Advantage of post-operative oral administration of UFT (Tegafur and Uracil) for completely resected p-stage I-IIIa non-small cell lung cancer (NSCLC)

Abstract

Objective: Although adjuvant therapy after surgery for non-small cell lung cancer (NSCLC) has been reported to be ineffective, it has been recently reported in prospective randomised studies conducted by two different groups in Japan that oral administration of a 5-fluorouracil (5-FU) derivative drug, UFT (a combination drug of tegafur and uracil) can improve the post-operative survival [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). Eu J Surg Oncol 1995;21:69–77; Wada, H., Hitomi, S., Teramatsu, T, West Japan Study Group for Lung Cancer Surgery. Adjuvant chemotherapy after complete resection in non-small-cell lung cancer. J Clin Oncol 1996;14:1048–1054]. To examine the efficacy of UFT as post-operative adjuvant therapy, a retrospective study was performed. Methods: A total of 655 consecutive patients who underwent complete tumor resection for pathologic stage I-IIIa, NSCLC at the Department of Thoracic Surgery, Chest Disease Research Institute, Kyoto University between 1976 and 1992 were retrospectively reviewed. As post-operative adjuvant therapy, UFT was administrated to 98 patients (UFT group), and was not administered to the other 557 patients (Control group). Results: The 5-year survival rate of the UFT group was 76.5%, which was significantly better than that of the Control group (5-year survival rate: 58.6%, P=0.005). Stratified with pathologic stage, the efficacy of UFT was seen in the p-stage I disease (5-year survival rate: 88.6% for the UFT group, 72.0% for the Control group, P=0.013) and in the p-stage IIIa, pN2 disease (5-year survival rate: 54.3% for the UFT group, 37.5% for the Control group, P=0.037). Multivariate analysis of the prognostic factors also revealed the efficacy of UFT (P=0.004, 95% confidence interval of relative risk: 0.325–0.840). Post-operative intravenous chemotherapy or radiation therapy did not prove to be significant factors affecting the prognosis. Conclusions: Efficacy of oral administration of UFT as post-operative adjuvant therapy for completely resected NSCLC was proposed. To confirm the efficacy, a prospective randomized study for a more homogenous patient group is needed.

Lung cancer, Non-small cell, Surgery Adjuvant therapy, UFT, 5-fluorouracil

Introduction

The post-operative prognosis of primary non-small cell lung cancer (NSCLC) remains poor, and 5-year survival rates for all patients having undergone surgery for NSCLC have been reported to be only 20–35% [1],[2],[3]. According to these reports, 5-year survival rates were only 57.0–75.5% even for pathologic stage I (p-stage I) disease, and those for p-stage II and p-stage IIIa diseases were 38.4–54.1% and 15.1–44.2% respectively. As clarified by a prospective randomized study demonstrating that the 5-year survival rate of patients who underwent surgery alone for p-stage IIIa, NSCLC was 0% [4], improvement in the prognosis by surgery alone is limited.

Although adjuvant therapy had been expected to improve the post-operative survival, it was concluded that radiation therapy did not improve the survival even though it might reduce the local recurrence rate after operation [5]. In addition, the efficacy of post-operative adjuvant chemotherapy for NSCLC has not been established [6],[7]. It was reported only that CAP therapy (cyclophosphamide: CPA+adriamycin: ADR+cisplatin: CDDP) might elongate the post-operative disease free interval [8],[9],[10],[11]. Recently, however, prospective randomized studies conducted by two different groups in Japan revealed that oral administration of UFT (a combination oral drug of tegafur and uracil) [12] was effective as post-operative adjuvant chemotherapy for completely resected NSCLC [13],[14].

