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Iron is an essential trace element important for hematopoiesis, oxygen transport and delivery, and other biologic functions. Iron uptake and utilization are strictly regulated but severely altered in anemia of chronic disease. In this condition, availability of iron for erythropoiesis is insufficient and a limiting factor for red blood cell production, in spite of normal or increased storage iron. Although concomitant oral iron supplementation is recommended in guidelines for treatment of cancer-associated anemia with erythropoietic agents, its efficacy is not documented. Recent studies evaluated the impact of parenteral iron supplementation in comparison with oral iron therapy and with control in anemic cancer patients treated with epoetin alfa or beta, or with darbepoetin. Concomitant treatment with parenteral iron proved superior to oral iron or no treatment. Hematologic response rates were higher, time to increase of hemoglobin was shorter, the need for red blood cell transfusions lower, and the quality of life better than in patients treated with oral or no iron at all. Severe side effects were rare and tolerance was remarkably good in most patients. However, information on long-term safety is not available as yet. Taken together, parenteral iron administration seems likely to evolve as an important adjunct to treatment with erythropoietic agents in patients with treatment-induced or chronic anemia of cancer.

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.

Anemia is a common clinical problem in critically ill patients and is associated with substantial red blood cell (RBC) transfusion requirements. However, RBC transfusion has significant risks, including adverse effects on the immune system. Although a low hemoglobin concentration may be tolerable, it may not be optimal for the critically ill patient. Thus, alternative therapies that can increase hemoglobin and avoid complications of RBC transfusion are desirable. Critically ill patients appear to have anemia identical to the anemia of chronic inflammatory disease with blunted erythropoietin production. Results of a recent randomized controlled trial in critically ill patients demonstrated that recombinant human erythropoietin (r-HuEPO, epoetin alfa) significantly reduced (by approximately 50%) the number of RBC units transfused (P.002) and significantly increased hematocrit (P.01) compared with placebo. There was no increase in mortality or adverse clinical events with therapy. Epoetin alfa may be an effective therapeutic approach to anemia in critically ill patients, decreasing the need for transfusion and achieving higher hemoglobin concentrations than generally attained with transfusion.

In cancer patients, anemia is common and has been found to impair quality of life and reduce locoregional disease control conferred by radiotherapy. The prognostic importance of anemia in the radiation oncology setting may be related to a reduction of molecular oxygen levels, thereby attenuating radiation-induced damage and ultimate cell death. Substantially higher doses of radiation are required to eradicate malignant cells under the hypoxic conditions commonly identified in solid tumors. Consistent with this, patients with hypoxic solid tumors have been found to have shorter postradiation disease-free survival rates relative to patients with well-oxygenated tumors. An attempt to enhance intratumoral oxygenation via correction of anemia, a highly prevalent but modifiable condition, is therefore a reasonable approach to optimize radiotherapy and chemoradiation outcomes. Clinical studies investigating recombinant human erythropoietin (epoetin alfa) as an adjunct to radiotherapy have demonstrated its ability to increase and maintain hemoglobin (Hb) levels during the course of radiotherapy. In a study involving anemic patients undergoing chemoradiation for head and neck cancer, epoetin alfa extended locoregional control and survival to rates reported for patients with normal pretreatment Hb levels. Given the high prevalence and prognostic significance of anemia during radiotherapy, strategies that safely and effectively increase Hb levels may be of value for optimizing radiotherapy and chemoradiation outcomes.

