A Prospective Randomised Study of Oral Tegafur plus Uracil as
Prolonged Adjuvant Treatment in Surgically-resected Colorectal Cancer

TSK Mok, TWT Leung, W Yeo, H Wong, J Steinberg, P Hui, P Teo, P Choi, ATC Chan
Department of Clinical Oncology, Prince of Wales Hospital,
The Chinese University of Hong Kong, Hong Kong, China

Abstract

A single centre, prospective, randomised trial was conducted in patients with Duke's B or C colorectal cancer to compare standard adjuvant chemotherapy with prolonged adjuvant chemotherapy with an additional year of oral tegafur plus uracil after completion of standard treatment. Patients who had completed standard adjuvant chemotherapy were eligible for enrolment. 140 of the 149 enrolled patients were randomised to receive either tegafur/uracil 200 mg twice daily for 1 year (n = 70) or no further active treatment (n = 70). The 3-year overall and disease-free survival for the patients in the tegafur/uracil group and the control group were 81% versus 80% and 64% versus 58%, respectively. After adjustment for the difference in the number of patients with Duke's C cancer in the 2 groups by stratified log-rank test, there was no difference in the survival rates. These data suggest that an extra year of tegafur/uracil after standard adjuvant chemotherapy does not improve the 3-year overall and disease-free survival in patients with Dukes' B or C colorectal cancer.

Key words: Adjuvant chemotherapy, Tegafur/uracil, Colorectal carcinoma

Introduction

Colorectal cancer is one of the most common malignancies in Western countries and the incidence in developed Asian countries is increasing.¹ Early stage colorectal cancer is potentially curable by surgery alone. In the advanced stages when the tumour has spread to involve the regional lymph nodes (Duke's C, stage IV), the 5-year survival rate is only 40 to 50%.² Many randomised trials have been performed to study the efficacy of postoperative adjuvant chemotherapy. Dube et al pooled the data of 39 randomised clinical trials published from 1959 to 1993 and performed a quantitative and qualitative meta-analysis.³ These authors concluded that a small survival benefit was observed in the patients treated with adjuvant chemotherapy. In a landmark study, Moertel et al reported on 929 patients with Duke's C colon cancer who were randomised to receive either postoperative adjuvant chemotherapy with 5-fluorouracil (5-FU) and oral levamisole for 1 year or observation only.⁴ The recurrence rate was reduced by 41% and the 5-year survival rate increased by 33% with adjuvant chemotherapy. Other multicentre studies from Western countries also reported a significant survival benefit of 5-FU-based adjuvant chemotherapy.^5-7 However, the optimal duration of treatment remains undetermined.

Tegafur is a prodrug of 5-FU. The bioavailability of this oral drug is high and its cytotoxicity is similar to 5-FU once it is activated by the hepatic microsomal enzyme system.⁸ However, the half-life is only 16 minutes, thus limiting its cytotoxic effect. Concomitant administration of uracil competes for binding sites of dihydropyrimidine dehydrogenase, the principle catabolic enzyme for inactivation of 5-FU. As a result of this antagonism, the duration of cellular exposure to 5-FU is prolonged. Oral capsules of tegafur and uracil at 1:4 molar ratio (UFT) have been shown to be cytotoxic in a variety of human tumour xenograph lines, including breast cancer, gastric cancer, pancreatic cancer, and colorectal cancer.^9,10 Phase II studies in Japan and the UK have confirmed the clinical efficacy of UFT in the treatment of metastatic colorectal carcinoma.^11,12 Intravenous 5-FU may not be feasible for prolonged administration due to the limitations of compliance and venous access. Therefore, UFT is an attractive alternative to intravenous infusion of 5-FU for investigation of the treatment duration. In this randomised study of the duration of adjuvant chemotherapy for colorectal cancer, we compared standard adjuvant treatment with prolonged adjuvant chemotherapy comprised of standard treatment plus an extra year of oral UFT.

Patients and Methods

Patients

The inclusion criteria were as follows:

• age between 18 and 75 years
• histologically confirmed Duke's B or C colorectal carcinoma according to the Astler-Coller staging system¹
• curative surgical resection of the primary tumour
• completion of a full course of standard adjuvant chemotherapy
• compliance with oral medication
• adequate bone marrow, renal, and liver function
• Karnofsky Performance Score 80
• mentally competent to consent to inclusion in the trial.

Patients with distant metastasis or incomplete surgical resection were excluded. Routine preoperative chest X-ray and abdominal ultrasound were performed for all patients. Adjuvant chemotherapy was started within 6 weeks of surgery.

