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© 2003 American Society for Clinical Oncology Surgery Plus Chemotherapy Compared With Surgery Alone for Localized Squamous Cell Carcinoma of the Thoracic Esophagus: A Japan Clinical Oncology Group Study—JCOG9204
From the Department of Surgery, Keio University School of Medicine; National Oji Hospital; the Department of Surgery, Tokyo Women’s Medical University; the Department of Surgery, National Cancer Center Hospital; the Department of Surgery, National Tokyo Medical Center; the Department of Surgery, Tokyo Medical and Dental University Faculty of Medicine; the Japan Clinical Oncology Group Data Center, Cancer Information and Epidemiology Division, National Cancer Center Research Institute, Tokyo; the Department of Surgery, Iwate Medical College, Morioka; the Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya; the Department of Surgery, Niigata University Faculty of Medicine, the Department of Surgery, Niigata Cancer Center Hospital, Niigata; the Department of Surgery, National Shikoku Cancer Center Hospital, Matsuyama; the Department of Surgery, Chiba University Faculty of Medicine, Chiba; the First Division of Surgery, Kanagawa Cancer Center, Yokohama; the Department of Surgery, Tokai University Faculty of Medicine, Isehara; the Department of Surgery, Kurume University School of Medicine, Kurume; the Department of Surgery, Osaka Medical Center and Cardiovascular Diseases, Osaka; the Department of Surgery, Kyoto University Faculty of Medicine, Kyoto; the Health Information & Epidemiology, Okinawa Prefectural College of Nursing, Okinawa, Japan. Address reprint requests to Nobutoshi Ando, MD, The Department of Surgery, Tokyo Dental College, Ichikawa General Hospital, 5-11-13 Sugano, Ichikawashi, Chiba, 272-8513 Japan; e-mail: nando{at}tdc.ac.jp.
Purpose: We performed a multicenter randomized controlled trial to determine whether postoperative adjuvant chemotherapy improves outcome in patients with esophageal squamous cell carcinoma undergoing radical surgery. Patients and Methods: Patients undergoing transthoracic esophagectomy with lymphadenectomy between July 1992 and January 1997 at 17 institutions were randomly assigned to receive surgery alone or surgery plus chemotherapy including two courses of cisplatin (80 mg/m2 of body-surface area x 1 day) and fluorouracil (800 mg/m2 x 5 days) within 2 months after surgery. Adaptive stratification factors were institution and lymph node status (pN0 versus pN1). The primary end point was disease-free survival. Results: Of the 242 patients, 122 were assigned to surgery alone, and 120 to surgery plus chemotherapy. In the surgery plus chemotherapy group, 91 patients (75%) received both full courses of chemotherapy; grade 3 or 4 hematologic or nonhematologic toxicities were limited. The 5-year disease-free survival rate was 45% with surgery alone, and 55% with surgery plus chemotherapy (one-sided log-rank, P = .037). The 5-year overall survival rate was 52% and 61%, respectively (P = .13). Risk reduction by postoperative chemotherapy was remarkable in the subgroup with lymph node metastasis. Conclusion: Postoperative adjuvant chemotherapy with cisplatin and fluorouracil is better able to prevent relapse in patients with esophageal cancer than surgery alone.
DURING THE past two decades, surgery has improved the survival of patients with advanced squamous cell carcinoma of the thoracic esophagus (pathologic stage IIA to IV). Nonetheless, the 5-year survival rate remains relatively modest at less than 40%.1 The radical surgical treatment of esophageal carcinoma includes transthoracic esophagectomy with extensive lymphadenectomy,2 which is the standard surgical treatment in Japan. As invasiveness of this procedure approaches the limit of tolerability for patients, more aggressive surgery is precluded. Therefore, to improve outcome for esophageal cancer patients, effective multimodality treatment must be developed. When the Japan Esophageal Oncology Group (JEOG), a subgroup of the Japan Clinical Oncology Group (JCOG),3 compared surgery alone with postoperative adjuvant chemotherapy using a combination of cisplatin and vindesine, no additive effect on survival of patients with esophageal squamous cell carcinoma (ESCC) was obtained beyond survival with surgery alone (JCOG8806).4 However, poor results of a JEOG phase II study (JCOG8703)5 of cisplatin and vindesine for patients with advanced esophageal cancer suggested that this particular combination of chemotherapy had only a modest effect. In contrast, a JEOG phase II study (JCOG8807)6 of cisplatin and fluorouracil demonstrated a promising response rate of 36%. We therefore initiated a randomized controlled trial to determine whether postoperative adjuvant chemotherapy using a combination of cisplatin and fluorouracil has an effect on disease-free survival and overall survival that is additive with the survival benefit of transthoracic esophagectomy including lymphadenectomy.
