Ann Thorac Surg 2006;82:293-297
© 2006 The Society of Thoracic Surgeons
Original article: General thoracic
Erythropoietin-alfa During Neoadjuvant Chemotherapy for Locally Advanced Esophagogastric Adenocarcinoma
Kathrin Abbrederis, MD
a
,
Florian Bassermann, MD
a
,
Christoph Schuhmacher, MD
b
,
Verena Voelter, MD
e
,
Raymonde Busch, MS
c
,
Nadine Roethling
d
,
Andreas Sendler, MD
b
,
Joerg R. Siewert, MD
b
,
Christian Peschel, MD
a
,
Florian Lordick, MD
a
,
*
a Third Department of Medicine (Hematology/Oncology), Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
b Department of Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
c Institute for Medical Statistics and Epidemiology, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
d Munich Center for Clinical Studies, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
e Multidisciplinary Oncology Center, University Hospital CHUV, Lausanne, Switzerland
Accepted for publication January 26, 2006.
* Address correspondence to Dr Lordick, Third Medical Department (Hematology/Oncology), Klinikum rechts der Isar, Technical University of Munich, Ismaninger Str 22, D-81675 Munich, Germany (Email: f.lordick{at}lrz.tu-muenchen.de).
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Abstract
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BACKGROUND: In a previous study we showed that many patients with esophagogastric adenocarcinoma experience anemia during neoadjuvant chemotherapy. We now investigated the role of erythropoietin in managing anemia during neoadjuvant chemotherapy.
METHODS: Patients with esophagogastric adenocarcinoma who experienced anemia (hemoglobin < 12 g/dL) during neoadjuvant treatment received erythropoietin 10,000 IE subcutaneously three times a week. Primary outcomes were the response to erythropoietin, safety, the need for allogeneic red blood cell transfusion, and the rate of postoperative complications.
RESULTS: Between April 2003 and December 2004, 24 patients (median age, 62 years) were enrolled. The mean hemoglobin level before chemotherapy was 12.5 g/dL and the mean hemoglobin level before patients received erythropoietin was 11.5 g/dL. One year after involvement in the trial, 4 of 17 analyzable patients were still anemic (hemoglobin level < 12 mg/dL). Twenty-two patients received erythropoietin, and 16 (73%) responded. We could observe a significant increase in hemoglobin concentrations under therapy with erythropoietin to 12.6 g/dL (p < 0.001). Two patients (8%) received allogeneic transfusions; the rate of postoperative complications was 16%. There were no erythropoietin-related adverse events.
CONCLUSIONS: Treatment with erythropoietin is effective and well tolerated in patients with esophagogastric adenocarcinoma who experience anemia during neoadjuvant chemotherapy.
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Introduction
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Cancer-related anemia decreases patients' quality of life and may negatively affect treatment results [1–3]. Anemia is independently associated with shorter survival times in patients with cancer [4], and correction of anemia may have a positive impact on treatment outcomes [5–8]. Therefore, optimal management of anemia appears to be a critical component of cancer treatment [1]. Moreover, newer chemotherapeutic agents and drug combinations have made anemia an even more clinically significant problem.
Reports in the literature indicate that allogeneic blood transfusions are associated with higher perioperative morbidity and a higher recurrence rate in patients with cancers of the gastrointestinal tract [9]. Furthermore, allogeneic blood transfusions potentially expose patients to bloodborne viruses such as hepatitis B and C and human immunodeficiency virus. Moreover, there is rising evidence that anemia and perioperative red cell blood transfusions are associated with poorer outcome after surgery in several tumor types [10–16]. A recent study of patients undergoing esophagectomy for carcinoma demonstrated that perioperative blood transfusions were associated with poorer survival [17].
In the 1990s the identification and clinical development of the recombinant hematopoietic growth factor, erythropoietin, led to more effective management of anemia. Anemia caused by malignancy may be related to direct infiltration of marrow elements by cancer cells, an impaired production process related to treatment, or other nonspecific processes, such as the inhibitory effect of tumor necrosis factor, which accounts for the anemia of chronic disorders, iron deficiency, or low endogenous erythropoietin levels. In 1989, the U.S. Food and Drug Administration approved Epoetin, the human recombinant form of erythropoietin, as a treatment for anemia in patients with chronic renal failure. Since then, numerous studies have examined its potential usefulness as an alternative to transfusion in the management of anemia in cancer patients.
