Japanese Journal of Clinical Oncology Advance Access originally published online on October 4, 2006
Japanese Journal of Clinical Oncology 2006 36(10):632-637; doi:10.1093/jjco/hyl096
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© 2006 Foundation for Promotion of Cancer Research
Preoperative Chemoradiotherapy for Esophageal Cancer Enhances the Postoperative Systemic Inflammatory Response*
Department of Surgery, National Defense Medical College, Tokorozawa, Saitama, Japan
For reprints and all correspondence: Hironori Tsujimoto, Department of Surgery, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama 359-8513, Japan. E-mail: Tsujiflorida{at}aol.com
Received April 7, 2006; accepted June 16, 2006
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Abstract |
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Background: Chemoradiotherapy (CRT) has been established to improve the long-term survival in patients with esophageal carcinoma. However, little is known about whether preoperative CRT may affect the postoperative systemic response.
Methods: We investigated the postoperative clinical course in terms of the systemic inflammatory response syndrome (SIRS) in patients with preoperative CRT (CRT group) and surgery alone (SA group).
Results: Both the postoperative heart and respiratory rate in the CRT group were significantly higher than in the SA group. The duration and incidence of SIRS, as well as the number of positive criteria for SIRS, were significantly greater than those in the SA group. There was no difference in the postoperative morbidity and mortality between the two groups.
Conclusions: Preoperative CRT was found to significantly enhance the postoperative SIRS, thus suggesting its potentially higher risk of complications.
Key Words: chemoradiotherapy • esophagectomy • systemic inflammatory response syndrome
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INTRODUCTION |
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The optimal treatment of squamous cell carcinoma of the esophagus remains to be elucidated. Advances in surgical techniques, postoperative care and treatment strategies have improved the surgical results of esophageal carcinoma in recent decades; however, many clinical trials have evaluated the role of adjuvant therapy, both preoperatively and postoperatively, with conflicting results (1–3).
The surgical trauma that an esophagectomy imposes is perhaps the greatest among all general surgical operations, often involving the abdomen, chest and neck. Such operative trauma activates peripheral blood neutrophils, monocytes, lymphocytes and endothelial cells, which results in the release of proinflammatory cytokines such as TNF
, IL-1ß, IL-6, IL-12 and IL-18 (4,5). The systemic release of these proinflammatory cytokines is known to play a pivotal role in the pathogenesis of subsequent systemic inflammatory disorders, such as acute lung injury, while also inducing the development of systemic inflammatory response syndrome (SIRS) (6–8). The SIRS criteria have been successfully used as a prognostic parameter for predicting the clinical course of patients with severe surgical stress. Haga et al. (9) previously reported that the duration of SIRS and the number of positive criteria for SIRS after surgery significantly correlated with the postoperative complications and the development of organ dysfunction in patients who undergo elective gastrointestinal operations.
However, very few studies have so far evaluated the impact of preoperative Chemoradiotherapy (CRT) on the occurrence of postoperative SIRS after an esophagectomy. In the present study, we wish to elucidate the systemic inflammatory response based on the SIRS criteria following a transthoracic esophagectomy in patients undergoing preoperative CRT for esophageal cancer.
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MATERIALS AND METHODS |
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PATIENTS
Fifty-two consecutive patients underwent a transthoracic esophagectomy for esophageal cancer at the National Defense Medical College Hospital from 1999 to 2004. Thirteen patients, who had a tumor invading the adjacent structures (T4) without any distant metastasis suspected by a CT scan and/or MRI, received preoperative chemoradiation therapy followed by surgery (CRT group). Out of the 39 patients without neoadjuvant therapy, 13 patients (SA group) with a transthoracic esophagectomy, who had a T4 tumor without any distant metastasis suspected by a CT scan and/or MRI, were enrolled in the study. The surgical procedures included a transthoracic esophagectomy through a right fifth or sixth thoracotomy and a cervical esophagogastrotomy via the antethoracic, retrosternal or posterior mediastinal route with a two- or three-field lymphadenectomy. Patients chose whether they receive preoperative CRT or not after having the information on the benefit and the risk of preoperative CRT. An informed consent was obtained from all individuals prior to the initiation of the study. These patients were retrospectively evaluated for the preoperative status, surgical procedures and the postoperative systemic response including the white blood cell (WBC) count, body temperature, heart rate, respiratory rate, oxygenation (FiO2/PaO2 ratio) and laboratory data until postoperative day (POD) 4, according to all medical and nursing charts. All patients had spontaneous respiration with the support of mechanical ventilation throughout the investigation period; maximal respiratory rate of the day was evaluated. All patients were continuously administered gabexate mesilate (ONO Pharmacol, Osaka, Japan) 1.5 mg/kg/h from the beginning of anesthesia until POD3 (10). The clinical stage of these patients was assigned according to the International Union Against Cancer's TNM classification of Malignant Tumors (11). The postoperative systemic inflammatory response was evaluated and SIRS was diagnosed according to the criteria proposed by the American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference (12). SIRS was defined as a condition including two or more of the following: (i) temperature > 38°C or <36°C; (ii) heart rate > 90 beats/min; (iii) respiratory rate > 20 beats/min or PaCO2 < 32 torr; and (iv) WBC count > 12 000 or 4000 < cells/mm3, or >10% immature band forms.
