The Oncologist, Vol. 9, No. 1, 97–107,
February 2004
© 2004 AlphaMed Press
ORIGINAL PAPER
Symptom Management and Supportive Care |
The Evolving Role of Epoetin Alfa in Cancer Therapy
David H. Henry
Joan Karnell Cancer Center, Pennsylvania Hospital, Philadelphia, Pennsylvania, USA
Correspondence:
David H. Henry, M.D., Joan Karnell Cancer Center, Pennsylvania Hospital, 230 West Washington Square, Philadelphia, Pennsylvania 19106, USA. Telephone: 215-829-6311; Fax: 215-829-6104; e-mail: dhhenry{at}juno.com
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LEARNING OBJECTIVES
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After completing this course, the reader will be able to:
- Describe the use of epoetin alfa in the prevention and treatment of anemia related to cancer and its treatment.
- Discuss ongoing clinical issues with epoetin alfa, including alternative dosing options and the benefits of early intervention for anemia.
- Identify additional nononcologic clinical applications for epoetin alfa currently under investigation.
Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com
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ABSTRACT
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Since its initial indication as hormone-replacement therapy in the anemia of chronic kidney disease, epoetin alfa has become a mainstay of therapy for chemotherapy-related anemia. Clinical studies have shown that epoetin alfa administered once weekly or three times weekly improves hemoglobin levels, decreases transfusion requirements, and improves quality of life independent of tumor response to chemotherapy. Ongoing research is now evaluating ways to improve the response rate to epoetin alfa, the potential benefits of alternative dosing regimens and early treatment intervention, and nonanemia-related indications (e.g., cognitive impairment, asthenia). In addition, scientists are exploring the role of epoetin alfa in preventing apoptosis and ischemic brain injury, as well as its activity in other nonerythroid tissues. Thus, the role of epoetin alfa is likely to expand in the cancer setting in the coming years.
Key Words. Epoetin alfa • Anemia • Cancer • Survival • Quality of life
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INTRODUCTION
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Recombinant human erythropoietin (r-HuEPO, epoetin alfa) has been used in the treatment of anemia of chronic kidney disease (CKD) since 1986 [1]. Curiously, when epoetin alfa was introduced, anemia associated with cancer and its treatment was seldom recognized as a clinically significant condition. Physicians and patients generally believed that fatigue and anemia were an inevitable result of cancer and its treatment [2, 3]. However, because of the effectiveness of epoetin alfa in treating CKD-related anemia, epoetin alfa therapy was evaluated in anemic cancer patients. Results of these early investigations led to the approval of epoetin alfa for the treatment of chemotherapy-related anemia in patients with nonmyeloid malignancies a decade ago.
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EPOETIN ALFA AND CANCER-RELATED ANEMIA
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Anemia is now recognized as a significant consequence of cancer and chemotherapy. Prospective clinical trials in patients with cancer-related anemia have determined that mild-to-moderate anemia (hemoglobin [Hb] level of 8–12 g/dl) occurs in up to 75% of cancer patients undergoing treatment with chemotherapy and/or radiation therapy [4]. The results of the European Cancer Anaemia Survey (ECAS) recently reported and confirmed the high prevalence of anemia among patients with cancer [5, 6]. The ECAS enrolled 15,367 cancer patients at 748 cancer centers in 24 European countries; these patients were followed for up to 6 months to evaluate the incidence and prevalence of anemia outside the clinical study setting [5, 6]. Overall, 72% of patients with hematologic malignancies and 66% of patients with solid tumors were anemic (Hb level <12 g/dl) at some point during the 6-month survey [6]. Of the 2,316 patients with multiple myeloma or lymphoma evaluable for analysis, 73% were anemic at some point during the survey [5].
The fatigue associated with anemia can have considerable negative effects on patient quality of life (QOL) [3, 7]. Cella et al. collected population normative data and established that QOL scores for anemic cancer patients were significantly lower than those for a normal population sample [7]. Results of that study also showed that epoetin alfa therapy leads to clinically important and statistically significant improvements in QOL in patients with cancer-related anemia [7]. However, recent survey results suggest that many anemic patients do not receive adequate treatment. In the ECAS survey report, only 47% of patients with hematologic malignancies (including 46% of those with multiple myeloma or lymphoma) and 36% with solid tumors who were anemic received treatment for their anemia [5, 6], and treatment was initiated at lower than recommended Hb levels (mean Hb levels of 8.8 g/dl, 8.9 g/dl, and 9.6 g/dl for hematologic malignancies, multiple myeloma/lymphoma, and solid tumors, respectively) [5, 6].