We have shown in a previous study that a high proportion of patients with esophagogastric adenocarcinoma who undergo neoadjuvant chemotherapy experience anemia. Every third patient requires preoperative transfusion and the postoperative complication rate is significantly elevated in this group [18]. We therefore initiated a study to investigate the role of erythropoietin in patients experiencing anemia during neoadjuvant chemotherapy for esophagogastric adenocarcinoma.
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Patients and Methods
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We initiated a single-center, prospective, nonrandomized, phase 2 clinical trial at the Klinikum rechts der Isar, Technical University of Munich. The study drug was Epoetin alfa (ERYPO or ERYPO FS; Janssen-Cilag GmbH, Neuss, Germany).
Patients older than 18 years with American Joint Committee of Cancer clinical stage T3 esophagogastric adenocarcinoma, a Karnofsky performance score of at least 60, and ongoing treatment with neoadjuvant platinum-based chemotherapy for at least 6 weeks were eligible for the study. Tumors of the esophagogastric junction were classified according to the Siewert classification [19]. The standard chemotherapy regimens were PLF (cisplatin 50 mg/m2 on day 1, 15, and 29, and leucovorin 500 mg/m2 and 5-fluorouracil [5-FU] 2,000 mg/m2 on day 1, 8, 15, 22, 29, and 36), OLF (oxaliplatin 85 mg/m2 on day 1, 15, and 29, and leucovorin 500 mg/m2 and 5-FU 2,000 mg/m2 on day 1, 8, 15, 22, 29, and 36) for patients with contraindications for cisplatin (ie, glomerular filtration rate 70 mL · min–1
· m–2 or less), or paclitaxel (80 mg/m2 on day 1, 15, and 29) and PLF for medically fit patients younger than 60 years of age.
Patients were also required to have a chemotherapy-induced reduction in hemoglobin level to less than 12 g/dL in the absence of active hemorrhage, uncontrolled arterial hypertension, and thromboembolic cardiovascular disease. Patients with cardiac, hepatic, or renal dysfunction as well as patients with epilepsy or vitamin B12 or folic acid deficiency were excluded.
Eligible patients received erythropoietin three times a week (10,000 IE) given subcutaneously. Treatment with erythropoietin was interrupted if the hemoglobin level increased to 13 g/dL or greater. If there was no increase of the hemoglobin level within 4 weeks, treatment with erythropoietin was discontinued. Blood transfusions were given if the hemoglobin level was lower than 10 g/dL or if they were presenting anemic symptoms. Oral Fe-II substitution (200 to 300 mg/day) was recommended to all patients if the level of serum ferritin was less than 100 ng/mL or if transferrin saturation was less than 20%.
The primary study end point was the response to therapy with erythropoietin. Secondary end points were the safety of treatment with erythropoietin during neoadjuvant chemotherapy for gastroesophageal adenocarcinomas, the preoperative need for allogeneic blood transfusions, and the rate of postoperative complications. Sample size was calculated according to Gehan's two-stage design [20]. With an 
error of 0.05 and a power 1 – ß of 0.95, 24 patients had to be included to demonstrate that the hemoglobin response after treatment with erythropoietin-alfa was 50% or greater.
Comparisons between the actual study population and data obtained in 29 patients of our previous study [18] were performed using Fisher ‘s exact test (Stat Xact, Version 4.0.1, Cytel Software Cooperation, Cambridge, MA).
The trial was approved by the ethics committee of the Technical University of Munich, and all patients provided written informed consent.
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Results
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Between April 2003 and December 2004, 24 patients were enrolled. There were 19 men and 5 women, with a median age of 62 years (range, 48 to 77 years; Table 1). The mean hemoglobin level before chemotherapy was 12.5 g/dL, and the mean hemoglobin level before first application of erythropoietin was 11.5 g/dL. Twenty-two of 24 patients received erythropoietin. One patient refused treatment, and another patient had a thromboembolic complication before the planned first application of erythropoietin and therefore did not receive the study drug.
