The effect of subcutaneous r-HuEPO in cancer patients receiving chemotherapy with anemia: a preliminary report

BACKGROUND: Chemotherapy-related anemia in cancer patients is often encountered in clinical practice. It can reduce patient's compliance and tolerance to continuing chemotherapy. The mechanism of anemia may be ascribed to either decreasing serum EPO concentration or reducing sensitivity of EPO. Exogenous supply of EPO has shown to be effective in control of cancer-related anemia in early reports. This study preliminarily explored the efficacy and safety of r-HuEPO for cancer patients with anemia during the cytotoxic chemotherapy period in Taiwan. METHODS: Sixteen cancer patients receiving cyclic chemotherapy with anemia (Hgb < or = 10.5 g/dl) and without other systemic organ dysfunction, cerebral metastasis, uncontrolled hypertension, or presence of anemia attributable to causes other than cancer and chemotherapy entered the study. All patients received r-HuEPO 150 u/kg subcutaneous injection tiw for a total of 16 weeks. The efficacy determinations was based on the effect of r-HuEPO on hematological parameters, transfusion requirements, quality of life assessment, and physician's global assessment. Safety was assessed based on clinical laboratory tests, vital sign measurements and the incidence and severity of adverse experiences. RESULTS: There were no changes of WBC and platelet count in 4, 8, 12 and 16 weeks of r-HuEPO therapy. The mean hemoglobin values at baseline, week 4, 8, 12, and 16 were 9.2 +/- 1.0 g/dl, 11.4 +/- 0.9 g/dl, 11.6 +/- 1.8 g/dl, 11.8 +/- 1.8 g/dl, and 12.2 +/- 2.3 g/dl, respectively (p < 0.001). The mean hematocrit values at baseline, week 4, 8, 12, and 16 were 28.3 +/- 3.4%, 36.0 +/- 2.8%, 36.3 +/- 5.7%, 37.8 +/- 6.0%, and 40.1 +/- 7.1%, respectively (p < 0.0005). The use of r-HuEPO had the marginal effect on the increase of patient's energy and activity. No adverse impacts on patient's vital signs were noted except 2 incidences of systolic hypertension and one episode of diastolic hypertension in the week 4. CONCLUSIONS: Subcutaneous injection of r-HuEPO at the dose of 150 u/kg tiw was safe and effective in increasing patient's hematocrit and RBC mass, and decreasing their blood transfusion requirement. Whether the current dosage of 150 u/kg tiw is the optimal treatment for chemotherapy-related anemia still needs further study.     

Clinical and in vitro effects of recombinant human erythropoietin in patients receiving intensive chemotherapy for small-cell lung cancer

PURPOSE: Recombinant human erythropoietin (r-Hu-EPO) is known to be effective in untreated cancer patients. Here we assess the possibility that r-Hu-EPO may also prevent or reduce anemia in patients who receive cytotoxic chemotherapy. METHODS: Thirty-six patients with small-cell lung carcinoma (SCLC) were enrolled onto a three-arm, randomized trial to investigate the effect of r-Hu-EPO on hemoglobin (Hb) levels and RBC and platelet (Plt) transfusions during chemotherapy. Bone marrow progenitors were studied before and after treatment. Two groups of patients received r-Hu-EPO at a dose of either 150 IU/kg (group 150) or 300 IU/kg (group 300) three times per week for the duration of chemotherapy. A control group did not receive r-Hu-EPO (group O). A maximum of six cycles of a chemotherapy regimen that consisted of vincristine, ifosfamide, carboplatin, and etoposide (VICE) were given to all patients. Hematologic parameters were measured weekly, and RBC or Plt transfusions were given for Hb levels less than 9 g/dL and Plt counts less than 20 x 10(9)/L. RESULTS: Hb levels decreased in all patients, but onset of anemia was delayed in groups that received r-Hu-EPO (P = .002). A total of 116 U RBC were transfused in group 0, 54 in group 150, and 52 in group 300 (P = .017). In addition, there was a nonsignificant trend toward higher Plt counts and fewer Plt transfusions in patients who received r-Hu-EPO. CONCLUSION: r-Hu-EPO at a dose of either 150 or 300 IU/kg three times weekly delays the onset of anemia and reduces RBC transfusion requirements in patients who undergo intensive chemotherapy for SCLC. A possible effect of r-Hu-EPO on platelet numbers deserves further study.     

