Surgery and/or radiation therapy has been used as a radical treatment for head and neck cancer. It has been reported that the mean period to recurrence in head and neck cancer after radical treatment is 36 weeks and that the rate of recurrence within 2 years is approximately 80%. Carcinoma at these sites recurs quickly; therefore, maintenance chemotherapy after radical treatment is necessary to improve the poor prognosis of advanced head and neck cancer. No standard maintenance chemotherapy has been established to date.
UFT (uracil and tegafur(Drug information on tegafur)), which was developed in Japan, has established antitumor effects on head and neck cancer, and is considered appropriate for maintenance chemotherapy after radical treatment because of its tolerability, safety, and oral administration. This study is a randomized, comparative trial of UFT as maintenance chemotherapy in patients who are undergoing radical surgery.
Patients who had undergone curative resection of histologically confirmed squamous cell carcinomas of the head and neck were enrolled in this study. Eligibility criteria were as follows: (1) clinically confirmed International Union Against Cancer (1987) stage II-IV and M0 disease of the maxillary sinus, oral cavity, oropharynx, hypopharynx, or larynx; (2) Eastern Cooperative Oncology Group (ECOG) performance status of 0-2; (3) age < 75 years; (4) no prior therapy; (5) normal hematologic, hepatic, and renal functions and leukocyte counts > 3,500 × 109/L and platelet counts > 100,000 × 109/L; (6) no active cancer in other sites; and (7) informed consent.
Patients were stratified according to primary site and clinical stage and then randomly assigned to either the observation group (control arm) or the therapy group receiving UFT (UFT arm). Patients assigned to the UFT arm were administered UFT 300 mg/d supplied in 100-mg capsules (100 mg of tegafur). The total daily dose was divided into three and administered orally. Administration was initiated within 7 days after clinical curative resection and continued on a daily basis for 1 year.
Eligibility, especially the curability of each patient, was determined by the central committee through a careful review of study forms and surgical reports. The time to recurrence was defined as the time between surgery and first recurrence. Patterns of first relapse (local/regional/distant) were recorded for analysis.
A total of 424 patients were enrolled in the study, 26 (6.1%) of which were considered ineligible (14 in the control arm and 12 in the UFT arm). Reasons for exclusion included ineligible tumor site (three patients), ineligible or noncurative resection (21 patients), and multiple primary tumors (two patients). There were 199 patients assigned to the control arm and 199 patients assigned to the UFT arm.
Patient characteristics are presented in Table 1. The groups were also comparable in terms of number of prognostic factors, including age, sex, ECOG performance status, primary site, and clinical stage. Compliance with UFT was monitored through questioning of the patients by physicians. Of the 199 patients assigned to the UFT arm, 152 patients (76.4%) successfully complied with the scheduled doses or complied until death or disease progression.
Adverse effects ³ grade 1 were found in 37 of 199 patients (18.6%) in the UFT arm. Gastrointestinal toxicity (anorexia, nausea/vomiting, epigastric pain, diarrhea) (6.5%), hepatotoxicity (6.0%), leukopenia (2.0%), and thrombocytopenia (3.0%) were noticed.
The follow-up rate for 3-year survival was 93%. The 3-year survival rates were 77.9% for the UFT group and 72.9% for the control group. There were no statistical differences between the two groups (Figure 1A). Three-year, relapse-free survival rates were 73.4% in the UFT group and 66.2% in the control group; there were no statistical differences between the two groups (Figure 1B).
Disease recurred in 117 of 398 patients (29.4%) who received curative resection. Thirty-four patients (8.5%) relapsed first at the local tumor site, 44 patients (11.1%) relapsed first in the neck, and 39 patients (9.8%) relapsed at distant sites. For patients who relapsed first at a distant site, the estimated 3-year failure rate was 7.9% in the UFT arm compared with 14.6% in the control arm. The incidence of distant failure was reduced significantly in the UFT arm compared with the control arm (P = .034, Figure 2). After adjustment for imbalances in variables (age, sex, performance status, primary site, and clinical stage) using the Cox proportional hazard model, the UFT arm was again found to have a significant advantage in time to first distant failure over the control arm (P = .038, hazard ratio = 0.49 [95% confidence interval: 0.25-0.96]).
Neither the 3-year survival rate nor the 3-year nonrecurrence rate, primary end points of this study, showed any significant difference between the two groups, but overall results tended to be better in the UFT treatment group. When the site of recurrence was examined, the recurrence rate at distant sites was significantly lower in the UFT group, which was confirmed after analysis by the Cox proportional hazard model. Therefore, maintenance chemotherapy with UFT after curative surgical treatment inhibits distant metastasis.
The Head and Neck Contracts Program[4,5] performed a comparative study of maintenance chemotherapy for advanced head and neck cancer on patients with operable advanced cancer in the following three groups: a control group with surgical operation plus radiation therapy, an induction chemotherapy (cisplatin [Platinol] and bleomycin(Drug information on bleomycin) [Blenoxane]) group plus standard therapy, and induction chemotherapy plus standard therapy followed by maintenance cisplatin(Drug information on cisplatin). No obvious differences were observed in survival and relapse-free survival rates, but the rate of distant metastasis was significantly decreased in the maintenance-chemotherapy group. Additionally, Laramore et al reported a decrease in the overall incidence of distant metastases with maintenance chemotherapy (cisplatin/fluorouracil).
With similar results for UFT in our study, and with no standard maintenance chemotherapy, UFT is expected to serve as a useful therapy. Further trials for patients with a clinical and biologic risk of distant metastasis are suggested.