Recombinant human erythropoietin therapy for anemic cancer patients on combination chemotherapy. Prevention of chemotherapy-induced anemia by the use of erythropoietin in patients with primary malignant bone tumors (a double-blind, randomized, phase III study). Treatment of the anemia of chronic renal failure with subcutaneous recombinant human erythropoietin. Recombinant human erythropoietin treatment in cisplatin-associated anemia: a randomized, double-blind trial with placebo. Erythropoietin treatment under polychemotherapy in patients with gynecologic malignancies: a prospective, randomized, double-blind placebo-controlled multicenter study. rHuEPO in the treatment of postpartum anemia: subcutaneous versus intravenous administration. Recombinant human erythropoietin in the treatment of chemotherapy-induced anemia and prevention of transfusion requirement associated with solid tumors: a randomized, controlled study. The decision to prematurely terminate a trial of R-HuEPO due to thrombotic events. Effect of early versus late administration of human recombinant erythropoietin on transfusion requirements in premature infants: results of a randomized, placebo-controlled, multicenter trial.
Patients with advanced cancer frequently experience clinically significant anemia, which is often exacerbated by myelosuppressive chemotherapy. Consistent with the anemia of chronic disease, studies have documented serum erythropoietin levels that are inappropriately low for the degree of anemia in cancer patients. Myelosuppressive chemotherapy impairs erythropoiesis, which may not fully recover between treatment cycles. Recombinant human erythropoietin (rHuEPO) has been used safely and effectively to treat anemia in AIDS patients receiving zidovudine (AZT) and in patients with chronic renal failure.
                This study was designed to evaluate the clinical role of rHuEPO in reducing symptomatic anemia in patients with advanced cancer who were receiving myelosuppressive chemotherapy (excluding cisplatin).
                We studied 153 anemic cancer patients receiving cyclic combination chemotherapy in a prospective multicenter, double-blind, placebo-controlled trial. The patients were randomly assigned to receive either rHuEPO (150 U/kg) or placebo subcutaneously three times a week for a maximum of 12 weeks or until the hematocrit level increased to 38%-40%. If the hematocrit reached this target level before 12 weeks, the rHuEPO dose could be reduced to maintain the hematocrit at that level for the duration of the study. Response to rHuEPO therapy was assessed by measuring changes in hematocrit level, transfusion requirements, and quality of life. Quality-of-life assessment was based on patients' responses to questionnaires before and after the courses of therapy.
                The increase in hematocrit in the rHuEPO-treated group compared with hematocrit in the placebo-treated group was statistically significant (P = .0001) as measured by percentage point of change from baseline to final evaluation, by an increase in hematocrit level of six percentage points or more unrelated to transfusion, and by a rise in hematocrit level to 38% or more unrelated to transfusion. There was a trend toward the reduction in mean units of blood transfused per patient during months 2 and 3 of therapy combined in rHuEPO-treated patients compared with placebo-treated patients (0.91 U versus 1.65 U; P = .056). In addition, rHuEPO-treated patients experienced a statistically significant improvement in energy level and ability to perform daily activities (P < or = .05). The two treatment groups showed no statistically significant differences in toxic effects except for increased incidence of diaphoresis (P < .05) and diarrhea (P = .05) in the rHuEPO-treated group.
                We conclude that rHuEPO is safe and effective for reversing anemia related to advanced cancer or to chemotherapy for cancer. Patients undergoing chemotherapy for treatment of malignancy frequently experience clinically significant anemia. Myelosuppressive chemotherapy impairs erythropoiesis, which may not fully recover between treatment cycles. Recombinant human erythropoietin (rHuEPO) has been effectively introduced in anemic patients suffering from chronic renal failure. The present study was designed to assess, first, whether rHuEPO treatment decreases transfusion requirements in chemotherapy-induced anemia and, second, whether high-dose rHuEPO application is safe. STUDY DESIGN and
                Thirty consecutive anemic patients (hemoglobin <11 g/dl) receiving combination chemotherapy for primary malignant bone tumors were studied in a prospective, double-blind, randomized, Phase III trial. Patients received chemotherapy according to one of two German protocols, depending on histologic diagnosis. All subjects enrolled were randomly assigned either to receive 600 IU of rHuEPO per kg of body weight intravenously twice a week or to receive a placebo during chemotherapy. To obtain comparable data, an observation period of 20 weeks was chosen. Twenty-nine patients fulfilled the criteria and were eligible for statistical evaluation.