PROTOCOL OF PREOPERATIVE CRT
The chemotherapeutic regimens included the administration of cisplatin (CDDP; 6 mg/m2 per day) by intravenous infusion before each radiation therapy. 5-Fluorouracil (5-FU; 350 mg/m2 per day) was also administered by continuous intravenous infusion throughout the CRT period. The concurrent radiation therapy was planned to be administered in daily fractions of 2 Gy for a total dose of 30–40 Gy (median 30.9 Gy). The mean period of CRT was 27.7 ± 1.8 days, and the esophagectomy was performed 27.6 ± 4.2 days after the completion of CRT. Only one patient stopped preoperative CRT half-way through the course of treatment because of progressive sepsis.
STATISTICAL ANALYSIS
The data are expressed as the mean ± SEM. Statistical analyses were performed using either Student's t-test or the chi-square test, and multivariate analysis was performed by using a Cox proportional hazards model. The P values <0.05 were considered statistically significant. All analyses were performed using a statistical software (StatView version 5.0; SAS Institute, Inc., Cary, NC, USA).
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RESULTS |
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PATIENTS
There were no differences in age, gender, location and depth of tumor, reconstruction route, organs for esophageal replacement, operation time, the amount of intraoperative blood loss, blood transfusion, and the methods of perioerative care including the degree of hydration, nutrition, ventilation support between the two groups. In addition, we could not find any difference between the two groups regarding the pathological tumor stage, the fields of lymphadenectomy, the duration of postoperative mechanical ventilation, or the length of stay in intensive care unit and the hospital stay (Table 1).
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LABORATORY DATA BEFORE SURGERY
The preoperative WBC count and preoperative absolute lymphocyte number in the CRT group were significantly less than in the SA group. The serum albumin levels of the CRT group before surgery were also less than in the SA group. No difference was seen in the tumor marker levels, including CEA and SCC, between the two groups (Table 2).
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CHANGES IN PERIOPERATIVE OXYGENATION, LIVER AND KIDNEY INJURY
The PaO2/FiO2 ratio of the CRT group was significantly lower than that in the SA group before surgery and on POD3 (Fig. 1). No differences were observed in the postoperative changes of the serum total bilirubin and CRP levels. In addition, there were no differences between the two groups regarding the AST, ALT, BUN, creatinine levels after surgery (data not shown).
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POSTOPERATIVE DEVELOPMENT OF SIRS
We could not have any difference between the duration of SIRS (days) and their pathological stage (IIa: 2.0 ± 1.0, IIb: 2.5 ± 0.33, III ± 2.5 ± 0.5, IV: 3.3 ± 0.7 days). We evaluated the postoperative changes for each factor of the SIRS criteria, i.e. the WBC count, heart rate, respiratory rate and body temperature (Fig. 2). Although preoperative WBC in the CRT group was significantly lower than in the SA group, the postoperative WBC in the CRT group was higher than that in the SA group throughout the investigation period, but the data did not demonstrate statistical significance. Both the heart rate and the respiratory rate in the CRT group were significantly higher than in the SA group on each POD. No difference was observed in the body temperature between the two groups.
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Next, the postoperative duration and frequency of SIRS were investigated (Fig. 3a–c). The duration of SIRS in the CRT group was significantly longer than that in the SA group (3.2 ± 0.3 versus 1.8 ± 0.4; P = 0.005), and the number of patients with SIRS in the CRT group was significantly greater than in the SA group, especially on POD1 and POD3 (P = 0.02 and 0.01, respectively). Moreover, the number of positive criteria for SIRS in the CRT group was significantly higher than in the SA group on POD1, POD3 and POD4 (P = 0.03, 0.01, and 0.04, respectively).
