Abstract
Aim: This study analyzed the safety and feasibility of alternate-day S-1, a mixture of tegafur, dehydroxypyrimidine and potassium oxonate, as adjuvant chemotherapy for head and neck cancers. Patients and Methods: Patients with head and neck squamous cell carcinoma (HNSCC) who underwent primary treatment received alternate-day S-1 (80 mg/day for 1 year). The primary end-point was treatment completion rate. The secondary end-point was adverse events. Three-year overall survival (OS) and disease-free survival (DFS) were calculated using the Kaplan-Meier method. Results: One-year completion rate was 65.6%. Out of 26 patients, 19.0% had grade III adverse events. All adverse reactions were tolerable and reversible. Three-year OS and DFS were 74.8% and 57.3%, respectively. Conclusion: S-1 therapy is an effective adjuvant treatment for head and neck cancer patients with relatively mild side-effects and does not adversely affect quality of life. A phase I/II study is warranted to investigate the appropriate dose for an alternate-day S-1 regimen.
Head and neck squamous cell carcinoma (HNSCC) ranks sixth among the most common cancers accounting for approximately 3.3% of all cancer cases (1). The disease is potentially curable at an early stage but 40-50% of patients present with locally advanced disease (2). After standard therapy (surgery and irradiation), only 30-50% of patients with locally advanced disease live for 3 years and loco-regional recurrences or distant metastases develop in 40-60% (3, 4). The treatment of patients with locally advanced head and neck cancers has evolved since the introduction of combined modality treatment for these patients. In an attempt to increase local control and distant metastases in advanced head and neck cancers, chemotherapy has been used before or after surgery and has been associated with a good clinical response. Adjuvant chemotherapy might be a candidate therapy. Several randomized trials of adjuvant chemotherapy in HNSCC have been conducted (5-7). A few randomized trials regarding adjuvant chemotherapy reported the possibility of survival benefits (5, 7). Previously, adjuvant chemotherapy with UFT (tegafur and uracil in a 1:4 molar concentration), one of the oral 5-fluorouracil (5-FU) agents, and S-1 showed significant survival benefit in a wide range of carcinomas (8-10). S-1 (TS-1; Taiho Pharmaceutical, Tokyo, Japan) is an oral anticancer drug consisting of a mixture of 1 M tegafur, 0.4 M 5-chloro-2,4-dehydro xypyrimidine and 1 M potassium oxonate. 5-chloro-2,4-dehydroxypyri midine is a potent, reversible inhibitor of fluorouracil degradation and potassium oxonate reduces the gastrointestinal toxicity induced by fluorouracil (11, 12). Additionally, the adjuvant chemotherapy with S-1 after curative treatment in patients with head and neck cancer (ACTS-HNC trial), a randomized phase III study, was conducted to investigate whether S-1 was superior to UFT in head and neck cancer. Miura and Shirasaka et al. reported that the administration of S-1 on alternate days can reduce the incidence of adverse effects without compromising the therapeutic effects of S-1 (13). The alternate-day regimen was equivalent to or better than the daily regimen in patients with other regimens for cancers in clinical trials (14). Thus, we expect that alternate-day administration of S-1 contributes to decreasing the side-effects. Therefore, a retrospective study of S-1 administered on alternate days as adjuvant therapy after surgery and chemoradiotherapy for HNSCC was conducted. The aim of this retrospective study was to analyze the safety and feasibility of this regimen.
Patients' characteristics.
Patients and Methods
Eligibility criteria. The following eligibility criteria were used: histologically confirmed HNSCC; a primary tumour in the nasopharynx, oropharynx, hypopharynx, larynx, oral cavity, parotid or submandibular gland; age over 20 years; Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2; white blood cell (WBC) count ≥3,500/mm3; absolute neutrophil count (ANC) ≥2,000/mm3; platelet count ≥100,000/mm3; haemoglobin level ≥9.0 g/dl; aspartate aminotransferase (AST), alanine transaminase (ALT) and alkaline phosphatase levels below 2.5 times the upper limit of normal (ULN); total bilirubin and creatinine levels below 1.5 times ULN; blood urea nitrogen (BUN) level below the ULN; and estimated glomerular filtration rate (eGFR) ≥80ml/min.
Treatment schedule. Patients who received S-1 for at least 12 months were defined as cases; patients who could be administered S-1 for over one year were continued on it for as long as possible. The daily dose of S-1 was fixed at 80 mg/day, administered orally in two equal amounts after breakfast and after the evening meal. S-1 was then administered according to the schedule for the alternate-day regimen. Written, informed consent was obtained from all patients after the Institutional review boards of Kyorin University School of Medicine approved the study protocol. This study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines.
Adverse events.
Administration period of S-1.
Reasons for discontinuation in cases with less than one year of drug administration.
Evaluation of toxicity. A complete blood cell count and measurements of liver and renal function were assessed at least every month during treatment. Non-haematological toxicities were also verified at least every month by patient interviews and physical examinations. Toxicity was evaluated according to the National Cancer Institute common toxicity criteria (NCI-CTC), version 3.0 (15). In the event of toxicity, the following treatment delays and dose reductions were planned: S-1 administration on day 1 in subsequent cycles was delayed when there was leucocyte count <2,000/mm3, neutrophil count <1,000/mm3; platelet count <75,000/mm3; haemoglobin <8.0 g/dl; AST and ALT 2.5 times the ULN; and creatinine>1.5 mg/dl. S-1 was withdrawn if any of the following occurred during the previous cycle: febrile neutropenia, platelet count <50,000/mm3 or grade 3 or higher non-haematological toxicities except nausea, vomiting, anorexia, fatigue and hypersensitivity. Treatment was continued until disease progression, unacceptable toxicity, patient's refusal or physician's decision. The completion rate and the incidences of adverse events were evaluated.