Data from several large, prospective, multicenter, clinical trials have shown that epoetin alfa at doses of 10,000–20,000 U or 150–300 U/kg administered three times weekly (tiw) or 40,000–60,000 U once weekly (qw) increased Hb levels, decreased transfusion requirements, and improved QOL in anemic cancer patients receiving platinum or nonplatinum chemotherapy [8–12]. These effects were apparent in patients with hematologic malignancies as well as solid tumors [13]. Further prospective [9] and retrospective [8] analyses revealed that improvements in QOL were independent of tumor response to chemotherapy. A multivariate regression analysis of data from a randomized, double-blind, placebo-controlled study [11] confirmed the QOL benefit of epoetin alfa in patients receiving nonplatinum chemotherapy (Fig. 1
) [14]. In addition, this analysis showed a positive correlation between Hb level and QOL over time, suggesting that epoetin alfa administration improved health-related QOL, which in turn was associated with treatment-related improvements in Hb levels [14]. Further analyses of data from the same randomized, double-blind, placebo-controlled study [11] demonstrated that a 1-g/dl increase in Hb levels in anemic cancer patients receiving epoetin alfa resulted in health-related QOL changes that were clinically meaningful, compared with patients receiving placebo [15]. Epoetin alfa therapy appears to have similar benefits in patients with cancer who are not undergoing chemotherapy [16, 17].
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Figure 1. QOL mean change scores by treatment group: results of univariate [11] and multiple linear regression analyses (Functional Assessment of Cancer Therapy-General [FACT-G] scale and FACT-Anemia [FACT-An] subscale). p values adjusted for multiple comparisons (sequentially rejective Bonferroni procedure). Reprinted with permission from Fallowfield et al. [14].
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In addition, a recent systematic, quantitative literature review suggests that anemia is an independent prognostic factor for survival in cancer patients, with the overall relative risk of death being 65% higher (95% confidence interval = 54%-77%) in patients with anemia than in patients without anemia [18]. Results of a study evaluating the activity of first-line sequential high-dose chemotherapy for patients with testicular cancer also showed a correlation between Hb values after treatment completion and survival [19]. In that study, patients with Hb levels 
10.5 g/dl after completion of four chemotherapy cycles had a 3-year overall survival rate of 87%, compared with 68% for patients with Hb levels <10.5 g/dl (p < 0.03) (Fig. 2) [19]. Results of a randomized, double-blind, placebo-controlled trial of epoetin alfa in anemic cancer patients undergoing chemotherapy further support these findings and suggest that, compared with placebo, treatment with epoetin alfa may improve survival in patients with cancer-related anemia [11]. However, that study was not powered to evaluate survival, and the protocol did not control for variables that may influence survival (e.g., disease stage, bone marrow involvement, chemotherapy intensity, disease progression) [11].
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Figure 2. Overall survival times of patients with Hb values 10.5 g/dl and <10.5 g/dl after four cycles of chemotherapy, calculated after completion of high-dose VIP (cisplatin, etoposide, ifosfamide) chemotherapy for testicular cancer. Reprinted with permission from Bokemeyer et al. [19].
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Thus, the collective body of evidence on epoetin alfa therapy over the last 10 years has established it as a safe, effective option to treat anemia in cancer patients undergoing chemotherapy [8–11, 20, 21]. In fact, recent evidence-based clinical practice guidelines from the American Society of Clinical Oncology and the American Society of Hematology recommend epoetin alfa as a treatment option for patients with chemotherapy-induced anemia and Hb levels 
10 g/dl [22]. For patients with Hb levels of 10–12 g/dl, the guidelines suggest epoetin alfa therapy should be offered at the clinician’s discretion, although there is growing evidence that both clinical outcomes and QOL benefits may improve by achieving and maintaining Hb levels of 12 g/dl or higher [11, 23–29].
