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Purpose Epoetin therapy is associated with a slight increase in thromboembolic event (TEE) incidence, although causality is uncertain. This metaanalysis compared TEE incidence in patients with cancer-related anemia treated with epoetin beta versus a control group (placebo or standard treatment) and investigated the impact of hemoglobin (Hb) parameters on thromboembolic risk. Patients and Methods Patients from 9 randomized trials were pooled (epoetin beta group, n = 800; control group, n = 613). Adverse event reports were reviewed for all TEEs recorded during treatment and 28 days thereafter. Thromboembolic event incidence was compared between 2 groups, and standard statistical analyses were conducted to investigate the potential of Hb parameters to modulate thromboembolic risk. Results For epoetin beta, 5.9% of patients (n = 47) experienced ≥ 1 TEE versus 4.2% of controls (n = 26; not significant). Thromboembolic-related mortality rates were 1% in both groups. Thromboembolic event rates in patients stratified by tumor type were consistent with the overall population. For epoetin beta, greater baseline-adjusted Hb area under the concentration-time curve and greater Hb increases during the first 4 weeks of treatment significantly correlated with reduced risk of TEEs. Conversely, treatment in those with higher baseline Hb levels was associated with increased TEE risk. Conclusion When administered in accordance with European Organization for Research and Treatment of Cancer guidelines, epoetin beta did not appear to be associated with increased thromboembolic risk. Although risk of TEEs might be marginally increased in patients with cancer treated with epoetin beta, there is no increased risk of thromboembolic mortality.

Anemia, defined as a lower than normal level of serum hemoglobin, is a common condition among the elderly, and it is often attributed to normal consequences of aging. Anemia in older individuals is frequently undiagnosed and untreated. The impact of untreated anemia can be severe, including increased risk of death, loss of independent functioning, physical decline, falls and fractures, frailty, cognitive decline, cardiovascular events and added economic burden to society. Treatment is available for many types of anemia. For anemia caused by nutritional deficiencies, treatments include simple dietary modifications and/or iron supplementation (e.g., iron, vitamin B12 or folate). Transfusion or erythropoietic agents (e.g., epoetin alfa, epoetin beta and darbepoetin alfa) are used for anemia of chronic diseases and their treatments (e.g., cancer/chemotherapy and chronic kidney disease). Evidence that highlights the benefits of erythropoietic therapies and their use in the treatment of anemia of chronic disease in the elderly is reviewed in this article.

Summary Background and objective: Cost control is becoming an increasingly important consideration for clinicians when planning how to provide the best treatment for anaemic cancer patients. Administration of erythropoiesis stimulating agents (epoetin alpha, epoetin beta and darbepoetin alpha) has become the standard of care for treatment of anaemia in cancer patients. However, only limited information is available on the economic comparability of epoetin alpha, epoetin beta and darbepoetin alpha, and thus this study was conducted to compare cost per patient of each of these agents for anaemic cancer patients. Methods: All prescriptions of the agents over 1 year were analysed by two Austrian regional public health insurance associations and cost per patient for each agent was calculated from invoicing data. Data from the two regions were combined to obtain total mean drug costs per patient per year. Results and discussion: Analyses showed significantly lower costs for epoetin alpha (€2743·27) than for darbepoetin alpha (€3627·98) or epoetin beta (€3292·28): epoetin alpha vs. darbepoetin alpha (P

Chemotherapy-induced anaemia (CIA) is a significant source of morbidity in patients receiving treatment for cancer. There are three products currently available for the treatment of CIA: epoetin alfa, epoetin beta and darbepoetin alfa. Several organisations have published recommendations for the use of these agents. Several randomised, controlled trials have been conducted comparing the most popular dosing regimens of epoetin alfa and darbepoetin alfa, with conflicting results. Information regarding survival and adverse event data related to these agents continues to create debate. This review considers four new agents that are under development for the treatment of CIA.

Background To assess the pharmacokinetic profile and time-course of trough concentrations and hemoglobin levels associated with subcutaneous weekly administration of epoetin beta in lung cancer patients with chemotherapy-induced anemia. Methods Epoetin beta was subcutaneously administered to 15 anemic lung cancer patients once weekly for 8 weeks at doses of 9000, 18,000 and 36,000 IU. Pharmacokinetic parameters (C(max), AUC(inf) and T(1/2)) were determined after the first single dose administration on a model-independent basis, and the relationship between the dose and these parameters was examined for linearity. Results Weekly administration of epoetin beta at 9000, 18,000 and 36,000 IU produced C(max) values of 308 +/- 117 (mean +/- standard deviation), 678 +/- 86.7 and 1316 +/- 766 mIU/ml, and AUC(inf) values of 15,300 +/- 9524, 54,574 +/- 16,265 and 88,501 +/- 55,687 hr mIU/ml, respectively, showing dose-proportional increases. Trough concentrations tended to increase in the presence of severe bone marrow suppression induced by chemotherapy or other factors. Extremely high values were seen in three patients, but there was no apparent trend toward an increase with repeated doses. After 8 weeks' administration at 9000, 18,000 and 36,000 IU, hemoglobin levels were changed by -0.37 +/- 1.26, 2.15 +/- 1.36 and 2.82 +/- 2.17 g/dl, respectively. Conclusions Epoetin beta exhibited linear pharmacokinetics when administered to anemic cancer patients at weekly doses of 9000-36,000 IU and did not cause drug accumulation. Hemoglobin levels increased with weekly doses of 18,000 or 36,000 IU.

Anaemia is a common occurrence in patients with cancer, resulting in symptoms such as fatigue that have a profound impact on quality of life. Anaemia is also associated with poor treatment outcome and overall survival. Epoetin beta, a recombinant human erythropoietin that has the same structure and function as the endogenous hormone, is an effective and safe treatment of cancer-related anaemia. Various studies in patients with solid tumours have shown that this agent effectively increases haemoglobin levels and reduces the need for emergency blood transfusions regardless of the type of concomitantly administered chemotherapy. Epoetin beta also improves the quality of life of anaemic patients with cancer, decreasing fatigue and improving the ability to perform usual daily activities. In addition, epoetin beta prevents severe anaemia and reduces transfusion requirements in patients with a high-risk of developing anaemia during chemotherapy, such as those receiving platinum-based regimens. A meta-analysis of epoetin beta trials showed that epoetin beta has no negative impact on survival or thrombosis-related survival and may reduce the risk of tumour progression in patients with solid or lymphoid malignancies. Another study has shown epoetin beta to be equally effective when administered once weekly or three times weekly. Therefore, epoetin beta offers an effective, safe and convenient therapy for the management of anaemia in patients with cancer.

Anaemia is a common complication of cancer and its treatment. It is also associated with substantial impairment of patient quality of life (QOL). Erythropoietic agents are primary treatment options for cancer-related anaemia (CRA). This review summarises evidence supporting clinical use of the approved erythropoietic agents (epoetin alfa, epoetin beta, darbepoetin alfa). A MEDLINE((R)) search from January 2000 to September 2004 using the search terms "epoetin alfa," "epoetin beta," "darbepoetin alfa," "erythropoietin," and "anaemia" was conducted to identify studies evaluating erythropoietic agents in the treatment of CRA. Recent presentations at professional meetings were also included. Erythropoietic agents increase haemoglobin levels, decrease transfusion requirements, and improve QOL in patients with CRA. However, variations in study design, patient populations, dose titration schedules, and outcome measures among available studies make data comparisons between clinical trials difficult. Head-to-head trials are comparing erythropoietic agents in a randomised setting; other trials are evaluating optimal dosage schedules. Clinically relevant differences among approved erythropoietic agents have not been determined in direct comparative trials; however, epoetin alfa appears to be at least as effective as darbepoetin alfa in treatment of CRA.