                Transfusion requirements were significantly decreased from Week 8 of therapy (p<0.05) in the treatment group. Therapeutic benefits were even more evident with continuation of therapy (Week 12, p = 0.03; Week 16, p = 0.016; Week 20, p = 0.002). The blood required was 2.1 units of red cells in the treatment group and 8.4 units of red cells in the placebo group. All patients tolerated rHuEPO with no serious side effects.
                These findings suggest that rHuEPO is an effective and well-tolerated therapeutic option for decreasing the transfusion requirements in chemotherapy-induced anemia. The purpose of this study was to determine the efficacy of recombinant human erythropoietin (rHuEPO) given subcutaneously three times/week in patients with chronic renal failure and anemia (predialysis).
                Eleven patients with predialysis chronic renal failure participated in a double-blind, placebo-controlled study of subcutaneously administered erythropoietin. For 12 weeks, patients received either rHuEPO 100 mu/kg body weight three times/week subcutananeously or a placebo. After 12 weeks of placebo, patients now also received rHuEPO in a dose up to 150 mu/kg three times/week until target hematocrit was achieved. Throughout the study, blood pressure was monitored closely and blood work was obtained regularly for hemoglobin, hematocrit, reticulocyte count, and iron profile determinations.
                At 12 weeks, the hematocrit of the treated group had risen from 29% +/- 2% to 35% +/- 2% (p less than 0.001). The placebo group baseline hematocrit was 28% +/- 2% and at 12 weeks 26% +/- 2% After 12 weeks of rHuEPO therapy, the hematocrit of the prior placebo group was 32% +/- 2% (p less than 0.001 versus baseline). No significant change in biochemical parameters was noted. Mean blood pressure values were comparable before and after treatment. All protein ultimately required iron supplementation. In two patients, the rate of progression of renal failure appeared to increase as their hematocrit rose and rHuEPO was discontinued.
                It is concluded that rHuEPO given subcutaneously is an effective and safe therapy for patients with chronic renal failure who are anemic and who are not receiving dialysis. To evaluate the effect of exogenous recombinant human erythropoietin (rHuEPO) on the increase of hemoglobin levels and on the transfusion requirements in patients with cisplatin (CDDP)-induced anemia, we performed a double-blind randomized trial with placebo.
                One hundred patients with CDDP-associated anemia (hemoglobin level < 90 g/L) were randomized to receive either placebo (saline solution) or rHuEPO (100 U/kg body weight subcutaneously) three times per week. The end points of this study were the increase in hemoglobin levels to greater than 100 g/L after 3, 6, and 9 weeks and the effect on transfusion requirements.
                Ninety-nine of 100 patients were assessable for response and toxicity. In the rHuEPO arm, mean hemoglobin levels were statistically significantly increased after the third, sixth, and ninth weeks of therapy (101.1 +/- 9.0, 102.4 +/- 6.6, and 105.1 +/- 9.4 g/L, respectively) compared with the mean baseline value (86.3 +/- 6.2 g/L). In the placebo arm, there were no increases in mean hemoglobin levels at the third, sixth, and ninth weeks (81.0 +/- 5.2, 81.3 +/- 9.2, and 81.2 +/- 11 g/L, respectively) compared with the mean baseline value (87.3 +/- 5.2 g/L). Furthermore only 20% of patients required blood transfusions in the rHuEPO arm versus 56% of patients in the placebo arm (P = .01), with a mean units of blood transfused per patient of 0.30 in the rHuEPO arm and 1.8 in the placebo arm (P = .01). Treatment was well tolerated, with no significant side effects.