In the postgenome era, development of novel targeted therapeutics is anticipated to accelerate, with the promise of specifically tailored strategies to treat specific molecularly characterized disease entities. Greater understanding of disease pathophysiology and pharmacologic actions at the molecular, cellular, and tissue levels have provided the basis for expanding the clinical application of available therapies such as recombinant human erythropoietin (r-HuEPO, epoetin alfa). The role of epoetin alfa in anemic cancer patients receiving chemotherapy has grown as our understanding of the relationship between anemia and quality of life in this patient population has evolved. With anemia and tumor hypoxia associated with poorer outcomes in various solid tumors, the potential impact of epoetin alfa on outcomes, as well as quality of life, in patients undergoing radiation or chemoradiation is of considerable interest. Anemia occurs almost universally in critically ill patients, resulting in substantial transfusion requirements. In this setting, the anemia appears to be consistent with anemia of chronic inflammatory disease and is potentially treatable by epoetin alfa. Recent preclinical studies indicate that erythropoietin exhibits neuroprotective effects in models of central nervous system injury, suggesting additional potential novel clinical applications for epoetin alfa worthy of careful investigation. Advances in the understanding of the ras genes and their functional proteins in signaling pathways involved in the development of cancer, particularly hematologic malignancies, over the last decade have prompted development of a new class of agents, farnesyl protein transferase inhibitors (FTIs), designed specifically to inhibit the initial step in Ras protein activation. Initial clinical evaluation of FTIs is ongoing, and preliminary results demonstrate antitumor activity in hematologic malignancies. Further identification and understanding of the function and complex interactions of proteins involved in diseases holds the promise of targeted therapies and improved patient outcomes.

Anemia is frequent and significantly adds to the morbidity of cancer patients, and has been associated with decreased quality of life (QOL). Three open-label community-based studies of epoetin alfa in cancer-related anemia (two using three-times-weekly dosing and one using once-weekly dosing) in more than 7,000 patients have been performed. Results indicate that epoetin alfa treatment significantly increases hemoglobin and reduces transfusion requirements by 8 to 12 weeks, and using quality assessment tools, it has been shown to be associated with improvement in QOL scores. Incremental analysis demonstrated that the greatest improvement in QOL outcomes was associated with an increase in hemoglobin level from 11 g/dL to 12 g/dL (range, 11 to 13 g/dL). Strategies for management of anemia may need to take into account the possible advantage of early intervention in improving functional status in cancer patients.

The adverse effects of tumor hypoxia and anemia on the efficacy of radiation therapy have been increasingly recognized. In vitro data indicate that radiation therapy under hypoxic conditions is approximately one third as effective as that under normoxic conditions. There is accumulating clinical evidence of significantly reduced local-regional tumor control and overall survival in anemic patients receiving radiotherapy for head and neck, respiratory tract, pelvic, or genitourinary cancers. In our own study using intraarterial high-dose cisplatin and radiation therapy, we observed that pretreatment hemoglobin level was significantly predictive of complete response (CR) at primary and nodal sites, local-regional failure-free survival, and overall survival by multivariate analyses. With the general lack of success in overcoming the effects of tumor hypoxia through such measures as hyperbaric oxygen and radiosensitizing agents, the focus of clinical research has shifted to directly correcting anemia. A planned randomized trial by the Radiation Therapy Oncology Group will assess the effects of correction of anemia with epoetin alfa on local-regional tumor control and survival in anemic head and neck cancer patients receiving radiation therapy.

The final stages of maturation of erythroid cells Into mature red blood cells are regulated by the growth factor erythropoietin. Circulating levels of erythropoietin are remarkably consistent across the range of normal hemoglobin levels; levels Increase markedly as hemoglobin declines below 12 g/dL In a manner suggesting that mechanisms in addition to the level of tissue oxygen are important in regulating increases in erythropoietin production and erythropoiesis. The erythropoietin receptor is found on a number of cell types in addition to erythroid progenitor cells, suggesting that erythropoietin may have specific biologic effects on other tissues, still to be carefully discerned. Clinical trials have demonstrated the effectiveness of recombinant human erythropoietin (epoetin alfa) in increasing hemoglobin level in iatrogenic and disease-related anemias. This increase has been associated with improving fatigue symptoms and enhancing overall quality of life. Questions remain, however, regarding the optimal increases in hemoglobin to be achieved in anemic patients with such therapy and whether optimal levels might vary in different patient groups.

Observational studies have consistently documented independent, strong associations of anemia--even if not severe--with major adverse functional outcomes in older adults. In this chapter, recent epidemiologic evidence linking mild anemia with decline in physical and cognitive function, frailty, and disability in community-dwelling older adults is reviewed. Altogether, these biologically plausible associations provide empirical, though not conclusive, support for the notion of mild anemia as a cause of adverse functional outcomes in older adults. Randomized clinical trial data assessing the impact of anemia correction on functional outcomes are lacking at this time.