Anemia is common in patients with hematologic malignancies, occurring in up to 70% of patients; it is associated with debilitating fatigue and weakness that negatively affect the ability of patients to conduct daily activities and cope with cancer. The severity of anemia in this population is dependent on the specific malignancy diagnosed, extent of disease, and the type and duration of chemotherapy received. Despite the well-known adverse consequences of anemia in patients with cancer, nearly half of patients with hematologic malignancies do not receive treatment for anemia. Clinical trials have demonstrated that treatment with erythropoietic agents (ie, epoetin alfa, epoetin beta, and darbepoetin alfa) in anemic patients with hematologic malignancies significantly increases hemoglobin (Hb) and reduces transfusion requirements. In addition, there is growing evidence to support the role of these agents in alleviating anemia-related symptoms and improving quality of life (QOL). Clinical practice guidelines issued by the National Comprehensive Cancer Network recommend erythropoietic therapy for patients receiving chemotherapy who have a Hb level ≤ 11 g/dL and symptoms or risk factors related to anemia. However, several trials of epoetin alfa therapy in patients with solid tumors or hematologic malignancies and mild-to-moderate anemia (Hb levels ≥ 8 g/dL to ≤ 12 g/dL) receiving chemotherapy have demonstrated a positive effect on hematologic and QOL outcomes. Final results from a recent clinical trial evaluating the effects of earlier treatment with epoetin alfa on hematologic outcomes, QOL, health care resource utilization, and work/productivity in patients with mild anemia will provide further information on the most appropriate strategy for anemia treatment in this population.

Cardiovascular disease (CVD) is a significant complication in chronic kidney disease (CKD) and a major cause of death in dialysis patients. Clinical studies have shown that anaemia is associated with reduced survival in patients with renal disease, heart failure or both. There is also evidence that, even in otherwise healthy individuals, anaemia is independently associated with an increased risk of CVD. The body adapts to anaemia by increasing cardiac output, which may result in cardiac remodelling and progression of left ventricular (LV) growth. Indeed, low haemoglobin (Hb) has been identified as an independent risk factor for LV growth in CKD patients, suggesting that there is a direct link between anaemia and adverse cardiac outcomes. This suggests that correction of anaemia with recombinant human erythropoietin (rhEPO; epoetin) may improve prognosis. Partial correction of anaemia produces partial regression of LV hypertrophy, while complete correction of anaemia can help to prevent LV dilatation in haemodialysis patients with normal LV volumes. Moreover, in non-dialysis patients with advanced CVD, pilot studies showed that a moderate increase in Hb improved cardiac function and reduced hospitalization rates. In addition, consistent epoetin treatment before the start of dialysis was associated with a reduced risk of developing cardiac disease in CKD patients. In contrast, in dialysis patients with advanced cardiac disease, Hb normalization increased mortality risk. Therefore, early correction of anaemia appears important. The Cardiovascular risk Reduction by Early Anaemia Treatment with Epoetin beta (CREATE) study is investigating whether this approach is associated with a measurable reduction in cardiovascular risk.

Many patients with breast cancer suffer from anaemia, as a consequence of the disease itself or its treatment. Anaemia has a negative impact on treatment outcome and overall survival, and affects the quality of life (QoL) of patients with cancer. Previously, cancer-related anaemia was treated with blood transfusion, but this is inconvenient, offers only temporary improvement in haemoglobin (Hb) level and is associated with several risks. Consequently, blood transfusion is usually reserved for patients with severe anaemia (Hb levels

Comparison of the efficacies of erythropoiesis-stimulating agents (ESAs) between different clinical trials is becoming increasingly common, although differences in study design and populations evaluated can have a considerable effect on results. A comparison of two seemingly similar trials of ESAs, one of epoetin alfa and the other of epoetin beta, showed that only 27% of the 115 patients with hematologic malignancies who received epoetin alfa in the epoetin alfa trial met the inclusion criteria for the epoetin beta trial. The mean hemoglobin increase from baseline to week 16 of epoetin alfa therapy in the patients who met these inclusion criteria was 3.3 g/dl. This is substantially higher than the mean hemoglobin increase of 2.2 g/dl from baseline to week 16 of epoetin alfa therapy in the patients who did not meet the epoetin beta study inclusion criteria. These results demonstrate the considerable effects that exclusion criteria can have on trial results and highlight the value of scrutinizing the study design details of clinical trials before comparing outcome data between trials.

Recent studies have suggested that epoetin treatment of anaemia may influence the survival of patients with cancer. We conducted an analysis of long-term survival in patients with lymphoproliferative malignancies treated with epoetin-beta or placebo in a large-scale study. This was a randomized, double-blind trial in which patients with transfusion-dependent anaemia and lymphoproliferative malignancy received epoetin-beta 150 IU/kg or placebo three times weekly for 16 weeks. Long-term survival data were analysed by standard Kaplan-Meier methods and differences between groups were assessed using a log-rank test. The intention-to-treat population consisted of 343 patients (epoetin-beta, n = 170; placebo, n = 173). There were no major differences between the two treatment groups in demographic or clinical characteristics/prognostic factors. A total of 110 (65%) patients died in the epoetin-beta group (censored, n = 60) and 109 (63%) died in the placebo group (censored, n = 64) up to the end of long-term follow up. Kaplan-Meier curves for survival were similar in both groups. Median survival was 17 months with epoetin-beta and 18 months with placebo. A log-rank test indicated no significant difference in survival (P = 0.76). This long-term follow up indicated that epoetin-beta has no significant effect on survival compared to placebo in anaemic patients with lymphoproliferative malignancies.

BACKGROUND Reducing the dosage frequency of subcutaneous epoetin in peritoneal dialysis (PD) patients is convenient and should improve patient satisfaction and, possibly, compliance. We investigated if a weekly dosage of epoetin beta in PD patients safely maintained haemoglobin (Hb) concentrations equivalent to those obtained with previous twice- or thrice-weekly administration. In addition, we investigated if a fortnightly dosage of epoetin beta was safe and as effective as previous weekly administration. METHODS After a 4 week run-in period, PD patients were switched to either weekly or fortnightly epoetin beta administration, depending on their previous treatment schedules, for 25 weeks. RESULTS The per-protocol cohort included 128 patients, of whom 54 received epoetin beta once weekly and 74 once fortnightly. The mean change in Hb concentration from baseline over weeks 13-25 and the 90% confidence intervals (CIs) remained within the target range (10-12 g/dl) and specified equivalence (+/-0.75 g/dl) limits in the weekly (-0.34 g/dl; 90% CI: -0.14 to -0.54 g/dl) and fortnightly (-0.39 g/dl; 90% CI: -0.24 to -0.55 g/dl) cohorts. The mean change from baseline in the epoetin beta dose was 1.4 IU/kg/week (90% CI: -3.8 to 6.6 IU/kg/week; 2%) in the weekly cohort and 4.4 IU/kg/week (90% CI: 1.7-7.2 IU/kg/week; 13%) in the fortnightly cohort. Both treatment regimens were well tolerated. CONCLUSIONS In stable PD patients switched from twice- or thrice-weekly to weekly epoetin beta treatment, Hb concentrations could be maintained within the specified range over 25 weeks without significant change in their mean epoetin beta doses. In patients switched from weekly to fortnightly treatment, Hb concentrations could also be maintained over 25 weeks. There was a small increase in the mean dose during this period, but >/=50% of patients could be maintained without dose increase. Reducing dosage frequency may improve compliance in PD patients who self-administer their epoetin.

Anaemia is frequently found in patients with chronic heart failure (CHF) and has been associated with an increase in mortality and morbidity, impaired cardiac and renal function and a reduced quality of life (QoL) compared with non-anaemic CHF patients. Correction of anaemia with recombinant human erythropoietin (epoetin) has been associated with an improvement in CHF in both controlled and uncontrolled studies. The present study describes our findings in a series of 78 consecutive patients with symptomatic CHF and anaemia (haemoglobin (Hb) level 90% of the patients had concomitant mild-to-moderate chronic kidney disease at baseline and study end (CKD), as defined by the accepted diagnostic criterion of a CCr Conclusions: The correction of the anaemia with epoetin beta together with initial intravenous iron supplementation, resulted in significant improvements in NYHA class and cardiac function, and a reduction in hospitalization rate. Moreover, renal function was maintained stable in most patients.

