Ann Thorac Surg 2005;80:1170-1175
© 2005 The Society of Thoracic Surgeons
Original article: General thoracic
Adjuvant Chemotherapy with 5-Fluorouracil and Cisplatin in Lymph Node-Positive Thoracic Esophageal Squamous Cell Carcinoma
Jeeyun Lee, MD
a
,
*
,
Kyoung-Eun Lee, MD
a
,
*
,
Young-Hyuck Im, MD
b
,
*
,
Won Ki Kang, MD
b
,
Keunchil Park, MD
c
,
Kwhanmien Kim, MD
c
,
Young Mog Shim, MD
c
a Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
b Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
c Department of Thoracic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Accepted for publication March 16, 2005.
* Address reprint requests to Dr Im, Division of Hematology/Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-gu, Seoul, 135-710 Korea (Email: imyh{at}smc.samsung.co.kr).
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Abstract
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BACKGROUND: In this study we explored the effectiveness of adjuvant chemotherapy in node-positive, resected thoracic esophageal squamous cell carcinoma patients.
METHODS: A prospective study of postoperative chemotherapy in N1 esophageal cancer patients who received curative resection was conducted and compared with the historical control group in regard to recurrence rate, patterns of failure, disease-free survival rate, and overall survival rate. The postoperative chemotherapy consisted of cisplatin (60 mg/m2 intravenously) and 5-fluorouracil (1,000 mg/m2 per day) in a continuous infusion for 4 days. Three cycles were administered at 3-week intervals.
RESULTS: Forty patients were accrued from January 1998 to January 2003 at Samsung Medical Center for adjuvant chemotherapy. The historical control group consisted of 52 patients who received curative resection but not adjuvant chemotherapy during the same period of time. The 3-year disease-free survival rate was 47.6% in the adjuvant group and 35.6% in the control group (p = 0.049). The estimated 5-year overall survival rates were 50.7% in the adjuvant group and 43.7% in the control group (p = 0.228). The significant predictive factors for tumor recurrence were the number of positive lymph nodes (p = 0.008) and the adjuvant chemotherapy (p = 0.030).
CONCLUSIONS: This study suggests that the postoperative chemotherapy may prolong disease-free survival in lymph node-positive, curatively resected esophageal cancer patients. The postoperative treatment modality for esophageal cancer patients should be determined according to the lymph node status and a randomized phase III clinical trial is warranted using adjuvant chemotherapy if the esophageal cancer is lymph node-positive.
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Introduction
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Esophageal cancer is a highly aggressive malignancy with poor prognosis. Although the esophagectomy remains the standard treatment in patients with localized esophageal cancer, the long-term treatment outcome is not satisfactory. The 5-year survival rate for esophageal cancer patients with surgery alone remains less than 20% [1–3]. The principle reason for surgical failure in curing esophageal cancer is a high rate of distant metastasis, which has been the rationale for using systemic chemotherapy in conjunction with surgery in patients with apparently localized disease. Those patients with regional lymph node metastases have a significantly lower survival rate than those without lymph node metastasis [4]. Surgery alone has its limits in improving long-term survival in locally advanced esophageal cancer, and therefore an effective multimodality treatment including radiotherapy or chemotherapy or combination therapy in either a preoperative or postoperative setting is required to obtain better survival rate, especially in node-positive esophageal cancer patients.
Several randomized clinical trials of neoadjuvant chemotherapy followed by surgery versus surgery alone have shown conflicting results. The major concern of preoperative chemotherapy is a potential delay in definitive treatment with the risk of further spreading the disease. This is an important issue because approximately half the patients do not respond to current chemotherapeutic regimens used for neoadjuvant treatment.
Little attention has been focused on surgery plus postoperative adjuvant therapy as a treatment option for patients with localized esophageal cancer. The survival benefit of surgery followed by adjuvant therapy has been demonstrated and widely accepted as a standard therapy in other gastrointestinal malignancies [5]. Adjuvant chemotherapy in patients who have had surgery alone as their primary curative treatment is more feasible from the standpoint of patient tolerance, but it remains unclear whether current agents confer a survival advantage. A recent study of 9,204 patients by the Japan clinical oncology group compared surgery alone with surgery followed by 2 cycles of postoperative chemotherapy with cisplatin and 5-fluorouracil (5-FU). They reported a significant prolongation in 5-year disease-free survival rate in node-positive patients (38% vs 52%; p = 0.041), but no benefit in node-negative patients in the subgroup analysis (70% vs 76%; p = 0.433) [6–7]. A prospective clinical study of adjuvant chemotherapy in only node-positive esophageal squamous cell carcinoma patients has not been conducted yet. We prospectively investigated the impact of postoperative chemotherapy on the survival of N1 esophageal cancer patients who received curative esophagectomy and compared it with the historical control group in regard to recurrence rate, patterns of failure, disease-free survival rate, and overall survival rate.