Kaplan-Meier estimates of overall survival (OS) and disease-free survival (DFS) with alternate-day S-1 treatment.
Statistical analysis. The 3-year overall survival (OS) and disease-free survival (DFS) were examined by the Kaplan-Meier method.
Results
Patients' characteristics. Between 2005 and 2012, patients with head and neck cancer who had completed primary treatment were started on S-1 administered on alternate days at the Kyorin University Hospital. The patients' characteristics are shown in Table I. Twenty-four (84%) of the patients were men and the median age was 62 years (range=42-99 years). The primary sites were the oral cavity in six patients, the nasopharynx in three patients, the oropharynx in four patients, the hypopharynx in seven patients, the larynx in four patients, the parotid gland in one patient and the submandibular gland in one patient. Six patients had a T1-2 primary lesion and twenty patients had a T3-4 primary lesion. Twenty patients had node-positive disease. The stage distribution according to the International Union Against Cancer 2002 classification (16) was as follows: four patients had stage II, seven patients had stage III and nineteen patients had stage IV disease.
Adverse events. The most common adverse events are listed in Table II. The only grade 3 or higher haematotoxicities reported were leukopenia (3.8%) and thrombocytopenia (3.8%) and most other instances remained below grade 2. Furthermore, the only grade 3 or higher non-haemato-toxicities reported were mucositis and nausea (3.8%); most of these adverse events were also below grade 2. Although gastrointestinal toxicities and myelosuppression were frequently observed with standard treatment, alternate-day treatment was manageable with appropriate medical care. There were no treatment-related deaths.
Completion rate. The 1-year completion rate of the present study was 65.6% (Table III), while over 7 months the completion rate of the present study was 80.9%. The reasons for discontinuation within 1 year are listed in Table IV. The medication was discontinued by the doctor in two cases. In one case, the patient stopped coming to the hospital.
Clinical outcomes. Local recurrence occurred in seven patients and distant metastases occurred in four patients. Secondary cancer occurred in one patient.
Overall survival and disease-free survival. The Kaplan-Meier survival curves are shown in Figure 1. The median follow-up time was 2.2 years (range, 0.4-5.5 years). The 3-year OS was 74.8% and the 3-year DFS was 54.3%.
Discussion
The pharmacokinetics of consecutive, orally administered S-1 reportedly show that the plasma fluorouracil concentration can be maintained at a level almost equal to or higher than those obtained following the continuous intravenous infusion of fluorouracil (17, 18). The cell cycle of normal cells is only 0.5 to 1.5 days, whereas that of tumour cells is 5 to 7 days (19). Shirasaka et al. hypothesized that, when fluorouracil is given on alternate days, the tumour cells would be exposed to fluorouracil at regular intervals resulting in sufficient antitumor effectiveness but, because of their shorter cell cycle, normal cells would only be exposed to fluorouracil every other day, thereby reducing toxicity (20, 21). Alternate-day treatment with S-1 was also associated with milder adverse events without compromising therapeutic effective ness in clinical or pre-clinical studies (22, 23). A few studies have suggested survival benefits (5, 7) and a decrease in the incidence of distant metastases with adjuvant chemotherapy (6, 24). Recently, adjuvant chemotherapy with UFT has shown a significant survival benefit in a wide range of carcinomas (8, 9). Furthermore, a prospective, randomized trial to evaluate the efficacy of adjuvant chemotherapy in HNSCC from 67 institutions in Japan showed that 1-year administration of UFT (300 mg/day) in cases receiving curative surgical treatment significantly prevented distant metastases, with a small survival benefit compared to control cases receiving curative surgery without adjuvant chemotherapy with UFT (25). The ACTS-HNC trial established the efficacy of adjuvant chemo therapy with S-1 after curative treatment in patients with advanced HNSCC. Patients with HNSCC who had received curative treatment and were confirmed to be tumour-free were randomly assigned to receive UFT or S-1 in a randomized, phase III study. The treatment regimen consisted of 3-week cycles in which, in principle, 80 mg of oral S-1 per square meter of body-surface area per day was given for 2 weeks and no chemotherapy was given for the following 1 week. S-1 administration for 3 years significantly improved OS in patients with Stage III, IVA or IVB head and neck cancer after curative treatment (26). The 3-year OS rate was 75% in the UFT group and 82.9% in the S-1 group. The 3-year DFS rate was 66.0% in the UFT group and 64.1% in the S-1 group. There were no significant differences in 3-year DFS; however, the 3-year OS was significantly better in the S-1 group. The incidence of the following grade 3 or 4 events was significantly higher in the S-1 group: oral muco sitis/sto matitis (2.4%), leukopenia (5.2%), neutropenia (3.6%) and thrombocytopenia (5.0%). Over 7 months, the completion rate was 59.4% in the ACTS-HNC trial. Over 7 months, the completion rate in the present study was 80.7% and the occurrence of adverse events tended to be less than in the ACTS-HNC trial. The different dose of S-1 and the alternate-day regimen may lead to a higher completion rate and fewer side effects. The 3-year OS and DFS were 74.8% and 54.3%, respectively, with alternate-day S-1. It was considered that the OS was similar with alternate-day S-1 and in the ACTS-HNC trial, although these are not direct comparisons. We, therefore, believe that alternate-day administration of S-1 is useful as adjuvant chemo therapy after curative surgery and chemoradiotherapy in patients with head and neck cancer. A phase I study is warranted to investigate the appropriate dose for the alternate-day S-1 regimen.
- Received October 2, 2014.
- Revision received November 1, 2014.
- Accepted November 4, 2014.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
