 1-g/dL rise after 4 or 8 weeks of treatment.39

Comparative Trials Two trials directly comparing the efficacy of epoetin alfa and darbepoetin alfa are currently ongoing, both assessing these agents at their most commonly used doses (epoetin alfa 40,000 U once weekly and darbepoetin alfa 200 ␮g twice weekly). One is a phase III trial, and the other is a pooled analysis of three phase II trials. Study design and preliminary results of these trials were reported recently at the 45th Annual Meeting of the American Society of Hematology24,40 and at the 2004 American Society of Clinical Oncology Annual Meeting.50 The phase III trial is a randomized, open-label, multicenter trial with an enrollment goal of 300 anemic (Hb ⱕ11 g/dL) patients with solid tumors who are scheduled to receive CT for at least 12 weeks.24,50 Patients are stratified by study center and platinum versus nonplatinum CT. Treatment duration is up to 16 weeks, and the primary end point is the percentage of patients achieving a ⱖ1-g/dL increase in Hb after 4 weeks of therapy (independent of transfusions within 28 days). Other end points include QOL changes from baseline, as measured by the LASA and FACT-An after 4 and 8 weeks of therapy and at the end of the study, Hb over time,

13 time to Hb response, and transfusion utilization. Dose escalation follows NCCN guidelines for both agents; if Hb does not increase by ⱖ1 g/dL, the dose of epoetin alfa is increased from 40,000 to 60,000 U once weekly after 4 weeks, and the dose of darbepoetin alfa is increased from 200 ␮g to 300 ␮g every 2 weeks after 6 weeks. Preliminary results showed that, after 4 weeks, mean Hb increased by 0.9 g/dL in the epoetin alfa group (n ⫽ 133) and by 0.4 g/dL in the darbepoetin alfa group (n ⫽ 129); 50.4% of patients in the epoetin alfa group and 38.0% of patients in the darbepoetin alfa group had a Hb increase ⱖ1 g/dL after 4 weeks. Mean Hb values for patients receiving epoetin alfa tended to be higher than those for patients receiving darbepoetin alfa throughout the study, with values at 8 weeks of 1.5 g/dL and 1.0 g/dL, respectively, and values at 12 weeks of 1.9 g/dL and 1.5 g/dL, respectively.50 Each of the three phase II trials included in the pooled analysis has an enrollment goal of 100 anemic (Hb ⱕ11 g/dL) patients with breast, lung, or gynecologic cancer who are expected to receive at least 8 additional weeks of CT.40 However, in contrast to the phase III trial described above, if CT is discontinued during the erythropoietin treatment period, patients are allowed to remain in the trial. Treatment duration is 16 weeks, and end points include mean change in Hb from baseline, proportion of patients with a Hb increase from baseline of ⱖ2 g/dL, proportion of patients with Hb ⱖ 12 g/dL or a Hb increase from baseline of ⱖ2 g/dL, incidence of transfusion, proportion of patients with and time to target Hb range of 11 to 12 g/dL, mean Hb after achieving target Hb range, and duration of treatment after achieving target Hb range. The dose-escalation method in these trials differs from that in the phase III comparative trial described above, in that the dose of both agents is increased after 4 weeks if Hb does not increase ⱖ1 g/dL. (The epoetin alfa dose is increased to 60,000 U once weekly, and the darbepoetin alfa dose is increased to 300 ␮g every 2 weeks.) One goal of this analysis is to evaluate a new QOL tool, the Patient-Satisfaction Questionnaires for Anemia Treatment (PSQ-AT), administered every 4 weeks, starting at week 5. Results of an interim analysis (N ⫽ 210) showed that, at study end point, both agents increased Hb and decreased transfusions to a similar extent.40 Specifically, after 16 weeks of treatment, the mean change from baseline Hb was 1.84 g/dL in the darbepoetin alfa group and 1.96 g/dL in the epoetin alfa group. Transfusions were required in 21% of patients in the darbepoetin alfa group versus 19% in the epoetin alfa group. Kaplan-Meier estimates showed that achievement of Hb in the range of 11 to 12 g/dL was similar for both agents.40 No QOL data were available at that time. Final results from these comparative trials should help to provide a clearer picture of the Hb response profiles as well as other benefits of each agent. Ideally, future trials should be phase III trials powered for statistical comparison that investigate end points such as Hb change and overall QOL improvement at weeks 4, 6, 8, and study end point, cumulative change in Hb, percentages of patients requiring dose escalation, and incidence of transfusion.