We had retrospectively reviewed the time trends of survival after operations for primary lung cancer during the past 15 years, and reported that the post-operative survival has improved remarkably in later years. Analysis of the prognostic factors revealed that the improvement was caused by increases in the rates of complete tumor resection, decreases in the rates of exploratory thoracotomy, and decreases in the rates of operation-related death [15]. In the report, however, adjuvant therapy was not investigated enough, and no new findings concerning post-operative adjuvant therapy could be revealed. Therefore, in the present report, we examined the influence of post-operative adjuvant therapy, especially oral administration of UFT, retrospectively.

Patients and methods

A total of 660 consecutive patients who underwent complete tumor resection and mediastinal Iymph node dissection for p-stage I-IIIa, NSCLC, from January 1, 1976 to December 31, 1992, at the Department of Thoracic Surgery, Chest Disease Research Institute, Kyoto University, were retrospectively reviewed. Complete tumor resection was defined as no microscopic malignant cells identified, neither in the margin of the resected tumor nor in the highest mediastinal lymph nodes dissected [15]. According to the current TNM classification revised in 1986 [2], pathologic stages (p-stage) were determined based on histopathological findings of the resected specimens at thoracotomy, and those of patients who underwent operation before 1986 were also re-evaluated according to the current TNM classification. Mediastinoscopy to evaluate mediastinal lymph node status was not routinely performed, with some exceptions. Histologic types were determined according to the classification of the World Health Organization [16]. Performance status (PS) was determined according to the `ECOG Performance Status Scale' [17]. Five patients who underwent operation-related death (operation-related death rate 0.76%) were excluded, and 655 patients were finally used as subjects for the study. Operation-related death patients, in this context, included all patients who died within 30 days after surgery and those who died of post-operative complications without being discharged from the hospital. Investigation was performed with all clinical records, chest roentgenograms, chest and whole-body CT scans, bone and gallium scans, operation records and histopathological specimens. Post-operative follow-up was thoroughly conducted for all the patients through the investigation of out-patient records and inquiries by telephone or letter. Post-operative follow-up was complete until patients had died or over a period of more than 5 years if alive, and the survival could be determined accurately. The starting day for counting post-operative survival was the day of the thoracotomy for the primary pulmonary tumor. As post-operative adjuvant therapy, UFT was administered to patients from whom informed consent had been taken. In principle, post-operative radiation was offered to pT3 patients. and intravenous chemotherapy to pN1 or pN2 patients.

Clinical characteristics of the patients (Table 1)

Table 1

Patients' characteristics and post-operative survival

There were 464 males and 191 females. Mean age at thoracotomy was 61.6±10.1 years (mean±standard deviation, range 17–83 years). PS was 0 or 1 for most patients. With respect to the histologic type, adenocarcinoma was most frequent (41.9%) followed by squamous cell carcinoma (40.6%). As for p-stage, the number of stage I patients was the highest (350 patients, 53.4%). Among 233 patients with p-stage III diseases, 139 had mediastinal lymph nodes metastasis (pN2 disease).

Statistical methods

Counts were compared using a χ² test. Continuous data were compared using Student's t-test when distributed normally or using the Mann–Whitney U test when not distributed normally. Survival after surgery was analyzed by the Kaplan–Meier method [18], and evaluation of the difference was conducted by log-rank test [19]. Multivariative analysis of the prognostic factors was conducted using Cox's regression model [20]. When P-values were less than 0.05, it was concluded that there was a significant difference. All the above-mentioned statistical analysis was performed using the SPSS for Windows software system (SPSS, Chicago, IL, 1993).

Results

For all the patients, the 5-year survival rate after surgery was 61.3%. When assessed according to the patient's background factors, no difference in the survival was observed between males and females. With respect to the histologic type, the 5-year survival rates for squamous cell carcinoma and for adenocarcinoma were 57.7% and 62.6%, respectively, showing no significant difference (P=0.222). Concerning PS at the time of thoracotomy, the 5-year survival rates for patients of PS 0, 1, and 2 were 63.7%, 45.1%, and 25.0%, respectively, demonstrating that the post-operative survival was significantly poor as the PS became worse (P≪0.001). The 5-year survival rates for p-stage I, II, and IIIa diseases were 74.7%, 57.5%, and 40.4%, respectively, with a significant difference between them (P≪0.001). Among p-stage IIIa diseases, the 5-year survival rate for pN2 disease was 34.0%, which was significantly worse than that for pT3N1-0 disease (48.6%, P=0.022) (Table 1).