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CLINICAL CONSIDERATIONS REGARDING EPOETIN ALFA THERAPY
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Response Rates
The success of epoetin alfa in oncology over the past few years has perhaps overshadowed some of the more interesting clinical details relating to treatment. Practicing oncologists and basic researchers are now in a position to consider some of these other clinical issues regarding epoetin alfa therapy. For example, epoetin alfa increases Hb levels in approximately two-thirds of treated patients with chemotherapy-induced anemia [10]. Up to 46% of patients who respond to epoetin alfa have an increase in Hb level of 1 g/dl within the first 4 weeks of therapy [9–11, 30], and 67% of patients experience an increase in Hb level 2 g/dl (or an increase in Hb level to 12 g/dl) at 8 weeks [30]. The question remains, however, as to why approximately one-third of patients do not respond to standard epoetin alfa doses within this time frame. It would benefit both patients and clinicians if certain patient characteristics could be elucidated to help identify potential "nonresponders" to epoetin alfa therapy. Recognizing specific characteristics may prompt oncologists to employ alternative (and possibly more aggressive) dosing regimens and/or alternative treatments, thereby avoiding delays in Hb and QOL improvements. Unfortunately, a recent review of possible predictors of response to epoetin alfa found no clinically useful pretreatment or early treatment measurements (e.g., Hb level, erythropoietin level, ferritin level, transferrin saturation, reticulocyte count) capable of predicting response [31]. Some patients remain nonresponders because of functional iron deficiency, a relative iron-deplete state that develops during periods of high erythropoietic demand, such as during epoetin alfa therapy [32]. In contrast to absolute iron deficiency, functional iron deficiency is characterized by the presence of sufficient iron stores within the body, but an inability to mobilize iron rapidly enough to support accelerated erythropoiesis [32]. Therefore, even when iron stores are adequate, iron supplementation may be necessary during epoetin alfa therapy to support erythropoiesis and achieve an optimal response to therapy [32]. Intravenous iron administration is usually the preferred route in this setting, as oral formulations typically do not supply iron rapidly enough to be effective except when used at high doses [32]. In a prospective, randomized, multicenter study, intravenous iron optimized response to epoetin alfa therapy in patients with cancer-related and cancer-treatment-related anemia and was significantly more effective than oral iron for this purpose [33]. Based on these data, patients with cancer-related anemia who are receiving epoetin alfa should be routinely monitored for iron deficiency both before and during treatment. Relative or absolute iron deficiency may be difficult to diagnose with accuracy in patients receiving epoetin alfa. Studies to evaluate the role of iron supplementation in this setting are ongoing.
Dosing
Encouraged by its efficacy in a variety of settings, oncologists are becoming increasingly interested in optimizing the dose and schedule of epoetin alfa. Although epoetin alfa is approved by the U.S. Food and Drug Administration for use in chemotherapy-induced anemia as a tiw regimen, an historical data comparison indicated that qw dosing is as effective as tiw dosing at increasing Hb levels, decreasing transfusion requirements, and improving QOL parameters [10, 12, 30, 34, 35]. Both dosing regimens elicited, on average, an increase in Hb of approximately 1 g/dl after 4 weeks and an increase in Hb of approximately 2 g/dl after 8 weeks of epoetin alfa treatment, with Hb increases remaining consistent after accounting for the effects of transfusion on Hb (Table 1) [8–10, 12]. In addition, data from healthy volunteers suggest that qw and tiw dosing schedules may be considered clinically equivalent [36]. A recent report indicates that 88.1% of patients in a multistate, U.S.-based oncology physician practice network who were prescribed epoetin alfa received a starting dose of 40,000 U qw [37].
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Table 1. Comparison of Hb responses in open-label, nonrandomized, community-based studies of qw and tiw epoetin alfa therapies
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More recently, alternative dosing regimens have been investigated that may be as effective as currently utilized regimens at increasing Hb levels, decreasing transfusion needs, and improving QOL, while providing greater flexibility and convenience to patients and physicians [38, 39]. In two pilot studies of patients with chemotherapy-related anemia (Hb level 11 g/dl), an initial epoetin alfa dose of 60,000 U qw increased Hb levels by 2.6 g/dl from baseline at 8 weeks [38, 39]. In one of those studies, patients whose Hb levels increased by 2 g/dl were placed on a maintenance dosing schedule of 120,000 U every 3 weeks. Little change in mean Hb level was observed from the end of initial therapy through the maintenance period, suggesting the benefit of higher initial qw epoetin alfa doses and less frequent dosing during maintenance [38].
