A randomized phase III trial of adjuvant chemotherapy with UFT for completely resected pathological stage I non-small-cell lung cancer: the West Japan Study Group for Lung Cancer Surgery (WJSG)—the 4th study

M. Nakagawa1, F. Tanaka1, N. Tsubota2, M. Ohta3, M. Takao4 and H. Wada1,* On behalf of the West Japan Study Group for Lung Cancer Surgery (WJSG){dagger}

1 Department of Thoracic Surgery, Kyoto University, Kyoto; 2 Department of Thoracic Surgery, Hyogo Medical Center for Adults, Akashi; 3 Department of Thoracic Surgery, National Okinawa Hospital, Okinawa; 4 Department of Thoracic and Cardiovascular Surgery, Mie University, Mie, Japan

* Correspondence to: Dr H. Wada, Department of Thoracic Surgery, Kyoto University Hospital, Shogoin-kawara-cho 54, Sakyo-ku, Kyoto, 606-8507, Japan. Tel: +81-75-751-3835; Fax: +81-75-751-4647; Email: wadah{at}kuhp.kyoto-u.ac.jp


    Abstract
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Purpose: To examine the efficacy of UFT, an oral 5-fluorouracil derivative agent, as post-operative adjuvant therapy for pathologic (p-) stage I non-small-cell lung cancer (NSCLC), because a previous randomized study had suggested it was efficacious for early-stage NSCLC patients.

Patients and methods: Patients with completely resected p-stage I, adenocarcinoma or squamous cell carcinoma were eligible. A total of 332 patients were randomized to the surgery-alone group (control group) and the treatment group (UFT 400 mg/m2 for 1 year after surgery, UFT group) after stratification by the histologic types.

Results: For all patients, the 5- and 8-year survival rates for the UFT group were 82.2% and 73.0%, and those for the control group were 75.9% and 61.2%, respectively; no statistically significant improvement of survival was achieved by UFT administration (P=0.105). For Ad patients, the 5- and 8-year survival rates of the UFT group (n=120) were 85.2% and 79.5%, respectively, which seemed better than those of the control group (n=121) (79.2% and 64.0%, respectively; P=0.081). For squamous cell carcinoma patients, there was also no difference in survival between the control group (n=48) and the UFT group (n=43) (P=0.762). For all pT1 patients, the 5- and 8-year survival rates of the UFT group were 83.6% and 82.1%, respectively, significantly better than those of the control group (77.9% and 57.6%, respectively, P=0.036); UFT was not significantly effective for pT2 patients. For pT1 adenocarcinoma patients, UFT administration markedly improved the survival (P=0.011).

Conclusion: Post-operative UFT administration did not significantly improve post-operative survival of p-stage I NSCLC patients. Subset analyses suggested that UFT might be effective in pT1N0M0 adenocarcinoma patients.

Key words: adenocarcinoma, adjuvant chemotherapy, lung cancer, squamous cell carcinoma, surgery, UFT


    Introduction
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Primary lung cancer is the leading cause of cancer deaths in most industrialized countries. Non-small-cell lung cancer (NSCLC) accounts for 75–85% of primary lung cancer, and the most effective curative therapeutic modality is complete resection. However, the post-operative prognosis remains unsatisfactory, and the 5-year survival rate of all operated patients is less than 50% [1Go–3Go]. Even in pathologic (p-) stage I diseases with no documented nodal metastasis or no distant metastasis, the 5-year survival rate remains less than 90%, and in pN2 diseases where mediastinal nodal metastasis is pathologically documented, the 5-year survival rate is only 20–30% [1Go–4Go]. To improve the prognosis, a variety of post-operative therapy regimens have been studied in clinical trials, but most studies failed to show the efficacy of post-operative adjuvant therapy [5Go–10Go]. Although a meta-analysis and a recent randomized study showed that cisplatin-based chemotherapy might improve the survival [11Go, 12Go], the efficacy of post-operative adjuvant therapy has not been firmly established.

In 1996, we reported results of the 2nd study of the West Japan Study Group for Lung Cancer Surgery (WJSG) demonstrating that post-operative oral administration of UFT can improve prognosis of completely resected NSCLC patients [13Go]. UFT is an oral chemotherapeutic agent composed of tegafur and uracil [14Go, 15Go]. Tegafur is gradually converted to 5-fluorouracil (5-FU) in the liver, and uracil is added to inhibit degradation of 5-FU; as a result, UFT can maintain a certain 5-FU concentration in serum and tumor tissues for a long time [14Go–16Go]. In the 2nd WJSG study, a total of 323 p-stage I–III cases were randomized, and the post-operative survival of patients who received UFT administration post-operatively was significantly better than that of surgery-alone patients (P=0.022) [13Go]. The most critical issue in the 2nd WJSG study was the heterogeneity of the characteristics of patients enrolled in the study, especially with regard to the p-stages. Because around two-thirds of patients (n=210) in the 2nd WJSG study had p-stage I disease and most patients (n=294) had squamous cell carcinoma or adenocarcinoma, we decided to focus specifically on p-stage I squamous cell carcinoma or adenocarcinoma patients to conduct a prospective study on the efficacy of post-operative UFT administration in this relatively homogeneous group of patients (the 4th WJSG study).