Post-operative adjuvant therapy and survival (Table 2)

Table 2

Post-operative adjuvant therapy and post-operative survival

Among all the 655 patients, 245 patients (37.4%) received radiation (30–40Gy) or intravenous chemotherapy post-operatively; 86 patients (13.1%) underwent radiation only, 140 (21.4%) underwent intravenous chemotherapy only, and 19 (2.9%) underwent intravenous chemotherapy combined with radiation. Post-operative radiation therapy was performed in 105 patients (16.0%) in total, and intravenous chemotherapy in 159 patients (24.3%) in total. As post-operative intravenous adjuvant therapy, CDDP-based chemotherapy was performed in 73 patients. One cycle of CDDP and VDS (with or without MMC) was performed in 59 patients, and two cycles in six patients, as the most common CDDP-based regimen. Combination chemotherapy without CDDP (non CDDP-based regimens) was performed in 86. Non CDDP-based regimens included CPA, 5-FU, ADM, and mitomycin-C (MMC). UFT was administered to 98 patients (15.0%) as post-operative adjuvant therapy. The dose of UFT was 300–400 mg/day per person, and administration was started within 1 month after surgery and continued for 17.2 months on average, ranging from 3 to 61 months.

The 5-year survival rate for patients who received post-operative radiation therapy was 49.5%, which was significantly inferior to that for those who did not receive it (5-year survival rate: 63.5%, P=0.002). However, 71.4% (75 patients) of those who received postoperative radiation had p-stage IIIa disease, and the number of patients having more advanced stages was significantly larger in those with post-operative radiation as compared with those without it (P≪0.001).

The 5-year survival rate of patients who received intravenous chemotherapy after surgery was 52.7%, with no significant difference from that of those who did not receive it (5-year survival rate 64.3%, P=0.114). The 5-year survival rate of patients who received CDDP-based intravenous chemotherapy was 67.2%, which was not significantly better than that of those who did not receive intravenous chemotherapy (P=0.513).

On the other hand, the 5-year survival rate of patients who received post-operative oral administration of UFT was 76.5%, which was significantly better than that of those who did not receive it (5-year survival rate: 58.6%, P=0.005) (Fig. 1 ). The efficacy of UFT was thus suggested, and it was focused on in the following investigation.

Fig. 1

Post-operative survival of patients with completely resected p-stage I-IIIa non-small cell lung cancer (NSCLC). Comparison between patients with oral administration of UFT (UFT group) and those without oral administration of UFT (Control group).

Post-operative oral administration of UFT

The characteristics of patients who underwent UFT administration (UFT group) and did not undergo UFT administration (Control group) are shown in Table 3[21]. There were no significant differences in gender, average age, or PS between these two groups. With respect to the histologic type, the percentage of patients with adenocarcinoma was 63.3% (62 among 98 patients) in the UFT group, compared to 49.9% (278 among 557 patients) in the Control group, which showed a significant difference (P=0.003). The percentage of patients with squamous cell carcinoma was 27.6% (27 among 98 patients) in the UFT group, compared to 40.6% (226 among 557 patients) in the Control group, with a significant difference (P=0.024). There was no significant difference in post-operative p-stages between these two groups.