Sixteen of 24 patients (67%) in the intent-to-treat population and 16 of 22 patients (73%) in the per-protocol population responded (Fig 1). The hemoglobin level after therapy with erythropoietin was significantly higher (p < 0.001) than before therapy (Table 2,
Fig 2). An increase in hemoglobin level of greater than 1 g/dL was seen in 10 patients (45%). Hemoglobin concentrations of less than 12 g/dL were observed in only 7 of 22 patients (32%) after therapy with erythropoietin.
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Fig 1. Effect of erythropoietin on hemoglobin levels in patients with esophagogastric adenocarcinoma undergoing neoadjuvant chemotherapy.
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Fig 2. Effect of erythropoietin (Erypo) on mean hemoglobin levels in patients with esophagogastric adenocarcinoma undergoing neoadjuvant chemotherapy. (95% CI = 95% confidence interval.)
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Two of 24 patients (8%) received allogeneic blood transfusions during the preoperative period. Postoperatively, 12 patients required blood transfusions; none of the patients received erythropoietin postoperatively.
Four of 24 patients (16%) experienced postoperative complications, including two anastomotic leakages, one infection of unknown origin, and one acute coronary syndrome with pneumonia (Table 3).
Treatment with erythropoietin was well tolerated. In the intent-to-treat population, 1 patient was reported to have a deep vein thrombosis. This event occurred after study inclusion but before the first application of erythropoietin. None of the erythropoietin-treated patients had any thromboembolic cardiovascular event. Apart from the usual toxicities associated with platinum and 5-FU–based chemotherapy, there was no evidence for additional erythropoietin-induced toxicity.
Median follow-up of the study population is 19 month. Until last observation (December 2005), 13 of 24 patients had a tumor relapse and 11 patients have died. Median relapse-free survival is 26 months. Median overall survival is 19 months. One year after involvement in the trial, 4 of 17 analyzable patients were still anemic (hemoglobin level less than 12 mg/dL).
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Comment
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Treatment with erythropoietin appears to be effective and well tolerated for the management of anemia during neoadjuvant chemotherapy in patients with locally advanced esophagogastric adenocarcinoma.
In a previous study, published in 2004, we investigated the incidence of anemia and blood transfusions in patients receiving neoadjuvant chemotherapy for locally advanced esophagogastric adenocarcinoma [18]. We found that the majority of patients sustained anemia during neoadjuvant treatment and that the postoperative complication rate was increased in those patients who received preoperative red blood cell transfusions. The results of the current study should be interpreted in view of our previous findings. The two study populations can be compared with each other because of similar patient characteristics and analogous treatment algorithms. In the previous study 29 patients (21 men; median age, 59.5 years) received at least one full cycle of neoadjuvant platinum-based chemotherapy. The same chemotherapy regimens as in the current study were given. The median hemoglobin level before the start of chemotherapy was 14.0 g/dL. None of these patients were treated with erythropoietin, and the median total decline of the hemoglobin level during the whole observation period was 2.9 g/dL [18]. In contrast, in the current study population, a decrease in the hemoglobin level was avoided by treating anemic patients with erythropoietin. Consequently, only 2 of 24 patients required preoperative red blood cell transfusions.
Of the 22 patients who received erythropoietin, 73% responded. In another study [21], response (defined as an increase in the hematocrit value of six or more percentage points) was observed in 48% of patients, whereas Ludwig and associates [22] identified a response (defined as an increase in hemoglobin of 2 g/dL or greater) in 50% of their patients. Notably, no erythropoietin-related adverse events such as thromboembolism were observed in this study.
We did not intend to stimulate erythropoiesis to the maximum because of the known increased risks for complications associated with unphysiologically high hemoglobin levels [23]. Erythropoietin was withdrawn in our trial when hemoglobin levels began to rise greater than 12 g/dL. Our main aim was to prevent a further drop to reduce the need for preoperative blood transfusions.