Red cell lipid peroxidation and antioxidant system in haemodialysed patients: influence of recombinant human erythropoietin (r-HuEPO) treatment

Oral fluids are convenient alternatives to blood sampling for evaluating significant metabolic components. Two forms of oral fluids, oral mucosal transudates (OMT) and saliva, were collected and compared for content of soluble products of immune activation. The data confirm that OMT and saliva represent distinct body fluids. The concentrations, outputs, and analyte/protein ratios of beta-2-microglobulin (beta2M), soluble tumor necrosis factor alpha receptor II (sTNFalphaRII), and neopterin were measured. Both the OMT and the saliva of most of the individuals in the control healthy populations had measurable levels of all three activation markers. When the immune system is activated, as in human immunodeficiency virus (HIV) infection, the levels of beta2M and sTNFalphaRII are increased in both OMT and saliva compared to those in a healthy control population. OMT levels correlated better with levels in serum than did saliva and appear to reflect systemic immune activation in HIV infection. Because acquisition of oral fluids is noninvasive and easily repeatable, measurement of beta2M and/or sTNFalphaRII content in OMT could be useful in the assessment of disease activity in patients with HIV infection or chronic inflammatory diseases.     

Effect of subcutaneous recombinant human erythropoietin in cancer patients receiving radiotherapy: final report of a randomized, open-labelled, phase II trial

The purpose of this study was to determine the safety, efficacy and impact on quality of life of recombinant human erythropoietin (r-HuEPO) for cancer patients undergoing radiotherapy (RT). An open-labelled randomized design was used, with patients randomized to either treatment or control arms. Patients in the treatment arm received r-HuEPO given by subcutaneous injection at a dose of 200 units kg(-1) day(-1) plus oral iron supplements (ferrous sulphate 325 mg p.o. t.i.d.). Entry was restricted to patients with carcinoma of the lung, uterine cervix, prostate or breast who presented for RT with anaemia parameters reflective of 'the anaemia of chronic disease'. Radiotherapy policies (portals, doses, fraction size, etc.) were determined by the site and stage of disease. Complete blood counts (CBCs) were obtained weekly. The target level of haemoglobin was 15 g dl(-1) for men and 14 g dl(-1) for women. Quality of life (QOL) was assessed weekly by using an analogue scale to judge energy, activities of daily living and overall quality of life. Forty-eight patients were entered in the study, 24 in the treatment arm and 24 in the control arm. The prerandomization demographic characteristics and mean laboratory values were comparable in both arms. The mean haemoglobin at completion was 13.6 g dl(-1) for r-HuEPO-treated patients compared with 11.0 g dl(-1) for control subjects (P = 0.0012). Patients who received r-HuEPO demonstrated a mean weekly haemoglobin increase of 0.41 g dl(-1) compared with a decrease in mean haemoglobin level in controls for 6 of the 7 weeks of the study (mean weekly decrease of 0.073 g dl(-1)). Target levels of haemoglobin were achieved by 41.6% of r-HuEPO-treated patients compared with none of the control subjects. The mean platelet count declined in both arms of the study with RT but the decline from pretreatment was less rapid in r-HuEPO-treated patients (11.2% decrease) compared with controls (26.3% decrease) and was statistically significant during weeks 4-6. Toxicity was minor with only mild irritation at the injection site. Mean quality of life end points were superior in the treatment arm but not statistically significant. r-HuEPO had a beneficial effect on weekly haemoglobin levels in patients undergoing RT with response rates similar to other studies. There was also a less rapid decline in weekly platelet counts in r-HuEPO-treated patients compared with control subjects. Further studies are needed to address the optimum dose and scheduling as well as the impact of r-HuEPO on clinical outcomes.     

Treatment of non-renal anemia with human recombinant erythropoietin (rHU-EPO

Four cases of Rett syndrome were ascertained among 19,060 girls born between 1978 and 1990 in a small, defined area of Northern Tuscany (Italy) (prevalence rate of 2.1 per 10,000). A fifth girl with a reported clinical picture of Rett syndrome, born in 1978 and deceased at age 13, was also found. One of the four Rett syndrome cases had a healthy female dizygote twin. Family tree studies going back as far as the 17th century were performed. A number of common ancestors were found in different generations leading to a single family tree encompassing all four Rett syndrome cases. In addition, a Rett girl with preserved speech, born in 1974, was found as part of this family tree. These observations confirm the role of genetic factors in the etiology of Rett syndrome and support the hypothesis that Rett syndrome is a clinically variable phenotype.     

