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
UFT (uracil and 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
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
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 [Blenoxane]) group plus standard therapy, and induction
chemotherapy plus standard therapy followed by maintenance 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.
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head and neck. Head Neck 13:277-281, 1991.
2. Enami B, Bignardi M, Spector GJ, et al: Reirradiation of recurrent
head and neck cancers. Laryngoscope 97:85-88, 1987.
3. Ota K, Taguchi T, Kimura K, et al: Report on nationwide pooled
data and cohort investigation in UFT phase II study. Cancer Chemother
Pharmacol 22:333-338, 1998.
4. Final Report of the Head and Neck Contracts Program: Adjuvant
chemotherapy for advanced head and neck squamous cell carcinoma.
Cancer 60:301-311, 1987.
5. Jacobs C, Makuch R: Efficacy of adjuvant chemotherapy for patients
with resectable head and neck cancer: A subset analysis of the Head
and Neck Contracts Program. J Clin Oncol 8:838-847, 1990.
6. Laramore GE, Scott CB, Al-Sarraf M, et al: Adjuvant chemotherapy
for resectable squamous cell carcinomas of the head and neck: Report
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