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Ann Thorac Surg 2004;78:1037-1041
© 2004 The Society of Thoracic Surgeons
a Centre Hospitalier Universitaire Vaudois, Multidisciplinary Oncology Center, Lausanne, Switzerland, and Third Medical Department, Klinikum rechts der Isar, Technische Universitaet, Muenchen, Germany
b Department of Surgery, Klinikum rechts der Isar, Technische Universitaet, Muenchen, Germany
c Institute for Medical Statistics and Epidemiology, Klinikum rechts der Isar, Technische Universitaet, Muenchen, Germany
Accepted for publication January 22, 2004.
* Address reprint requests to Dr Voelter, Multidisciplinary Oncology Center, CHUV-BH 06, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland;
verena.voelter{at}hospvd.ch
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Abstract |
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METHODS: The charts of 29 patients (21 males; median age, 59.5 years; range, 37 to 73), receiving neoadjuvant chemotherapy for cT3 esophagogastric adenocarcinoma operated at a single university center in the year 2002, were retrospectively reviewed to assess the incidence of anemia and blood transfusions.
RESULTS: Twenty-six patients received platinum-based chemotherapy over a period of 12 weeks and three patients more than 6 weeks. The median hemoglobin level (Hb level) before chemotherapy was 14.0 g/dL (range, 10.4 to 15.9 g/dL), the median decline of the Hb level was 2.9 g/dL (range, 0.3 to 6.3 g/dL); this drop was statistically significant (p < 0.001, 95% confidence interval). Patients who received preoperative blood transfusions (n = 8, 28%) had a significantly increased risk of developing postoperative complications (p = 0.028).
CONCLUSIONS: Preoperative chemotherapy for locally advanced esophagogastric cancer induces anemia and therefore leads to preoperative blood supplementation in a considerable number of patients. Data indicate that this may counteract the beneficial effects of neoadjuvant treatment.
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Introduction |
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Cisplatin still is the cornerstone of cytostatic treatment of upper gastrointestinal cancer; however, platinum-based chemotherapy frequently leads to anemia [5]. As a result, the need for preoperative blood transfusions might be increased in patients who have been treated with platinum-based chemotherapy. Allogenic blood transfusions, furthermore, expose the patient to blood-borne 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 following surgery in several tumor entities [6–12]. A recent study of patients who underwent esophagectomy for carcinoma demonstrated that perioperative blood transfusions were adversely related to survival [13]. Even though these patients did not receive any preoperative therapy, it has to be questioned whether patients who are given neoadjuvant chemotherapy with a curative intent are exposed to toxicity that may worsen their prognosis.
We have found no data available in the literature about the incidence of anemia and subsequent blood transfusion requirements at the time of surgery in patients with esophagogastric cancer who had received neoadjuvant chemotherapy. We therefore assessed the frequency of anemia and the need for red cell blood transfusions in patients undergoing neoadjuvant platinum-based polychemotherapy for locally advanced esophagogastric cancer.
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Material and methods |
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All patients were staged by means of endoscopy, endoscopic ultrasound, computer tomographic scan of the chest and abdomen, as well as positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG). Patients had to have completed at least one full cycle (6 weeks) of platinum-based chemotherapy before surgery to be included in the analysis.
In our institution patients with adenocarcinoma of the esophagus and the esophagogastric junction (AEG I and II) stage greater than or equal to cT3, N0/+, M0 were included in an ongoing neoadjuvant protocol to evaluate the early metabolic response by FGD-PET (day 14 of chemotherapy). In those cases in which there was a greater than or equal to 35% reduction of tumor, FGD uptake patients will complete the 2 cycles of chemotherapy [16, 17]. The standard regimen was PLF: cisplatinum 50 mg/m2 d 1, 15, 29, 5-FU 2,000 mg/m2 d 1, 8, 15, 22, 29, 36 and leucovorin 500 mg/m2 d 1, 8, 15, 22, 29, 36; repeated on day 50. Paclitaxel 80 mg/m2 d 1, 15, 29 was added to PLF for patients younger than 60 years of age. Patients who showed no metabolic tumor response at day 14 were to undergo immediate surgery.
