|
|
Ann Surg. 2003 March; 237(3): 417–421. doi: 10.1097/01.SLA.0000055275.38740.56. | PMCID: PMC1514310 |
Copyright © 2003 Lippincott Williams & Wilkins, Inc. Perioperative Erythropoietin Administration in Patients With Gastrointestinal Tract Cancer Prospective Randomized Double-Blind Study Nicholas Kosmadakis, MD, Evangelos Messaris, MD, Antonis Maris, MD, Stylianos Katsaragakis, MD, PhD, Emmanouel Leandros, MD, PhD, Manoussos M. Konstadoulakis, MD, PhD, and George Androulakis, MD, PhD, FACS From the First Department of Propaedeutic Surgery, Hippokration General Hospital, Athens Medical School, University of Athens, Athens, Greece
Objective To investigate the effect of recombinant human erythropoietin (r-HuEPO) administration on perioperative hemoglobin concentrations and on the number of blood transfusions in patients undergoing surgery for gastrointestinal tract malignancies. Summary Background Data Erythropoietin has been shown to improve the yield of autologously predonated blood and to reduce the subsequent requirements for homologous blood transfusions in cancer patients. Methods In this double-blind placebo-controlled study, 31 cancer patients received subcutaneous r-HuEPO in a dose of 300 IU/kg body weight plus 100 mg iron intravenously (study group) and 32 patients received placebo medication and iron (control group). All patients received the medications daily for at least 7 days before and 7 days after the operation. Results Patients who received erythropoietin received significantly fewer transfusions intraoperatively and postoperatively. Postoperatively, the study group had significantly higher hematocrit, hemoglobin, and reticulocyte count values compared to the control group. The use of erythropoietin was also associated with a reduced number of postoperative complications and improved 1-year survival. Conclusions Patients with gastrointestinal tract cancer and mild anemia benefit from perioperative erythropoietin administration in terms of stimulated erythropoiesis, reduction in the number of blood transfusions, and a favorable outcome. Allogenic blood transfusions have been reported to be associated with a high cost, higher perioperative morbidity, and higher recurrence rate in patients with gastrointestinal tract cancers. Several attempts have been undertaken to reduce the use of blood transfusions by initiating autologous blood transfusion programs. 1–7 Erythropoietin has been used, in an experimental manner, to improve the yield of autologously predonated blood and to reduce the subsequent requirements for homologous blood transfusions, especially in orthopedic and colon cancer patients. 5,8In cancer patients, possible causes for anemia include bleeding, nutritional deficiencies, hemolysis, and suppressed hematopoiesis. Furthermore, inappropriately low levels of endogenous erythropoietin, lower than in patients with iron deficiency anemia at comparable hemoglobin values, have been reported. 9–11 To study the effect of exogenous perioperative erythropoietin administration in reducing the need for heterologous blood transfusions in cancer patients, we performed this prospective double-blind randomized study. Between January 2000 and May 2001, 75 patients with nonmetastatic cancer of the gastrointestinal tract treated in the A’ Department Of Propaedeutic Surgery of Athens Medical School were included in the study. The study inclusion criteria were a diagnosis of nonmetastatic gastrointestinal malignancy (stomach, 15; colon, 38; rectum 22), age between 40 and 90 years, and moderate anemia (hemoglobin values 8.5–13 g/dL). Exclusion criteria included severe concomitant disease, history of thromboembolic disease, pregnancy, history of hepatic or kidney dysfunction, systemic hematologic disease and blood transfusions within 30 days before surgery, or hemoglobin values more than 13 or less than 8.5 g/dL. Patients were randomized either into the study group, receiving 300 iv/kg body weight Epoietinum Alfa (Janssen-Cilag AG, Europe) subcutaneously each day, or into the control group, receiving placebo medication. All patients were given 100 mg iron (Venofer, Switzerland) intravenously each day. Erythropoietin or placebo applications were given for 14 days perioperatively, starting 7 days before the operation. Patients received the regimens on an outpatient basis. The regimens were administered and blood samples were obtained in our 1-day clinic, where patients were admitted for 2 hours in an outpatient manner while remaining under continuous surveillance for possible adverse effects. Informed consent was obtained from all patients. Both patients and investigators were blinded for the performed