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Preoperative Epoetin Alfa in Colorectal Surgery: A Randomized, Controlled Study

Department of Surgical Oncology, University Hospital, Medical School University of Crete, PO Box 1352, 71110, Herakleion, Greece

Correspondence: Address correspondence and reprint requests to: Dimitris D. Tsiftsis, MD, PhD, FACS, for the Hellenic Surgical Oncology Perioperative EPO Study Group; E-mail: tsiftsis{at}med.uoc.gr.

	ABSTRACT

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Background: Colorectal cancer patients are often anemic before surgery, and this leads to an increased requirement for allogeneic blood transfusion. This may result in transfusion-induced immunosuppression, which in turn leads to increased morbidity and possibly an increased rate of tumor relapse. We investigated the possible benefits of perioperative epoetin alfa administration in anemic patients to correct hemoglobin levels and reduce transfusion needs.

Methods: A total of 223 colorectal cancer patients with anemia scheduled for surgery were randomized to a group that received epoetin alfa 150 or 300 IU/kg/day subcutaneously for 12 days (day –10 to +1) or to a control group. All received iron (200 mg/day by mouth) for 10 days before surgery. Hemoglobin levels, hematocrit, and the number of blood units transfused were recorded.

Results: A total of 204 patients were eligible for analysis. Mean hemoglobin levels and hematocrit were significantly higher in the 300 IU/kg group than in the control group, both 1 day before surgery (hemoglobin, P = .008; hematocrit, P = .0005) and 1 day after surgery (hemoglobin, P = .011; hematocrit, P = .0008). Blood loss during and after surgery was similar in all groups. Patients who received epoetin alfa 300 IU/kg required significantly fewer perioperative transfusion units than control patients (.81 vs. 1.32; P = .016) and significantly fewer postoperative units (.87 vs. 1.33; P = .023). There were no significant differences in the number of units in the 150 IU/kg group.

Conclusions: Preoperative epoetin alfa (300 IU/day) increases hemoglobin levels and hematocrit in colorectal surgery patients. These effects are associated with a reduced need for perioperative and postoperative transfusions.

Key Words: Colorectal cancer • Epoetin alfa • Recombinant human erythropoietin • Hematocrit • Hemoglobin • Transfusion

	INTRODUCTION

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Blood transfusion requirements by patients undergoing operation for malignant tumors depend on the tumor type, the magnitude of the surgical procedure, and the presence of preoperative anemia. Of colorectal cancer patients, 45% to 85% require a transfusion during surgery because they present with anemia due to chronic blood loss.^1,2 However, allogeneic transfusion is accompanied by serious complications and may increase the risk of immunosuppression³; it has also been reported to increase the risk of cancer recurrence, although this is controversial.^4–12

Because of these risks, various alternatives to homologous transfusion have been investigated, including autologous blood predonation, hemodilution, and autotransfusion. However, there are still serious limitations and concerns about such alternatives, including the relatively low percentage (as low as 35%) of colorectal patients eligible for autotransfusion.^7,13 There is also the risk of reintroducing tumor cells into the patient.^14,15 The established anemia and the scheduling of an operation shortly after diagnosis often prevent predonation.

Results from prospective controlled trials of patients undergoing autologous phlebotomy for predonation suggest that the endogenous erythropoietin response to a reduced hemoglobin concentration has the potential to increase the red blood cell volume by 19% to 26% (equivalent to two or three units of blood) under conditions of aggressive phlebotomy (see Goodnough et al.¹⁶ for review). However, erythropoietin therapy has the p otential to increase red blood cell volume by 28% to 79% (two to nine units of blood) in a dose-related manner under similar phlebotomy conditions.¹⁶ Several clinical studies, including those in orthopedic, cardiac, and major abdominal surgical patients, have therefore assessed the use of epoetin alfa (recombinant human erythropoietin) to facilitate autologous predonation. Such studies have demonstrated that epoetin alfa can increase the number of preoperative autologous blood donations and, hence, decrease the requirement for allogeneic transfusion.^17–21 Little is known, however, about the ability of erythropoietin to reduce transfusion requirements per se or about its effects in patients undergoing operation for solid malignancies. We therefore initiated a randomized, controlled trial to evaluate the effects of preoperative and perioperative administration of epoetin alfa on hematological parameters (hematocrit and hemoglobin level) and on the requirement for blood transfusions in anemic patients undergoing elective surgery for colorectal cancer.