Patients with tumors of the cardia (AEG II and III) and the stomach stage greater than or equal to cT3, N0/+, M0 were randomized for participation in the European Organization for Research and Treatment of Cancer 40954, a study in which neoadjuvant chemotherapy with PLF is being compared to surgery alone.
Progression-free survival (PFS) was estimated according to the Kaplan-Meier method and the interaction of anemia and PFS was tested using a log-rank test. The correlation between postoperative complication rate and drop of Hb level and transfusions was assessed by Fischer's exact test. Significance level was set to 5% and all tests were performed two-sided.
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Results |
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There were 21 men and 8 women, the median age was 60 years with a range of 37 to 73 years (Table 1). All had histologically confirmed esophagogastric adenocarcinoma stage cT3 (Table 2). There were 11 patients presenting with an adenocarcinoma of the esophagogastric junction (AEG) type 1, 8 patients with type 2, and 3 patients with type 3, as well as 7 patients with adenocarcinoma of the stomach.
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Twenty-six patients received the total of two planned 6-week cycles of chemotherapy representing almost 3 months of preoperative treatment; three patients had only one cycle. All patients underwent surgery within four weeks after the end of chemotherapy. None of the patients died within 30 days postoperatively. No patient received radiotherapy before surgery.
Before the start of chemotherapy, 20 patients (69%) had normal Hb levels and 9 patients (31%) presented with mild grade 1 anemia (Table 3). The median Hb level at that time was 14.0 g/dL with a range of 10.4 to 15.9 g/dL (Table 4). At the end of chemotherapy, however, all patients were anemic: 20 patients (69%) with grade 1 anemia and 9 patients (31%) with grade 2 anemia. Six patients (20%) had the same degree of anemia (grade 1) before and after chemotherapy. The median nadir of hemoglobin was 10.8 g/dL with a range of 8.8 to 13.2 g/dL. The median decline of hemoglobin during chemotherapy was 2.9 g/dL (range, 0.3 to 6.3 g/dL; p < 0.001, 95% confidence interval [CI]). In 83% of patients the drop of hemoglobin was more than 2 g/dL. Figure 1 illustrates the decline of Hb levels during chemotherapy and demonstrates that all patients were anemic before surgery. However, the drop of hemoglobin did not influence PFS (p = 0.37).
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Eleven patients (38%) experienced postoperative complications during the hospitalization period, including 2 anastomotic leakages, 2 ascites, 2 pleural empyema, 1 peripancreatic abscess, 1 atrial fibrillation, 1 transient amaurosis, 1 catheter-induced septicemia, and 1 infection of unknown origin. The association between drop of Hb level and postoperative complication rate demonstrated no statistical difference. In contrast, patients who received preoperative transfusions had a significantly higher probability of developing postoperative complications (19% vs 75%, p = 0.028).
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Comment |
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It has become increasingly apparent that perioperative blood transfusions exert an immunomodulatory effect which can be either beneficial (allogenic kidney transplant) [20] or detrimental [7]. The mechanism of this effect is still unclear. Numerous studies have documented an association between perioperative transfusions on the one side and recurrence rates and survival on the other [6–11]. Interestingly enough, there seems to be no difference whether autologous or allogenic red cell blood is transfused [6]. But several studies confirm that it is the high amount of blood transfused (
3 U) that has a negative impact on further outcome [13, 21, 22]. Nevertheless, some reports could not demonstrate a relationship between perioperative transfusion and outcome [23, 24]. Although findings on this issue are apparently conflicting, a meta-analysis of more than 5,000 patients is in favor of the hypothesis that perioperative red cell blood transfusions are detrimental for cancer patients [25]. In summary, blood-transfusion-related adverse effects cannot be excluded and have to be further investigated.