application. Intraoperative blood loss was estimated by the amount of blood collected in the aspirator and by the weight of the gauzes used. The indication for blood transfusion was a hemoglobin value of 8.5 g/dL or less. In all patients, blood cell counts and serum chemistries were performed every second day until discharge. In addition, reticulocytes, ferritin, and iron were measured at admission, the day of operation, and at discharge. Patients and Data Management In a 16-month period, we enrolled 75 patients in the study. Twelve randomized patients were excluded from the study because they did not fulfill the inclusion criteria. Two had had blood transfusions within 1 month before study, four dropped out for personal reasons, two were excluded due to protocol violation, and four were proven at operation to have distant metastases. Statistical Analysis The Student t test was used to compare means of measures. The paired sampled t test was used to compare values of hematocrit, hemoglobin, and reticulocytes in all the patients in different time points. Chi-square and Fisher exact tests were used where applicable. The Kaplan-Meier curve was used for univariate survival analysis, while outcome measures were evaluated using a multivariate Cox regression analysis. Statistical significance was achieved at P < .05. Randomization Sixty-three patients were randomized, 31 (49.2%) into the study group and 32 (50.8%) into the control group. Clinicopathological data are depicted in Table 1. Hematologic profiles at admission revealed no significant differences between the two groups ( Table 2). Comparable hemoglobin and hematocrit values at admission and comparable fluid administration and losses at operation indicate similar transfusion status for both groups. | Table 1. CLINICOPATHOLOGIC DATA |
| Table 2. HEMATOLOGIC PROFILE |
Operative and Postoperative Transfusions During operation, 28 (44.4%) patients were transfused because of intraoperative blood loss (10 of them were also transfused postoperatively) with a hemoglobin level of less than 8.5 g/dL. Of these, nine patients (29%) who received transfusions (total of 20 units of packed red blood cells) had received erythropoietin preoperatively. Nineteen patients (59.3%) who did not receive erythropoietin before surgery were also transfused (total of 46 units of packed red blood cells). The difference in the operative transfusion rate between the study and the control group was statistically significant (9 patients with a total of 20 units vs. 19 patients with a total of 46 units; P = .023). In addition, during the postoperative period a markedly increased number of patients (n = 9 [28%]) from the control group received an allogenic transfusion compared to only one patient (3.2%) in the study group who was transfused ( P = .001) ( Table 3). | Table 3. TRANSFUSION DATA |
Hemoglobin and Reticulocyte Counts in Study Group A statistically significant increase in hemoglobin levels between study onset and the operation was observed in the erythropoietin group (P = .01). A similar increase in hemoglobin values in patients treated with erythropoietin was observed between the initiation of the treatment and the seventh postoperative day (P = .01), as well as between the operation day and the seventh postoperative day (P = .02) (). To investigate whether this increase was due to stimulated hematopoiesis, the course of reticulocyte counts was analyzed, and a comparable highly significant increase was detected between the day of study onset and the seventh postoperative day in the study group (P = .0001) (). Comparison of Hematocrit, Hemoglobin, and Reticulocyte Counts in the Two Groups An increase in preoperative hematocrit and hemoglobin values was detected in the treatment group compared to the placebo group, but it was not statistically significant ( P > .05). However, in the postoperative period, the mean hemoglobin and hematocrit values in erythropoietin-treated patients were consistently higher compared to patients in the control group. Significant differences in the mean hemoglobin and hematocrit values between the two groups were observed at the third ( P = .04, P = .01), fifth ( P = .04, P = .04), and seventh ( P = .003, P = .001) postoperative days (see ). Significant differences in reticulocyte values, the major marker of stimulated hematopoiesis, were also observed between the two groups on the fifth ( P = .008) and first ( P = .001) preoperative days as well as on the fifth ( P = .002) and seventh ( P = .001) postoperative days (see ). Transfusion data of patients at discharge are presented in Table 4. | Table 4. HEMATOLOGIC PROFILE AT DISCHARGE |