Prediction of response to recombinant human erythropoietin (rHuEpo) in anemia of malignancy

BACKGROUND: Since only a portion of anemic patients outside the uremia setting benefit from erythropoietin treatment, a reliable means of predicting potential responders and nonresponders would be very useful. MATERIALS AND METHODS: We retrospectively reviewed the clinical records of 58 patients with refractory anemia associated with various malignant disorders who had been treated with subcutaneous rHuEpo. The starting rHuEpo dose was 375 U/kg/week for 4 weeks, and was increased to 750 U/kg/week for another 4 weeks if no response was observed. Response was defined as a Hb increase > or = 2 g/dL with no need for blood transfusion. We examined the value of various laboratory parameters (baseline levels, 2-week and 4-week changes) as predictors of response. Endogenous erythropoietin production was evaluated by its serum level and erythroid activity was assessed through reticulocyte count and circulating transferrin receptor. RESULTS: Forty-eight individuals were evaluable, 58% of whom responded to rHuEpo within 8 weeks. Multiple regression analysis showed that 53% of the variation in the 8-week Hb concentration was explained by variations in baseline serum erythropoietin and the 2-week change in serum transferrin receptor (p < 0.001). Based on these two parameters, response prediction in individual patients would have resulted in a sensitivity of 96%, a specificity of 79% and an overall accuracy of 88%. In addition, 58% of the variation in the 8-week Hb was explained by variations in the 4-week changes in Hb and reticulocyte count (p < 0.001). Utilizing these latter parameters and baseline serum erythropoietin, response prediction in individual patients would have resulted in a sensitivity of 92%, a specificity of 82% and an overall accuracy of 88%. CONCLUSIONS: This retrospective analysis suggests that response to rHuEpo can be reasonably predicted by pretreatment serum erythropoietin together with early changes in simple laboratory parameters.     

The benefits of treatment with recombinant human erythropoietin in cancer patients]

IMPROVED QUALITY OF LIFE WITH EPOETIN BETA: In a study against a placebo, there was evidence that the quality of life scores were significantly improved in patients treated with epoetin beta, whether they exhibited a solid tumour or a malignant lymphoma. The same was noted in children with cancer exhibiting severe neoplasia and treated with chemotherapy. The efficacy and tolerance to treatment were equivalent, whatever the administration regimen. IN PATIENTS SUFFERING FROM MYELODYSPLASTIC SYNDROMES: A particular entity among malignant blood diseases, myelodysplastic syndromes are at the origin of anaemia against which repeated transfusions and growth factors are proposed with varying results and disadvantages, and against which erythropoietin may be moderately effective (a mean of 25% in non-selected cohorts of patients). DEPENDING ON THE PROTOCOLS OF ERYTHROPOIETIN ADMINISTRATION IN CASES OF MYELODYSPLASTIC SYNDROMES: Recombinant human erythropoietin, irrespective of its concentration in myelodysplastic cell culture, does not appear capable of restoring normal erythropoiesis. The influence of prolonged treatment is not admitted by all. The effects of the addition of growth factors (notably G-CSF) are obvious but some are controversial because of the costs and the prolonged duration of such treatments.     

Treatment of anemia in patients with chronic renal insufficiency with recombinant human erythropoietin

The discovery of recombinant human erythropoietin has enabled treatment of anaemia in patients whose anaemia was primarily caused by the lack of erythropoietin. This agent was most widely used in the treatment of anaemia in chronic renal failure patients. Non-regulated hypertension is considered to be the only absolute contraindication for recombinant human erythropoietin application, but thrombocytosis, predisposition to thromboses of arterio-venous fistulae, and convulsions are regarded as relative contraindications. Recombinant human erythropoietin may be administered intravenously, but the subcutaneous route is considered more rational. The treatment is initiated by low doses with gradual dose increase, what enables gradual anaemia correction and prevents the appearance of adverse effects. Haemoglobin level of around 100 g/l is considered the target haemoglobin level. The majority of patients respond well to treatment by human recombinant erythropoietin and the absence of anaemia improvement may be the result of iron deficiency, occult haemorrhages, chronic infection, inadequate dialysis, secondary hyperparathyroidism, aluminium intoxication. Anaemia improvement during the treatment with recombinant erythropoietin leads to the improvement of function of most organs and the quality of life in general as well as avoidance of blood transfusions and their adverse effects. The most frequent adverse effect of recombinant erythropoietin is the development of iron deficiency or hypertension aggravation.     