Drug Treatment and Randomisation

All enrolled patients had to have completed one of the following standard adjuvant chemotherapy regimens:

• 5-FU 500 mg/m² daily x 5 and weekly from day 29 plus oral levamisole 50 mg 3 times daily for 3 days biweekly for 48 weeks
  or
• 5-FU 500 mg/m² plus leucovorin 20 mg/m² daily for 5 days every 28 days for 6 cycles.

At completion of the adjuvant chemotherapy, the patients were randomised to receive either oral UFT 200 mg twice daily for 1 year (treatment group) or no further active treatment (control group). All patients were followed bimonthly for 1 year and every 4 months for the second year.

Recurrence and Survival

The date of recurrence was defined as the time when the investigators concluded from clinical evidence that the colo-rectal cancer had relapsed. Second primary colorectal cancer was not considered to be recurrence. The last event was the clinical status of the patient at the last visit. Disease-free survival was defined as the time between the dates of randomisation and recurrence. Overall survival was defined as the time between the dates of randomisation and the last event. The study endpoints were recurrence and death. The disease-free survival curves and overall survival curves were constructed using the Kaplan-Meier method and comparisons were performed using the log rank test. Adjustment for the difference in the number of patients with Duke's C cancer in the 2 groups was made using the stratified log rank test. The data was analysed by the SAS/STAT^TM software statistic program Version 6.03.

Results

Patients' Characteristics

149 patients were enrolled in the study between July 1991 and July 1995. Nine patients were excluded for the following reasons:

• 2 patients defaulted shortly after enrolment
• 4 patients developed a second primary malignancy
• 1 patient had delayed adjuvant chemotherapy for more than 2 months
• 2 patients were found to have metastatic disease at enrolment.

140 patients were eligible for randomisation with 70 patients in each group. The characteristics of the patients are listed in Table 1. There was no significant difference between the 2 groups in terms of age, sex, tumour site, and type of adjuvant chemotherapy, but significantly more patients in the treatment group had Duke's stage C cancer (p = 0.025).

Recurrence and Survival

All patients were followed up regularly with the final evaluation made in August 1997. The median follow-up was 33 months. Fifty two patients had recurrent disease (23 in the treatment group and 29 in the control group). Among these patients, 31 had a single site of recurrence and 21 had multiple sites of recurrence. The most common sites of recurrences were liver and lung (Table 2). The distribution of the sites of recurrence was similar in both groups. Among the 38 patients who had died from recurrent colorectal cancer at the time of the final evaluation, 20 were in the UFT group and 18 were in the control group. Thirteen patients with recurrent disease are still alive and 1 patient died of an unrelated condition. The 3-year disease-free survival rates for patients in the UFT group and the control group were 64% and 58%, respectively (p = 0.314) [Figure 1]. The hazard ratio of disease-free survival at 3 years for patients in the UFT arm was 0.78 (95% confidence interval [CI], 0.45 to 1.35). The 3-year overall survival rates for patients in the UFT group and the control group were 81% and 80%, respectively (p = 0.638) [Figure 2]. The hazard ratio of overall survival for patients in the UFT group was 1.22 (95% CI, 0.64 to 2.34). The 3-year disease-free survival rate of patients with Duke's B cancer (77%) was better than that of patients with Duke's C cancer (54%) [p = 0.025; Figure 3]. However, the 3-year overall survival rates were not significantly different (88% versus 77%). Adjusted for the difference in the number of patients with Duke's C cancer in the 2 groups, there was no significant difference in disease-free and overall survival rates between the two groups.

Toxicity and Compliance

The toxicity of UFT was mild. Only 12.9% of patients reported nausea and vomiting. Grade 1 leukopenia was observed in 17.1% of patients. There was no sepsis or peripheral neuro-pathy associated with UFT. Two patients reported diffuse maculopapular rash. However, compliance with medication was poor. Eighteen of the 70 patients (25.7%) completed less than 6 months treatment with UFT. Two patients stopped as a result of early tumour recurrence. Three patients developed intolerable toxicity with severe vomiting or skin rash leading to early termination of treatment. The long duration of therapy was the primary reason for discontinuation of treatment for the remaining patients.