Erythropoietin is a peptide hormone that stimulates erythropoiesis. There are several agents in clinical use and in development, which either act as ligands for the cell surface receptors of erythropoietin or promote erythropoietin production that stimulates erythropoiesis. These are known as erythropoietic agents. The agents already in use include epoetin alfa, epoetin beta, and darbepoetin alfa. Newer agents stimulating erythropoiesis (such as continuous erythropoietin receptor activator (CERA) or proline hydroxylase inhibitors that increase HIF-1 thereby stimulating erythropoietin production and iron availability and supply) are under active investigation. Erythropoietic agents have been shown to promote neuronal regeneration and to decrease post-stroke infarct size in mouse models. They have also been reported to shorten survival when used to treat anemia in many cancer patients and to increase thromboembolism. In contrast, rapid decrease of erythropoietin levels as observed in astronauts and high-altitude dwellers upon rapid descent to sea level leads to the decrease of erythroid mass, a phenomenon known as neocytolysis. The relative decrease in the serum erythropoietin level is known to occur in some subjects with otherwise unexplained anemia of aging. Anemia by itself is a predictor of poor physical function in the elderly and is a significant economic burden on society. One out of every five persons in the United States will be elderly by 2050. Erythropoietic agents, by preventing and treating otherwise unexplained anemias of the elderly and anemia associated with other disease conditions of the elderly, have the potential to improve the functional capacity and to decrease the morbidity and mortality in the elderly, thereby alleviating the overall burden of medical care in society.

Understanding the tissue distribution of erythropoietin receptors and cellular actions of erythropoietic agents may facilitate the development of wider applications for these compounds. Erythropoietin receptors have been identified in the central nervous system (CNS), retina, heart, vascular endothelium, kidney, lung, liver, gastrointestinal and reproductive tracts, and erythroid bone marrow precursors. Potential benefits of erythropoietic agents in several therapeutic areas may result from actions other than hematopoiesis stimulation. Their hematopoietic effects may also have broader applications in treating anemia of the elderly and non-chemotherapy (CT)-related anemia in patients with cancer. Furthermore, because hypoxic tumor cells tend to be more resistant to radiation therapy (RT) and some forms of CT, and more aggressive than normoxic cells, increased oxygenation resulting from anemia correction may increase RT and CT sensitivity, possibly impacting treatment outcomes. However, clinical studies addressing this hypothesis have conflicting results. Preliminary evidence suggests erythropoietin has CNS neuroprotective effects, including potential clinical benefits in ischemic stroke. In addition, data suggest that erythropoietin (epoetin alfa) may attenuate declines in cognitive function during CT for early-stage breast cancer. Erythropoietin may have benefits in retinal disease, peripheral neuropathy, and myocardial ischemia. Thus, accumulating evidence suggests that erythropoietic agents may have clinical utility outside CT-related anemia.

Anemia is prevalent among cancer patients with hematologic malignancies, with fatigue and weakness, major symptoms of anemia, contributing to diminished quality of life (QOL). Data from several randomized, placebo-controlled clinical trials and three large community-based studies in patients with hematologic malignancies indicate that recombinant human erythropoietin (r-HuEPO, epoetin alfa) can correct anemia, reduce transfusion requirements, and improve QOL. Moreover, a positive relationship has been found between increased hemoglobin (Hb) levels and improvements in QOL assessments, regardless of disease state, with the greatest incremental improvement occurring when Hb increases from 11 g/dL to 12 g/dL (range, 11 to 13 g/dL). This suggests that patients with mild-to-moderate anemia may achieve the greatest QOL benefit from epoetin alfa therapy. Evidence from community-based studies suggests that epoetin alfa administered once weekly has a similar safety and efficacy profile as three-times-weekly administration. Further research is ongoing with less frequent dosing regimens. The beneficial effects of epoetin alfa therapy have been reported in studies involving patients with chronic lymphocytic leukemia (CLL), multiple myeloma, and lymphomas. Evidence also exists that epoetin alfa can benefit patients with myelodysplastic syndromes (MDS), although these results have not been as impressive. Combining epoetin alfa with other cytokine growth factors may confer some additional benefit in these patients, but more rigorous investigation is required. Semin Hematol 39(suppl 3):25-31. Copyright 2002, Elsevier Science (USA). All rights reserved.