    Patients and methods
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Eligibility
Patients who had undergone complete resection for histologically confirmed p-stage I (T1–2N0M0) squamous cell carcinoma or adenocarcinoma were eligible for this study. P-stage was determined according to the tumor-mode-metastasis (TNM) system revised in 1986 [17Go]. Patients were required to be 75 years old or less, and to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 [18Go]. Patients were also not to have had any preoperative anticancer treatment, and to have no previous cancer or synchronous cancer. Other inclusion criteria were adequate hematologic (leukocytes ≥4000/µl, platelets ≥100 000/µl), renal (blood urea nitrogen ≤25 mg/dl, creatinine ≤1.5 mg/dl, creatinine clearance ≥50 ml/min, no proteinuria) and liver function [total protein ≥6.0 g/dl, aspartate transaminase (AST) ≤100 IU/l, alanine transaminase (ALT) ≤100 IU/l].

After informed consent was obtained, patients were randomly assigned to the control or UFT group with stratification according to histological type (squamous cell carcinoma versus adenocarcinoma). The randomization was carried out by a central telephone registration office at Kyoto University within 3 weeks after each operation.

Treatment plan and evaluation of toxicity
Patients assigned to the control group were observed with no post-operative treatment. Patients assigned to the UFT group received oral administration of UFT at a dose of 400 mg/day, given in two separate doses, for 1 year; the administration being started within 3 weeks after operation. If the patient's weight was not greater than 40 kg, UFT was administered at a dose of 300 mg/day. Toxicity related to UFT administration was determined according to the criteria of the Japan Society of Clinical Oncology, which are equivalent to the World Health Organization criteria with minor modifications [19Go].

Study design
The primary end point in this study was the overall survival which was defined as the time from operation until death from any cause, and the secondary end point was safety assessment of UFT administration. The sample size was calculated by the method of Schoenfeld and Richter [20Go] under the following conditions: a 5-year survival rate of 70% for the control group, a 10% improvement in the overall survival at 5 years in the UFT group, the 2-year accrual period, the 5-year follow-up, a significance level for a one-sided test of 0.05, and a statistical power of 80%. In a previous study (the 2nd WJSG study) [13Go], we documented a 14% survival improvement by UFT-treatment in p-stage I patients. Based on this result, we expected a 10% survival benefit in this study. The calculated target number of patients in each group was 200, and the total number was 400. Follow-up data were collected from each institute every 12 months after operation.

Statistical analysis
Survival was estimated by the Kaplan–Meier method, and any differences in survival were computed using the log-rank test. Multivariable analyses using the Cox proportional hazard model were used to estimate the simultaneous effects of prognostic factors on survival [21Go]. The SAS statistical software package was used for all calculations. The data were considered to be statistically significant when the P value was 0.05 or less. All statistical tests were two-sided.


    Results
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
Patient characteristics
Between March 1991 and April 1994, 367 patients from 38 institutions were enrolled in the trial and were randomly assigned to either no treatment (control group) or the post-operative UFT administration (UFT group). Among all 367 patients, 35 patients were found to be ineligible for the following reasons: ineligible p-stage states in nine patients, ineligible histologic type in nine patients, incomplete resection in 18 patients, and delay in the registration of seven patients. Therefore, a total of 332 eligible patients (169 patients in the control group and 163 patients in the UFT group) were evaluated for overall survival and toxicity (Table 1). Some patients came from lung cancer screening programs, and others had clinically detected lung tumors. There were no statistically significant differences in the baseline patient characteristics between the control group and the UFT group.


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Table 1. Patient characteristics

 
Toxicity and treatment delivery
All 163 patients assigned to the UFT group actually received an oral administration of UFT. Only one patient experienced grade 3 nausea and vomiting. There was no other grade 3 or grade 4 toxicity. The percentage of compliance for UFT administration was 88.3% at 3 months, 80.4% at 6 months, 73.6% at 9 months and 50.9% at 12 months.