Anaemia has a detrimental impact on quality of life and it is important that this condition is recognised and treated in patients with cancer. Epoetin beta is an effective and well-tolerated treatment of anaemia in patients with a wide range of solid and haematological malignancies. A study in patients with lymphoid malignancies confirms that epoetin beta is equally effective at the same overall weekly dose (30,000 IU weekly) when given once-weekly or three-times weekly. This once-weekly regimen has also proved effective in patients with solid tumours. Once-weekly treatment is more convenient for the patient, potentially improving compliance and is associated with reduced hospital administration costs. The majority of patients with cancer will respond to epoetin therapy with an increase in haemoglobin levels. However, it is of value to identify those patients who are likely to respond, so that cost-effectiveness can be improved. Despite much research into potential predictive factors, follow-up studies are required and clinical judgement remains key to managing the anaemia of cancer. In addition, studies suggest that intravenous iron supplementation can improve response to epoetin therapy in patients with functional iron deficiency. Epoetin beta offers an effective, safe and convenient therapy for the management of anaemia in patients with cancer. Ongoing studies are expected to lead to a greater understanding of the optimal use of epoetins in cancer-related anaemia.

Anemia has a high prevalence in patients with cancer. Its frequency and severity depend on tumor type, tumor stage, duration of disease, and treatment status. The etiology of cancer-related anemia is multifactorial and includes myelotoxicity of treatment, bone marrow infiltration, impaired erythropoietin production, blood loss, and the anemia of chronic disease. Anemia affects health-related quality of life (QOL) and may impact on tolerance or even outcome of anticancer therapy. Despite its high prevalence and impact on QOL, anemia is often under-recognized and under-treated. Treatment should correct etiologic factors, whenever possible. Symptomatic treatments are red blood cell transfusions and administration of erythropoietic growth factors. Transfusions result in rapid improvement of anemia-related symptoms but are usually only given to patients with moderate to severe anemia. Administration of epoetins (epoetin alfa, epoetin beta) or darbepoetin alfa increases hemoglobin levels, reduces the need for blood transfusions, and improves QOL in patients with cancer-related anemia. Trials determining the exact association of anemia with both response to chemo(radio)therapy and survival are ongoing. Physicians should be aware of the clinical relevance of and treatment options for anemia in cancer patients.

Anemia develops in most persons with progressive chronic kidney disease. When it becomes severe, the administration of erythropoiesis-stimulating agents (ESAs) is generally required, along with the repletion of iron stores and the correction of other causes of anemia. The introduction of ESAs 30 years ago markedly improved the lives of many patients with chronic kidney disease, who until then had severe, often transfusion-dependent anemia.1 Two types of recombinant human erythropoietin (epoetin alfa and epoetin beta) have been available since ESAs first came into use; both types are highly effective but short-acting (approved for dosing three times a week). Subsequently, two . . .

Lung cancer is associated with the one of the highest rates of anaemia of all solid tumours. Anaemia has a negative impact on treatment outcome and overall survival of patients with cancer and also affects their quality of life. Recombinant human erythropoietin (epoetin) provides an effective and safe treatment of cancer-related anaemia without the risks associated with red blood cell transfusion. Epoetin therapy increases haemoglobin levels, reduces the need for blood transfusions and improves the quality of life of patients with anaemia and lung cancer. Epoetin beta is also effective for preventing the development of anaemia and decreasing transfusion requirements when administered with concomitant platinum-based chemotherapy. In addition, preliminary evidence suggests that treatment with erythropoietic agents may improve survival of lung cancer patients, although this needs to be verified in prospective clinical trials specifically designed to evaluate survival. Therefore, early initiation of epoetin beta to prevent chemotherapy-associated anaemia may represent the best strategy for patients with lung cancer being treated with chemotherapy.

Anaemia is frequently diagnosed in patients with cancer, yet it is difficult to identify a single cause due to its multifactorial aetiology. We conducted a systematic literature review (1996-2003) to produce evidence-based guidelines on the use of erythropoietic proteins in anaemic patients with cancer (see ). Level I evidence exists for a positive impact of erythropoietic proteins on haemoglobin (Hb) levels when administered to patients with chemotherapy-induced anaemia or anaemia of chronic disease, when used to prevent cancer anaemia, in patients undergoing cancer surgery and following allogeneic bone marrow transplantation. The Hb level at which erythropoietic protein therapy should be initiated is difficult to determine as it varied between studies; a large number of Level I studies in patients with chemotherapy-induced anaemia or anaemia of chronic disease enrolled patients with a Hb concentration/=105 g/L, but none compared the effect of different baseline Hb levels on the response to treatment. Similarly, several studies defined the target Hb concentration as 120-130 g/L following treatment with erythropoietic proteins, but none specifically addressed the correlation between target Hb level and clinical benefit in a randomised fashion. Level I evidence shows that red blood cell (RBC) transfusion requirements are significantly reduced with erythropoietic protein therapy in patients with chemotherapy-induced anaemia or when used to prevent cancer anaemia (approximately 20% reduction compared with controls). We found indirect Level I and III evidence that patients with chemotherapy-induced anaemia or anaemia of chronic disease initially classified as non-responders to standard doses proceed to respond to treatment following a dose increase (absolute increases in response rate ranged from 8% to 18%). However, none of these studies examined the effect on response rates of a longer treatment period at the lower dose, or performed a randomised comparison of a dose increase versus an unchanged dose. There is Level I evidence to show that quality-of-life (QOL) is significantly improved in patients with chemotherapy-induced anaemia and in those with anaemia of chronic disease, particularly in patients achieving a Hb response to erythropoietic protein therapy. There are insufficient data to determine the effect on survival following treatment with erythropoietic proteins in conjunction with chemotherapy or radiotherapy. There is Level I evidence that dosing of erythropoietic proteins less frequently than three times per week (TIW) is efficacious when used to treat chemotherapy-induced anaemia or prevent cancer anaemia. There is Level III evidence that initial doses of erythropoietic proteins considered to be higher than current standard practice produce higher haematological responses in patients with chemotherapy-induced anaemia or anaemia of chronic disease. Level I evidence demonstrates that several baseline patient parameters (e.g., low endogenous erythropoietin [EPO] concentration, age60 years, Hb concentration/=90 g/L) impact upon the response to erythropoietic proteins when used to treat chemotherapy-induced anaemia or prevent cancer anaemia. Evidence indicates that endogenous EPO concentration impacts on response in patients with lymphoproliferative malignancies, but is not a valid parameter in patients with solid tumours. There is Level I evidence that fixed doses of erythropoietic proteins can be used at the start of therapy to treat patients with chemotherapy-induced anaemia, but maintenance doses should be titrated individually. There is no evidence that pure red cell aplasia (PRCA) occurs following treatment with erythropoietic proteins in patients with chemotherapy-induced anaemia or when used prophylactically in patients with cancer. There is Level I evidence that the risk of thromboembolic events and hypertension are slightly elevated in patients with chemotherapy-induced anaemia receiving erythropoietic proteins. Level I evidence supports the effectiveness of erythropoietic proteins to prevenroteins to prevent anaemia in non-anaemic cancer patients receiving chemotherapy or radiotherapy or in those undergoing cancer surgery. However, these are non-licensed indications and we do not currently recommend the prophylactic use of erythropoietic proteins to prevent anaemia in patients who have normal Hb values at the start of treatment. Additional trials are warranted, especially on the issues of iron replacement and cost-effectiveness of erythropoietic protein therapy, as well as on tumour response/progression and survival.