Discussion

This study addressed the question of the duration of adjuvant chemotherapy for colorectal cancer. Based on this data, there is 95% confidence that prolonged chemotherapy with an extra year of UFT did not improve the 3-year disease-free and overall survival of patients with Dukes' B or C colorectal cancer who had completed a standard course of adjuvant chemotherapy. There have been few clinical studies specifically designed to address the duration of adjuvant chemotherapy for colorectal cancer. O'Connell et al randomised 915 patients with high-risk colon cancer to receive either 5-FU plus levamisole or 5-FU plus levamisole and leucovorin.¹³ The patients in each treatment group were also randomised to 6 or 12 months of chemotherapy. These researchers concluded from this study that there was no significant improvement of survival with the same regimen given for 12 months compared with 6 months. A European Cooperative Oncology Group study compared 6 months treatment with 5-FU plus leucovorin to 12 months of 5-FU plus levamisole. The interim abstract from 1996 suggested that there was no significant difference in survival.⁵ In our study, all enrolled patients received standard 5-FU-based adjuvant chemotherapy before randomisation to an extra year of UFT. Patients in the UFT group would have received 18 to 24 months of adjuvant chemotherapy in total. The 3-year disease-free survival rate of patients in the UFT group and the control group were 64% and 58%, respectively. The results were comparable to that of Moertel's study⁴ and the International Multi-center Pooled Analyses of Colon Cancer Trials (IMPACT) study.⁶ This suggests that our patients had already obtained the maximum benefit from standard adjuvant chemotherapy. A prolonged course of adjuvant treatment did not appear to improve the survival.

The benefit of adjuvant chemotherapy in colorectal cancer is indisputable. More than 30 randomised clinical trials have been performed to study the impact of adjuvant chemotherapy on the survival of patients with Dukes' B and C colorectal cancer during the past 3 decades.¹⁴ Earlier studies showed a slight improvement in disease-free survival but no significant benefit was observed in the overall survival.¹⁵ Only in the 1980s, when the combination of levamisole and 5-FU was used as the adjuvant therapy by the North Central Cancer Treatment Group study, was a significant overall survival observed in patients with Duke's C cancer.¹⁶ This finding was subsequently confirmed by Moertel et al, who convincingly showed that the combination of weekly 5-FU infusion and biweekly oral levamisole reduced the risk of tumour recurrence by 41% and decreased the death rate by 33% in patients with Duke's C colon cancer (Table 3).⁴ The efficacy of 5-FU-based adjuvant chemotherapy in Duke's B2 disease remains controversial. The United States National Cancer Institute Consensus Development has promptly adopted this protocol as standard postoperative therapy for Duke's C colon.¹⁷ Meanwhile, 3 other centres in France, Canada, and Italy conducted adjuvant studies using the combination of 5-FU and high-dose leucovorin for 6 months after surgery. Their results were pooled and analysed in the IMPACT study report.⁶ Similar to the results of Moertel's study, these researchers reported a reduction in recurrence of 35% and a decrease in mortality of 22%. These findings confirmed that 5-FU-based adjuvant chemotherapy improves survival but failed to address the duration of treatment. Our study has contributed to the limited literature on this issue.

Limited by the population size, we do not have sufficient statistical power to draw a definitive negative conclusion. The fact that hazard ratios of the 3-year disease-free survival and overall survival were contradictory is evidence of weakness in statistical power. The ranges of 95% confidence intervals of the hazard ratios are wide and both embrace the value of 1.00. It is possible to improve the statistical power by increasing the number of patients. However, with the given event rates of this study, we estimated that more than 2000 patients are required in each randomised group to detect a 10% difference in the hazard ratio.

Tegafur/uracil has been studied as adjuvant chemotherapy for Duke's B and C colorectal cancer in Japan. The Cooperative Study Group of Surgical Adjuvant Chemotherapy of Colorectal Cancer reported a randomised study of 1138 patients who were treated prospectively with bi-monthly mitomycin C plus UFT at dosages of 600 mg/day or 400 mg/day.²⁰ The 3-year disease-free survival rate was better for patients receiving UFT 600 mg/day but the 3-year overall survival rates were similar. Another comparative study between tegafur and UFT as adjuvant chemotherapy showed 5-year survival rates of 72.5% and 82.4% in Dukes' B and C colorectal cancer, respectively.²¹ Mitomi et al randomised 476 colorectal cancer patients to receive postoperative mitomycin C plus UFT 400 mg/day or mitomycin C alone.²² The 3-year disease-free survival rate was higher among patients receiving UFT (p = 0.026). However, none of these studies focused on duration of treatment. Our study has established the feasibility of using UFT as a part of prolonged adjuvant chemotherapy for colorectal cancer. In spite of the limited efficacy with UFT, future investigation may focus on prolonged chemotherapy with a combination of oral UFT and leucovorin.

In conclusion, prolonged chemotherapy with an extra year of UFT after standard adjuvant treatment is unlikely to improve survival of patients with Duke's B or C colorectal cancer, although clinical benefit cannot be completely excluded.