Patients were entered onto this study according to the following eligibility criteria: 1) histologically proven squamous cell carcinoma of the thoracic esophagus; 2) no microscopic residual tumor (R0); 3) pathologic stages IIA, IIB, III, or IV due to distant node involvement (M1 lym) only; 4) an Eastern Cooperative Oncology Group performance status [PS] of 0 to 2; 5) an age of 75 years or younger; 6) an essentially normal clinical laboratory profile (WBC  4,000/mm3; hemoglobin 10g/dL; platelet count [Plt] 100,000/mm3; total serum bilirubin  1.2 mg/dL; AST and ALT no higher than twice the normal level; creatinine [CRTN] 1.2 mg/dL; creatinine clearance [CCr] 60 mL/min; arterial oxygen tension 65 Torr; and 7) oral or written informed consent obtained before randomization in accordance with JCOG policy in 1992. Patients were ineligible if they had an additional synchronous or metachronous cancer. After assessment of pathologic findings in the resected specimens, patients were randomly assigned to two arms within 2 months following surgery: no further treatment (surgery alone; arm A) and postoperative chemotherapy (surgery plus chemotherapy; arm B). A minimization method was used so institution and pathologic lymph node status (pN0 v pN1) would be balanced. Randomization was performed centrally at the JCOG Data Center (JCOG DC), with the order transmitted by telephone or fax.
Surgery
Chemotherapy
The second course of chemotherapy was suspended for WBC < 2,000/mm3, Plt < 50,000/mm3, CRTN > 1.5 mg/dL, or CCr < 40 mL/min. The dose of cisplatin was decreased by 50% in cases where 1.2 mg/dL was less than CRTN
Study Design and Statistical Analysis The primary end point was disease-free survival. The secondary end points were overall survival and toxicities. This study was designed to include 290 randomly assigned patients over 5-year accrual with 5 years of additional follow-up to detect a 13% improvement in 5-year disease-free survival (40% in arm A v 53% in arm B), with a one-sided alpha of 0.05 and 0.80. Clinicopathologic parameters are expressed according to the tumor-node-metastasis system Classification of the International Union Against Cancer.8 Overall survival was measured from the date of surgery to the date of death or last follow-up, and censored at the last contact date in surviving patients. Disease-free survival was measured from the date of randomization to the date of first evidence of relapse or death as a result of any cause, whichever was observed first. For patients who had not relapsed or died, disease-free survival was censored at the last date that the absence of relapse was confirmed. Recurrences were documented by means of clinical examination, chest radiography, computed tomography of the chest and abdomen, or ultrasonography of the neck and abdomen. Overall and disease-free survival curves were calculated by the Kaplan-Meier method and compared by the unstratified log-rank test. Confidence intervals of survival distribution were based on Greenwood’s formula. A proportional hazards regression model was used for the adjustment of confounding baseline variables and the estimation of relative risks by means of hazard rate ratio.9 Comparison between the arms had been monitored semi-annually by the Data and Safety Monitoring Committee of the JCOG until 1996. After that date, no comparison was performed before the end of accrual in compliance with the amended JCOG policy. This study was designed and conducted on the basis of one-sided testing, and the results are presented with one-sided P values. All calculations were performed with SAS software (SAS/STAT User’s Guide, Version 6, Cary, NC, SAS Institute, 1990) by the JCOG DC.