The European Cancer Anaemia Survey (ECAS) was conducted to prospectively evaluate the prevalence, incidence and treatment of anaemia (haemoglobin

Most, if not all, nephrologists are aware of the explosion of epoetin-associated cases of pure red cell aplasia, particularly in Europe, from 1998 onwards [1–4]. The dramatic increase in reported cases was largely associated with a particular brand of epoetin alfa (Eprex; Erypo) [5], but a few cases have also been reported with epoetin beta [3]. Epoetin-associated pure red cell aplasia is characterized by a sudden loss of response to the drug, with the haemoglobin falling to 5 or 6 g/dl, and requiring regular blood transfusions to maintain a more respectable haemoglobin. The white cell and platelet counts are characteristically normal, but there is usually a profound decrease in circulating reticulocytes (to

BACKGROUND Various studies have demonstrated the prognostic significance of the pretherapeutic blood hemoglobin concentration for patients with head and neck cancer following surgery or primary definitive or adjuvant radio- or radiochemotherapy. It was the aim of this study to evaluate whether the prognosis of these patients might be improved when correcting decreased pretherapeutic hemoglobin values by administering erythropoietin. METHOD In a prospective placebo-controlled double-blind study (Cochrane "evidence-based medicine" level Ib) the effect of erythropoietin was analyzed in patients with locally advanced head or neck tumours with low blood hemoglobin values (women: 60 following primary definite or adjuvant radiotherapy (up to 70 Gy). The time to local tumour progression and survival was evaluated. Kaplan-Maier estimates were applied and, the relative risk of well-known prognostic factors tested for with a Cox Proportional Hazards model. RESULTS 157 patients of the Freiburg University ENT-clinic were recruited from 1997 to 2001. Study conduct was performed according to the GCP guidelines. A rapid increase of the blood hemoglobin value happened during the first five weeks of treatment under epoetin beta. Placebo patients experienced only minor changes of the hemoglobin value. Following adjuvant radiotherapy local tumour control probability at two years was 68 % +/- 7 % and 72 +/- 7 % for placebo and epoetin beta patients, respectively (p = 0.64). Patients who had undergone primary definite radiation experienced a local control probability of 36 % +/- 11 % in the placebo arm after two years, compared to epoetin beta with 23 % +/- 11 % (p = 0.05). CONCLUSION Epoetin beta resulted in prompt and stable correction of blood hemoglobin values in anemic patients with advanced head or neck tumours, but tumour control and survival was impaired particularly in patients with a high tumour burden.

Anaemia is a key component of diabetic nephropathy, but its importance has only recently been recognised. Recombinant human erythropoietin (epoetin) is an established treatment for renal anaemia, and may help to reduce complications associated with diabetic nephropathy, such as cardiovascular disease. The limited experience with the use of epoetin in this patient group prompts the urgent need for clinical data on anaemia correction in early diabetic nephropathy, particularly with regard to benefits on cardiovascular risk reduction. The Anaemia CORrection in Diabetes (ACORD) study will investigate the effects of anaemia correction on cardiac structure and function in patients with early diabetic nephropathy. This 15-month multicentre study will recruit 160 adult patients with diabetes, mild or moderate chronic kidney disease (with creatinine clearanceor=30 ml/min at screening) and moderate anaemia (haemoglobin [Hb], 10.5-13.0 g/dl). Patients will be randomised to one of two groups: the early treatment group will receive subcutaneous epoetin beta (NeoRecormon) at study entry to maintain target Hb levels of 13-15 g/dl, while the control group will reflect current practice and will not receive epoetin therapy until Hb levels decline below 10.5 g/dl. The primary efficacy variable, change in left ventricular mass index, will be evaluated at 15 months following randomisation; secondary efficacy variables will include changes in cardiac structure and function over the study period. The ACORD study should provide valuable information on the benefits of anaemia correction in patients with early diabetic nephropathy. The study will also increase awareness of the importance of treating anaemia associated with diabetes.

Anaemia develops in most patients undergoing cancer therapy and invariably induces fatigue, which is a major determinant of QOL. Blood transfusions are reserved for patients with severe anaemia, since blood is a scarce resource and provides a short-lived benefit. Epoetins are recombinant proteins capable of alleviating therapy-related anaemia in 40-60% of cancer patients. The number of patients needed to be treated with epoetins to avoid the transfusion of one unit of blood ranges from 2.6 to 5.2; however, the absolute risk reduction depends on patients' characteristics and dose-escalation. The ratio between acquisition costs of epoetins and blood transfusion requirement is very high; thus, many thousands of dollars needs to be spent on epoetins to save 1 blood unit. Despite this, epoetins have been widely adopted by industrialised countries, where cancer patients are about 2% of the total population. The resulting budget impact of epoetins can be calculated at about 10% of the overall direct cost for cancer care, and it is expected to continue growing by about 20% each year, due to the expanding cancer population and the intensification of cancer therapies. The economic burden of epoetins needs to be weighed against the improvement of patients' QOL and society's willingness to pay for a non-life-saving therapy. All published economic evaluations of epoetins invariably report that this supportive therapy is not cost effective. Society should be made aware of the opportunity cost of treatments and should be allowed to elicit preferences for healthcare interventions and prioritisation criteria. In the near future we expect that a wider range of epoetins, drug patent expiry, a more appropriate patient selection criteria and an improved dosage schedule may help increase the efficiency of cancer-related anaemia management.

UNLABELLED Epoetin beta (NeoRecormon) is a recombinant form of erythropoietin. It increases reticulocyte counts, haemoglobin (Hb) levels and haematocrit. Epoetin beta administered subcutaneously once weekly corrected anaemia and had equivalent efficacy to that of epoetin beta administered three times weekly in patients with haematological malignancies. Subcutaneous epoetin beta reduced transfusion requirements and increased Hb levels versus no treatment in patients with solid tumours and chemotherapy-induced anaemia in nonblind, randomised trials. Anaemia and quality of life were also improved, and blood transfusion requirements were reduced to a significantly greater extent than placebo or no treatment (with supportive blood transfusion) in patients with haematological malignancies. Most patients were receiving chemotherapy. Subcutaneous epoetin beta was well tolerated by patients with cancer; adverse events with the drug occurred with a similar incidence to those with placebo or no treatment (with supportive blood transfusion). Hypertension was relatively uncommon with epoetin beta in clinical trials. Patients with haematological malignancies and a baseline platelet count > or =100 x 10(9)/L, Hb levels of > or =9 g/dL or lower erythropoietin levels have demonstrated better responses to epoetin beta than other patients in clinical trials. However, neither baseline erythropoietin level nor the observed to predicted ratio of erythropoietin levels correlated with the response to epoetin beta in patients with solid tumours and chemotherapy-induced anaemia. A decrease of

Anaemia is associated with poor cancer control, particularly in patients undergoing radiotherapy. We investigated whether anaemia correction with epoetin beta could improve outcome of curative radiotherapy among patients with head and neck cancer.We did a multicentre, double-blind, randomised, placebo-controlled trial in 351 patients (haemoglobin120 g/L in women or130 g/L in men) with carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received curative radiotherapy at 60 Gy for completely (R0) and histologically incomplete (R1) resected disease, or 70 Gy for macroscopically incompletely resected (R2) advanced disease (T3, T4, or nodal involvement) or for primary definitive treatment. All patients were assigned to subcutaneous placebo (n=171) or epoetin beta 300 IU/kg (n=180) three times weekly, from 10-14 days before and continuing throughout radiotherapy. The primary endpoint was locoregional progression-free survival. We assessed also time to locoregional progression and survival. Analysis was by intention to treat.148 (82%) patients given epoetin beta achieved haemoglobin concentrations higher than 140 g/L (women) or 150 g/L (men) compared with 26 (15%) given placebo. However, locoregional progression-free survival was poorer with epoetin beta than with placebo (adjusted relative risk 1.62 [95% CI 1.22-2.14]; p=0.0008). For locoregional progression the relative risk was 1.69 (1.16-2.47, p=0.007) and for survival was 1.39 (1.05-1.84, p=0.02).Epoetin beta corrects anaemia but does not improve cancer control or survival. Disease control might even be impaired. Patients receiving curative cancer treatment and given erythropoietin should be studied in carefully controlled trials.

Although erythropoietin (EPO) deficiency is not responsible for the anemia of myelodysplasia, pharmacologic doses of recombinant human EPO (rHuEPO, epoetin alfa) and epoetin beta have been studied extensively as treatment of anemia in myelodysplastic syndrome (MDS). When an epoetin is used as a single growth factor in patients with MDS, clinically meaningful responses occur in only a small minority of patients (16%). Patients who are transfusion-dependent are less likely to respond than patients who are transfusion-independent. Serum EPO level has a weak association with response rate and cannot be used to select or exclude patients from empirical trials of epoetins. The dose schedule commonly used as initial treatment 40,000 U/week, is consistent with clinical observations, but an optimal dose schedule has not been determined. The combination of an epoetin and granulocyte colony-stimulating factor (G-CSF) produces a higher erythroid response rate (36%) than the regimen of epoetin alone, but we have found no randomized trial data to support this point. However, the design of the clinical trials, which included adding G-CSF after epoetin alone had failed, supports the hypothesis that combined use of growth factors, rather than just higher doses of epoetin, is responsible for the high response rate observed with the combination of epoetin and G-CSF. Unfortunately, as in the case of epoetin alone, patients who are transfusion-dependent (> or =2 U red blood cells/month) are less likely to respond to combined growth factor therapy. Although the ability of patients with MDS to show an erythroid response to epoetin is of biologic interest, because of high costs and the limited response rate in transfusion-dependent patients, epoetin therapy, with or without G-CSF, cannot be regarded as a definitive therapy for the anemia of MDS.