References

1. Boring CC, Squires TS, Tong T. Cancer statistics. CA Cancer J Clin 1993;43:7.

2. Wolmark N, Fisher B, Wieand H. The prognostic value of the modifications of the Dukes' C class of colorectal cancer. Ann Surg 1986;203:115-122.

3. Dube S, Heyen F Jenicek Ml. Adjuvant chemotherapy in colorectal carcinoma. Dis Colon Rectum 1997;40:35-41.

4. Moertel CG, Fleming TR, MacDonald JS, et al. Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. New Engl J Med 1990;322:352-358.

5. Haller D, Catalano P, MacDonald J, Mayer RJ. Fluorouracil, leucovorin and levamisole adjuvant therapy for colon cancer: preliminary results of INT-0089. Proc ASCO 1996;15:486.

6. International Multi-center Pooled Analyses of Colon Cancer Trials (IMPACT) investigators. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. Lancet 1995;345:939-944.

7. Wolmark N, Rockette H, Fisher B, et al. The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: results from National Surgical Adjuvant Breast and Bowel Project Protocol C-03. J Clin Oncol 1993;11:1879-1887

8. El Sayed Y, Sadee W. Metabolic activation of ftorafur: the microsomal oxidative pathway. Biochem Pharmacol 1982;31: 3006-3008.

9. Niimi K, Nishiyama M, Hirabayashi N, et al. In vivo chemosensitivity test for UFT and FT-207. Chemosensitivity test on human tumor xenografts transplanted in nude mice. Gan To Kagaku Ryoho 1987;14:1281-1286.

10. Shirasaka T, Nakano K, Takechi T, et al. Antitumor activity of 1M tegafur-0.4M 5-chloro-2,4-dihydroxypyridine-1M potassium oxonate (S-1) against human colon carcinoma orthotopically implanted into nude rats. Cancer Res 1996;56:2602-2606.

11. Watanabe H, Yamamoto S, Naito T. Clinical results of oral UFT therapy under cooperative study. Jpn J Cancer Chemother 1980; 7:1588-1596.

12. Malik STA, Talbot D, Clarke P, et al. Phase II trial of UFT in advanced colorectal and gastric cancer. Br J Cancer 1990;62: 1023-1025.

13. O'Connell M, Laurie JA, Kahn M, et al. Prospectively randomized trial of postoperative adjuvant chemotherapy in patients with high-risk colon cancer. J Clin Oncol 1998;16(1):295-300.

14. Labianca R, Pessi M, Zamparelli G. Treatment of colorectal cancer. Current guidelines and future prospects for drug therapy. Drugs 1997;53:593-607.

15. Buyse M, Zeleniuch-Jacquotte A, Chalmers T. Adjuvant therapy of colorectal cancer: why we still don't know. J Am Med Assoc 1988;259:3571-3578.

16. Laurie J, Moertel CG, Fleming TR, et al. Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. J Clin Oncol 1989;7:1447-1456.

17. National Institutes of Health Consensus Conference. Adjuvant therapy for patients with colon and rectal cancer. J Am Med Assoc 1990;264:1440-1450.

18. Wolmark N, Rockette H, Mamounas E, et al. Clinical trial to assess the relative efficacy of fluorouracil and leucovorin, fluorouracil and levamisole, and fluorouracil, leucovorin, and levamisole in patients with Dukes' B and C carcinoma of the colon: results from National Surgical Adjuvant Breast and Bowel Project C-04. J Clin Oncol 1999;17:3553-3559.

19. Mok TSK, Leung T, Chan A, et al. A phase III randomized study of oral UFT (tegafur + uracil) as maintenance therapy in adjuvant treatment of surgically resected colorectal cancer patients [abstract]. Proc Am Soc Clin Oncol 1998;34:1042.

20. Kunitomo K, Kikuchi K, Inokuchi K, et al. Cooperative study of surgical adjuvant chemotherapy of colorectal carcinoma: 3-year survival after surgery of non-curatively resected patients. Gan To Kagaku Ryoho 1989;16:3409-3415.

21. Takashima S, Tomita, Saito H, et al. Clinical effect of postoperative adjuvant chemotherapy for advanced colorectal cancer: comparisons of between tagafur (FT) and UFT. Gan To Kagaku Ryoho 1991;18:2315-2324.

22. Mitomi T, Tsuchiya S, Hiki Y, et al. A randomized controlled study on adjuvant chemotherapy with UFT in curatively resected colorectal cancer. Proc ASCO 1993;12:690.