The effect of recombinant human erythropoietin on cardiovascular responses to postural stress in dialysis patients

The normal response to 45 degrees head-up tilt (decreased stroke volume and cardiac output and increased heart rate and peripheral resistance) is not seen in the majority of haemodialysis patients. This is due to both an abnormal baroreceptor reflex and increased venous tone which may be explained by a number of factors including hypoxia, acidosis and sodium retention. We have studied this response by impedance cardiography in eight chronic haemodialysis patients, both before and after 3 months of treatment with human recombinant erythropoietin. Before treatment the cardiovascular parameters were abnormal both at rest and on tilting in each patient. The change in each measurement following tilting was: stroke volume, 0.5 +/- 6%; cardiac output, 6 +/- 5%; peripheral resistance, -8 +/- 4%; and heart rate, 10 +/- 4%. After 3 months of erythropoietin (150 U/kg/week intravenously) the mean haematocrit had risen from 19.5 +/- 3% to 32.9 +/- 4% and all patients felt physically fitter. Impedance showed no change in the supine-indices but after tilting there was a dramatic fall in stroke volume (-26 +/- 7%) and cardiac output (-17 +/- 7%) and an increase in heart rate (15 +/- 4%) and peripheral resistance (28 +/- 10%) each moving towards the normal response. These results indicate that human recombinant erythropoietin normalizes the response to postural stress in these patients and suggest that anaemia is the principal cause of the abnormal venoconstriction seen in haemodialysis patients. The mechanisms involved warrant further investigation.     

Increased autologous blood donation in rectal cancer by recombinant human erythropoietin (rhEPO)

A randomised, placebo-controlled trial was conducted to study whether the subcutaneous administration of recombinant human erythropoietin (rhEPO) increases the donated red cell blood volume in patients with rectal cancer. Patients with resectable rectal cancer and a haemoglobin (Hb) level > or = 12.5/ > 12 g/dl (males/females) were scheduled to receive pre-operatively either erythropoietin (200 U/kg body weight daily) (n = 28) or placebo (n = 26) subcutaneously for 11 days. During this period autologous blood was collected. No serious adverse events were attributed to erythropoietin. 20 of 28 patients treated with rhEPO were able to donate > or = 3 units (71%) compared with 11 of 26 control patients (42%). The mean cumulative volume of red cells donated was 29% higher in the patients who received rhEPO (571 versus 444 ml, P = 0.02). The change in the mean reticulocyte value from baseline to the last pre-operative value was significantly higher in the rhEPO group (10.4 to 61.6/1000 versus 11.0 to 20.1/1000, P = 0.0001). The fall in the mean haematocrit from baseline to the last pre-operative value was significantly lower in the rhEPO group (41.4 to 37.6% versus 41.8 to 34.8%, P = 0.0004). rhEPO increases the ability of cancer patients to donate autologous blood during a short pre-operative period and enhances the restoration of haematological values after the donation period.     

Autoantibodies to human recombinant erythropoietin in patients with systemic lupus erythematosus: correlation with anemia

OBJECTIVE: To investigate the existence of circulating autoantibodies to erythropoietin (EPO) in sera from patients with systemic lupus erythematosus (SLE), and to correlate their presence with anemia and clinical activity. METHODS: Ninety-two consecutive patients with SLE, 80 patients with rheumatoid arthritis, and 42 normal individuals were studied. The patients with SLE were categorized into 3 groups according to hemoglobin (Hgb) level: group A (45 patients with Hgb > 12 gm/dl), group B (26 patients with Hgb 10.1-12 gm/dl), and group C (21 patients with Hgb < or = 10 gm/dl). In all patients with SLE, the disease activity was evaluated using the European Consensus Lupus Activity Measurement scale. Antibodies to EPO were detected using an enzyme-linked immunosorbent assay and purified recombinant human EPO as antigen. The specificity of the method was evaluated with homologous and cross-reactive inhibition assays. RESULTS: Antibodies to EPO were found in 15.2% of the SLE patient sera. The distribution of these antibodies among the 3 groups of SLE patients was as follows: 8.8% (4 of 45) from group A, 15.4% (4 of 26) from group B, and 28.6% (6 of 21) from group C. The prevalence of antibodies to EPO in patients with severe anemia (group C) was statistically significantly higher compared with patients without anemia (chi(2) = 4.31, P < 0.05). Patients with antibodies to EPO had higher disease activity scores (P < 0.005) and lower levels of the C4 component of complement (P < 0.05) compared with patients without antibodies to EPO. CONCLUSION: In this study, the presence of antibodies to EPO in the sera of SLE patients is demonstrated for the first time. The presence of these antibodies is associated with severe anemia and active disease.     

