A Trial of Metronomic Chemotherapy With Tegafur/Uracil for Patients With Locally Advanced (Stage III~IVB) Head and Neck Squamous Cell Carcinoma (HNSCC)

Head and neck squamous cell carcinoma (HNSCC) (excluding nasopharyngeal cancer) accounts for 4% to 5% of the cancer incidence in Taiwan.1 Localized disease is curable by surgery and irradiation. Two-thirds of patients present with advanced stages of the disease (stage III and IV), and are treated with multimodality therapy, including surgery, radiation and chemotherapy. Despite the achievement of complete responses in patients who receive multimodality therapy, however, recurrences might occur in some of patients within two years after multimodality therapy.

HNSCC has been regarded as a chemosensitive tumor since the early 1980s.Cisplatin-based combination therapy with fluorouracil (5-FU) is the most common chemotherapy regimen for patients with HNSCC. Concomitant chemoradiotherapy (CCRT) is conceptually supported by the natural history of head and neck cancer, which indicates a primary need to improve locoregional therapy and only a secondary need to improve systemic therapy. CCRT has frequently been studied in inoperable patients or in those with unresectable disease4. Several recent studies and meta-analyses have indicated superior locoregional control and/or survival rates after CCRT when compared with radiotherapy alone3-12.

"Two similar, large-scale, prospective randomized independent trials designed by the European Organization for Research and Treatment of Cancer (EORTC) and the Radiation Therapy Oncology Group (RTOG) were conducted to evaluate the role of concurrent administration of cisplatin with radiation in the postoperative treatment of high-risk head and neck tumors. The EORTC (#22931) 29 study revealed that combination therapy was more efficacious than radiotherapy alone in patients with locally advanced head and neck cancer and that the treatment did not cause an undue number of late complications. The RTOG (#9501)30 trial found that postoperative CCRT significantly improved the rates of local and regional control and disease-free survival in high-risk patients with resected head and neck cancer; however, the combined treatment was associated with a substantial increase in adverse effects.

Multimodality therapy may achieve higher complete response rate for patients with locally advanced HNSCC, however, patients still face high recurrent rate that might decrease survival time. For these reasons, the development of reliable methods (for example) and metronomic therapy to prevent relapse at locally advanced setting may improve the outcome of treatment.

Uracil-tegafur (UFT), an oral fluoropyrimidine prodrug, is available commercially in Japan and in several other countries. It is composed of 1-(2-tetrahydrofuryl)-5-fluorouracil (5-FU) (FT; also ftorafur or tegafur) and uracil in a molar ratio of 1:4. FT is readily absorbed through the gut without degradation and is converted in the liver to 5-FU and subsequently degraded to 2-fluoro-b-alanine. Thus, UFT shares the chemotherapeutic mechanism of action of 5-FU. The 5-FU metabolite FdUMP binds and inhibits the enzymatic activity of thymidylate synthase (TS), thereby inhibiting DNA synthesis.13-17 Uracil strongly inhibits the degradation of 5-FU to 2-fluoro-b-alanine by competitive inhibition of dihydropyrimidine dehydrogenase (DPD), the rate-limiting enzyme in the metabolism of 5-FU.18,19 This alteration of 5-FU disposition seems to be tumor selective. When taken orally, UFT and FT give a comparable distribution of 5-FU in blood and other normal tissues, but UFT results in 5-10 times greater distribution of 5-FU in tumors.20 Co-administration of uracil and/or FT, therefore, enhances the anti-tumor activity of FT.21 The cytotoxic effects of 5-FU (and, thus, FT) can be enhanced markedly if sufficient amounts of reduced folate cofactor, such as leucovorin (LV), are present. Cellular folate pools are considered an important biochemical determinant of FdUMP enzyme binding.22-28 One basic study has shown that in mice bearing RENCA tumors, tegafur/uracil treatment resulted in significant prolongation of their life span, which was associated with the inhibition of angiogenesis. This should be recomposed. For example, "Tegafur/uracil treatment of mice with RENCA tumors has been shown to inhibit angiogenesis, leading to a significant prolongation of life span.Two metabolites of tegafur/uracil, namely, GHB33,34 and GBL were found to be responsible for these effects. In another study, the formation of cancer vasculature, essential for the initiation of metastasis and the inhibition of tumor angiogenesis, is one of the targets in tumor dormancy therapy. The efficacy of tegafur/uracil in postoperative adjuvant chemotherapy has been demonstrated in several clinical trials. The basic data from these studies indicate a possible contribution of the anti-angiogenic activity of tegafur/uracil to its overall anti-tumor activity, which until now has been thought to be mediated by the cytotoxic effects of 5-FU. Thus, tegafur/uracil seems to be particularly useful in a chronic postoperative adjuvant chemotherapy regimen to control metastasis.