Postoperative Adjuvant Chemotherapy for Non-Small-Cell Lung Cancer

ABSTRACT: Given that no therapeutic methods of postoperative adjuvant chemotherapy for non-small-cell lung cancer have been established, we selected UFT (tegafur and uracil) for investigation because UFT is less injurious to the host than intensive chemotherapies. The second study of the West Japan Study Group for Lung Cancer Surgery showed that the 5-year survival rates were 64.1% in the UFT group (UFT 400 mg/day for 1 year after surgery) and 49.1% in the control group (surgery alone). Thus, the survival rate for all patients was improved significantly in the UFT group as compared with the control group (log rank test, P = .033; generalized Wilcoxon test, P = .019). To establish the usefulness of long-term oral administration of UFT as an adjuvant therapy for completely resected non-small-cell lung cancer, the nationwide Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy is now conducting a comparative study of surgery alone versus surgery and UFT in patients with pathologic stage I adenocarcinoma. [ONCOLOGY 11(Suppl 10):98-102, 1997]

Introduction

Various studies using intense chemotherapies as postoperative adjuvant treatments for non-small-cell lung cancer have been published. There are, however, very few published reports addressing the usefulness of these adjuvant chemotherapies,[1,2] and thus no standard therapeutic method has yet been established. We consider that chemotherapies that can be administered continuously over the long term will prove to be effective in eradicating micrometastases, which cannot be identified macroscopically. Our focus is on Tegafur and Uracil (UFT), which was developed based on the biochemical-modulation theory. UFT, administered orally, maintains fluorouracil (5-FU) concentrations in blood for long periods. In Japan, UFT has been investigated widely as a postoperative adjuvant therapy for gastrointestinal and breast cancers and is said to be less injurious to hosts than other chemotherapeutic options, centering as it does on the immunobiologic system.

With this presentation, we report the results of a randomized controlled trial using UFT as postoperative adjuvant chemotherapy for non-small-cell lung cancer. The study was conducted in hospitals in western Japan that specialize in treating lung cancer. We also refer to a future study to confirm the efficacy of UFT conducted in nationwide Japanese hospitals.

West Japan Study Group for Lung Cancer Surgery

The West Japan Study Group for Lung Cancer Surgery (WJSG) was established in 1982 as an organization for collaborative studies among hospitals specializing in lung cancer surgery in western Japan. Its goal was to evaluate the usefulness of postoperative adjuvant chemotherapies for non-small- cell lung cancer through randomized controlled study.

West Japan Study Group for Lung Cancer Surgery Study 1

In the first West Japan Study Group for Lung Cancer Surgery study,[3] patients whose adenocarcinoma had been resected completely received initial intravenous administration of mitomycin (Mutamycin) 20 mg on the day of the operation and 10 mg on the next day. Tegafur, administered at 600 mg divided into two daily doses for 1 year was compared with UFT, administered at 400 to 600 mg/day divided into two daily doses for 1 year, in patients with adenocarcinoma following complete resection. Patient characteristics were similar in these two groups in terms of sex, age, histologic classification, pathologically staged (p)T, N, or disease stage (Table 1).

For the 181 patients analyzed, no difference was observed in 5-year survival rates between the treatment groups. The results of a subset analysis showed that the prognosis of pN2 patients was better in the UFT-treated group compared with those who received tegafur alone (Figure 1). The main adverse reactions to tegafur and UFT in the patients with non-small-cell lung cancer were appetite loss, nausea, and vomiting, but these were slight and tolerable. There were no problems regarding the safety of the long-term administrations.

West Japan Study Group for Lung Cancer Surgery Study 2

The second West Japan Study Group for Lung Cancer Surgery study[4] was an exploratory research project in which patients with completely resectable non-small-cell lung cancer were randomly assigned to one of three comparative treatment groups: cisplatin (Platinol) + vindesine + UFT (CVUFT group); UFT (UFT group); or no treatment following surgery (control group).

Selected patients had no history of cancer chemotherapy but had undergone complete resection of primary non-small-cell lung cancer between December 1985 and July 1988. Completely resected patients were carefully selected by the central telephone method for compliance with the registration selection criteria. Eligible patients were then randomly allocated to one of the three treatment groups, in order of registration. The patients in the CVUFT group were given cisplatin 50 mg/m² (70 to 90 mg/m²) and vindesine 2 to 3 mg weeks 1 through 3 after surgery, followed by vindesine 2 to 3 mg twice at 1- or 2-week intervals. Beginning 2 weeks after this initial treatment, patients received oral UFT 400 mg/day for 1 year. The patients in the UFT group were given oral UFT for 1 year beginning 1 to 3 weeks after surgery. The patients in the control group were given no adjuvant chemotherapy. The Kaplan-Meier method was used to calculate survival rates, with a log rank test and generalized Wilcoxon test for analysis. Multivariate analysis using Cox’s proportional hazard model was conducted to investigate factors affecting prognosis.