                CDDP-induced anemia is corrected by rHuEPO, which results in reduced blood transfusion requirements. In order to examine the influence of erythropoietin (rHuEPO) on serum hemoglobin levels, transfusion requirements, and quality of life in patients with gynecologic malignancies under polychemotherapy and chronic tumor anemia (hemoglobin <11 g/dl), we performed a prospective, randomized, double-blinded placebo-controlled clinical trial. Between October 1992 and October 1993, 35 patients from 5 gynecologic departments were entered into this trial. Inclusion criteria were hemoglobin level <11 g/dl, ferritin level >29 ng/ml, stool negative for occult blood, and life expectancy for more than 3 months. Patients received either 150 U/kg body wt rHuEPO (Erypo by Cilag-Janssen) sc three times a week for 12 weeks (n = 23) or a placebo (n = 12). If the hemoglobin levels of the 4th, 8th, or 12th week were >2 g/dl above the baseline value and/or >12 g/dl, the patient was classified as a responder. Patients who required blood transfusions (hemoglobin <8 g/dl, erythrocytes <3 x 10(6)/ml, or clinical symptoms of anemia) were classified as nonresponders. A nonvalidated quality of life questionnaire was completed by the patient at the beginning of the treatment and then every fourth week before receiving chemotherapy. In the rHuEPO group 56.6% of the patients responded to the treatment (chi2 = 10.79, P = 0.001) and only 5 patients (21.7%) required blood transfusions, whereas 8 of 12 patients in the placebo group (66.6%) had to be transfused (chi2 = 6.81, P = 0.009). Quality of life did not differ significantly between the rHuEPO group and the placebo group of patients. Within the rHuEPO group those patients that responded showed a significant increase in physical activity after response in comparison to the preresponsive phase (P = 0.02, paired t test). We therefore concluded that rHuEPO significantly increases serum hemoglobin levels and decreases transfusions requirements while maintaining quality of life in patients with gynecological malignancies who are undergoing polychemotherapy. The aim of this study was to determine whether single-shot therapy with recombinant human erythropoietin (rHuEPO) is as effective as divided dosing in postpartum anemia for both subcutaneous and intravenous administration. In a randomized prospective study we treated 95 women with postpartum anemia (Hb < 10 g/dl) within 72 h after delivery with rHuEPO (total dose 300 U/kg body weight) and oral iron supplementation in four treatment groups: group A rHuEPO 150 U/kg s.c. once daily for two consecutive days; group B rHuEPO 150 U/kg i.v. once daily for two consecutive days; group C rHuEPO 300 U/kg s.c. once only; group D rHuEPO 300 U/kg i.v. once only. No significant intergroup differences were found in the mean increase of hemoglobin (P = 0.93 for a difference of 1 g/dl). The mean increase in the single-shot groups was 3 g/dl in 14 days. There was a significant reduction of iron stores in all groups. We conclude that single-shot rHuEPO 300 U/kg body weight corrects anemia just as effectively as divided doses on both intravenous and subcutaneous administration. The overall increase in Hb is only slight but preliminary results indicate that the effect can be enhanced by administrating iron intravenously and by an interval therapy with high-dose rHuEPO. Anemia is a common side effect of anticancer chemotherapy. Blood transfusion, previously the only available treatment for chemotherapy-induced anemia, may result in some clinical or subclinical adverse effects in the recipients. Recombinant human erythropoietin (rhEPO) provides a new treatment modality for chemotherapy-induced anemia.
                To evaluate the effect of rhEPO on the need for blood transfusions and on hemoglobin (Hb) concentrations, 227 patients with solid tumors and chemotherapy-induced anemia were enrolled in a randomized, controlled, clinical trial. Of 189 patients evaluable for efficacy, 101 received 5000 IU rhEPO daily s.c., while 88 patients received no treatment during the 12-week controlled phase of the study.
                The results demonstrate a statistically significant reduction in the need for blood transfusions (28% vs. 42%, P = 0.028) and in the mean volume of packed red blood cells transfused (152 ml vs. 190 ml, P = 0.044) in patients treated with rhEPO compared to untreated controls. This effect was even more pronounced in patients receiving platinum-based chemotherapy (26% vs. 45%, P = 0.038). During the controlled treatment phase, the median Hb values increased in the rhEPO patients while remaining unchanged in the control group. The response was seen in all tumor types.