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Patients and Methods
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Patient Selection
From January 1998 to January 2003, 40 patients who underwent curative esophagectomy were prospectively enrolled in this study. Eligible criteria included (1) histologically proven squamous cell carcinoma of the thoracic esophagus; (2) curative R0 resection (no microscopic residual tumor); (3) transthoracic esophagectomy with radical lymphadenectomy such as cervico-thoracoabdominal three-field lymphadenectomy or thoracoabdominal total two-field lymphadenectomy; (4) a pathologic classification of any size tumor (T1-T4), regional lymph node metastases (N1), and no distant metastases (except M1a) (pathologic stage IIb, III, IVa); (5) 18 
age 75, and performance status of Eastern Cooperative Oncology Group zero to 2; (6) adequate bone marrow function (absolute neutrophil count > 1,500/mm3, platelet count > 100,000/mm3, hemoglobin 
10 g/dL); and (7) normal renal and hepatic functions (serum creatinine < 1.5mg/dL, total bilirubin < 3.0 mg/dL, serum transaminases < 2.5 times the normal level). Patients with cervical esophageal tumors, adenocarcinoma, small cell carcinoma, and negative regional lymph node (N0) stage were excluded from this study. Preoperative evaluation included computed tomographic scan of the chest, ultrasonography of upper abdomen or abdominal computed tomographic scan, endoscopic ultrasonography, positron emission tomography, and bronchoscopy in cases of upper and middle thoracic esophageal cancer. A complete history and physical examination were performed in all patients prior to chemotherapy. All patients provided a written, informed consent according to the guideline provided by the institutional review board. The total two-field lymphadenectomy included resection of the peri-esophageal nodes, bilateral recurrent laryngeal nerve nodes, infracarinal nodes, infra-aortic arch nodes, posterior mediastinal nodes, paracardiac nodes, lesser curvature nodes, left gastric nodes, common hepatic nodes, splenic nodes, and celiac nodes. The cervical lymphadenectomy including the cervical paraesophageal and supraclavicular nodes was added during three-field lymphadenectomy.
Historical Controls
Fifty-two esophageal cancer patients who underwent curative esophagectomy using the same surgical approach during the same period of time and who were not treated with postoperative chemotherapy were selected for the control group. All patients had squamous cell esophageal carcinoma and pathologic N1 disease. All patients were treated and monitored at our institution.
Adjuvant Chemotherapy
The postoperative chemotherapy consisted of cisplatin (60 mg/m2, intravenously) and 5-FU (1000 mg/m2 per day) in a continuous infusion for 4 days. Three cycles were administered at 3-week intervals. The first cycle of adjuvant chemotherapy was administered 4 to 8 weeks after surgery.
Toxicity and Follow-Up
Toxicity was assessed for each cycle and graded according to the World Health Organization toxicity criteria [8]. Complete blood counts and blood chemistry were obtained before the beginning of each cycle. The protocol allowed the dose of 5-FU to be reduced by 25%, in cases in which the absolute neutrophil count was between 1,000/mm3 and 1,500/mm3, or the platelet count was between 75,000/mm3 and 100,000/mm3. The dose of cisplatin was reduced by 50%, in cases in which the serum creatinine was between 1.5 mg/dL and 2.0 mg/dL. Next, chemotherapy was withheld for 1 week until recovery in cases in which the absolute neutrophil count was less than 1,000/mm3, or the platelet count was less than 75,000/mm3, or the serum creatinine was greater than 2.0 mg/dL. All patients were followed-up every 3 months for the first 2 years, and every 6 months afterwards. Patterns of failure were defined as the first site of recurrence. Locoregional failure included the primary tumor and local or regional lymph nodes. Systemic failure was defined as any other distant site of recurrence.
Statistical Analysis
The primary endpoint of the study was disease-free survival. Overall survival was calculated from the date of surgery to the date of death or the last follow-up date; disease-free survival was defined as the date of surgery to the date of recurrence or the last follow-up date. Overall survival and disease-free survival were estimated using the Kaplan-Meier method, and groups were compared with the log-rank test [9]. A P value less than 0.05 was considered statistically significant. We used the Pearson 
2 test or the Fisher exact test for comparison of categorical variables. Prognostic factors were determined by using the Cox logistic regression analysis.
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Results
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Patient Characteristics
During the period from January 1998 to January 2003, 40 consecutive patients were entered into the study. The clinical characteristics of the enrolled patients are provided in Table 1. The historical control group consisted of 52 patients. All patients in both arms had squamous cell carcinoma of esophagus and pathologically confirmed regional lymph node metastases (pN1). Both groups had similar pathologic characteristics in tumor status, location, histology, and differentiation. However, the median age of the control group was higher than that of the study group (p = 0.041). The median follow-up duration for all living patients was 32.7 months (95% confidence interval, 19.7 to 45.7). The median follow-up for living patients in both groups did not differ significantly with 32.9 months for the surgery group (95% confidence interval, 14.5 to 51.3) and 29.5 months for the control group (95% confidence interval, 11.6 to 47.4).