These preliminary findings are encouraging and support the continued evaluation of flexible epoetin alfa dosing regimens in an effort to optimize therapy, as well as patient convenience and QOL. In fact, a retrospective analysis of computerized clinical data from a multistate, U.S.-based oncology physician practice network showed that administration regimens of epoetin alfa weekly, every 2 weeks, and every 3 weeks or more were used in 50%, 32%, and 17%, respectively, of patients prescribed a starting epoetin alfa dose of 40,000 U s.c. every week (88% of 1,238 study participants) [37]. That analysis further demonstrated that response rates to epoetin alfa (defined as: a 1 g/dl Hb change from baseline at week 4; or a 2 g/dl change or an Hb level 12 g/dl at week 8, 12, or 16 after epoetin alfa initiation and without transfusion) at week 4 and week 16 were not significantly different among the three dosing schedules (week 16 overall response rates: weekly, 65.3%; every other week, 72.1%; once every 3 weeks or longer, 63.1%) [37].
Timing of Epoetin Alfa Therapy
Another issue of interest to clinicians is the appropriate timing of intervention with epoetin alfa therapy. A number of recent studies have shown that early intervention with epoetin alfa can prevent or significantly ameliorate the negative effect of anemia on transfusion requirements and QOL in patients who are at risk for developing mild-to-moderate anemia during chemotherapy [25–29]. Two studies compared the effect of early epoetin alfa intervention with that of delayed epoetin alfa treatment (i.e., initiation of treatment when anemia became more pronounced) [26, 27]. Littlewood et al. showed that patients with higher Hb levels (>10.5 g/dl) at initiation of epoetin alfa at 150 U/kg tiw had a lower transfusion rate (7.1% versus 28.1%), achieved a higher peak Hb level (13.8 g/dl versus 12.7 g/dl), and reached a target Hb level of 12 g/dl more quickly (after 4 weeks versus 12 weeks) than patients who received treatment when their Hb levels fell to 10.5 g/dl [27]. Similarly, Straus et al. reported that baseline Hb levels increased significantly in patients receiving immediate epoetin alfa therapy at 40,000 U s.c. weekly (mean baseline Hb level = 12.1 g/dl ± 1.4 g/dl; mean change = +0.8 g/dl ± 2.5 g/dl; p = 0.007) but decreased significantly in patients undergoing delayed epoetin alfa treatment (i.e., observation until Hb levels fell to <9 g/dl) (mean baseline Hb level = 12.4 g/dl ± 1.4 g/dl; mean change = -0.8 g/dl ± 1.0 g/dl; p < 0.001; between-group p = 0.005) [26]. In addition, patients receiving early epoetin alfa intervention reported a significant (p < 0.05) improvement in QOL, and QOL changes were significantly correlated with change in Hb level (r = 0.20; p < 0.05). Further, patients receiving early intervention with epoetin alfa had significantly fewer subsequent clinic visits (p = 0.002) and days requiring general assistance with usual daily activities (p < 0.001) [26].
Two additional studies evaluated the effects of initiating epoetin alfa concurrently with chemotherapy, regardless of baseline Hb level [25, 28]. Richart et al. reported that baseline Hb levels were maintained after 4 months in patients who received epoetin alfa at doses of 40,000 U s.c. weekly at chemotherapy initiation (0.0 g/dl [range = -3.2–2.9 g/dl]), compared with patients who received epoetin alfa when Hb levels fell to <10 g/dl (-1.0 g/dl [range = -2.6–5.0 g/dl]) [28]. In addition, patients receiving early epoetin alfa therapy experienced less fatigue. In an open-label, nonrandomized, multicenter, community-based study, Hudis et al. evaluated the effects of epoetin alfa at doses of 40,000 U s.c. weekly on Hb level and QOL in 1,597 female patients (mean baseline Hb = 12.3 g/dl ± 1.0 g/dl) with breast cancer receiving adjuvant chemotherapy for 3–6 months [25]. Once-weekly epoetin alfa therapy maintained Hb levels (mean Hb increase = 1.2 g/dl ± 1.5 g/dl), significantly improved QOL compared with baseline, and was well tolerated [25].