Outcome of Patients Twenty patients (31.7%) experienced postoperative complications, such as anastomotic leak (1 [1.6%]), abscess/fistula formation (1 [1.6%]), hemorrhage (5 [7.9%]), wound infection (6 [9.5%]), pulmonary complications (4 [6.3%]), and complications from blood transfusions (3 [4.8%]). Complications were mostly observed in patients who did not receive erythropoietin treatment (n = 13 [40.6%] vs. n = 4 [12.9%]) (P = .02). Additionally, patients receiving transfusions had a higher complication rate (n = 13 [46.4%]) compared to the control group (n = 4 [11.4%]) (P = .004). Furthermore, the duration of hospitalization was significantly increased in the control group (13 ± 0.9 days vs. 10 ± 0.5 days;P = .022). The 1-year survival rate was found to be significantly higher in patients receiving erythropoietin treatment (80.6% vs. 59.3%, P = .04). In a multivariate model of analysis, we evaluated the impact of erythropoietin treatment on the survival of patients with gastrointestinal cancer and found that the use of erythropoietin improves the outcome of operated cancer patients ( Table 5). | Table 5. MULTIVARIATE ANALYSIS OF PROGNOSTIC FACTORS |
Side effects possibly attributable to erythropoietin were observed in five cases. Three patients reported mild and transient hypertension and two clinical deep venous thrombosis. Still, there were also two patients in the control group with mild hypertension and one with deep venous thrombosis. Those events were considered by the investigators as unrelated to the administration of the studied drug. No major allergic reactions were reported. Anemia is common in cancer patients, although the prevalence is influenced both by the type of malignancy and the choice of treatment. In most cases it is a mild to moderate, hyporegenerative anemia with a relatively reduced reticulocyte count, a process in which erythropoietin and iron play prominent causative roles. 12Most anemic patients with cancer of the gastrointestinal tract have iron deficiency due to subclinical blood loss; therefore, an iron supplement has been advocated. 2,13 Still, iron supplementation has not been found to be able to stimulate erythropoiesis to a sufficient degree to facilitate autologous blood donation or to reduce the need for allogenic blood transfusions in cancer patients. 2 This could be due to a reticuloendothelial blockage of iron, characteristic of several other conditions seen in these patients. 12The percentage of patients transfused differs widely among various centers, ranging from 0% to 78%. 14 The overall risk associated with transfusions of heterologous blood has been reduced due to extensive laboratory testing, but recipients are still at risk for transfusion reactions, transmission of unknown diseases, and immunosuppression. Furthermore, the number of transfusions is believed to be associated with worse prognosis in cancer patients. 5,15–17Several studies have examined the yield of autologous predonated blood following erythropoietin administration. In the study by Braga et al., preoperative erythropoietin treatment was found to facilitate autologous blood donation in anemic patients with cancer of the gastrointestinal tract, resulting in a reduction of perioperative homologous blood transfusions. 2 Still, the delay in the time of operation of cancer patients prohibits its widespread use. This randomized double-blind study has demonstrated that supplementing erythropoietin and iron for at least 14 days can stimulate the hematopoiesis of patients with gastrointestinal tract cancer–induced anemia. We administered iron intravenously to obtain the full effect of erythropoietin, as recommended in patients with a baseline serum ferritin of less than 100 ng/mL. 18 The dependency of the hemoglobin response on iron availability indicates a potential therapeutic synergism of intravenously administrated iron and erythropoietin. 19An increase in the doses of erythropoietin (20,000 units) offers a further possibility for enhancing the effectiveness of erythropoietin because it is not the peak but the maintenance of its blood levels that seems to be the major determinant of its efficiency. 