Untreated anemia is common in cancer patients. Previous studies have demonstrated that both the existence of cancer and treatment with chemotherapy can suppress the normal endogenous erythropoietic response to anemia, making some cancer patients transfusion cadidates. In placebo-controlled phase III studies, administration of recombinant human erythropoietin (epoetin alfa) increased hemoglobin (Hb) levels and decreased transfusion requirements in patients undergoing cancer chemotherapy. In these studies, an increase in self-perceived energy level, functional status, and overall quality of life (QOL) was noted in the subset of patients in whom hematocrit levels increased byor = 6%. To examine more closely the relationship between epoetin alfa therapy and QOL issues in patients undergoing chemotherapy, we conducted an open-label phase IV study involving 2,030 patients treated at 570 community cancer centers in the United States. Patients initially received epoetin alfa 150 U/kg subcutaneously (s.c.) three times per week for 4 months; if response was judged inadequate, the dosage was increased after 8 weeks to 300 U/kg s.c. three times per week. Hb levels and transfusion requirements were monitored monthly. Before and after the study, each patient completed a linear analog self-assessment scale designed to measure energy level, daily activity, and overall QOL. During epoetin alfa therapy, there was a progressive and significant increase (P.001) in Hb concentrations. Significantly fewer (P.001) patients were transfused and fewer transfusions were administered per patient per month after the first month of epoetin alfa therapy. Fifty-eight percent of the patients who required a transfusion during the first month of epoetin alfa therapy did not require a transfusion during the subsequent 3 months of the study. The entire patient population demonstrated a significant increase in mean scores for energy level, daily activity, and overall QOL. The magnitude of the increase in these scores correlated with the magnitude of the increase in Hb concentration. Statistically significant improvement in energy scores, daily activity, and overall QOL (P.05) were observed, regardless of tumor response. These observations require confirmation on placebo-controlled trials, but the implications for oncology practice are important. They suggest that in cancer patients undergoing chemotherapy, the tradition of leaving anemia untreated may compromise patients' ability to function and their QOL.

In order to avoid exposure to allogeneic blood, perisurgical administration of epoetin alfa has been proposed as an alternative to autologous blood (AB) predonation in patients who are unable or unwilling to donate AB prior to elective surgery. The efficacy of perisurgical epoetin alfa to reduce allogeneic blood exposure was investigated in a randomized, double-blind, placebo-controlled study in 200 patients unable to participate in an AB predonation program who were scheduled for orthopedic surgery with expected blood lossor = 2 units. Epoetin alfa (100 IU/kg or 300 IU/kg) was administered daily by subcutaneous (s.c.) injection, commencing 10 days preoperatively and continuing until day 4 postoperatively (15 doses in total). All patients received oral iron supplementation. Patients treated with epoetin alfa required significantly fewer (P.001) allogeneic transfusion compared with placebo, and this effect of epoetin alfa was particularly evident in the subgroup of patients with baseline hemoglobin (Hb) levels of more than 10 toor = 13 g/dL. In terms of the reduction in allogeneic blood exposure, no significant difference was evident between epoetin alfa regimens. Epoetin alfa was well tolerated. Although 15 s.c. doses of epoetin alfa 100 IU/kg appears to be the optimum dosage regimen in patients scheduled for orthopedic surgery, a presurgical simulation study in 24 healthy volunteers suggested that two s.c. doses of epoetin alfa 600 IU/kg in 10 days prior to expected surgery may be a suitable regimen for further study. However, the optimum timing of epoetin alfa administration in relation to surgery remains to be established. A finding consistent to all studies is that adequate iron supplementation (most probably in parenteral form) is necessary to optimize the erythropoietic response to epoetin alfa in the surgical setting.