Study Course Since the accrual period had exceeded 4 years and the accrual rate was low, the study chair (N.A.) decided to terminate accrual in March 1997. The primary analyses were performed in October 1998. According to the favorable disease-free survival in chemotherapy arm (one sided P = .051, unadjusted log-rank test) even with no difference in overall survival, JEOG decided to adopt adjuvant chemotherapy with fluorouracil and cisplatin as a control arm in the next phase III trial. Updates of follow-up data and re-analyses were performed in December 2001 for this publication.
Patient Characteristics There was one ineligible patient with positive resected margin in arm A, and two ineligible patients in arm B (one was entered at 8 months after surgery, the other was 76 years old). However, these three cases were included in all analyses.
In arm B, 29 patients were not able to fully complete planned courses of postoperative chemotherapy. Twenty-one of these patients underwent only one course of chemotherapy because of either toxicity or patient refusal. Eight underwent no chemotherapy, six because of refusal. Baseline prognostic variables, such as tumor location, pT, pN, pM, and pathologic stage were well balanced between arms (Table 1
Characteristics of Surgery Esophagectomy via right thoracotomy was performed in 120 patients in both arms. Left thoracotomy was performed in two patients in arm A only. No patients underwent transhiatal esophagectomy without thoracotomy, in compliance with exclusion criteria of this study. Two-field lymphadenectomy (regional mediastinum and abdomen) was performed in 61 patients in arm A and in 46 patients in arm B. Three-field lymphadenectomy (regional mediastinum and abdomen plus neck) was performed in 61 patients in arm A and in 74 patients in arm B.
Toxicity
Disease-Free and Overall Survival As of the updated analyses, the median follow-up time from randomization in all randomly assigned patients was 62.8 months. Disease-free survival curves are shown in Figure 1  . The 5-year disease-free survival was 45% (95% CI, 36% to 54%) in arm A and 55% (95% CI, 46% to 64%) in arm B (P = .037). The unadjusted relative risk estimate (hazard rate ratio) of arm B against arm A was 0.73 (95% CI, 0.51 to 1.03). Relative risk estimates of arm B versus arm A for disease-free survival adjusted for baseline prognostic variables by a multivariate proportional hazard model was 0.75 (95% CI, 0.52 to 1.07), which did not differ from the unadjusted estimates. Baseline prognostic variables included age, sex, performance status, tumor location, pathologic T-stage, intramural metastasis, pathologic N-stage, pathologic M-stage, and extent of lymphadenectomy.
Disease-free survival curves according to lymph node metastasis and adaptive stratification factor are shown in Figure 2 . Risk reduction in arm B was remarkable in the subgroup with lymph node metastasis. To identify the other subgroups in which more patient benefit might be expected, we assessed interactions in terms of disease-free survival among treatment effects and baseline variables as well as lymph node status. Disease-free survival difference by arms tended to be larger in higher T stage (T3 to T4) and better PS (PS = 0; data not shown).
Overall survival curves are shown in Figure 3 . The 5-year overall survival was 52% (95% CI, 43% to 61%) in arm A and 61% (95% CI, 52% to 70%) in arm B (P = .13). Subgroup analyses for overall survival showed no remarkable differences.
Site of Recurrence and Subsequent Therapy After Recurrence Cancer recurrences developed in 63 patients in arm A and in 45 patients in arm B. The frequency of local recurrences in lymph nodes, particularly in the cervical and mediastinal nodes, was slightly higher in arm A than in arm B. Of 63 patients in arm A with cancer recurrence, 54 (86%) underwent local or systemic treatments for recurrence; 36 (80%) of 45 patients did so in arm B. The frequency of chemoradiotherapy was higher in arm A than in arm B (Table 3 ).