Multiple myeloma (MM) is commonly associated with anemia. Several causes have been implicated, but anemia of chronic disease with inadequate erythropoietin (EPO) production related to the inflammatory cytokines appears to be of utmost importance. Interleukin-1 and tumor necrosis factor are capable of suppressing erythropoiesis. Anemia has broad implications. First, the low hemoglobin and hematocrit are associated with poor quality of life and performance and affect daily activity. Second, anemia has an impact on the cardiovascular system. Considering that most MM patients are elderly, this may be even more important. Anemia has been shown to induce or aggravate hypoxia and ischemic complications. Third, anemia has been shown to be a poor prognostic factor in MM. Traditionally, patients with symptomatic anemia were treated with red blood cell transfusions as needed. The introduction of epoetin alfa and epoetin beta into clinical practice opened new avenues to these patients. The administration of epoetins to patients with MM and anemia have been shown to be very useful. Several studies in more than 1000 patients have demonstrated a high response rate (range, 25%-85%; mean, 60%). This response is characterized by a significant increase of hemoglobin, hematocrit, and the number of red blood cells together with a reduction in the blood transfusion requirements. This is also associated with an improved quality of life. Although there is no complete agreement about the role of pretreatment serum EPO levels, many investigators believe that relatively low levels may help in predicting response, thereby limiting the number of potential candidates to receive this expensive therapy. The epoetins are safe and well tolerated with minimal toxicity; however, some concern has been recently raised regarding several dozen patients who developed pure red cell aplasia while on epoetin therapy. However, this adverse effect appears to be extremely rare. Recent data suggest that EPO has additional biologic effects, such as longer-than-expected survival in patients with MM. This observation is further supported by animal studies, demonstrating an antimyeloma effect of EPO in mice models. This effect has been shown to be immune mediated. If these exciting data are confirmed in future clinical trials, this may have significant implications on the treatment of MM.

This phase 3, randomized, double-blind, placebo-controlled study was designed to evaluate the efficacy and safety of darbepoetin alfa in anaemic patients with lymphoproliferative malignancies. Patients (n = 344) with lymphoma or myeloma received darbepoetin alfa 2.25 microg/kg or placebo s.c., once weekly for 12 weeks. The percentage of patients achieving a haemoglobin response was significantly higher in the darbepoetin alfa group (60%) than in the placebo group (18%) (P < 0.001), regardless of baseline endogenous erythropoietin level. However, increased responsiveness was observed in patients with lower baseline erythropoietin levels. Darbepoetin alfa also resulted in higher mean changes in haemoglobin than placebo from baseline to the last value during the treatment phase (1.80 g/dl vs 0.19 g/dl) and after 12 weeks of treatment (2.66 g/dl vs 0.69 g/dl). A significantly lower percentage of patients in the darbepoetin alfa group received red blood cell transfusions than in the placebo group (P < 0.001). The efficacy of darbepoetin alfa was consistent for patients with lymphoma or myeloma. Improvements in quality of life were also observed with darbepoetin alfa. The overall safety profile of darbepoetin alfa was consistent with that expected for this patient population. Darbepoetin alfa significantly increased haemoglobin and reduced red blood cell transfusions in patients with lymphoproliferative malignancies receiving chemotherapy.

Summary. Epoetin beta, three-times weekly (t.i.w.), is effective in reversing anaemia in lymphoproliferative disorders. The current study investigated whether an epoetin beta dose of 30 000 IU given subcutaneously once weekly (q.w.) was at least as effective as 10 000 t.i.w. administration in anaemic patients with lymphoproliferative malignancy and defective endogenous erythropoietin (Epo) production. Overall, 241 anaemic patients with multiple myeloma, low-grade non-Hodgkin's lymphoma or chronic lymphocytic leukaemia, all with serum Epo values ≤ 100 mU/ml, were randomized to receive the q.w. (n = 119) or t.i.w. (n = 122) regimen for 16 weeks. The primary efficacy criterion, i.e. the time-adjusted area under the haemoglobin–time curve from weeks 5–16, was comparable between the q.w. and t.i.w. groups [difference = − 0·20 g/dl (90% confidence interval − 0·52–0·11)]. Moreover, response rates were high and similar in both arms (72%vs 75%, q.w. and t.i.w. groups respectively). Baseline serum Epo was predictive of response: the lower serum Epo, the higher the likelihood of response (P = 0·002). Thus, epoetin beta administered q.w. is an effective and convenient treatment for anaemia in patients with lymphoproliferative disorders. Tailoring this treatment modality to subjects with defective endogenous Epo production represents a rational use of epoetin from both a medical and a community perspective.

This open-label, prospective study was conducted to compare the impact of epoetin beta vs standard care on quality of life (QoL) in anaemic patients with lymphoid or solid tumour malignancies. A total of 262 anaemic patients (haemoglobin [Hb]or=11 g dl(-1)) were randomised to a 12-week treatment with s.c. epoetin beta (initial dose 150 IU kg(-1) three times weekly) or standard care. Transfusions were recommended for both groups at an Hb threshold of 8.5 g dl(-1). The primary efficacy variables were improvement in QoL as measured using the Short-Form-36 physical component summary (SF-36 PCS) score and the Functional Assessment of Cancer Therapy fatigue and anaemia subscales (FACT-F and FACT-An). A visual analogue scale (VAS) was also used as a global QoL measure. Clinical response was defined as aor=2 g dl(-1) increase in Hb level without need of transfusion after the initial 4 weeks of treatment. Baseline to final visit changes in SF-36 PCS, FACT-F and VAS scores were significantly greater with epoetin beta than with standard care (P0.05); changes in FACT-An subscale score tended to be greater with epoetin beta (P=0.076). Epoetin beta significantly increased Hb concentrations relative to standard care (responders: 47% vs 13%; P0.001). Levels of endogenous erythropoietin50 mIU ml(-1) were significantly predictive of response (OR 2.496, 95% CI: 1.21-5.13). Epoetin beta therapy significantly improves QoL compared with standard care in anaemic patients with solid tumours and lymphoid malignancies.

L'erythropoietine humaine recombinante (alpha et beta) est utilisee depuis la fin des annees 80 par les athletes dans le but d'augmenter le transport d'oxygene, le pouvoir aerobie, et de ce fait la performance. D'autres molecules apparentees comme la darbepoietine ont ete detournees de leur usage medical a des fins de dopage par certains sportifs. Nous nous proposons, tout d'abord, de presenter les formes d'erythropoietine existantes ainsi que toutes les molecules et methodes susceptibles, a plus ou moins long terme, d'augmenter la production d'erythropoietine ou de mimer son action. Nous exposerons, ensuite, les methodes directes et indirectes de depistage d'un dopage a l'erythropoietine. Enfin, nous discuterons la pertinence de leur utilisation et leur possible application au depistage d'un dopage par de nouvelles formes d'erythropoietine ou par des molecules mimant son action.