Treatment Summary
A total of 119 cycles of the regimen were administered and 39 patients completed three cycles of postoperative chemotherapy. One patient refused the third cycle of the treatment. The median time to the first administration of chemotherapy was 35 days (range, 23 to 58 days). All patients were evaluated for toxicities. The common grade 3 to 4 toxicities were neutropenia (25.0 %) and nausea and vomiting (10.0%) (Table 2). Peripheral neuropathy was not significant and only 10% experienced grade 1 neurotoxicity. One patient was hospitalized for the management of neutropenic fever. There has been no recorded death related to adjuvant chemotherapy. No patients stopped chemotherapy due to intolerable toxicities. There was no statistically significant difference in the surgical approaches between the two groups (p = 0.163) or in the incidence of postoperative complications (p = 0.262) (Table 3).
Disease-Free Survival, Overall Survival, and Patterns of Failure
The disease-free survival was significantly longer in the adjuvant group than in the control group (p = 0.049; Fig 1). The 3-year disease-free survival rates were 47.6% in the adjuvant group and 35.6% in the control group. The significant predictive factors for tumor recurrence on multivariate Cox analysis were the number of positive lymph nodes (p = 0.008) and adjuvant chemotherapy (p = 0.030). Age, sex, Eastern Cooperative Oncology Group status, T status, and the type of surgery were not influential on the disease-free survival in this analysis. The estimated 5-year overall survival rates were 50.7% in the adjuvant group and 43.7% in the control group (Fig 2) (p = 0.228). To date, 16 patients in the adjuvant arm have died. Of these 16 patients, 7 patients died of complications from local recurrence, and 9 patients died of systemic metastases including metastases to the liver, lung, bone, and adrenal gland. Three patients in the adjuvant group are alive with recurred locoregional disease and are currently receiving chemotherapy for recurrence. In the control group, 28 patients eventually relapsed. There was no notable difference in the pattern of recurrences between the two groups, although the incidence of distant metastasis seemed to be higher in the control group (Table 4).
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Fig 1. Disease-free survival curves stratified by ± adjuvant chemotherapy. (X = surgery only; » = surgery + chemotherapy.)
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Fig 2. Kaplan-Meier survival curves stratified by ± adjuvant chemotherapy. (X = surgery only; » = surgery + chemotherapy.)
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Comment
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A high frequency of metastatic disease as the cause of death in resected esophageal cancer patients has resulted in intense exploration for the application of systemic therapy in the treatment of esophageal cancer. Recently, chemotherapy with or without other local modality of surgery or radiation has been introduced as neoadjuvant, definitive, or adjuvant settings; however, the confirmatory clinical trials showing survival advantages in any of these settings to date are lacking [10–23]. In particular, neoadjuvant chemotherapy has been advocated and studied in several clinical trials in the Western countries. Two largest studies that were recently published were the Medical Research Council (MRC) OEO2 study [21] and the United States intergroup-0113 study [18] showed conflicting results. In the MRC OEO2 trial, both disease-free survival and overall survival rates were significantly prolonged in the neoadjuvant chemotherapy group (disease-free, hazard ratio, 0.75; 95% confidence interval, 0.63 to 0.89; P = 0.0014; overall survival, hazard ratio 0.79; 95% confidence interval, 0.67 to 0.93; P = 0.004) [21]. However, in the Unites States intergroup-0113 study, no differences in disease-free survival and overall survival were found between the surgery alone and the neoadjuvant chemotherapy group [18]. Different conclusions reached by the recent two meta-analyses with regard to survival benefits of neoadjuvant treatment have further confused the issue. Most neoadjuvant trials conducted by the Western countries were in esophageal adenocarcinoma patients. Therefore, the role of neoadjuvant treatment in resectable esophageal adenocarcinoma or squamous cell carcinoma remains undefined.
The effectiveness of preoperative chemoradiation therapy has been reported in four randomized studies [24–27]; however, three of the four are underpowered and showed no survival advantage. The only randomized trial with positive survival data for preoperative chemoradiation therapy in esophageal adenocarcinoma has been criticized for the small sample size, poor surgical outcome, and inconsistent preoperative staging [25].