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Figure 3 Mean Hb levels after a higher weekly starting dose (60,000 U once weekly) and maintenance dosing (120,000 U every 3 weeks) of epoetin alfa. (A) Mean Hb increased 1.0 ⫾ 1.1 g/dL at week 4 and 2.9 ⫾ 1.9 g/dL at week 8. Once-weekly epoetin alfa was reduced to 40,000 U in seven patients, and every-3-weeks epoetin alfa was reduced to 100,000 U in two patients. aWeek 4 and week 8 values represent mean Hb during the once-weekly dosing phase. bBy week 12, 10 patients were receiving every-3-weeks maintenance dosing. (B) In the maintenance phase, every-3-weeks dosing maintained mean Hb levels. Baseline ⫽ Hb at entry into maintenance phase. an ⫽ number of patients with an Hb value recorded for given week; this may not be the same as the number of patients still on study or the number of patients receiving study drug that week. Reprinted with permission from Patton et al, Oncologist 9:90-96, 2004.34 http://www.TheOncologist.com.

R.J. Waltzman malignancies receiving CT.34 Mean baseline Hb was 10.1 g/dL. Those patients whose Hb increased ⱖ2 g/dL after a minimum of 8 weeks of once-weekly treatment were allowed to enter the maintenance phase, during which they received epoetin alfa 120,000 U every 3 weeks. The total duration of treatment did not exceed 24 weeks. By week 4, the mean increase in Hb was 1.0 g/dL, and by week 8, the mean increase in Hb was 2.9 g/dL (Fig 3A). Mean Hb upon entry into the maintenance phase was 12.8 g/dL, and 85% of patients had Hb increases of ⱖ2 g/dL. During the every-3-weeks maintenance phase, mean Hb remained above 12 g/dL (Fig 3B). The dosage regimen was well tolerated.34 These results suggest that higher starting doses of epoetin alfa followed by less frequent maintenance dosing may be feasible for the treatment of CT-related anemia. Fixed and weight-based doses of darbepoetin alfa have also been assessed on similar schedules.22 Anemic (Hb ⬍11 g/dL) patients (N ⫽ 242; mean baseline Hb ⫽ 10.2 g/dL) who were receiving CT for nonmyeloid malignancies received higher starting doses of darbepoetin alfa of 325 ␮g once weekly (n ⫽ 122) or 4.5 ␮g/kg once weekly (n ⫽ 120). In contrast to the study by Patton and colleagues,34 patients in this study were able to enter the maintenance phase at first achievement of target Hb 12 g/dL. In the maintenance phase, patients received the same dose (darbepoetin alfa 325 ␮g or 4.5 ␮g/kg) on an every-3-weeks schedule. Treatment duration was 16 weeks. Results for both arms were similar and illustrated that with this higher initial starting dose/maintenance dose regimen, darbepoetin alfa can successfully increase and maintain Hb levels between 12 and 13 g/dL (Fig 4). Both dosage regimens were well tolerated.22 Additional trials are underway to investigate alternate dosing regimens of both agents, and the collection of data will ultimately determine if these newer dosing strategies are achieving the goals of earlier response and patient benefit.

New Paradigms in the Administration of Erythropoietic Agents New approaches for erythropoietic agent administration are under investigation. One such method is to use a higherthan-standard starting dose on a once-weekly schedule until Hb reaches a certain target, and then switch to a less frequent dosing schedule to maintain Hb at or above this level. Often termed “front-loading,” administration of a higher dose initially aims to increase the number of patients who respond, shorten the time it takes to achieve a response (Hb increase ⱖ1 g/dL), and shorten the time it takes to identify nonresponders. A recently published proof-of-concept study investigated the use of a 60,000 U once weekly starting dose of epoetin alfa in 20 anemic (Hb ⬍11 g/dL) patients with nonmyeloid

Figure 4 Mean Hb levels after a higher weekly starting dose and maintenance dosing of darbepoetin alfa. Patients received a fixed dose (325 ␮g [once weekly starting dose, every 3 weeks maintenance dose]) or a weight-based dose (4.5 ␮g/kg [once weekly starting dose, every 3 weeks maintenance dose]). Results did not differ significantly between groups. Reprinted with permission from Hesketh et al.22 CANCER Vol. 100, No. 4, 2004, pp 859-868. Copyright © 2004 American Cancer Society. Reprinted by permission of Wiely-Liss, Inc., a subsidiary of John Wiley & Sons.

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Conclusions Anemia is a common and serious complication of CT and cancer that must be managed effectively to provide oncology patients with optimal care. In patients with CT-related anemia, treatment with erythropoietic agents can achieve today’s goals of anemia management, ie, increase Hb, improve overall QOL, and reduce the need for transfusion. Head-to-head trials are now in progress to determine differences and clinical benefits of the most commonly used doses of these agents. Future comparative trials should be well-controlled and adequately powered, and investigate numerous key clinical end points, such as Hb change and overall QOL improvement at various time points during therapy, and cumulative change in Hb. As new applications and dosing schedules evolve, it is essential for treatment considerations to include balancing convenience with efficacy. New dosing paradigms that involve a higher starting dose followed by less frequent maintenance dosing may optimize outcomes in anemia management, as both epoetin alfa and darbepoetin alfa appear to be effective in increasing and maintaining Hb in such paradigms.

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