The issue of whether to add chemotherapy to esophageal cancer surgery remains under investigation. Neither preoperative chemotherapy10–14 nor postoperative chemotherapy15 with a combination of cisplatin and fluorouracil improved survival of the patients with ESCC and/or adenocarcinoma. Recently, the Medical Research Council Esophageal Cancer Working Party16 found in a study of 802 patients that preoperative chemotherapy with the same combination improved survival relative to outcome with surgery alone. However, 30% of patients treated with surgery alone underwent incomplete resection, and survival in the group with surgery alone was unusually poor (median, 13 months). In the Western countries, preoperative (neoadjuvant) chemotherapy or chemoradiotherapy17,18 predominates. We preferred to wait until after surgery to avoid increasing operative morbidity, considering the invasiveness of the standard procedure used in Japan (transthoracic esophagectomy with extensive lymphadenectomy). In this study, we chose disease-free survival as the primary end point, because after recurrence patients could be treated with any therapy considered useful. We found that disease-free survival in the surgery-plus-chemotherapy arm was superior to that with surgery alone with marginal statistical significance, even though no difference was shown for overall survival. We can offer two hypotheses to explain the divergence between disease-free survival and overall survival. One would be the effect of imbalance in extent of lymphadenectomy between the arms. Three-field lymphadenectomy comprised 62% (74 of 120 patients) of the surgery-plus-chemotherapy arm, but 50% (61 of 122 patients) of the surgery arm. Recurrence in cervical and mediastinal lymph nodes was more frequent in the surgery arm than in the surgery-plus-chemotherapy arm. Therefore, the difference in disease-free survival between the arms might be caused by a difference in extent of lymphadenectomy rather than by chemotherapy. However, the 5-year disease-free survival with two-field lymphadenectomy was 42% in arm A and 50% in arm B (P = .25), while with three-field lymphadenectomy, it was 47% in arm A and 58% in arm B (P = .23). Adjustment with the Cox proportional hazard model showed no remarkable interaction between lymphadenectomy extent and arm concerning disease-free survival. Thus, imbalance in lymphadenectomy extent was not considered to be the cause of the difference in disease-free survival between the arms. Another explanation involves distortion of overall survival data. We believe that the difference in disease-free survival between the two study arms probably resulted from eradication of intranodal and perinodal micrometastatic disease by chemotherapy. The benefit of chemotherapy for overall survival was diluted by subsequent therapy given after recurrence. The frequency of local recurrence in lymph nodes was slightly higher in arm A than in arm B. Consequently, as treatment for recurrence, subsequent chemoradiotherapy was given more frequently in arm A (35%) than in arm B (25%). Lack of a difference in overall survival between the study arms might reflect subsequent chemoradiotherapy given to patients in arm A on discovery of local recurrences. We favor this second hypothesis and consider disease-free survival prolongation by adjuvant chemotherapy to reflect the true patient benefit. Although an overall survival benefit was not observed, toxicity during chemotherapy was tolerable. A fatal adverse reaction occurred only in one patient. The observed difference of approximately 10% increase in 5-year disease-free survival and a hazard ratio of 0.73 would be considered clinically meaningful even with marginally statistical significance. Bosset et al17 also reported prolonged disease-free survival without improved overall survival in a comparison of chemoradiotherapy followed by surgery with surgery alone in 282 patients with squamous cell carcinoma of the esophagus. They also concluded that improved disease-free survival reflected mainly a local effect, as suggested by a longer interval free of local disease in the combined-treatment arm. As for generalizability of the results, observed differences in disease-free survival between the arms are remarkable in the subsets defined by node metastasis, higher pT, and better PS. These would suggest that the benefit from adjuvant chemotherapy would be expected mainly in patients with good performance status but advanced tumor extension. The weakness of this study can be summarized as follows: early termination of accrual limited the sample size and the primary analyses and the updated analyses were not in the prospectively designed manner; however, we performed only twice comparisons of efficacy end points after termination of accrual, therefore, possible bias due to multiple comparison should not affect our conclusion; only 76% of patients could complete both courses of chemotherapy; there were several patients lost to follow-up, four patients in arm A and three patients in arm B; however, all randomly assigned patients were included in the analyses in compliance with the intent-to-treat principle. On the basis of these data, we concluded that postoperative adjuvant chemotherapy with cisplatin and fluorouracil has a detectable preventive effect on relapse in patients with ESCC compared with surgery alone. Accordingly, a randomized controlled trial comparing postoperative adjuvant chemotherapy with neoadjuvant chemotherapy using cisplatin and fluorouracil is ongoing (JCOG9907).