Earlier intervention with epoetin alfa to prevent anemia and maintain Hb levels has also elicited beneficial results in two open-label, randomized trials in patients with non-small cell lung cancer (NSCLC) and in patients with breast cancer receiving chemotherapy. In a study by Crawford et al., epoetin alfa at doses of 40,000 U s.c. weekly (n = 107) for up to 16 weeks was compared with no epoetin alfa unless the Hb level fell to 10 g/dl (n = 105) in chemotherapy-naïve patients with stage III/IV NSCLC and Hb levels of 11–15 g/dl (mean Hb level was approximately 13 g/dl in each group) [40]. Hb level was maintained in patients receiving epoetin alfa at the start of chemotherapy, but decreased relative to baseline in control patients (mean Hb level = 12.9 g/dl versus 11.6 g/dl, respectively, at week 16/final value; p = 0.0001 versus control) [40]. Significantly more control patients had Hb levels that decreased to <10 g/dl compared with patients treated with epoetin alfa (44% versus 18%, respectively; p = 0.0001). Even in control patients who received delayed epoetin alfa therapy for Hb levels 10 g/dl, the mean Hb level at the study end never reached that observed in the epoetin alfa cohort, suggesting that earlier anemia intervention is important in this patient population [40]. In a study by Chang et al., patients with breast cancer were randomized to receive either epoetin alfa at doses of 40,000 U s.c. weekly for up to 16 weeks (n = 174) or best supportive care (BSC; n = 176). Mean baseline Hb levels were 11.2 g/dl in both groups. In an interim analysis of week 12 data, the mean Hb level increased significantly to 12.3 g/dl in the epoetin alfa group (n = 131), but decreased to 10.7 g/dl in the BSC group (n = 130) (p < 0.0001) [41]. Hematologic response rates (defined as a mean Hb area under the concentration time curve >12 g/dl during weeks 4–12) were 52% for epoetin alfa patients and 6% for BSC patients (p < 0.001). Transfusion utilization was significantly lower with epoetin alfa (6.9%; n = 9) than with BSC (24.0%; n = 32) (p < 0.0001) [41]. Epoetin alfa patients also had significant improvements in QOL, while BSC patients had decreases in QOL.
Collectively, these findings suggest that epoetin alfa can maintain or improve Hb levels, protect against anemia, and attenuate decreases in QOL when administered early during the course of chemotherapy and/or to patients with mild-to-moderate anemia. In particular, early intervention allows patients to maintain a relatively high QOL, including a positive sense of well-being and ability to function; to experience less fatigue during chemotherapy administration, potentially avoiding the deterioration in QOL associated with more severe anemia; and to maintain productivity while decreasing health care resource utilization [25–28]. Given the findings of Cella et al. regarding the clinical significance of decreases in QOL observed in patients with cancer-related anemia [7], these studies demonstrate the benefits of epoetin alfa therapy in maintaining Hb levels and a clinically significant QOL.
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ADDITIONAL APPLICATIONS FOR EPOETIN ALFA
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The recognized benefits of epoetin alfa therapy for the treatment of anemia in cancer patients receiving chemotherapy have prompted investigators to explore other potential clinical applications for the compound. Evidence indicates that the action of erythropoietin (EPO) is not limited to the erythroid system [42]. Erythropoietin receptors (EPO-Rs) have been detected on a variety of nonerythroid cell types, and interactions between EPO and its receptor induce multiple cellular responses, including mitogenesis, chemotaxis, angiogenesis, mobilization of intracellular calcium, and inhibition of apoptosis [42]. Further, evidence suggests that erythropoietin acts not only as an endocrine hormone in the kidney/bone marrow system, but can act as a paracrine factor in the oviduct and the brain, possibly protecting against hypoxic injury (Fig. 3) [42].
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Figure 3. The expanding portfolio of erythropoietin target cells and tissues. Reprinted with permission from Lappin et al. [42].
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Cognitive Function
Cognitive impairment and asthenia (fatigue) are recognized complications of cancer and its therapy, particularly in patients with breast cancer [43–47]. Both symptoms can persist for months or years after completion of therapy [43, 48] and have been significantly associated with decreased Hb levels during treatment [46]. These findings, combined with the ability of epoetin alfa to improve QOL in patients with chemotherapy-associated anemia, provide a plausible rationale for evaluating a potential role for epoetin alfa in ameliorating cognitive deficits in anemic cancer patients receiving chemotherapy.