The optimum dosage of subcutaneous (s.c.) epoetin alfa was assessed in a double-blind study in 31 patients scheduled for cardiac surgery. Patients received a total of four doses of either epoetin alfa 150 IU/kg (n = 11), epoetin alfa 300 IU/kg (n = 10), or placebo (n = 10) administered as single s.c. injections at weekly intervals starting 23 days prior to surgery. AB was collected with isovolemic replacement prior to each of the first three doses of medication. During the AB donation period, Hb levels decreased significantly (P.05) from baseline to surgery in the placebo group (16.5%), compared with no significant decrease in either of the epoetin alfa groups (8.1% and 9.7% in the 150 IU/kg and 300 IU/kg groups, respectively). In addition, the difference between groups with regard to the decrease in Hb level reached statistical significance (P.05) for the 150 IU/kg group versus placebo. Epoetin alfa treatment was also associated with significantly higher reticulocyte counts and serum erythropoietin levels in the preoperative period compared with placebo.

Predonation of autologous blood (AB) represents an attractive alternative to allogeneic blood transfusion in patients scheduled for elective orthopedic surgery. However, anemic patients may not be able to donate sufficient AB prior to surgery, thus increasing the risk of exposure to allogeneic blood. This group of patients may benefit from the administration of epoetin alfa to facilitate AB donation. A recent multicenter, double-blind, placebo-controlled study in 204 patients with a low hematocrit (Hct;or = 39%) scheduled for orthopedic surgery demonstrated that the intravenous administration of epoetin alfa (600 IU/kg twice weekly for 3 weeks) significantly increased the number of AB units predeposited and the percentage of patients able to donateor = 4 AB units. Furthermore, epoetin alfa attenuated the decrease in Hct associated with AB donation and significantly (P = .027) reduced allogeneic blood exposure in these patients.

In previous studies, treatment with epoetin alfa facilitated preoperative donation of autologous blood (AB). However, some patients may not be able to donate sufficient AB to meet their surgical blood requirements when the time to surgery is short. In this multicenter, double-blind, placebo-controlled study, the ability of epoetin alfa combined with normovolemic hemodilution (NVHD) to facilitate the collection ofor = 4 AB units within 2 weeks of surgery was investigated in 112 nonanemic patients scheduled for elective orthopedic or vascular surgery. All patients received oral iron supplementation and were treated with three intravenous (i.v.) injections of epoetin alfa (300 or 600 IU/kg) on days 1,4, and 7; surgery, in combination with NVHD, was performed on day 13. A total of 4 units of AB were predeposited if the patient's hemoglobin (Hb) level exceeded 11 g/dL at each donation. Compared with placebo, epoetin alfa dose-dependently increased reticulocyte counts prior to surgery and significantly minimized the decrease in hematocrit (Hct) associated with AB donation, although there were no significant differences between dosages. While significantly more patients treated with epoetin alfa were able to donateor = 4 AB units compared with placebo, there was no difference between the groups in exposure to allogeneic blood. This effect of epoetin alfa was particularly apparent in female patients. I.v. epoetin alfa 300 IU/kg, administered three times within 1 week, appears to be the optimum dose for facilitating the collection ofor = 4 units of AB in nonanemic patients scheduled for elective surgery and NVHD within 2 weeks.

A low predonation hematocrit (Hct) can preclude the collection of sufficient autologous blood (AB) to meet the transfusion requirements of patients scheduled for orthopedic surgery. Subcutaneous (s.c.) administration of epoetin alfa, in conjunction with intravenous (i.v.) iron supplementation, has proved effective for the facilitation of AB donation by such patients. Compared with untreated controls and patients treated with i.v. iron alone, epoetin alfa 50 to 150 IU/kg SC plus i.v. iron twice weekly for 3 weeks prior to surgery significantly increased total red blood cell (RBC) production (P.01) and the volume of RBCs donated (P.05). Epoetin alfa was particularly effective in females and patients with a predicted blood volume (PBV) less than 5 L. Treatment with epoetin alfa led to an increase (albeit nonsignificant) in the number of AB units predonated compared with i.v. iron alone. However, in patients with a PBV less than 5 L, a substantially greater percentage of epoetin alfa-treated patients donatedor = 4 AB units (80% v 30%). Allogeneic blood requirements were reduced, albeit not significantly (P = .051), in patients treated with epoetin alfa. However, in comparison with untreated controls, there was a significant reduction in the mean volume of allogeneic blood transfused per transfused patient in the epoetin alfa groups. The optimum s.c. dose of epoetin alfa in patients with a low predonation Hct scheduled for orthopedic surgery appears to be between 100 and 150 IU/kg twice weekly for 3 weeks.