Background: The ability to reduce the administration frequency of subcutaneous (SC) epoetin could provide benefits. This multicenter open-label study investigated the therapeutic equivalence of SC epoetin β once-weekly and thrice-weekly administration regimens in maintaining anemia correction in stable hemodialysis (HD) patients. Methods: One hundred seventy-three patients were randomly assigned to either once-weekly epoetin β (n = 84) or their original thrice-weekly regimen (n = 89) for 24 weeks. All patients were administered intravenous iron supplementation, as required. Results: The per-protocol analysis included 134 patients (69 patients, once-weekly group; 65 patients, thrice-weekly group). Mean hematocrits in both groups remained stable throughout the study. The difference in mean time-adjusted area under the curve for hematocrits between the once-weekly and thrice-weekly groups (−0.54 vol%) and 90% confidence intervals (−1.27 to 0.19) were within the prespecified equivalence range (−2 to +2 vol%). There was no significant change in epoetin β dose during the study. The ratio of mean weekly epoetin β doses in the once-weekly and thrice-weekly groups (1.11) and 90% confidence interval (0.99 to 1.23) also remained within the prespecified range (0.8 to 1.25). Intention-to-treat analysis results were similar to per-protocol analysis results. Both regimens were well tolerated. Conclusion: Once-weekly and thrice-weekly SC epoetin β administrations are statistically equivalent in terms of maintaining both stable hematocrits and epoetin β dose requirements in HD patients. These findings may improve compliance among patients. © 2002 by the National Kidney Foundation, Inc.

Within a period of three years, we identified 13 patients in whom pure red-cell aplasia developed during treatment with recombinant human erythropoietin (epoetin). We investigated whether there was an immunologic basis for the anemia in these patients.Serum samples from the 13 patients with pure red-cell aplasia were tested for neutralizing antibodies that could inhibit erythroid-colony formation by normal bone marrow cells in vitro. The presence of antierythropoietin antibodies was identified by means of binding assays with the use of radiolabeled intact, deglycosylated, or denatured epoetin.Serum from all 13 patients blocked the formation of erythroid colonies by normal bone marrow cells. The inhibition was reversed by epoetin. Antibodies from 12 of the 13 patients bound only conformational epitopes in the protein moiety of epoetin; serum from the remaining patient bound to both conformational and linear epitopes in erythropoietin. In all the patients, the antibody titer slowly decreased after the discontinuation of treatment with epoetin.Neutralizing antierythropoietin antibodies and pure red-cell aplasia can develop in patients with the anemia of chronic renal failure during treatment with epoetin.

Immunosuppressive treatment using antithymocytic globulin (ATG) is the treatment of choice for severe aplastic anemia patients [1, 2]. Iron chelation therapy is also effective for patients with frequent blood transfusions [3–5]. However, the effects of these treatments on hemodialysis patients have not been reported. Here, we present a case of severe aplastic anemia on hemodialysis, treated with immunosuppressive and iron chelation therapy. A 49-year-old male presented in December 2007 with fever and pancytopenia. He required regular hemodialysis following history of chronic renal failure 25 years earlier, and had also been treated with recombinant epoetin beta. Laboratory studies revealed a white blood cell count of 1.2 9 10/ll, neutrophil cell count of 468/ll, platelet count of 0.9 9 10/ll, hemoglobin concentration of 5.4 g/dl, and reticulocytes at only 0.9 9 10/ll. Bone marrow biopsy revealed severe hypoplasia. He was diagnosed with severe aplastic anemia, and required frequent transfusions of PC and RBC to maintain a 2 9 10/ll platelet level and 8.0 g/dl hemoglobin concentration. He was given the antibiotic, meropenem, for febrile neutropenia, which rapidly controlled his fever. The same drug, epoetin beta, was continued for treatment. Cyclosporin A and granulocyte colony-stimulating factor (G-CSF) were given as the first therapy for severe aplastic anemia, but his bone marrow remained hypoplastic. Horse ATG was added at a dose of 15 mg/kg for 5 days. Methylprednisolone was used at a dose of 2 mg/kg/day for 5 days, and then tapered off. The only adverse event was a grade 2 allergic reaction. His hematopoietic system recovered slightly, and G-CSF was lowered, but transfusion frequency could not be reduced. An anabolic steroid was added, but yielded no improvement. Then, 8 months after the first ATG, a second rabbit ATG was given at a dose of 5 mg/kg for 5 days. Methylprednisolone was given concomitantly, and no significant adverse event was seen, except an acute allergic reaction. Total red-blood cell transfusion volume was over 80 Japanese units, so deferasirox was given. Bone marrow biopsy revealed a moderate number of positive granules on iron staining, which were not observed at the initial examination. The initial dose was 10 mg/kg/day, due to renal failure, but the serum ferritin level remained above 3000 ng/ml. The dose was increased to 20 mg/kg/day. Six months later, the serum ferritin level was below 1000 ng/ml. Transfusion frequency was reduced. One year later after the second ATG therapy, he became transfusionfree (Fig. 1). Bone marrow biopsy revealed the recovery of hematopoiesis, but on iron staining, a moderate number of positive granules were still observed. During this course of treatments, he continued dialysis three times per week in an open space, and bacterial infection was not a threat. J. Hiraga (&) R. Sakemura S. Mizuno Department of Hematology, Toyota Memorial Hospital, 1-1 Heiwa-cho, Toyota 471-8513, Japan e-mail: junji_hiraga@mail.toyota.co.jp

Background Several erythropoiesis-stimulating agents (ESAs) are available for treating anaemia in people with chronic kidney disease (CKD). Their relative efficacy (preventing blood transfusions and reducing fatigue and breathlessness) and safety (mortality and cardiovascular events) are unclear due to the limited power of head-to-head studies. Objectives To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, or methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs, against each other, placebo, or no treatment) to treat anaemia in adults with CKD. Search methods We searched the Cochrane Renal Group's Specialised Register to 11 February 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. Selection criteria Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, or biosimilar ESA) with another ESA, placebo or no treatment in adults with CKD and that reported prespecified patient-relevant outcomes were considered for inclusion. Data collection and analysis Two independent authors screened the search results and extracted data. Data synthesis was performed by random-effects pairwise meta-analysis and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore for sources of heterogeneity or inconsistency. We assessed our confidence in treatment estimates for the primary outcomes within network meta-analysis (preventing blood transfusions and all-cause mortality) according to adapted GRADE methodology as very low, low, moderate, or high. Main results We identified 56 eligible studies involving 15,596 adults with CKD. Risks of bias in the included studies was generally high or unclear for more than half of studies in all of the risk of bias domains we assessed; no study was low risk for allocation concealment, blinding of outcome assessment and attrition from follow-up. In network analyses, there was moderate to low confidence that epoetin alfa (OR 0.18, 95% CI 0.05 to 0.59), epoetin beta (OR 0.09, 95% CI 0.02 to 0.38), darbepoetin alfa (OR 0.17, 95% CI 0.05 to 0.57), and methoxy polyethylene glycol-epoetin beta (OR 0.15, 95% CI 0.03 to 0.70) prevented blood transfusions compared to placebo. In very low quality evidence, biosimilar ESA therapy was possibly no better than placebo for preventing blood transfusions (OR 0.27, 95% CI 0.05 to 1.47) with considerable imprecision in estimated effects. We could not discern whether all ESAs were similar or different in their effects on preventing blood transfusions and our confidence in the comparative effectiveness of different ESAs was generally very low. Similarly, the comparative effects of ESAs compared with another ESA, placebo or no treatment on all-cause mortality were imprecise.All proprietary ESAs increased the odds of hypertension compared to placebo (epoetin alfa OR 2.31, 95% CI 1.27 to 4.23; epoetin beta OR 2.57, 95% CI 1.23 to 5.39; darbepoetin alfa OR 1.83, 95% CI 1.05 to 3.21; methoxy polyethylene glycol-epoetin beta OR 1.96, 95% CI 0.98 to 3.92), while the effect of biosimilar ESAs on developing hypertension was less certain (OR 1.18, 95% CI 0.47 to 2.99). Our confidence in the comparative effects of ESAs on hypertension was low due to considerable imprecision in treatment estimates. The comparative effects of all ESAs on cardiovascular mortality, myocardial infarction (MI), stroke, and vascular access thrombosis were uncertain and network analyses for major cardiovascular events, end-stage kidney disease (ESKD), fatigue and breathlessness were not possible. Effects of ESAs on fatigue were described heterogeneously in the available studies in ways that were not useable for analyses. Authors' conclusions In the CKD setting, there is currently insufficient evidence to suggest the superiority of any ESA formulation based on available safety and efficacy data. Directly comparative data for the effectiveness of different ESA formulations based on patient-centred outcomes (such as quality of life, fatigue, and functional status) are sparse and poorly reported and current research studies are unable to inform care. All proprietary ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, and methoxy polyethylene glycol-epoetin beta) prevent blood transfusions but information for biosimilar ESAs is less conclusive. Comparative treatment effects of different ESA formulations on other patient-important outcomes such as survival, MI, stroke, breathlessness and fatigue are very uncertain.For consumers, clinicians and funders, considerations such as drug cost and availability and preferences for dosing frequency might be considered as the basis for individualising anaemia care due to lack of data for comparative differences in clinical benefits and harms.