	PATIENTS AND METHODS

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Inclusion and Exclusion Criteria
Between January 1999 and June 2002, 223 patients aged >18 years undergoing elective colorectal surgery for resectable colorectal cancer in 18 centers throughout Greece were eligible for the study. Baseline hemoglobin levels were required to be >9 and <12 g/dL. Patients were excluded if they had severe concomitant disease, a history of thromboembolic disease or uncontrolled hypertension, an active infection, or indications of autoimmune hemolysis or if they had received androgen therapy, a blood transfusion, or agents that could suppress hemopoiesis (e.g., immunosuppressants) within the last 30 days. Pregnant women and patients with postoperative hemorrhage were also excluded. Patients were withdrawn if their hemoglobin level before the operation increased >15 g/dL, if there was postoperative hemorrhage, or the patient required reoperation.

Treatment and Study Design
This was an open-label clinical study in which patients were randomized (by a third party) into two treatment groups and a control group. The two treatment groups received subcutaneous epoetin alfa (either 150 or 300 IU/kg/day) plus oral elementary iron supplements (200 mg/day) for 10 days before the day of surgery until the day after surgery. The control group received supplemental elementary iron only (current and best clinical practice for Greek surgeons is to administer elementary iron before surgery). Supplemental iron was continued after surgery only in patients with iron deficiency and was administered as an intravenous dose of 40 mg of iron sulfate daily until the day of discharge. All patients received folic acid (15 mg/day) for the first 10 days after randomization. Patients in the two treatment groups were blind to the dosage received.

The primary study end point was the decrease in the need for blood transfusions. Secondary end points were the effects on hematocrit, hemoglobin, and reticulocyte count.

The institutional review board approved this study, and each patient gave informed consent. The study was performed in accordance with the Declaration of Helsinki and with European guidelines for good clinical practice.

Indications for Transfusion
Before surgery, patients received a transfusion if their hemoglobin was <11 g/dL and they had severe heart disease, chronic obstructive lung disease, or arterial disease; were receiving ß-blockers; or (for patients >60 years old) had lost a significant amount of blood. Younger patients (<60 years old) or those otherwise in generally good health also received a preoperative transfusion if their hemoglobin was <9 g/dL.

Perioperatively, patients received transfusions when blood loss exceeded 300 mL if they had heart or lung disease or arterial disease, were receiving ß-blockers, or were elderly. Younger patients or those otherwise in generally good health also received a preoperative transfusion when blood loss was >400 mL.

Patients received a transfusion if their hemoglobin was <10 g/dL after surgery and they had poor prognostic features (as described previously); for younger patients and those otherwise in generally good health, transfusion was initiated when their hemoglobin was <8 g/dL. In all cases, the investigator made the final judgment on whether to transfuse, on the basis of the protocol and the clinical condition of the individual patient.

Laboratory Evaluation
A physical examination was performed before randomization, and a complete medical history was taken. Hematological investigations were performed before epoetin alfa treatment, on the day before surgery, on the day of surgery (6 hours after the operation), and on days 1, 3, 7, and 15 after surgery. Full blood counts, reticulocyte counts, and iron, ferritin, and transferrin saturation were measured. Before epoetin alfa administration, vitamin B₁₂ levels and folic acid concentrations were measured: renal function, liver function, and nutritional status were also evaluated by using standard tests.

Statistical Analyses
Statistical analysis was performed with the SPSS 10.0 package (SPSS Inc., Chicago, IL). Data are expressed as mean ± SD, and a P value <.05 was considered to indicate statistical significance. Student’s t-test was used to compare pairs of mean values. The nonparametric Mann-Whitney test was used for mean values derived either from samples that did not follow normal distribution or from small samples. Comparisons of percentages and independence testing of two qualitative variables were performed with a ² test. Analysis of variance for repeated measurements was used to compare mean values of different parameters for different sampling times, and analysis of variance with two factors was used to determine interactions between the group and different samplings. A Bonferroni correction was applied when multiple comparisons of independent or related variables were made.

	RESULTS

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Of 223 patients in the intention-to-treat population, 204 (91.5%) were assessable for response (per-protocol population). Nineteen patients were excluded for protocol violations: three refused operation, seven refused to complete the study, four underwent operation before the scheduled time, two were allocated to the wrong group, and three received a preoperative transfusion outside study eligibility (of them, one required a nephrectomy, and one experienced a ruptured anastomosis). All patients were included in the safety analysis. Table 1 shows the demographic and baseline pathologic characteristics of the per-protocol population. The three groups were comparable with regard to age, weight, sex, height, and location of the primary tumor in the colon.

View larger version (19K): [in this window] [in a new window]   FIG. 1. Hemoglobin values during the study period. *P < .02 after Bonferroni correction. Baseline values are before any transfusion.