In an effort to better understand the relationship between Hb and cognition, O’Shaughnessy et al. evaluated the feasibility of quantifying the effects of epoetin alfa on asthenia and chemotherapy-related impairment of cognitive and executive (ability to think, decisiveness) functions in breast cancer patients receiving either adjuvant or neoadjuvant anthracycline-based chemotherapy [29]. The results of this double-blind, placebo-controlled pilot study demonstrated that, in addition to maintaining or improving Hb levels and attenuating declines in overall QOL, energy, and activity levels (also demonstrated by Hudis et al. [25]), weekly epoetin alfa therapy was associated with less cognitive decline during chemotherapy [29]. These data suggest that there may be a relationship between decline in Hb level and cognitive dysfunction during adjuvant chemotherapy, supporting a role for epoetin alfa in patients with breast cancer who are at risk for developing cognitive deficits following administration of adjuvant or neoadjuvant chemotherapy. A larger, controlled study is currently in progress to further explore possible links between increases in Hb levels and improvements in cognitive and executive function in this setting.
Central Nervous System Disorders
Several studies have shown that, in addition to expression in hematopoietic tissues, the EPO-R is expressed in nonhematopoietic tissues (e.g., gastric mucosa, vascular smooth muscle, brain neurons) [49–52]. In brain neurons, a role for EPO-R signaling during ischemia-associated neuronal angiogenesis has been suggested. Experiments have shown that the central nervous system (CNS) responds to hypoxic insults by upregulating the expression of EPO and the EPO-R by cells within the border zone surrounding the necrotic core of an injury over the 12–24 hours following the insult [53, 54].
The mechanisms of action of epoetin alfa in tissue protection may include protection of neurons from death, reduction of inflammatory responses, or both [55]. EPO acts to inhibit programmed cell death (apoptosis) in erythroid progenitor cells [56], as well as in neurons following cerebral ischemia and metabolic stress [57]. In ischemic brain injury, it appears that EPO does not function strictly to promote growth but actually prevents death by inhibiting apoptosis via activation of the bcl-2 family of antiapoptotic proteins, particularly the long form of BCLx (Bcl-xL) [55]. In addition, EPO also modulates the inflammatory reaction to brain injury by modulating members of the NF-
B family that act as primary regulators of the inflammatory genes [55]. Capillary endothelial cells that form the blood-brain barrier also express high levels of EPO-R [57], which are upregulated following hypoxia [55]. The protective effects of EPO on the vasculature may not be limited to capillaries; EPO may also protect vascular smooth muscle cells from injury-induced apoptosis [58].
Other proposed neuroprotective mechanisms for EPO include antioxidation [59] and a direct neurotrophic effect [60]. Preclinical data have demonstrated that peripherally administered epoetin alfa crosses the blood-brain barrier, and reports suggest that both endogenous EPO and epoetin alfa may provide neuroprotective and cognition-enhancing effects, as well as enhanced neurological recovery from spinal cord trauma [61–63]. Recent data in stroke patients also suggest a neuroprotective effect of epoetin alfa [64]. Overall, preclinical findings firmly establish the presence of an endogenous EPO/EPO-R system within the CNS that acts outside of hormonal (feedback) control to protect neurons and endothelial cells from hypoxia [55].