Background/Aims: We investigated the method of switching EPO to CERA that does not cause a decrease in the Hb level. Methods: Fifty EPO-treated patients were randomly divided into two groups in which CERA was administered every two weeks (Q2W) or every four weeks (Q4W). After 8 weeks of treatment, the frequency of administration was changed to Q4W in the former. Follow-up was performed for 24 weeks. Results: There was no difference in the Hb level between the two groups until 6 weeks. In the Q2W group, the Hb maintained a stable level throughout a study period. However, in the Q4W group, the Hb level was significantly lower than in the Q2W group at weeks 9, 11, and 13. Conclusion: EPO switching to CERA without a decrease in the Hb level could be achieved by administering CERA every two weeks, but not every four weeks, for a specific period after switching. © 2014 S. Karger AG, Basel

Note: Values for continuous variables given as mean 6 standard deviation or median [interquartile range]; values for categorical variable, as number (percentage). The t test was used for normally distributed and Wilcoxon signed rank test for skewed parameters. The proportion of patients with IV iron dose . 300 mg/mo was tested with c test. Abbreviations: HD, hemodialysis; IV, intravenous; LV, left ventricular. Ferricarboxymaltose in 83 patients; iron(III)-hydroxide dextran complex in 14 patients. In the 13 patients who used epoetin beta, the weekly epoetin beta dose was divided by 200 to achieve darbepoetin equivalence. To the Editor: Assa et al describe an association between circulating inflammatory cytokine concentrations and hemodialysis-induced left ventricular (LV) systolic dysfunction. The authors speculate that inflammation could adversely affect endothelial or myocyte function in the heart. Intravenous (IV) iron preparations cause inflammation, endothelial dysfunction, and oxidative stress, as reviewed by Van Buren et al. However, Assa et al did not address the possible etiologic contribution of IV iron. The proportion of patients receiving IV iron has increased substantially over the past 15 years, as have iron doses. In an international analysis, we recently reported an association between higher doses of IV iron and mortality among hemodialysis patients. We encourage the authors to examine whether there is an association (or a trend) between high IV iron doses and intradialytic LV dysfunction. We suggest comparing patients who received doses $ 300 mg/mo versus ,300 mg/mo, based on our mortality findings. It also would be of interest to see whether serum ferritin concentration, a marker of iron burden, correlates with LV dysfunction after adjustment for the other inflammatory markers. However, it is possible that the sample size of only 29 patients with LV dysfunction will prove too small to permit inferences.

Renal anemia of chronic kidney disease (CKD) is generally treated by erythropoiesis-stimulating agents (ESAs). However, there are individual differences in patients’ responsiveness to ESA, which may affect the prognosis of CKD. The effect of ESAs on hemoglobin was followed in 297 CKD patients with renal anemia. Three types of ESA, epoetin alfa or beta, darbepoetin alfa, and epoetin beta pegol, were used in this study and dose of ESA was converted to that of epoetin using a dose conversion ratio (epoetin:darbepoetin alfa:epoetin beta pegol = 200:1:0.93). After initial 12-week administration of ESAs, the patients were divided into three groups: poor, intermediate, and good responders based on ΔHb/week/epoetin dose as an index. Hemoglobin values were followed for 144 weeks. Initial patient characteristics—including age, body mass index, hemoglobin, estimated glomerular filtration rate, transferrin saturation, ferritin, albumin, calcium, parathyroid hormone, C-reactive protein, and urine protein—were similar in the three responder groups, except phosphate in the poor responder group was significantly higher than in the other two groups. The period from ESA use to renal death (RD) was significantly shortest in the poor responder group, and the number of RD patients was fewer in the good responder group. Multivariate Cox regression revealed that low final ΔHb(ΔHb from ESA use to just before dialysis)/week/epoetin dose, and low Hb after 12-week ESA use were significant factors related to responsiveness to ESA, suggesting that hyporesponsiveness to ESA was a risk factor for RD. Cox regression also found that hyperphosphatemia and diabetic nephropathy were risks for RD as well. The study results suggest that hyporesponsiveness to ESA after the first 12-week administration as well as after 12 weeks is a risk for RD in pre-dialysis CKD patients. Furthermore, hyperphosphatemia and diabetic nephropathy are risk factors for RD.

Aim. To compare the effects of preoperative treatment with recombinant human erythropoietin (EPO) and iron with iron only on hemoglobin levels (Hb) in anemic women prior to hysterectomy. Methods. The study was an open-labelled randomized parallel study. Fifteen women scheduled for hysterectomy due to uterine myoma were given oral iron and EPO (NeoRecormon®) 4 weeks prior to surgery (group I) and 16 women were given oral iron only (group II). Results. Group I showed a significantly greater increase in mean Hb during the pre-surgery study period compared with group II (p=0.007). Two weeks postoperatively, however, there was no significant difference in mean Hb between the two groups. Conclusion. We found that a significantly greater increase in Hb was achieved with iron in combination with EPO, although in most cases iron only seemed to be as efficacious as iron+EPO in correcting anemia in myoma patients pre-operatively.

PURPOSE: To prospectively evaluate the effectiveness, safety, and clinical benefits of once-weekly epoetin alfa therapy as an adjunct to chemotherapy in anemic cancer patients. PATIENTS AND METHODS: A total of 3,012 patients with nonmyeloid malignancies who received chemotherapy were enrolled onto this multicenter, open-label, nonrandomized study conducted in 600 United States community-based practices. Patients received epoetin alfa 40,000 U once weekly, which could be increased to 60,000 U once weekly after 4 weeks dependent on hemoglobin response. Treatment was continued for a maximum of 16 weeks. RESULTS: Among the 2,964 patients assessable for efficacy, epoetin alfa therapy resulted in significant increases in hemoglobin levels, decreases in transfusion requirements, and improvements in functional status and fatigue as assessed by the linear analog scale assessment (energy level, ability to perform daily activities, and overall quality of life) and the anemia subscale of the Functional Assessment of Cancer Therapy–Anemia questionnaire. Improvements in quality-of-life parameters correlated significantly (P < .001) with increased hemoglobin levels. The direct relationship between hemoglobin and quality-of-life improvement was sustained during the 16-week study period, which is similar to findings of large community-based trials of three-times-weekly dosing. Once-weekly epoetin alfa was well tolerated, with most adverse events attributed to the underlying disease or concomitant chemotherapy. CONCLUSION: The results from this large, prospective, community-based trial suggest that once-weekly epoetin alfa therapy increases hemoglobin levels, decreases transfusion requirements, and improves quality of life in patients with cancer and anemia who undergo concomitant chemotherapy. Based on the results of this study, the clinical benefits and the adverse event profile of once-weekly epoetin alfa therapy in community-based practice are similar to those observed in the historical experience with the three-times-weekly dosage schedule.