Table 3

Characteristics of patients (comparison between patients with and without UFT administration)

Pre-operative intravenous chemotherapy was performed in three patients (3.1%) in the UFT group (non CDDP-based regimen in one and CDDP-based regimen in two patients) and in 24 patients (4.3%) in the Control group (non CDDP-based regimens and CDDP based regimens in 12 patients each); no significant difference was observed in the percentages of patients who received pre-operative induction chemotherapy between these two groups. Pre-operative radiation therapy was performed in seven patients (7.1%) in the UFT group and 31 patients (5.6%) in the Control group, showing no significant differences in the percentages of patients who received pre-operative radiation (P=0.538).

As for post-operative adjuvant therapy other than UFT, eight patients (8.2%) in the UFT group and 78 patients (14.0%) in the Control group received intravenous chemotherapy without CDDP, with no significant difference between these two groups (P=0.114). No significant difference was observed between these two groups either in the number of patients who received CDDP-based combination chemotherapy or in the number of those who received radiation therapy.

The effect of UFT was then investigated according to the p-stage (Table 4 ). For patients with p-stage I disease, the 5-year survival rate was 88.6% in the UFT group and 72.2% in the Control group, showing a significantly better post-operative survival in the UFT group (P=0.013, Fig. 2 ). On the other hand, for patients with p-stage I1 disease, the 5-year survival rates were 71.4% and 56.2% in the UFT group and the Control group, respectively, with no significant difference between these two groups (P=0.556). For patients with p-stage IIIa disease, the 5-year survival rates were 58.1% and 37.5% in the UFT group and in the Control group, respectively, showing no significant difference, although prognosis tended to be better in the UFT group (P=0.096). Patients with p-stage IIIa disease were then divided into pT3NO-1 patients and pN2 patients. There proved to be significant difference between the UFT group and the Control group for pN2 patients (the 5-year survival rate of the UFT group: 54.3%, that of the Control group: 29.6%, P=0.037, Fig. 3 ), whereas there was no significant difference between the UFT group and the Control group for pT3NO-1 patients (the 5-year survival rate for the UFT group: 68.8%, that for the Control group: 46.7%, P=0.406). Quality of life of patients had not been degraded by oral administration of UFT.

Table 4

Post-operative survival of patients with and without UFT administration according to pathologic stages

Fig. 2

Post-operative survival of patients with completely resected p-stage I non-small cell lung cancer (NSCLC). Comparison between patients with oral administration of UFT (UFT group) and those without oral administration of UFT (Control group).

Fig. 3

Post-operative survival of patients with completely resected p-stage IIIa, N2 non-small cell lung cancer (NSCLC). Comparison between patients with oral administration of UFT (UFT group) and those without oral administration of UFT (Control group).

Multivariative analysis of prognostic factors (Table 5)

Table 5

Multivariate analysis of prognostic factors

Multivariative analysis of the prognostic factors using Cox's regression mode revealed that post-operative oral administration of UFT was a significant factor which improved the prognosis (P=0.004, 95% confidence interval (CI) of relative risk (RR) 0.325–0.840). Higher age, better PS, and lower p-stage also proved to a significant factor which improved the prognosis. Gender, histologic type, post-operative intravenous chemotherapy and radiation therapy proved not to be significant factors affecting the post-operative prognosis.

Discussion

Although a large number of adjuvant chemotherapy regimens have been conducted for completely resected NSCLC, their efficacy has not been established yet [6]. This may pose a problem in applying intensive chemotherapeutic regimens, which has been reported to be effective for non-resectable NSCLC from the point view of response rate, to patients in whom the tumor had been already resected completely during surgery. Moreover, as the immunity of patients might have been already reduced by operation, post-operative intensive chemotherapy may make the patients' natural resistance to tumor cells worse, and may even induce activation of tumor cells. Furthermore, compliance with drug administration may become very poor due to their excessive side effects. In fact, the efficacy of CDDP-based combination chemotherapy for completely resected NSCLC was proved to be ineffective in the present report.