Compared with our previous study the incidence of preoperative transfusions declined from 28% of all patients in the comparison group to 8% in the current trial, which corresponds to a 71% decline in transfusion rate. Concurrently, a trend to a reduction in the postoperative complication rate compared with the previous study population was observed, although this did not reach statistical significance (16% versus 38%; Table 3). We demonstrated in our previous trial that patients who receive a transfusion are at a significantly increased risk of having postoperative complications [18]. Findings from a meta-analysis of more than 5,000 patients support the hypothesis that perioperative allogeneic blood transfusions may be detrimental for cancer patients [17, 24]. In the current trial we could show that erythropoietin administration was associated with a low complication rate. These findings are noteworthy although they do not necessarily support a causal relationship between preoperative anemia treatment and a decline in postoperative complications.
Perhaps more importantly, anemia itself appears to be an independent prognostic factor for local control [25] and survival in cancer patients [26]. This has largely been investigated in the context of combined modality treatment for head and neck cancer patients. Patients with normal hemoglobin levels or those who received erythropoietin to correct anemia had a significantly better response to treatment, improved local control, and survival [7]. Conversely, however, a study in 351 patients with head and neck tumors undergoing radiotherapy showed that there was no benefit in terms of locoregional progression or survival despite a reliable rise in hemoglobin concentration [27]. It is important to point out that in this later trial hemoglobin levels in the erythropoietin group were unphysiologically high (median, 15.4 g/dL). Therefore, detrimental side effects as a result of overtreatment must be assumed.
The design of our study does not allow us to make any conclusions regarding the impact of erythropoietin on local control or survival. Nevertheless, our findings are important because there are no data published to date regarding the efficacy and safety of treatment with erythropoietin in patients with upper gastrointestinal cancer receiving neoadjuvant chemotherapy. The observed reduction in preoperative transfusions during treatment with erythropoietin and the associated low rate of perioperative complications are interesting. As evidence supporting the use of neoadjuvant chemotherapy in the treatment of esophagogastric carcinoma increases [28–30], a randomized trial evaluating the role of erythropoietin in this setting is clearly warranted.
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Acknowledgments
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This study was supported in part by a research grant from Ortho Biotech, a division of Janssen-Cilag GmbH. We thank Dr Germershaus for her scientific support.
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References
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- Demetri GD. Anaemia and its functional consequences in cancer patientscurrent challenges in management and prospects for improving therapy. Br J Cancer 2001;84(Suppl 1):17-23.
- Ludwig H, Strasser K. Symptomatology of anemia Semin Oncol 2001;28(Suppl 2):7-14.[Medline]
- Glaspy J. Anemia and fatigue in cancer patients Cancer 2001;92(Suppl 6):1719-1724.[Medline]
- Caro JJ, Salas M, Ward W, et al. Anemia is an independent prognostic factor for survival in patients with cancer Cancer 2001;91:2214-2221.[Medline]
- Littlewood TJ, Bajetta E, Nortier JWR, et al. Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapyresults of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 2001;19:2865-2874.[Abstract/Free Full Text]
- Grogan M, Thomas GM, Melamed I, et al. The importance of hemoglobin levels during radiotherapy for carcinoma of the cervix Cancer 1999;86:1528-1536.[Medline]
- 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.[Medline]
- Blohmer JU, von Minckwitz G, Paepke S, et al. Sequential adjuvant chemo-radiotherapy with vs. without erythropoietin for patients with high-risk cervical cancer—second analysis of a prospective randomized, open and controlled AGO- and NOGGO-intergroup study[Abstract] Proc Am Soc Clin Oncol 2002;21:206A(abstract 823).