View larger version (18K): [in this window] [in a new window]   FIG. 2. Hematocrit values during the study period. *P < .05 versus control; P < .05 versus epoetin alfa 150 IU/kg, after Bonferroni correction. Baseline values are before any transfusion.

Mean platelet counts were significantly lower in the 300 IU/kg epoetin alfa group at baseline (day -10; 2.81 x 10⁵/mL) and day +7 (2.55 x 10⁵/mL) compared with the control group (3.06 x 10⁵ and 2.77 x 10⁵/mL; P = .013 and P = .0013, respectively). Reticulocyte and white blood cell counts in both the 150 and 300 IU/kg epoetin alfa groups were significantly lower than in the control group at baseline (day –10; P < .05). There were no other significant differences in hematological values at any time point. Iron stores in all groups were low at baseline but increased during the study because of the oral iron supplements. Mean ferritin concentrations in both epoetin alfa groups were significantly lower than in the control group at baseline (Table 2) and also at day +1 after surgery. By postoperative day +15 there were no significant differences among the three groups with respect to iron, ferritin, or transferrin saturation. In all patient groups, ferritin levels were significantly higher at study completion (day +15) than at baseline (Table 2).

Two patients were withdrawn because of adverse events. One patient in the 150 IU/kg epoetin alfa group developed a local rash that was judged as likely to be due to the study treatment. This patient received epoetin alfa for 12 days. Another patient in the control group had an urticarial allergy to iron.

There were five postoperative fatalities: three from cardiac arrest in the 300 IU/kg group and one from cardiac arrest and one from embolism in the 150 IU/ kg group. Other postoperative complications included three cases of cardiorespiratory failure in the 150 IU/kg group and one in the 300 IU/kg group, one case of grade 2 atrial fibrillation in the control group, and one case each of grade 2 neutropenia, peritonitis, and unexplained grade 2 urticaria in the 150 IU/kg group. All these nonfatal toxicities were resolved, and none of the complications was reported as being related to the study drug.

	DISCUSSION

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In this study, we have shown that epoetin alfa 300 IU/kg/day combined with an oral iron supplement significantly increases the hemoglobin concentration at the time of operation and increases hematocrit levels in patients undergoing elective colorectal surgery. Sustained significant increases in hematocrit and hemoglobin were not seen at a lower dosage (150 IU/kg/day), although trends were evident (Figs. 1 and 2). The 300 IU/kg/day epoetin alfa dosage reduced the requirement for perioperative blood transfusion (mean, .81 vs. 1.34 units per patient in control patients) and the requirement for postoperative transfusion (.87 vs. 1.35 units per patient in control patients). The benefits of 300 IU/kg epoetin alfa were also evident in the reduced number of patients who required transfusion, both perioperatively and postoperatively, although the reductions were not statistically significant.

It is likely that the increased hematocrit and hemoglobin levels in the 300 IU/kg group can explain the reduced requirement for transfusion. This hypothesis is strengthened by the data from patients who received 150 IU/kg epoetin alfa, in whom lesser effects on hematocrit and hemoglobin were associated with lesser (nonsignificant) effects on the requirement for transfusion.

Although related studies have been reported previously, they used different doses of epoetin alfa and different dosing schedules. Qvist et al.²² used a loading dose of 300 IU/kg followed by 150 IU/kg/day from 4 days before surgery to day +3 after surgery in colorectal surgery patients with hemoglobin 8.5 g/ dL. They reported that epoetin alfa significantly increased hemoglobin levels at the time of operation and during the following week and reduced the requirement for blood transfusion in the treatment group, but the difference was not significant. In contrast, the design of our study concentrated most on the patients’ preparation for successful surgery. We compared two different doses of recombinant human erythropoietin, which allowed us to address the possibility of administering lower doses should the two different dosage regimens have comparable efficacy. Our study has the additional advantage that more patients were included (223 vs 100 patients in the study of Qvist et al).

