Squamous cell carcinoma of the head and neck is a potentially curable neoplasm if it is detected while restricted to the head and neck. Stage I and II neoplasms are often curable with either radiation or surgery as the sole modality of treatment. Stage III and IV disease, however, recurs in the majority of patients despite aggressive initial management with surgery and/or radiation therapy. If the disease recurs in the head and neck region, salvage may be attempted with additional surgery or radiation, but the long-term survival after salvage is only about 20%. Metastatic recurrence of disease is not curable, except in the rare case of isolated metastatic disease managed with surgical metastasectomy. In general, therefore, patients with recurrent unresectable local disease or metastatic disease are treated without curative intent.
The role of chemotherapy in the treatment of squamous cell carcinoma of the head and neck has been evolving, with chemotherapy now playing an important role in palliative management of patients with either locally advanced or metastatic disease. The drugs used traditionally in the management of squamous cell carcinoma of the head and neck include cisplatin (Platinol), carboplatin (Paraplatin), 5-fluorouracil (5-FU), methotrexate, and bleomycin (Blenoxane).[1-6] More recently, the taxanes (docetaxel [Taxotere], paclitaxel [Taxol]) have been evaluated for their efficacy in squamous cell carcinoma of the head and neck.[7-9] Additionally, tegafur and uracil in a 1:4 molar ratio (UFT), available for years in Japan for the treatment of squamous cell carcinoma of the head and neck, is now being explored in the United States, Canada, and Europe for potential use in the management of squamous cell carcinoma of the head and neck and other malignancies.
When used individually as palliative therapy, these drugs produce overall response rates of only 15% to 40% and response durations are brief, usually less than 6 months.[8-11] Because of the low rate of response to single-agent chemotherapy, many clinical trials have concentrated on combination regimens. While response rates have been shown to be improved, studies to date have failed to reproducibly demonstrate an improvement in response duration or median survival when combination regimens are compared to standard surgery and radiation therapy.[1,12-15] On the other hand, aggressive (high dose) combination chemo- therapy for palliation has doubled the 1-year survival rate from 20% to 40%. This progress comes at a significant cost in terms of increased toxicity, hospitalization, and restricted patient eligibility.[16,17]
Combination Regimens for Induction Therapy
Beginning in the 1970s, combination chemotherapy has been studied in the induction setting in potentially curable patients with squamous cell carcinoma of the head and neck. Initial studies using combination platinum and 5-FU demonstrated that complete remission rates exceeding 50% were achievable. Additionally, studies demonstrated a benefit of cisplatin over carboplatin and of infusional 5-FU over bolus 5-FU.[1,14] Further, refinement of this combination involved the addition of leucovorin as a stabilizer of the 5-fluorodeoxyuridine-1-phosphate (F-dUMP)/thymidylate synthase complex and yielded even higher overall response rates. [6,12,18,19] A recent report of an induction regimen utilizing a combination of docetaxel, 5-FU, cisplatin, and leucovorin demonstrated that pathologic response rates approaching 100% were achievable at the primary site in squamous cell carcinoma of the head and neck.
Most trials using an induction regimen based on cisplatin and 5-FU have included definitive radiation therapy as an integral part of the curative treatment regimen. It is clear that patients who respond to chemotherapy have an excellent prognosis following definitive radiation therapy. Some investigators, however, attribute this chemotherapeutic response to the antineoplastic activity of the induction chemotherapy, while others view it merely as a predictor of tumor radiosensitivity.
While it has been demonstrated in a randomized setting that both induction chemotherapy followed by radiation therapy, and combined chemotherapy plus once-daily radiation therapy are superior in terms of overall survival to once daily radiation alone in the setting of unresectable locally advanced squamous cell carcinoma of the head and neck,[21,22] similar data are not available for potentially resectable disease. Of interest, a small but significant group of patients with locally advanced disease can be cured with induction chemotherapy alone, but at present there is no reliable way to identify these patients. Results of hyperfractionation-radiation programs have suggested increased response rates relative to daily radiation programs, but the roles of hyperfractionated or accelerated radiation used with induction therapy, or concomitant chemotherapy/hyperfractionated radiation regimens, are just beginning to be explored and should be regarded as investigational.
Stage III and IV Disease in nonmetastatic stages III and IV squamous cell carcinoma of the head and neck, the traditional approach to curative management has included surgery and radiation therapy, with typical long-term survival rates in the range of 20% to 40%. Unfortunately, many patients who undergo curative resection are left with major, permanent functional deficits, including loss of speech and severely impaired swallowing capability. The United States Veterans Administration trial in 1991 and, more recently, a trial by the European Organization for the Research and Treatment of Cancer have shown in a randomized setting that induction therapy with Platinol 100 mg/m2 and infusional 5-FU (PF) 1,000 mg/m2/d
´ 5 d followed by definitive once-daily radiation therapy can preserve organ function in two thirds of surviving patients with locally advanced laryngeal cancer, without compromising overall survival in comparison with patients treated with surgery and adjuvant radiation therapy.[26,27] Overall survival in this setting, however, is still only on the order of one in three patients.
A number of currently active studies have been designed with the goal of improving on the results of the Veterans Administration and European Organization for the Research and Treatment of Cancer experience. As mentioned, several studies have attempted modulation of the effect of 5-FU using leucovorin, and, although multiple phase II studies have documented an increase in response rates, there are no convincing data to suggest that these leucovorin-containing regimens extend survival. As a result, explorations of alternative fluorinated pyridine analogues such as tegafur, which has been in use in Japan for a number of years, are beginning in Europe and the United States in patients with squamous cell carcinoma of the head and neck.
Tegafur, also known as Ftorafur, is effectively a 5-FU prodrug converted into 5-FU by hepatic cytochrome P-450 enzymes.[28-30] In comparison with 5-FU, tegafur has the added advantage of reliable absorption in the small intestine and thus it can be administered orally. Studies also have shown that when tegafur is administered concomitantly with uracil, there is an enhanced tumor-to-plasma concentration ratio for FdUMP, the active metabolite of tegafur. The mechanism for this enhancement appears to be uracil-mediated inhibition of the 5-FU degradative enzyme dihydrouracil dehydrogenase in tumor tissue, without significant inhibition of FdUMP binding to thymidylate synthetase. This effect of uracil on intratumor tegafur metabolism is thought to result from the different binding constants of the uracil and FdUMP moieties with respect to dihydrouracil dehydrogenase and thymidylate synthetase.
A 1:4 molar ratio of tegafur to uracil has been found to result in the highest tumor-to-plasma concentration and the highest tumor kill in experimental systems. Based on these observations, uracil and tegafur have been combined at this ratio for a formulation known as UFT, which has been in clinical use in Japan for many years. Combined phase II data suggest that it is an active antineoplastic agent with an activity spectrum similar to that of 5-FU. Of interest, UFT activity in Japanese patients with squamous cell carcinoma of the head and neck has been reported in the range of 24% to 30%.[34,35]
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