                RhEPO administration at a dose of 5000 IU daily s.c. increases hemoglobin levels and reduces transfusion requirements in chemotherapy-induced anemia, especially during platinum-based chemotherapy. Recombinant human erythropoietin (r-HuEPO) corrects cancer-related anemia and, thereby, improves quality of life. The purpose of the present study was to measure the impact of erythropoietin on hemoglobin and mood state in patients with metastatic breast cancer and mild anemia (Hgb < 12.0 g/dL). Women were randomized to receive usual care (G1) or usual care plus r-HuEPO (G2). Usual care included transfusions as necessary and fatigue education. R-HuEPO was begun at 40,000U subcutaneously per week. At 4 weeks, the dose was increased to 60,000U if Hgb had not increased > or = 1.0 g/dL. The drug was discontinued at 8 weeks if hemoglobin improvement was < 1.0 g/dL. The study was terminated early (n = 27, G1 = 13, G2 = 14) when 4/14 (28.5%) subjects in G2 developed thrombotic events (deep vein thrombosis [DVT] in 1; DVT plus pulmonary embolism [PE] in 1; DVT plus PE 1 month after drug discontinuation in 1; and brachial vein thrombosis with infected Mediport in 1). In all four patients, Hgb levels were normal at the time of the event. No patient in G1 developed a thrombotic event. There were no significant differences in demographic characteristics or current chemotherapy regimen in G1 vs. G2. The decision to terminate the trial was made after considerable deliberation. The increased incidence of thrombotic events in the r-HuEPO (G2) arm of this study exceeds that in prior studies in this population and prior r-HuEPO trials. This may relate to the administration of r-HuEPO in this high-risk population, but the small sample size and possible predisposing risk factors preclude definitive conclusions. The administration of recombinant human erythropoietin (rHuEPO), started after the first 2 weeks of life, reduces the transfusion requirement in premature infants. However, its use throughout the first 2 weeks of life, when anemia results predominantly from phlebotomy losses, remains controversial. We investigated whether early use of rHuEPO would reduce the total transfusion requirement and/or the number of transfusions throughout the first 2 weeks of life.
                We randomized 114 infants with birth weight (BW) <1250 g to receive rHuEPO (1250 units/kg/week; IV; early group: n = 57) or placebo (late group: n = 57) from day 2 to day 14 of life; subsequently, all the patients received rHuEPO (750 units/kg/week, subcutaneously) for 6 additional weeks. All infants were given oral iron (6 mg/kg/day) and folic acid (2 mg/day).
                The early group showed higher hematocrit and reticulocyte counts than the late group in the first 3 weeks of life, but there was no difference in the total number of transfusions (early: 1.8 +/- 2.3 vs late: 1.8 +/- 2.5 transfusion/patient) or the transfusion requirement throughout the first 2 weeks of life (early:.8 +/- 1.1 vs late:.9 +/- 1.3) could be demonstrated. In infants with BW <800 g and total phlebotomy losses >30 mL/kg (n = 29), a lower number of transfusions was received by infants in the early group, compared with late group, from the second week to the end of the treatment (early: 3.4 +/- 1.1 vs late: 5.4 +/- 3.7 transfusion/patient). No clinical adverse effects were observed. Thrombocytosis was detected during the treatment with rHuEPO in 31% of the infants.
                In the whole population, the early administration of rHuEPO induced a rise of reticulocyte counts, but not enough to reduce the transfusion requirement. The most severely ill infants (BW <800 g and phlebotomy losses >30 mL/kg) seemed to benefit from early use of rHuEPO, and this deserves additional study.
This updated Cochrane review provides evidence that rHuEPO compared with placebo does not reduce mortality, does not reduce transfusion requirements, did not increase hemoglobin levels, and did not improve quality of life in HIV-infected patients with anemia. The results are based on six RCTs with high risk of bias. Therefore prescription of this intervention for treating anemia in patients with AIDS is not justified, unless new evidence from a large high quality trial alters this conclusion.