Adjuvant chemotherapy may be more advantageous in terms of better tolerability and obviating the risk of delay in definitive surgery when compared with neoadjuvant chemotherapy. Despite these potential benefits, the adjuvant chemotherapy has been least studied in resectable esophageal cancer. We prefer the adjuvant chemotherapy rather than preoperative chemotherapy or chemoradiation therapy because the pathologic stage at the time of surgery is an important predictor of survival outcome and allows effective selection of patients (ie, N1 disease) for adjuvant treatment. The Japanese Esophageal Oncology Group trial conducted two separate randomized trials and reported no survival benefit in patients receiving postoperative chemotherapy compared with surgical resection alone [6–7]. A more recent report by the same group compared surgical resection alone with adjuvant chemotherapy consisting of two cycles of cisplatin plus 5-FU in a randomized phase III trial [6, 28]. At a median follow-up of 62.8 months, overall survival rates were 52% for the control group and 61% for the postoperative chemotherapy group (p = 0.13). However, in the subgroup analysis they showed that the 5-year disease-free survival rates differed more significantly in node-positive patients (38% vs 52%; p = 0.041) than in node-negative patients (70% vs 78%; p = 0.433) [28]. Besides this study, there are a small number of studies suggesting a positive role of adjuvant chemotherapy in resected node-positive esophageal carcinoma [29–31]. The role of adjuvant radiotherapy remains investigational. Although the incidence of local failure after esophageal resection is high enough to warrant the evaluation of postoperative radiotherapy, several randomized trials have failed to demonstrate a survival benefit [11, 12]. We conducted a prospective study of adjuvant chemotherapy with three cycles of cisplatin and 5-FU in homogenous group of patients, who had N1 disease, squamous cell carcinoma, and underwent curative radical resections. We believe that there has been no clinical trial conducted in this clinical setting.
In this study, there was a significant difference in 3-year disease-free survival between the two groups (47.6% in the adjuvant group vs 35.6% in control group; p = 0.049). The number of lymph nodes involved was an important predictive factor for recurrence in multivariate analysis and thus, patients with a greater number of positive lymph nodes may benefit more from adjuvant chemotherapy. There was no significant survival benefit in the adjuvant group. Major limitation of our study was the nonrandomized study design using historical control, which may have resulted in selection bias. The age distribution was younger in the adjuvant group. A Kaplan-Meier analysis stratified by age (< 60 years vs > 60 years) showed no influence on survival or disease-free survival (p = 0.645; p = 0.1928, respectively). Except for age, the two groups did not show considerable difference in clinical characteristics. We would like to clarify that the study regimen was given in patients with squamous cell carcinoma of esophagus, and thus our study results may not be extrapolated to patients with adenocarcinoma, which is know to have a different natural history and response to chemotherapy.
The 5-FU and cisplatin combination regimen has become the standard for several years with a 50% response rate in localized cancer and a 35% response rate in advanced esophageal cancer [32]. Promising results were reported on the use of a continuous infusion regimen of 5-FU in advanced gastroesophageal cancer [32], and thus we used a combination of continuous infusion of 5-FU and cisplatin in an adjuvant setting and administered three cycles of the regimen postoperatively. The adjuvant chemotherapy was well tolerated by most patients with a low toxicity profile. Although the most common grade 3 to 4 toxicity was neutropenia, no patients experienced a febrile episode that required hospitalization, and there was no treatment-related mortality.
There are several unresolved issues that need to be settled in the adjuvant treatment of locally advanced esophageal cancer. First, the optimal chemotherapeutic agents for adjuvant chemotherapy should be defined. Combination chemotherapy with cisplatin and infusion of 5-FU remains the most commonly used regimen, but it is somewhat outdated. Several phase II studies have demonstrated the efficacy of newer drugs such as taxanes and irinotecan, but phase III trial results should validate the efficacy. Second, the adequate number of cycles of adjuvant chemotherapy has been controversial. Previous negative trials on postoperative chemotherapy were challenged by the inadequate dosage of chemotherapeutic agents or suboptimal duration of chemotherapy as an adjuvant setting. The Japanese Esophageal Oncology Group trial used two courses of combination chemotherapy with cisplatin (70 mg/m2) and vindesine (3 mg/m2), which might have been inadequate to effectively control micrometastatic disease [7]. The Eastern Cooperative Oncology Group is currently conducting a phase II trial (E8296) evaluating adjuvant cisplatin and paclitaxel for four courses in patients with resected, node positive adenocarcinomas of the esophagus, gastroesophageal junction, and cardia.
In conclusion, we showed that the postoperative chemotherapy with three cycles of 5-FU and cisplatin combination chemotherapy in node-positive esophageal cancer patients may prolong disease-free survival compared with patients with curative surgery alone. The postoperative treatment modality for esophageal cancer patients should be determined according to the lymph node status and a multicenter, large scale randomized phase III clinical trial on adjuvant chemotherapy in lymph node-positive resected esophageal cancer is warranted.
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Footnotes
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* These authors contributed equally to the article. 
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Abstract
Introduction