- Kosmadakis N, Messaris E, Maris A, et al. Perioperative erythropoietin administration in patients with gastrointestinal tract cancerprospective randomized double-blind study. Ann Surg 2003;237:417-421.[Medline]
- Busch O, Hop W, Hoynck van Papendrecht M, Marquet RL, Jeekel J. Blood transfusions and prognosis in colorectal cancer N Engl J Med 1993;328:1372-1376.[Abstract/Free Full Text]
- Burrows L, Tartter P. Effect of blood transfusions on colonic malignancy recurrent rate Lancet 1982;2:662.[Medline]
- Fong Y, Karpeh M, Mayer K, Brennan MF. Association of perioperative transfusions with poor outcome in resection of gastric adenocarcinoma Am J Surg 1994;167:256-260.[Medline]
- Jones KR, Weissler MC. Blood transfusion and other risk factors for recurrence of cancer of the head and neck Arch Otolaryngol Head Neck Surg 1990;116:304-309.[Medline]
- Rosenberg SA, Seipp CA, White DE, Wesley R. Perioperative blood transfusions are associated with increased rates of recurrence and decreased survival in patients with high-grade soft-tissue sarcomas of the extremities J Clin Oncol 1985;3:698-709.[Abstract]
- Yamamoto J, Kosuge T, Takayama T, et al. Perioperative blood transfusion promotes recurrence of hepatocellular carcinoma after hepatectomy Surgery 1994;115:303-309.[Medline]
- Dresner SM, Lamb PJ, Shenfine J, Hayes N, Griffin SM. Prognostic significance of peri-operative blood transfusion following radical resection for oesophageal carcinoma Eur J Surg Oncol 2000;26:492-497.[Medline]
- Langley SM, Alexiou C, Bailey DH, Weeden DF. The influence of perioperative blood transfusion on survival after esophageal resection for carcinoma Ann Thorac Surg 2002;73:1704-1709.[Abstract/Free Full Text]
- Voelter V, Schuhmacher C, Busch R, Peschel C, Siewert JR, Lordick F. Incidence of anemia in patients receiving neoadjuvant chemotherapy for locally advanced esophagogastric cancer Ann Thorac Surg 2004;78:1037-1041.[Abstract/Free Full Text]
- Siewert JR, Stein HJ. Classification of adenocarcinoma of the oesophagogastric junction Br J Surg 1998;85:1457-1459.[Medline]
- Gehan EA. The determination of the number of patients required in a preliminary and a follow-up trial of a new chemotherapeutic agent J Chronic Dis 1961;13:346-353.[Medline]
- Abels RI, Larholt KM, Krantz KD, Bryant EC. Recombinant human erythropoietin (rHuEPO) for the treatment of the anemia of cancer Oncologist 1996;1:140-150.[Abstract/Free Full Text]
- Ludwig H, Fritz E, Kotzmann H, Hocker P, Gisslinger H, Barnas U. Erythropoietin treatment of anemia associated with multiple myeloma N Engl J Med 1990;322:1693-1699.[Abstract]
- Bokemeyer C, Aapro MS, Courdi A, et al. EORTC guidelines for the use of erythropoietin proteins in anaemic patients with cancer Eur J Canc 2004;40:2201-2216.
- Chung M, Steinmetz OK, Gordon PH. Perioperative blood transfusion and outcome after resection for colorectal carcinoma Br J Surg 1993;80:427-431.[Medline]
- Lutterbach J, Guttenbacher R. Anemia is associated with decreased local control of surgically treated squamous cell carcinomas of the glottic pharynx Int J Radiat Oncol Biol Phys 2000;48:1345-1350.[Medline]
- Frommhold H, Guttenberger R, Henke M. The impact of blood hemoglobin content on the outcome of radiotherapy. The Freiburg experience Strahlenther Onkol 1998;147(Suppl 14):31-34.
- Henke M, Laszig R, Schäfer U, et al. Erythropoietin to treat head and neck cancer patients with anemia undergoing radiotherapyrandomized, double-blind, placebo-controlled trial. Lancet 2003;362:1255-1260.[Medline]
- Lordick F, Stein HJ, Peschel C, Siewert JR. Neoadjuvant therapy for oesophagogastric cancer Br J Surg 2004;91:540-551.[Medline]
- Medical Research Council Oesophageal Cancer Working Party Surgical resection with or without preoperative chemotherapy in oesophageal cancera randomized controlled trial. Lancet 2002;359:1727-1733.[Medline]
- Cunningham D, Allum WH, Stenning SP, Weeden S. Perioperative chemotherapy in operable gastric and lower oesophageal cancerfinal results of a randomised, controlled trial (the MAGIC trial, ISRCTN 93793971). Proc Am Soc Clin Oncol 2005;24(abstract 4001).
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Abstract
Introduction