The introduction of autologous blood (AB) donation programs has led to a decrease in the number of orthopedic surgery patients exposed to allogeneic blood, although there is still room for improvement. For example, some patients may not be able to donate sufficient AB to meet their expected blood requirements. Virtually all nonanemic patients can donate 3 AB units prior to orthopedic surgery before further AB donation is limited by the development of anemia. In preliminary studies, the administration of epoetin alfa (150 IU/kg subcutaneously (s.c.) on alternate days; six doses) following the donation of 3 AB units reversed phlebotomy-induced anemia and enabled a further 2 units of AB to be collected. The ability of this therapeutic approach to increase AB procurement and reduce allogeneic blood requirements is being investigated in an ongoing, placebo-controlled study. An alternative approach may be to combine perisurgical treatment with epoetin alfa and normovolemic hemodilution (NVHD) prior to orthopedic surgery. Although such studies have yet to be initiated, they may demonstrate a reduction in allogeneic blood exposure in patients unable to donate AB prior to orthopedic surgery, a group of patients traditionally at high risk of exposure to allogeneic blood.

Autologous blood (AB) donation can minimize exposure to allogeneic blood in patients scheduled for coronary artery bypass graft (CABG) surgery. During AB donation in this group of patients, minimization of the accompanying decrease in hemoglobin (Hb) levels is important to reduce the risk of provoking silent myocardial ischemia and/or arrhythmias. Recombinant human erythropoietin (rHuEPO) has been used to facilitate AB donation and minimize the accompanying decrease in Hb levels in patients scheduled for cardiac surgery. In 24 patients scheduled for CABG surgery, once-weekly subcutaneous (s.c.) administration of rHuEPO (epoetin alfa 400 IU/kg) plus oral iron supplementation for 4 weeks prior to surgery caused marked stimulation of erythropoiesis and significantly increased collection of autologous red blood cells (RBCs) compared with oral iron alone. Furthermore, epoetin alfa minimized the decrease in Hb levels associated with AB donation and significantly attenuated allogeneic blood requirements by facilitating the collection of 4 AB units prior to surgery. During AB donation, no changes in the incidence or severity of ischemic attacks or ST-segment changes were observed using electrocardiographic monitoring. Epoetin alfa was well tolerated. Once-weekly s.c. administration of epoetin alfa for 4 weeks therefore represents a practical means of facilitating AB donation by patients scheduled for CABG surgery.

In patients scheduled for major orthopedic surgery, the presence of anemia can preclude the donation of sufficient autologous blood (AB) to meet transfusion requirements. Although a number of studies have investigated the use of epoetin alfa (in conjunction with parenteral iron supplementation) to facilitate AB donation and reduce exposure to allogeneic blood in this patient population, the optimum treatment regimen and route of administration has yet to be defined. In rheumatoid arthritis (RA) patients with a low predonation hematocrit (Hct;or = 39%), intravenous (i.v.) treatment with epoetin alfa 300 IU/kg twice weekly for 3 weeks was the optimum dosage for facilitation of AB donation and minimization of the decrease in Hct prior to elective orthopedic surgery. However, the subcutaneous (s.c.) route of epoetin alfa administration may allow lower dosages of epoetin alfa to be used. Indeed, epoetin alfa 100 IU/kg s.c. twice weekly for 3 weeks (in conjunction with a single i.v. bolus of 200 IU/ kg at the first s.c. dose) was as effective as 300 IU/kg i.v. administered according to the same schedule. The number of AB units collected, total red blood cell (RBC) volume donated, and peak proportion of reticulocytes were similar regardless of the route of administration. Both treatment groups were associated with a significant reduction in allogeneic blood exposure compared with historical controls. Findings consistent to all of these studies were that epoetin alfa was well tolerated, and that i.v. iron supplementation was necessary to maximize its beneficial effects.