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ERYTHROPOIETIN RECEPTORS AND RECEPTOR BINDING AFFINITIES
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The pharmacokinetics and pharmacodynamics of EPO have been widely studied. However, the metabolic fates of EPO and manufactured forms of the cytokine have not been fully elucidated. Further, the clinical relevance of this knowledge remains unclear. Recently, a novel erythropoiesis-stimulating protein (NESP, darbepoetin alfa; AranespTM; Amgen Inc., Thousand Oaks, CA) was approved for use in the U.S. Darbepoetin alfa has an approximately threefold longer half-life than epoetin alfa and a fourfold lower binding affinity for the EPO-R than epoetin alfa [65, 66]. Relative binding affinities of epoetin alfa and darbepoetin were determined by radiolabeled competition assays that measured the strength of binding to the EPO-R. In those assays, the inhibitory concentration at which 50% of radiolabeled epoetin alfa was displaced (IC50) was 703 pM for darbepoetin and 138 pM for epoetin alfa, a fourfold relative difference [67]. Further, relative biologic activity, measured by determining in vitro proliferation effects of both agents on the UT7/EPO cell line, indicated that epoetin alfa had a fourfold greater biologic activity than darbepoetin alfa in that cell line. The effective ligand concentration to obtain 50% biologic activity (EC50) was 58.9 pM for darbepoetin alfa and 11.5 pM for epoetin alfa. Both the longer half-life and the lower binding affinity of darbepoetin alfa result from the greater sialic acid content of the analog [65]. EPO binding to the EPO-R results in EPO-R dimerization, which in turn leads to cell signaling, signal transduction, and red blood cell production [68]. The conformational structure of the D2 receptor when the ligand is formed is thought to be the critical component in EPO-R signaling. It is not known whether the lower binding affinity of NESP results in a different conformational change and signaling in the EPO-R. However, the greater half-life and lower binding affinity of darbepoetin alfa have not translated into notable differences in clinical efficacy to date. For example, although epoetin alfa and darbepoetin alfa have different half-lives, both are effective when given weekly, eliciting similar hematopoietic response rates in patients with chemotherapy-related anemia [10, 69]. Thus, the impact on clinical practice of the longer half-lives and lower binding affinities of hyperglycosylated r-HuEPO analogues, compared with those of epoetin alfa, remains to be determined.
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SUMMARY
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During the past decade, epoetin alfa has demonstrated a significant therapeutic role beyond its initial use as hormone-replacement therapy in patients with CKD-related anemia. Oncologists now recognize epoetin alfa as a major therapeutic option for anemia management in cancer patients receiving chemotherapy. Early treatment of milder anemia has been associated with fewer clinic visits [26], fewer days requiring general assistance [26], and fewer epoetin alfa dose escalations to increase or maintain adequate Hb levels [27] compared with delayed intervention [26, 27]. Further, data support the benefits of treating patients to an Hb level of 12 g/dl, with patients experiencing the greatest benefits in QOL when Hb increased from 11 g/dl to 12 g/dl (range = 11–13 g/dl) [23, 24]. Collectively, these results suggest that epoetin alfa has a role in the treatment of patients with mild-to-moderate anemia receiving chemotherapy [7, 25, 29, 40, 41].
Despite these data, practitioners may be reluctant to prescribe epoetin alfa, particularly in an increasingly cost-contained and cost-conscious clinical environment [14]. Because the benefits of appropriate anemia therapy have been well documented, providers are faced with a situation similar to that which occurred following the introduction of 5HT3-receptor antagonists for the amelioration of chemotherapy-related nausea and vomiting. Although nausea and vomiting were severely debilitating and of great concern to most patients, many clinicians were reluctant or unable to prescribe these products because of cost [14]. Fortunately, this argument was overcome by the fact that uncontrolled symptoms reduce QOL and may preclude treatment completion, leading to hidden or unmeasured costs. Thus, 5HT3-receptor antagonists are now considered standard therapy for chemotherapy-related nausea and vomiting, greatly improving the tolerability of chemotherapy and overall QOL for cancer patients [14]. Similarly, clinicians now have documented evidence of the clinical significance of impairments in QOL that are observed in patients with cancer-related anemia [7] and the ability of epoetin alfa to maintain Hb levels while ameliorating any deterioration in QOL [10, 11]. Hopefully, this information will overcome many concerns about the cost of epoetin alfa therapy for chemotherapy-related anemia.
Research continues into using alternative dosing regimens for epoetin alfa while maintaining optimal increases in Hb levels. In addition, other potential benefits of epoetin alfa are being described, including its ability to improve asthenia symptoms, attenuate QOL decline, and improve mood and cognitive function in cancer patients receiving chemotherapy. Results of these studies, in addition to clinical questions such as how to maximize the benefits of epoetin alfa in all treated patients, are likely to provide exciting avenues for expanding the use of this compound in cancer patients and beyond.
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ACKNOWLEDGMENT
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Dr. Henry is a recipient of research support from Ortho Biotech Products, L.P. and receives honoraria for serving on the Ortho Biotech Speaker’s Bureau.
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Received September 12, 2003;
accepted for publication November 24, 2003.
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