Hemoglobin levels <10 g/dL are required to induce the endogenous release of erythropoietin.²³ However, anemic cancer patients have a blunted response to erythropoietin,²⁴ such that increased levels of erythropoietin may be required to trigger erythropoiesis. Earlier studies, such as that by Heiss et al.,²⁵ suggested that erythropoietin must be combined with supplemental iron, because they observed a strong correlation between ferritin levels/transferrin saturation and the hemoglobin response in anemic colorectal cancer patients. Qvist et al.²² used supplemental iron, as we did, but reported no intergroup differences in transferrin, ferritin, or iron levels at study end. We found transferrin, ferritin, and iron levels to be comparable between groups at study end, although ferritin levels in both the 150 and 300 IU/kg groups were significantly lower than in the control group at baseline (Table 2). Such a reduction in ferritin is not unexpected: subjects treated with erythropoietin are known to show a rapid decrease in ferritin concentrations.¹⁶ It is likely that this ferritin reflects the iron content of a smaller, more labile pool of iron in equilibrium with the erythropoietic compartment and storage iron.¹⁶

In the study by Kettelhack et al.,²⁶ 20,000 U/day of epoetin beta did not significantly reduce transfusion requirements or increase hemoglobin levels in moderately anemic (hemoglobin, 8.5–13.5 g/dL) colorectal cancer patients. In that study, supplemental iron was administered only on demand (although most patients in both groups received it). Also, iron and transferrin saturation levels were significantly lower in the epoetin beta group at baseline, and iron levels remained lower in the epoetin beta group throughout the study; these factors possibly contributed to the lack of a significant increase in erythropoiesis. Univariate logistical analysis of our data indicates that lower hemoglobin levels and transferrin saturations are predictors of transfusion; this again suggests that the 300 IU/kg/day epoetin alfa dosage is necessary to increase hemoglobin levels and reduce the need for transfusion.

We chose a relatively high dose of epoetin alfa—300 IU/kg/day—because of the time constraints for preoperative administration in most surgical patients (5–10 days). Our dosage is roughly comparable to the dosage of epoetin beta used by Kettelhack et al.²⁶ In the chronic anemia of end-stage renal disease and in anemic cancer patients, several weeks’ treatment with 200 to 300 IU/kg epoetin alfa three times per week is necessary to increase hemoglobin levels markedly.^27,28 For this reason, and because of the results of previous studies in colorectal cancer patients using only 150 IU/kg,^22,25,29 we chose to use the relatively high 300 IU/kg/day dose, administered daily for 10 days before surgery. Significant erythropoiesis occurred by the end of the first week and was correlated with a reduced requirement for blood transfusions.

Erythropoietin was well tolerated in both groups; only one incidence of grade 2 rash was recorded. A review of the safety of erythropoietin in various indications revealed no significant problems when it was used as indicated.³⁰ The five fatalities during the course of the study and the postoperative follow-up represent 2% of colorectal patients: this is not an unexpected rate of loss in this patient population.

This study shows that perioperative administration of epoetin alfa (300 IU/day) combined with oral iron supplementation significantly reduces the number of blood transfusion units in patients with mild anemia who are undergoing operation for colorectal cancer. Although previous studies have suggested that 45% to 85% of these surgical patients normally require perioperative blood transfusion,^1,2 in our study only 37.3% of patients receiving 300 IU/kg epoetin alfa required perioperative transfusion. The administration of epoetin alfa to patients with colorectal cancer is well tolerated and safe. Further studies are necessary to define the most efficient and cost-effective dose and schedule of epoetin alfa during colorectal cancer surgery.

	APPENDIX 1: INVESTIGATORS FOR THE HELLENIC SURGICAL ONCOLOGY PERIOPERATIVE EPO STUDY GROUP

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E. Tsimogianis, Ioannina Hospital; E. Sanidas and P. Taflampas, Herakleion University Hospital; T. Chrisidis and K. Saliagas, Edessa Hospital; A. Tentes, Didimotiho Hospital; N. Chatzigeorgiou, G. Chrisafis, and S. Oikonomou, Theagenio Hospital; P. Vrachnos, KAT Hospital; C. Christakis, B’IKA Hospital; C. Farfarelos and V. Zompolas, Metaxa Hospital; J. Bramis, Laiko University Hospital; J. Androulakis and M. Stavropoulos, Patra University Hospital; D. Tsantilas, Hippokratio Thes. University Hospital; S. Skaltsas and S. Triantafilidis, Patision Hospital; E. Molis, Drama Hospital; K. Karamosxos, Papageorgiou Hospital; K. Chatzitheofilou and M. Spyridakis, Larisa University Hospital; P. Vasilopoulos and G. Platoniotis, Agios Savas Hospital; and A. Kapas and M. Fatouros, Ioannina University Hospital.

	FOOTNOTES

 
See Appendix 1 for a list of investigators in the Hellenic Surgical Oncology Perioperative EPO Study Group.

Received for publication June 22, 2004. Accepted for publication February 23, 2005.

	REFERENCES

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Christodoulakis, M. Search for Related Content PubMed PubMed Citation Articles by Christodoulakis, M.