A total of 323 patients were enrolled in the study (115 in the CVUFT group, 108 in the UFT group, and 100 in the control group), with 310 patients eligible (109 in the CVUFT group, 103 in the UFT group, and 98 in the control group). Thirteen patients were found to be ineligible for analysis. No differences were observed between the groups of eligible patients in terms of sex, age, histologic classification, pT, pN, or disease stage (Table 2). The main adverse reactions (grade 1 or less) for the CVUFT group and the UFT group were fatigue (64.2% for the CVUFT group and 42.7% for the UFT group), anorexia (63.3% for the CVUFT group and 33.8% for the UFT group), and nausea and vomiting (42.2% for the CVUFT group and 15.5% for the UFT group). The incidence of hematologic disorder, hepatic dysfunction, and stomatitis were low. In most cases, adverse reactions were not serious enough to interfere with scheduled adjuvant chemotherapy. The 5-year survival rates, evaluated for all patients, were 60.6% for patients in the CVUFT group, 64.1% for the UFT group, and 49.0% for the control group (Figure 2), with differences noted among the three groups (log rank test, P = .053; generalized Wilcoxon test, P = .044). A significant difference in 5-year survival was observed between the UFT and control groups (log rank test, P = .033; generalized Wilcoxon test, P = .019). Results of the subset analyses showed that prognosis was better for patients with disease stages I + II and IIIA, and for those with adenocarcinoma, in the UFT group compared with those in the control group.

Based on the results of multivariate analysis (Cox’s hazard model) of sex, age, histologic type, pT, pN, and therapeutic method, it is concluded that pT, pN, and therapeutic method are significant prognostic factors (Table 3). In regard to treatment results, the CVUFT group and the UFT group were compared separately with the control group. Their respective hazard ratios were 0.64 (95% confidence interval, 0.42 to 0.97) and 0.55 (95% confidence interval, 0.36 to 0.86).

The Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy

The secondary study of the West Japan Study Group for Lung Cancer Surgery suggested the usefulness of long-term oral administration of UFT as adjuvant chemotherapy for patients with non-small cell lung cancer who have undergone completeresection. It is necessary, however, to verify the survival-benefit of long-term oral administration of UFT alone in a comparable group of patients with non-small cell-lung cancer of the same pathologic stage and histologic type.

Thus, the nationwide Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy (JLCRG) is now conducting a comparative study of surgery alone vs surgery and UFT in patients with stage I (T1N0M0, T2N0M0) adenocarcinoma after complete resection. By differential analysis, prognosis was superior for the UFT group compared with the control group.

Conclusion

Given that there are no standard regimens of postoperative adjuvant chemotherapy for non-small-cell lung cancer, we selected UFT for investigation because it is less injurious to the host than intensive chemotherapies. As a result of an investigation of the 5-year survival rate in the West Japan Study Group for Lung Cancer Surgery second study, we found that survival rates were 64.1% in the UFT group and 49.1% in the control group. Thus, the survival rate for all patients was improved in the UFT group compared with the control group.

In central Japan, surgery alone and administration of cisplatin, doxorubicin (Adriamycin), and UFT were compared in patients with non-small cell lung cancer after complete resection. After correction for prognostic factors using Cox’s proportional hazard model, improved survival rates were observed in the UFT-treated group.[5]

UFT could be an effective therapeutic option for adjuvant chemotherapy for non-small-cell lung cancer. We await results of the randomized controlled study conducted by the Japan Lung Cancer Research Group on Postsurgical Adjuvant Chemotherapy.

References:

1. Holmes EC, Gail M: Lung Cancer Study Group: Surgical adjuvant therapy for stage II and stage III adenocarcinoma and large cell undifferentiated carcinoma. J Clin Oncol 4:710-715, 1986.

2. Niiranen A, Niitamo-Korhonen S, Kouri M, et al: Adjuvant chemotherapy after radical surgery for non-small cell lung cancer: Randomized study. J Clin Oncol 10:1927-1932, 1992.

3. Shimizu N, Teramoto S, Hitomi S, et al: A randomized controlled postoperative adjuvant chemotherapy trial of MMC + Tegafur and MMC + UFT for adenocarcinoma of the lung – first study. Jpn J Lung Cancer 31:1011-1019, 1991.

4. Wada H, Hitomi S, Teramatsu T, et al: Adjuvant chemotherapy after complete resection in non-small cell lung cancer. J Clin Oncol 14:1048-1054, 1996.

5. The Study Group of Adjuvant Chemotherapy for Lung Cancer (Chubu Japan): A randomized trial of postoperative adjuvant chemotherapy in non-small cell lung cancer (the second cooperative study). Eur J Surg Oncol 21:69-77, 1995.