The authors indicated no potential conflicts of interest.
We thank the JCOG Data Center staff, Ms Yukiko Fujikura, and Dr Miyuki Niimi for data management, and Dr Naoki Ishizuka for the updated analyses.
Supported by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor, and Welfare of Japan (5S-1, 8S-1, 11S-3, 11S-4) and from the Second Term Comprehensive 10-Year Strategy for Cancer Control (H10-Gan-027, H12-Gan-012). Presented in part at the 35th Annual Meeting of the American Society of Clinical Oncology, Atlanta, GA, May 15–18, 1999.
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3. Shimoyama M, Fukuda H, Saijo N, et al: Japan Clinical Oncology Group (JCOG) Jpn J Clin Oncol 28:158–162, 1998
4. Ando N, Iizuka T, Kakegawa T, et al: A randomized trial of surgery with and without chemotherapy for localized squamous carcinoma of the thoracic esophagus: The Japan Clinical Oncology Group study. J Thorac Cardiovasc Surg 114:205–209, 1997
5. Iizuka T, Kakegawa T, Ide H, et al: Phase II evaluation of cisplatin and vindesine in advanced squamous cell carcinoma of the esophagus: Japan Esophageal Oncology Group Trial. Jpn J Clin Oncol 21:176–179, 1991
6. Iizuka T, Kakegawa T, Ide H, et al: Phase II evaluation of cisplatin and 5-fluorouracil in advanced squamous cell carcinoma of the esophagus: Japan Esophageal Oncology Group Trial. Jpn J Clin Oncol 22:172–176, 1992 7. World Health Organziation: WHO Handbook for reporting results of cancer treatment. Geneva, 1979 8. International Union Against Cancer. TNM classification of malignant tumors. Fifth fully revised edition. New York, Springer-Verlag, 1997 9. Armitage P, Berry G: Survival analysis in statistical methods in medical research. Third ed. Oxford, Blackwell Scientific Publications, 1994 10. Ajani JA, Roth JA, Ryan B, et al: Evaluation of pre- and postoperative chemotherapy for resectable adenocarcinoma of the esophagus or gastroesophageal junction. J Clin Oncol 8:1231–1238, 1990[Abstract]
11. Law S, Fok M, Chow S, et al: Preoperative chemotherapy versus surgical therapy alone for squamous cell carcinoma of the esophagus : A prospective randomized trial. J Thorac Cardiovasc Surg 114:210–217, 1997
12. Kelsen D, Ginsberg R, Pajak T, et al: Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 339:1979–1984, 1998 13. Ancona E, Ruol A, Santi S, et al: Only pathologic complete response to neoadjuvant chemotherapy improves significantly the long term survival of patients with resectable esophageal squamous cell carcinoma. Cancer 91:2165–2174, 2001[CrossRef][Medline] 14. Urschel JD, Vasan H, Blewett CJ: A meta-analysis of randomized controlled trials that compared neoadjuvant chemotherapy and surgery to surgery alone for resectable esophageal cancer. Am J Surg 183:274–279, 2002[CrossRef][Medline] 15. Pouliquen X, Levard H, Hay JM, et al: 5-fluorouracil and cisplatin therapy after palliative surgical resection of squamous cell carcinoma of the esophagus. A multicenter randomized trial. French Associations for Surgical Research. Ann Surg 223:127–133, 1996[CrossRef][Medline] 16. Medical Research Council Oesophageal Cancer Working Party: Surgical resection with or without pre-operative chemotherapy in oesophageal cancer: a randomized controlled trial. Lancet 359:1727–1733, 2002[CrossRef][Medline]
17. Bosset JF, Gignoux M, Triboulet JP, et al: Chemoradiotherapy followed by surgery compared with surgery alone in squamous-cell cancer of the esophagus. N Engl J Med 337:161–167, 1997
18. Urba SG, Orringer MB, Turrisi A, et al: Randomized trial of preoperative chemoradiation versus surgery alone in patients with locoregional esophageal carcinoma. J Clin Oncol 19:305–313, 2001 Submitted December 16, 2002; accepted September 12, 2003.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