Effect of recombinant human erythropoietin on platelet production in dialysis patients

Two hundred forty-four anemic hemodialysis patients were randomized into recombinant erythropoietin and placebo-treated groups during a 12-wk double-blind phase, followed by a 24-wk open-label period. Mean platelet count rose from the baseline value of 242 x 10(9)/L to 264 x 10(9)/L on day 5 of epoetin therapy (P < 0.001, paired t test). Mean platelet count peaked at 290 x 10(9)/L on day 40 and remained at a significantly elevated level below the peak thereafter. The peak platelet count did not exceed the normal range in a majority of cases. Platelet count was unaffected by placebo. Patients without an erythropoietic response during the first few weeks of therapy exhibited a rise in platelet count comparable to that in patients with a satisfactory erythropoiesis. Patients with low initial serum ferritin concentrations had baseline platelet counts comparable to those with normal or high ferritin values and showed a similar rise in platelet count during therapy. As a group, patients with baseline platelet counts above 400 x 10(9)/L showed no rise in platelet count, whereas those with normal or reduced platelet counts showed a marked thrombopoietic response to epoetin. Erythropoietin therapy did not significantly alter the incidence of blood access thrombosis when compared with placebo treatment.     

Spontaneous gastroduodenal perforation in cancer patients receiving chemotherapy

BACKGROUND/AIMS: Spontaneous gastroduodenal perforation is a rare and lethal complication in cancer patients receiving chemotherapy. METHODOLOGY: Data of 9 patients with spontaneous gastroduodenal perforation occurring during chemotherapy were reviewed. RESULTS: All 9 patients were male with an average age of 54.4+/-2.5 years. The primary malignancies included 5 head and neck cancers, 2 esophageal cancers, 1 malignant lymphoma, and 1 hepatocellular carcinoma. Abdominal pain was the most common symptom. The average interval between the onset of symptoms and surgery was 2.9+/-0.7 days (range: 16 hours to 7 days). Perforation was located on the duodenum (6 patients) and on the lower part of the body of the stomach (3 patients). Simple closure of the perforation was performed on 8 patients, and subtotal gastrectomy on 1 patient. Culture of the ascitic fluid of 8 patients revealed E. coli, Klebsiella pneumoniae, streptococcus viridans, and enterococcus. Four patients (44.4%) had post-operative complications. The 30-day post-operative mortality was 44.4% (4/9). Three patients died of sepsis with multiple organ failure, and 1 died of hepatic failure. Age, anaemia, leukopenia, serum albumin levels, impaired renal or liver functions are not significant operative risk factors. Pre-operative shock is a significant factor in predicting operative mortality and complications. CONCLUSIONS: High index with suspicion of the disease with early treatment may improve survival of cancer patients with spontaneous gastroduodenal perforation.     

Correction of anaemia in haemodialysis patients with recombinant human erythropoietin

The binding and degradation of radiolabelled immune complexes by cultured rat glomerular mesangial cells were measured and compared with the binding and degradation by thioglycollate-elicited rat peritoneal macrophages. Mesangial cells are generally considered to be a modified pericyte with smooth muscle-like properties, but they were able to bind and degrade soluble immune complexes at rates comparable to those of the macrophages. In a second study, the ability of cultured mesangial cells to bind and degrade immune complexes of varying molecular weight was assessed. Very large, insoluble complexes were found to bind to mesangial cells more avidly than small soluble complexes, but unlike the small complexes, the large complexes did not appear to undergo degradation. These findings support a role for the intrinsic mesangial cell in the elimination of small soluble immune complexes as they arrive in the glomerulus. They also provide a possible explanation for the paradox that large immune complexes--i.e., electron-dense deposits--can persist in the mesangium next to the intrinsic mesangial cells without being rapidly destroyed.     

Effect of recombinant human erythropoietin on transfusion risk in coronary bypass patients

BACKGROUND: Patients having a cardiac operation frequently require allogeneic blood transfusions despite surgical blood-conservation techniques. Recombinant human erythropoietin (Epoetin alfa) may augment this conservation by stimulating erythropoiesis. The safety and efficacy of perioperative use of Epoetin alfa to reduce the need of allogeneic transfusion was studied. METHODS: A multicenter double-blind, placebo-controlled, parallel-group study involved 182 patients having coronary artery bypass grafting and randomized to receive Epoetin alfa (300 or 150 IU/kg) or placebo subcutaneously for 5 days before, on the day of, and for 2 days after operation. RESULTS: Perioperative Epoetin alfa resulted in greater increases in baseline to preoperative hemoglobin levels and hematocrit (300 IU/kg) and in presurgery to postsurgical day 1 reticulocyte counts versus placebo (p < or = 0.05). However, there was no significant difference in transfusion requirements. Incidences of adverse events were similar in all study groups. CONCLUSIONS: Lower incidences of allogeneic blood exposure were observed in both Epoetin alfa-treated groups; however, the differences between all treatment groups were not significant. This was probably due to the relatively short 5-day preoperative course of Epoetin alfa therapy. There were no significant differences between the three groups relative to safety. Epoetin alfa was well tolerated in this population.