PURPOSE: This randomized, double-blind, placebo-controlled clinical trial assessed the effects of epoetin alfa on transfusion requirements, hematopoietic parameters, quality of life (QOL), and safety in anemic cancer patients receiving nonplatinum chemotherapy. The study also explored a possible relationship between increased hemoglobin and survival. PATIENTS AND METHODS: Three hundred seventy-five patients with solid or nonmyeloid hematologic malignancies and hemoglobin levels ≤ 10.5 g/dL, or greater than 10.5 g/dL but ≤ 12.0 g/dL after a hemoglobin decrease of ≥ 1.5 g/dL per cycle since starting chemotherapy, were randomized 2:1 to epoetin alfa 150 to 300 IU/kg (n = 251) or placebo (n = 124) three times per week subcutaneously for 12 to 24 weeks. The primary end point was proportion of patients transfused; secondary end points were change in hemoglobin and QOL. The protocol was amended before unblinding to prospectively collect and assess survival data 12 months after the last patient completed the study. RESULTS: Epoetin alfa, compared with placebo, significantly decreased transfusion requirements (P = .0057) and increased hemoglobin (P < .001). Improvement of all primary cancer- and anemia-specific QOL domains, including energy level, ability to do daily activities, and fatigue, was significantly (P < .01) greater for epoetin alfa versus placebo patients. Although the study was not powered for survival as an end point, Kaplan-Meier estimates showed a trend in overall survival favoring epoetin alfa (P = .13, log-rank test), and Cox regression analysis showed an estimated hazards ratio of 1.309 (P = .052) favoring epoetin alfa. Adverse events were comparable between groups. CONCLUSION: Epoetin alfa safely and effectively ameliorates anemia and significantly improves QOL in cancer patients receiving nonplatinum chemotherapy. Encouraging results regarding increased survival warrant another trial designed to confirm these findings.

BACKGROUND Anemia is common in cancer patients, although the prevalence is influenced both by the type of malignancy and the choice of treatment. Individual studies have compared the survival of patients with and without anemia and have shown reduced survival times in patients with various malignancies, including carcinoma of the lung, cervix, head and neck, prostate, lymphoma, and multiple myeloma. The objective of this study was to systematically review, to summarize, and to obtain an overall estimate of the effect of anemia on survival in patients with malignant disease. METHODS A comprehensive literature review was carried out using the MEDLINE data base and reviewing the reference lists from published studies. Two hundred papers were identified. Of these, 60 papers that reported the survival of cancer patients according to either hemoglobin levels or the presence of anemia were included. Among these papers, 25% related to patients with lung carcinoma, 17% related to patients with head and neck carcinoma, 12% related to patients with multiple myeloma, 10% related to patients with prostate carcinoma, 8% related to patients with cervicouterine carcinoma, 7% related to patients with leukemia, 5% related to patients with lymphoma, and 16% related to patients with other types of malignancies. RESULTS The relative risk of death increased by 19% (95% confidence interval, 10–29%) in anemic patients with lung carcinoma, by 75% (37–123%) in anemic patients with head and neck carcinoma, by 47% (21–78%) in anemic patients with prostate carcinoma, and by 67% (30–113%) in anemic patients with lymphoma. The overall estimate increase in risk was 65% (54–77%). CONCLUSIONS Anemia is associated with shorter survival times for patients with lung carcinoma, cervicouterine carcinoma, head and neck carcinoma, prostate carcinoma, lymphoma, and multiple myeloma. Cancer 2001;91:2214–21. © 2001 American Cancer Society.

This randomized, multicentre, parallel-group study assessed the efficacy of epoetin beta in reducing the transfusion frequency in patients ineligible for autologous blood donation prior to surgery. The patients (n = 194) received either epoetin beta (125 or 250 IU/kg, once weekly) or no therapy for 3–4 weeks before surgery. The pre-operation haemoglobin levels were markedly increased in the epoetin beta groups (125 IU/kg: +1.1 g/dl; 250 IU/kg: +1.6 g/dl), but not in the control group. The transfusion frequency was significantly reduced in both epoetin groups as compared with the control group (p = 0.046). Epoetin beta was well tolerated, and no serious adverse events were observed. Low-dose administration of epoetin beta before elective surgery reduces the transfusion frequencies in patients not eligible for autologous blood donation.

The aim of this study (SITEPO) is to evaluate the influence of the intravenous injection site (drip chamber injection site, venous injection site or venous fistula needle) on plasma concentration of epoetin beta (Neorecormon, Roche), a recombinant Human Erythropoietin (rHuEPO), at the end of in vitro hemodialysis sessions. No practical administration guidelines are available. Twenty 1-h dialysis sessions are performed. Before each dialysis, the circuit is filled with 270ml, of heparinized total human blood whose hematocrit is adjusted to 35%. A common dosage of epoetin beta in clinical practice (3000IU) is studied for the three injection sites and for reference experiments in which rHuEPO is not injected into the dialysis circuit. Plasma concentrations of erythropoietin are measured by ELISA. The physiologically endogenous erythropoietin concentration is systematically determined and removed from the total epoetin beta concentration. Average epoetin beta plasma levels returned are not significantly different between the three injection sites and no significant rHuEPO loss is observed after injection into the drip chamber, the venous injection site and the venous fistula needle compared with reference experiments. The three intravenous injection sites of rHuEPO can be used at the end of dialysis without significant epoetin beta loss.

Sir, Generally, end-stage renal disease (ESRD) due to sickle cell anaemia (SCA) occurs in 2000 vs >2000 ng/mL), transferrin saturation indices (72.6 ± 19.5 vs 76.5 ± 21.2%), numbers of hospitalizations (5.5 times per year—min. 3, max. 8 vs 6.0 times per year—min. 2, max. 9) and blood transfusion needs and rates (minimum 1–2 U/2–3 months, maximum 1–3 U/1–2 months) before and after Epo treatment. The haemoglobin levels of the patients still decreased to between 4.0 and 4.5 g/dL once or twice during the year Epo was being administered (Table 1). There was no newly developed thromboembolic event in any of the patients during Epo treatment. Table 1 Characteristics of SCA and ESRD patients and summary of Epo response Epo treatment was continued (14 ± 2.2 months) in one pre-dialysis and two peritoneal dialysis patients and was ceased in five patients due to unresponsiveness to treatment. In one of the patients in whom Epo treatment was ceased, the treatment had been administered from May 2001 to September 2006, ceased in 2006 and the patient died in 2008. The mean time of Epo treatment in the other four patients in whom Epo had been stopped due to unresponsiveness was 18 ± 6.3 months. In this retrospective study, the unresponsiveness of Epo treatment, resulting in target haemoglobin levels not being reached in patients with concurrent SCA and ESRD, could possibly be due to the fact that the precise cause of anaemia in this patient group is not Epo insufficiency. On the other hand, since basal endogenous Epo levels in SCA patients are shown to be higher than in the normal population, the Epo requirement may also be much higher than for other ESRD patients following the development of renal failure [4]. With regard to the variable individual response to Epo treatment, until more precise data are available, with a higher number of patients with SCA and ESRD from different centres, it would be appropriate to attempt treatment with the maximum possible dose for a period and then to stop this expensive treatment if the expected response cannot be achieved. Conflict of interest statement. None declared.

Background. Anaemia in haemodialysis patients can be effectively treated with erythropoietin. We investigated whether subcutaneous (SC) epoetin β administered once weekly was as effective as the same weekly dosage given in two to three divided doses. Methods. One hundred and fifty-eight patients (delivered Kt/V >1.0, where K=dialyser-renal urea clearance, t=dialysis time and V=filtration volume, obtained by urea kinetic modelling) were randomized to treatment with SC epoetin β either once weekly (n=118), or to their original dosage two or three times weekly (control group, n=40) for 24 weeks. All patients received intravenous iron supplementation when necessary. Results. Eight-eight patients in the once weekly group and 30 patients in the control group were treated for at least 16 weeks and are included in the analysis. Stable haemoglobin levels were maintained without epoetin dose increases in 73% of patients in both groups. Mean haemoglobin levels at randomization and after 16 and 24 weeks were 11.4, 11.1 and 11.1 g/dl, respectively, in the once weekly group compared with 11.2, 11.3 and 11.2 g/dl, respectively, in the control group. The mean weekly epoetin β dosages at randomization and after 16 and 24 weeks were 102, 103 and 106 IU/kg bodyweight, respectively, in the once weekly group compared with 109, 109 and 115 IU/kg bodyweight, respectively, in the control group. No statistically significant between-group differences were apparent for changes in haemoglobin levels or epoetin β dosages at week 24. Conclusions. Once weekly SC administration of epoetin β is as safe and effective in maintaining haemoglobin levels in stable haemodialysis patients as two or three times weekly administration of the same total dose. By using the once weekly regimen, patients can avoid up to 104 injections per year. This would reduce clinic time for patients who do not self administer, and may also encourage self-administration and improve overall compliance.