Erythropoietin (EPO) plays a central role in the regulation of red blood cell (RBC) production. Since iron is an essential element for erythropoiesis and hemoglobin (Hb) synthesis, its importance is heightened in patients treated with epoetin alfa. Stimulation of erythropoiesis following the administration of epoetin alfa is associated with several changes in iron metabolism; indeed, plasma ferritin levels fall as a result of increased utilization of iron by the expanding erythroid marrow. The administration of epoetin alfa can therefore lead to a state of relative iron deficiency. Thus, iron supplementation is essential to maximize the effect of epoetin alfa-induced erythropoiesis.

The ability of epoetin alfa to increase hematopoiesis in a dose-dependent manner when administered by the intravenous (i.v.) or subcutaneous (s.c.) route has been demonstrated in pharmacokinetic studies in healthy volunteers. Epoetin alfa may therefore be a useful adjunct to autologous blood (AB) donation. By facilitating AB donation, the use of allogeneic blood could be reduced. In patients scheduled to undergo orthopedic surgery, i.v. administration of epoetin alfa 600 IU/kg twice weekly for 3 weeks prior to surgery (in conjunction with oral iron supplementation) significantly increased the number of AB units and total red blood cell (RBC) volume donated and increased the number of patients able to donateor = 4 AB units. However, there was no difference between epoetin alfa and placebo groups with respect to allogeneic blood exposure.

In the setting of elective orthopedic surgery, epoetin alfa has been shown to facilitate autologous blood (AB) donation and reduce allogeneic blood requirements. However, the most appropriate dose and route of administration remains to be defined. A randomized, double-blind, placebo-controlled study was therefore conducted to compare the effect of different subcutaneous (s.c.) doses of epoetin alfa on hemoglobin (Hb) and endogenous erythropoietin (EPO) levels and transfusion requirements in 62 patients donating AB prior to hip surgery. Epoetin alfa (100 or 200 IU/kg s.c. on days -30, -23, -16, and -9 prior to surgery, in conjunction with oral iron supplementation) dose-dependently ameliorated the reduction in Hb levels associated with AB donation. No patient treated with epoetin alfa required allogeneic blood compared with two placebo recipients (one of whom required additional blood because of reoperation). The results of this study confirm that relatively low dosages of epoetin alfa minimize the decrease in Hb levels during AB donation and help to reduce exposure to allogeneic blood in patients scheduled for elective orthopedic surgery.

In patients scheduled to undergo major orthopedic surgery, predonation of autologous blood (AB) has emerged as a means of avoiding subsequent exposure to allogeneic blood. However, patients with a baseline hematocrit (Hct) less than 40% may not be able to donate sufficient AB to fully meet their requirements. In female patients with a baseline Hctor = 39%, epoetin alfa (300 to 600 IU/kg twice weekly for 3 weeks) significantly increased the amount of AB donated prior to elective orthopedic surgery and significantly reduced allogeneic blood requirements in comparison with placebo. Iron availability was a critical factor in determining the response to epoetin alfa. In these patients, parenteral supplementation with iron saccharate significantly increased the amount of AB donated and the volume of red blood cells (RBCs) collected in comparison with oral iron alone. Parenteral iron supplementation, therefore, ensures that sufficient iron is available to meet the demands of epoetin alfa-accelerated erythropoiesis in patients enrolled in an AB donation program.