20A cost-effectiveness analysis may be difficult to perform because the costs of the potential risks from blood transfusions are difficult to calculate and the cost of erythropoietin may not be so expensive, considering the benefits of the treatment. The cost of allogenic transfusion in our hospital is estimated at 400 euros per unit. Conversely, the administration of erythropoietin costs 180 euros per day (supplemental iron administration: 20 euros per day), and it was found to be related to a lower postoperative complication rate and better survival outcome. We demonstrated that allogenic transfusions were associated with an increased number of postoperative complications, leading to a longer hospital stay. The daily cost of hospitalization is 400 euros. Although erythropoietin administration costs more than expected, an uncomplicated postoperative period and better survival time cannot be calculated in a simple cost/benefit equation. Furthermore, in patients who consider blood transfusions to be unethical for religious reasons, erythropoietin administration represents the only alternative. This study showed that short-term perioperative administration of recombinant human erythropoietin decreases the need for allogenic blood transfusions in anemic patients undergoing surgery for gastrointestinal tract cancer. Erythropoietin also appears to be associated with a favorable complication and survival outcome for these cancer patients. 1. Benoist S, Panis Y, Pannegeon V, et al. Predictive factors for perioperative blood transfusions in rectal resection for cancer: A multivariate analysis of a group of 212 patients. Surgery. 2001; 129: 433–439. [PubMed] 2. Braga M, Gianotti L, Vignali A, et al. Evaluation of recombinant human erythropoietin to facilitate autologous blood donation before surgery in anaemic patients with cancer of the gastrointestinal tract. Br J Surg. 1995; 82: 1637–1640. [PubMed] 3. Braga M, Gianotti L, Gentilini O, et al. Erythropoietic response induced by recombinant human erythropoietin in anemic cancer patients candidate to major abdominal surgery. Hepato-Gastroenterology. 1997; 44: 685–690. [PubMed] 4. Braga M, Gianotti L, Gentilini O, et al. Erythropoiesis after therapy with recombinant human erythropoietin: a dose-response study in anemic cancer surgery patients. Vox Sang. 1999; 76: 38–42. [PubMed] 5. Jeekel J. Autologous blood donation and erythropoietin alfa in cancer surgery. Semin Hematol. 1996; 33 (2 Suppl 2):43–46. 6. Madura JA. Use of erythropoietin and parenteral iron dextran in a severely anemic Jehovah’s Witness with colon cancer. Arch Surg. 1993; 128: 1168–1170. [PubMed] 7. Pedain C, Herrero J, Kunzel W. Serum erythropoietin levels in ovarian cancer patients receiving chemotherapy. Eur J Obstet Gynecol Reprod Biol. 2001; 98: 224–230. [PubMed] 8. Bennett TA, Wingert J. Criteria for use of erythropoietin alfa in adult cancer and orthopedic-surgery patients. Clin Pharm. 1993; 12: 925–928. [PubMed] 9. Ludwig H, Fritz E, Leitgeb C, et al. Erythropoietin treatment for chronic anemia of selected hematological malignancies and solid tumors. Ann Oncol. 1993; 4: 161–167. [PubMed] 10. Adamson JW, Spivak JL. Physiologic basis for the pharmacologic use of recombinant human erythropoietin in surgery and cancer treatment. Surgery. 1994; 115: 7–15. [PubMed] 11. Glimelius B, Linne T, Hoffman K, et al. Erythropoietin beta in the treatment of anemia in patients with advanced gastrointestinal cancer. J Clin Oncol. 1998; 16: 434–440. [PubMed] 12. Means RT Jr, Krantz SB. Progress in understanding the pathogenesis of the anemia of chronic disease. Blood. 1992; 80: 1639. [PubMed] 13. Heiss MM, Tarabichi A, Delanoff C, et al. Perisurgical erythropoietin application in anemic patients with colorectal cancer: A double-blind randomized study. Surgery. 1996; 119: 523–527. [PubMed] 14. Sirchia G, Giovanetti AM, McClelland DBL, et al, eds. Use of blood products and artificial colloids in 43 European hospitals. Medicine and Health. 1994;EUR15398:75–99. 15. Levine EA, Laborde C, Hambrick E, et al. Influence of erythropoietin on transfusion requirements in patients receiving preoperative chemoradiotherapy for rectal cancer. Dis Colon Rectum. 1999; 42: 1065–1069. [PubMed] 16. Kettelhack C, Hones C, Messinger D, et al. Randomized multicentre trial of the influence of recombinant human erythropoietin on intraoperative and postoperative transfusion need in anaemic patients undergoing right hemicolectomy for carcinoma. Br J Surg. 1998; 85: 63–67. [PubMed] 17. Glaser CM, Millesi W, Kornek GV, et al. Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys. 2001; 50: 705–715. [PubMed] 18. Goldberg MA. Erythropoiesis, erythropoietin, and iron metabolism in elective surgery: preoperative strategies for avoiding allogenic blood exposure. Am J Surg. 1995;(Suppl 6A):37S. 19. Mercuriali F, Zanella A, Barosi G, et al. Use of erythropoietin to increase the volume of autologous blood donated by orthopedic patients. Transfusion. 1993; 33: 55–60. [PubMed] 20. Bommer J, Barth HP, Zeief M, et al. Efficacy comparison of intravenous and subcutaneous recombinant human erythropoietin administration in hemodialysis patients. J Nephrol. 1991; 88: 136–143.
|
This article has been 