Survival
The median follow-up for patients was 2273 days. The overall survival rates at 5 and 8 years after operation in the control group were 75.9% and 61.2%, and those in the UFT group were 82.2% and 73.0%; the UFT group had better, but not statistically significant survival (P=0.105) (Table 2 and Figure 1). Female patients showed a significantly better survival than male patients by univariate analysis (Table 2), which was confirmed by multivariate analysis (Table 3). Adenocarcinoma and pT1 were significant factors to predict favorable survival by univariate analysis (Table 2), but multivariate analysis did not show that these were independent prognostic factors (Table 3).


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Table 2. Univariate analysis of prognostic factors

 


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Figure 1. Overall survival of all patients assigned to the control group (n=169) and the UFT group (n=163).

 

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Table 3. Multivariate analysis of prognostic factors

 
In a subgroup analysis according to pT-factor which was the stratification factor before randomization in the study, UFT administration significantly improved the survival of pT1 patients (P=0.036), but not that of pT2 patients (P=0.807) (Table 4).


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Table 4. Overall survival in the control group and in the UFT group

 
In addition, adenocarcinoma patients in the UFT group had a better survival than those in the control group, although the difference did not reach statistical significance (P=0.081); there was no survival difference between the UFT and the control group in squamous cell carcinoma patients (Table 4). When confined to pT1 adenocarcinoma patients, the UFT group showed a significantly better survival than the control group (P=0.011) (Table 4).


    Discussion
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 Abstract
 Introduction
 Patients and methods
 Results
 Discussion
 References
 
This study showed that post-operative UFT administration did not significantly improve the survival of patients with completely resected p-stage I NSCLC patients, although the post-operative survival of UFT-treated patients seemed to be better compared with that of surgery-alone patients. The target number of eligible patients in this study was 400, which had been calculated under the condition that the 5-year survival rate in the control group was 70% and a 10% improvement in the 5-year survival rate in the UFT group was expected. However, the accrual of patients was slow, and only 332 eligible patients were actually enrolled whereas the accrual period was prolonged from 2 to 3 years. Because the actual 5-year survival rate of the control group was higher (75.9%), the difference in the post-operative survival between the control group and the UFT group might not reach statistical significance even when 400 eligible patients were enrolled.

Subset analyses in this study showed that UFT was effective for pT1N0M0 patients, especially pT1N0M0 adenocarcinoma patients, but not effective for pT2N0M0 patients. In accordance with previous studies [13Go], this study also showed that UFT was effective in adenocarcinoma, but not in squamous cell carcinoma. With regard to p-stages where UFT was effective, a recent large-scale randomized study conducted by the Japan Lung Cancer Research Group (JLCRG) showed that post-operative UFT administration was effective for pT2N0M0, not pT1N0M0, adenocarcinoma patients; the 5-year survival rate of pT2 patients was 85% in the UFT-treated group and 74% in the surgery-alone group (P=0.005), whereas the 5-year survival rate of pT1 patients was 89% in the UFT-treated group and 89% in the surgery-alone group [22Go]. These results were not inconsistent with the results documented in other studies, including this study showing that UFT was effective in pT1N0M0 disease, but not effective in pT2N0M0 disease. The exact reason for the discrepancy is unclear, but we can advance some speculation. In the JLCRG study, the 5-year survival rate for pT1 adenocarcinoma in the surgery-alone group was high (89%), which might be too high to be further elevated by any additional post-operative therapy. According to an analysis of the lung cancer registry for resected patients in 1994 which was conducted by the Japanese Association for Chest Surgery and the Japan Lung Cancer Society, the 5-year survival rates of pT1N0M0 patients (n=2142) and pT2N0M0 patients (n=1488) were 79% and 60%, respectively [23Go], almost identical to those documented in this study. The marked favorable outcome of pT1 patients documented in the JLCRG study might be caused by the increased numbers of pT1 tumors with small size, i.e. less than 2 cm in diameter, due to the recent spread of computed tomography in Japan [22Go, 24Go, 25Go].

We did not assess co-morbidities such as chronic obstructive pulmonary disease (COPD), which might have an influence on post-operative prognosis of resected NSCLC patients. In addition, we did not include a disease-free survival as an end point in this study. In future studies, co-morbidities should be checked, and a disease-free survival should be assessed.