Intravenous (i.v.) administration of epoetin alfa facilitates the collection of autologous blood (AB) prior to elective orthopedic surgery. However, the optimum dose and dosage regimen remains to be defined. The aim of this multicenter, randomized, placebo-controlled study was to determine the optimum i.v. dose of epoetin alfa (300 IU/kg or 600 IU/kg) that would allow nonanemic patients to donateor = 4 units of AB within 14 to 21 days of elective orthopedic surgery. All patients (n = 103) received oral iron supplementation and were treated with epoetin alfa or placebo three times during 1 week, within 3 weeks of surgery. Eighty patients were evaluable in the efficacy analysis. Compared with placebo, significantly more evaluable patients treated with epoetin alfa were able to donateor = 4 AB units. Furthermore, epoetin alfa dose-dependently increased the preoperative reticulocyte count and attenuated the decrease in hematocrit associated with AB predonation. There was no significant difference with respect to allogeneic blood exposure between the epoetin alfa and placebo treatment groups. In addition, the 600 IU/kg dose was not significantly more effective than the 300 IU/kg dose for most efficacy parameters assessed. Several patients became iron-deficient, suggesting that oral supplementation is not an adequate source of iron in these patients. Epoetin alfa 300 IU/kg therefore appears to be the optimum i.v. dose for facilitating the collection ofor = 4 units of AB within 14 to 21 days of elective orthopedic surgery.

Patients undergoing cancer surgery frequently require blood, and the transfusion of allogeneic blood in these patients has been controversially linked to an increased risk of tumor recurrence. This patient population may therefore benefit from preoperative autologous blood donation (ABD) with or without epoetin alfa therapy, although the precise impact of autologous blood transfusion has not been fully explored. In some trials, preoperative ABD reduced allogeneic blood exposure by 50% in patients undergoing surgery for cancer resection, while, in another study, perioperative treatment with epoetin alfa significantly increased hematocrit (Hct) levels preoperatively and led to a reduction in postoperative allogeneic blood exposure. A combination of epoetin alfa and preoperative ABD seems a reasonable approach to reducing allogeneic blood exposure in patients undergoing cancer surgery.

Several strategies have been investigated as a means of reducing allogeneic blood requirements in patients undergoing surgery, including the perioperative administration of epoetin alfa. In a multicenter, double-blind, placebo-controlled study in 208 patients undergoing elective hip replacement surgery, subcutaneous administration of epoetin alfa (300 IU/kg daily) for 14 or 9 days perioperatively (commencing 10 and 5 days preoperatively, respectively) significantly reduced the incidence of primary outcome events (any allogeneic blood transfusion or a postoperative hemoglobin [Hb] level8.0 g/dL) compared with placebo (P = .003). Furthermore, the transfusion requirements of epoetin alfa-treated patients were significantly lower than those of patients treated with placebo (P = .007). Preoperative and postoperative Hb levels and reticulocyte counts were higher in epoetin alfa-treated patients compared with placebo. Epoetin alfa was well tolerated, and the incidence of deep vein thrombosis (DVT) was not different from that observed in placebo recipients. Thus, perioperative administration of epoetin alfa reduces the allogeneic blood requirements of patients undergoing elective hip replacement surgery and is of particular benefit in the subgroup of patients whose baseline Hb levels are less than 13.5 g/dL.

The development of anemia is one factor that can limit the donation of sufficient autologous blood (AB) to meet a patient's expected blood requirements following elective orthopedic surgery. Two clinical studies have been conducted in nonanemic patients to investigate the use of epoetin alfa as an adjuvant to AB predonation to facilitate AB procurement and minimize the development of anemia. Both studies demonstrated that patients with a normal hematocrit (Hct) can donateor = 3 units of AB prior to surgery. However, treatment with epoetin alfa minimized the decrease in Hct associated with AB donation. While there was a trend toward a reduction in allogeneic blood exposure in patients treated with epoetin alfa, the difference relative to placebo was not significant. This observation may be explained by a limited requirement for blood in this patient population that was met by predonation of 3 AB units. Thus, the use of epoetin alfa as an adjunct to AB predonation is likely to be of most benefit in patients with a normal Hct scheduled for surgical procedures where the expected blood requirements exceed 3 units. In addition, epoetin alfa may enable patients with a low Hct, low body weight, or low predicted blood volume to participate in or to complete an AB donation program, thus reducing the possibility of exposure to allogeneic blood.