A few series have been published on this issue dealing with esophageal tumors. One recently published study of 234 patients who underwent esophagectomy for carcinoma by a single surgeon, as well as a Japanese series of 235 patients and a British series of 235 patients with mainly adenocarcinomas, demonstrated a significantly decreased survival for patients who had received blood transfusions [12, 13, 21]. Another analysis of 524 retrospectively reviewed patients demonstrated a significant association with short-term survival (1 year) after esophagogastrectomy, whereas long-term survival was not affected [26].
Furthermore, anemia itself appears to be an independent prognostic factor for local control [27] and survival in cancer patients [28]. This has largely been investigated in combined modality treatment for head and neck cancer patients. Patients with normal Hb levels or who received erythropoietin to correct anemia had significantly better response to treatment, local control, and survival [29]. Additionally, anemia may compromise the efficacy of chemotherapy and worsen pathologic response to preoperative chemoradiation [30, 31]. This observation may be explained by the principle of poor tumor oxygenation [32]. Additionally, preclinical data suggest that anemia reduces the cytotoxicity of chemotherapeutic agents in tumor models [33].
The present data confirm that most patients with esophagogastric cancer will become anemic during neoadjuvant chemotherapy. One third of them will require blood transfusions before surgery although they had not presented with anemia at the time of diagnosis. We demonstrated that these transfused patients are at significantly increased risk of developing postoperative complications. Admittedly, the number of patients included in this study is small. Therefore, this result should be interpreted with caution.
It can be hypothesized that anemia itself, as well as blood transfusions, may directly impair the benefit of preoperative chemotherapy by decreasing response to treatment, local control, and overall survival. No prospective data are available concerning the prevention of anemia with erythropoietin in patients undergoing neoadjuvant chemotherapy for esophagogastric cancer and whether treatment induced anemia does also compromise the postoperative outcome.
Erythropoiesis stimulating proteins are known to be effective for the treatment of anemia in cancer patients [34]. Several randomized trials demonstrated a significant decrease of transfusion requirements in patients receiving myelosuppressive chemotherapy [35–37]. Furthermore, erythropoietin significantly improves quality of life of cancer patients with solid and hematological malignancies irrespective of tumor response [38, 39].
We therefore initiated a prospective pilot trial investigating the role of erythropoietin-alfa concomitant to neoadjuvant platinum-based chemotherapy in patients with adenocarcinoma of the esophagogastric junction. The aim of this trial is to maintain Hb levels above 12 g/dL and to prevent blood transfusions during the preoperative chemotherapy period. Most studies indicate that optimal quality of life and freedom of symptoms is assured by Hb levels above 12 g/dL [40]. Additionally, postoperative complications seem to increase as Hb levels drop below 12 g/dL [41]. We intend to prospectively assess the influence of erythropoietin-alfa on quality of life and on the perioperative morbidity and mortality. To answer the question whether the maintenance of normal Hb levels might improve the outcome of these patients we plan to further proceed with a randomized trial of erythropoietin-alfa versus blood transfusion.
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This article has been cited by other articles:
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  R. S. Weber, N. Jabbour, and R. C. G. Martin II Anemia and Transfusions in Patients Undergoing Surgery for Cancer Ann. Surg. Oncol., January 1, 2008; 15(1): 34 - 45. [Abstract] [Full Text] [PDF]
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 K. Abbrederis, F. Bassermann, C. Schuhmacher, V. Voelter, R. Busch, N. Roethling, A. Sendler, J. R. Siewert, C. Peschel, and F. Lordick Erythropoietin-alfa during neoadjuvant chemotherapy for locally advanced esophagogastric adenocarcinoma. Ann. Thorac. Surg., July 1, 2006; 82(1): 293 - 297. [Abstract] [Full Text] [PDF]
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