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We investigated the association between clinical factors and the duration of SIRS (Table 3). On univariate analyses, preoperative CRT and route of reconstruction were significantly associated with it. Only the preoperative CRT remained significant by multivariate analysis with a Cox model.
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POSTOPERATIVE MORBIDITY AND MORTALITY
Postoperative complications were only included when medical or interventional treatments were required. There was no difference in the postoperative morbidity and mortality rate between the two groups. Furthermore, we could not find any difference between the 2 groups only when the frequency of infectious complications, such as pneumonia, was compared. One patient in the SA group died after developing acute respiratory distress syndrome (ARDS) (Table 4).
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DISCUSSION |
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TOPAbstractINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONReferences |
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In the present study, we investigated the postoperative clinical course and systemic inflammatory response in patients with preoperative CRT followed by an esophagectomy or with surgery alone. We demonstrated that patients with preoperative CRT had a marked postoperative systemic inflammatory response according to the SIRS criteria in comparison with the patients without neoadjuvant therapy.
Combination therapy treatment protocols for esophageal carcinoma were developed to attempt to increase the local tumor control and reduce the incidence of distant treatment failure after surgery and to improve the postsurgical survival in patients with locally advanced disease. However, the effect of preoperative CRT on the immediate outcomes after the esophagectomy remains to be elucidated, and little is known about its impact on the systemic inflammatory response after surgery.
In the present study, we demonstrated that preoperative CRT significantly prolonged the duration of postoperative SIRS in comparison with surgery alone. In an attempt to decrease the excessive amount of inflammatory cytokines due to surgical stress, the perioperative administration of a small amount of steroids or prostaglandin E1 may be useful (13,14). In addition, we previously reported that the preoperative administration of gabexate mesilate, a serine protease inhibitor, could significantly shorten the duration of postoperative SIRS in patients undergoing an esophagectomy in a randomized control study (10), and we have routinely administered gabexate mesilate to all patients undergoing an esophagectomy at the beginning of anesthesia since 1999 in order to decrease the degree of excessive surgical stress.
A transthoracic esophagectomy is known to be one of the most invasive surgical procedures in gastrointestinal surgery. We have previously demonstrated that a transthoracic esophagectomy induced much higher postoperative serum IL-6 levels and a greater TNF production of peripheral monocytes than a distal gastrectomy for gastric cancer (4). We also reported that an esophagectomy led to an extensive activation of granulocyte and monocytes as judged by their CD11b/CD18 expression (4). As a result, an esophagectomy may produce an excessive inflammatory response, which thus leads to its frequent postoperative complications. It has been reported that postoperative pulmonary complications occur in 
30% of all cases, including atelectasis, pneumonia and respiratory failure (15,16). We demonstrated that postoperative hypooxygenation was seen in both groups, and preoperative CRT tended to cause severe hypooxygenation on POD 3 (PaO2/FiO2 ratio = 236.1 ± 23.9: 300.0 ± 23.6), although no difference was seen between the two groups regarding liver and kidney injury.
Although our study was limited due to the small number of patients evaluated, we did not observe any difference in the postoperative complications between the two groups in this study. It remains controversial whether preoperative CRT may increase the postoperative morbidity. Avendano et al. (17) suggested that preoperative CRT might reduce the forced expiratory volume, thus resulting in an increasing risk of pulmonary complications after surgery. On the other hand, Doty et al. (18) reported that the morbidity and length of stay in hospital in patients with preoperative CRT were comparable with those in patients with an esophagectomy alone. These conflicting results may be due to differences in the CRT procedures or the tumor type, such as adenocarcinoma or squamous cell carcinoma, and in order to resolve this issue, further studies are thus called for.
In conclusion, preoperative CRT indicated a longer duration and the higher incidence of SIRS as well as a lower degree of oxygenation after an esophagectomy, although we did not detect any difference in the frequency of postoperative complications in comparison with surgery alone. However, patients with preoperative CRT may have a potentially higher risk of demonstrating an excessive inflammatory response after surgery, and novel strategies for decreasing excessive surgical stress, such as the use of protease inhibitor, may thus be recommended in patients with esophageal cancer.
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Notes |
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* Presented in part at the 59th Annual Meeting of the Japan Esophageal Society, Tokyo, Japan, 23 May, 2005.
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References |
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