In contrast, recently reported prospective randomized studies revealed that oral administration of UFT (tegafur and uracil) was effective as post-operative adjuvant therapy for NSCLC [13],[14]. Tegafur (1-[2-tetrahydrofuryl]-5-fluorouracil) is a prodrug which continuously releases 5-FU and can maintain blood 5-FU concentration. Uracil is added to inhibit degradation of the released 5-FU. The West Japan Study Group for Lung Cancer Surgery conducted a prospective randomised study for completely resected p-stage I-IIIb NSCLC, and reported that 5-year-survival rates were 64.1% in a group having received UFT alone (UFT group), 60.6% in a group haying received UFT following chemotherapy using CDDP+VDS (CVuft group), and 49.0% in a group without any post-operative adjuvant therapy (Control group) [13]. The Study Group of Adjuvant Chemotherapy for Lung Cancer (Chubu, Japan) also reported that the 5-year survival rate and the disease-free interval were improved significantly in a group having received UFT for 6 months following post-operative administration of CDDP+ADM as compared with a surgery alone group [14]. These results suggest that oral administration of 5-FU derivative chemotherapeutic agent, UFT, may suppress occurrence of post-operative distant metastasis and improve the survival. In the present retrospective analysis as well, the efficacy of post-operative oral administration of UFT was suggested.

Although 5-FU is an anti-cancer agent widely used as a basic drug for various solid cancers, it has been reported to be ineffective for primary lung cancer. However, all these results showing that 5-FU was ineffective for primary lung cancer were obtained from intravenous bolus injection of 5-FU. 5-FU is pharmacokinetically not a dose-dependent anti-tumor agent, but a time-dependent anti-tumor agent. It has been proved by in vivo and in vitro studies that 5-FU shows a remarkably small direct anti-tumor effect when in contact over a short time, even at high drug concentrations, and that it shows a high anti-tumor effect when in contact over a long time period even at low drug concentrations [22]. Also, in practical clinical use, Lokich and coworkers reported that continuous intravenous infusion of 5-FU exhibited a significantly high response rate for liver metastases of colorectal cancer as compared with bolus intravenous injection [23].

Therefore, continuous maintenance of 5-FU concentration in blood is an optimal administration method of 5-FU and the derivatives. Considering maintenance of 5-FU concentration in blood, oral administration of UFT is an administration method that is remarkably effective pharmacologically [24].

It is true that UFT is inferior to new anti-tumor agents such as CDDP and CPT-11, in terms of direct anti-tumor activity and response rate for NSCLC. However, UFT is very effective in various ways, when considering characteristics of post-operative adjuvant chemotherapy for patients in whom the tumor has been completely resected. Thus, UFT can maintain a certain 5-FU concentration in blood over a long time without reducing the immunity of the host, and it may suppress post-operative micrometastasis. Recent reports [25],[26] have revealed that anti-tumor agents such as 5-FU can induce apoptosis of tumor cells at a drug concentration much lower than that causing necrosis. As apoptosis plays an important role in suppression of growth of tumor cells in hematogenous micrometastatic loci [27], it may be proposed that oral administration of UFT promotes apoptosis in micrometastatic loci after surgery and improves the post-operative survival.

The present retrospective, non-randomized study has various problems such as selection of patients to whom UFT was administered and heterogeneity of patients' characteristics. UFT was administered to all patients from whom informed consent was taken, and the number of patients was only 98, whereas the number of patients in the Control group was 557. The intended duration of post-operative UFT administration was 1 year, but it varied from 3 to 61 months depending on the condition of patients and on demand. In order to confirm the efficacy of oral administration of UFT as post-operative adjuvant therapy for completely resected NSCLC, a prospective randomized study for a more homogenous patient group is needed. In Japan, a prospective randomized study of post-operative oral administration of UFT for completely resected p-stage I adenocarcinoma is now ongoing, and about 1000 patients have been already gathered.

We thank Nobuyuki Hamajima M.D., M.P.H. (Division of Epidemiology, Aichi Cancer Research Institute, Aichi, Japan) for helpful comment and critical reading of the statistical section of the manuscript.