UFT alone shows a minimal anti-tumor effect, and the overall response rate of UFT-alone treatment in patients with advanced stage lung cancer is only 6–8% [16Go, 26Go]. The reason why UFT might be effective in the post-operative adjuvant setting whereas the direct anti-tumor effect of UFT and 5-FU is minimal remains unclear. Recent experimental studies have revealed that UFT and its metabolites other than 5-FU can inhibit tumor angiogenesis [27Go]. UFT may inhibit development of micro-metastases for a long time, through inhibition of tumor angiogenesis, which may result in improvement of post-operative survival. We have already revealed in a retrospective study that the efficacy of post-operative UFT administration may correlate with tumor angiogenesis and p53 status [28Go, 29Go]. Predictive factors and the mechanism of action of UFT should be assessed in future clinical studies including analyses of biomarkers. In any case, this study as well as other studies showed UFT to have a low-toxicity profile and could be given safely for a long period even for patients who had undergone thoracotomy, which might be a critical issue of post-operative adjuvant therapy. In spite of the low toxicity, only 50.9% of patients completed the planned 1-year UFT treatment. The exact reason for the unsatisfactory treatment compliance was unclear because we did not collect the reason for discontinuing UFT treatment from each investigator, which should be assessed in future studies on UFT treatment.

Recently, results of a meta-analysis on the efficacy of UFT administration for completely resected NSCLC have been reported [30Go]; six randomized studies were reviewed, and UFT-treated patients showed a significantly more favorable survival than surgery-alone patients [relative risk = 0.77 (95% CI, 0.63–0.94); P=0.001]. Each randomized study showed somewhat inconsistent results especially with regard to p-stages where UFT was effective, but the meta-analysis also showed that UFT was effective for both pT1N0M0 and pT2N0M0 patients. These results combined with the results in this study and the JLCRG study suggest that post-operative UFT is effective for p-stage I adenocarcinoma patients. In future studies, effective therapy for p-stage II–III patients should be assessed.


    Acknowledgements
 
The authors are indebted to Professor J. Patrick Barron of the International Medical Communications Center of Tokyo Medical University for his review of this manuscript. Funded by Taiho Pharmaceutical Co., Ltd., Tokyo, Japan. Part of this article was presented at the 11th European Cancer Conference (ECCO) on 22 October, 2001 (Lisbon, Portugal).

Participating Centers and Investigators—Kyoto University, Kyoto (H. Wada); Kanazawa University, Ishikawa (M. Oda); Toyama Medical and Pharmaceutical University, Toyama (T. Misaki); Shiga University of Medical Science, Shiga (S. Fujino); Nara Medical University, Nara (N. Narita, Y. Kounoike); Mie University, Mie (S. Namikawa); The University of Tokushima, Tokushima (Y. Monden, T. Uyama); Kansai Medical University, Osaka (Y. Saito); Osaka Medical College, Osaka (M. Kawakami); Okayama University, Okayama (N. Shimizu); Kawasaki Medical School, Okayama (N. Okimoto); Hiroshima University, Hiroshima (M. Yamakido); Shimane University, Shimane (T. Sasaki); Yamaguchi University, Yamaguchi (K. Hamano); Kurume University, Fukuoka (K. Shirouzu, A. Hayashi); Nagasaki University, Nagasaki (T. Nagayasu); Kagoshima University, Kagoshima (K. Aiko); Wakayama Medical College, Wakayama (Y. Naitou, S. Maebeya); Kagawa Medical School, Kagawa (M. Maeda, K. Nakamura); National Okinawa Hospital, Okinawa (K. Ishikawa); Hiroshima City Hospital, Hiroshima (N. Senou); Kurashiki Central Hospital, Okayama (J. Tamada); Tenri Hospital, Nara (M. Kitano, A. Tatsumi); Katsura Hospital, Kyoto (Y. Matsubara); Toyama Prefectural Central Hospital, Toyama (H. Noto); Fukui Red Cross Hospital, Fukui (A. Yamanaka); National Sanyo Hospital, Yamaguchi (Y. Umemori, K. Sugi); Kyoto City Hospital, Kyoto (T. Osako); Kochi Municipal Hospital, Kochi (N. Miyamoto); National Shikoku Cancer Center, Ehime (S. Takashima); Fukui University, Fukui (K. Tanaka); Hyogo Medical Center for Adults, Hyogo (N. Tsubota); National Kyoto Hospital, Kyoto (K. Nishiwaki); Hyogo Prefectural Amagasaki Hospital, Hyogo (K. Itoi); National Himeji Hospital, Hyogo (Y. Miyamoto); Takamatsu Red Cross Hospital, Kagawa (J. Morita); Kyoto Prefectural University, Kyoto (K. Nishiyama); Matsue Red Cross Hospital, Shimane (N. Isowa).


    Notes
 
{dagger} Participating investigators and institutions are listed in the Acknowledgements. Back

Received for publication May 6, 2004. Revision received July 31, 2004. Accepted for publication August 2, 2004.


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