Chemotherapy for Recurrent or Metastatic Disease

Chemotherapy was initially used for palliation of advanced, unresectable tumors, and systemic disease. Numerous agents have been found to have activity in this setting, including methotrexate, bleomycin, 5-fluorouracil (5-FU), cisplatin, and carboplatin, with response rates ranging from 10% to 35%. Most of these responses are partial, and few are lasting, with median duration of only 4 to 6 months.3,4 Methotrexate has been used most extensively and despite numerous phase II trials, no other single agent has demonstrated a clear superiority over this drug. One trial has reported an improved response and survival benefit using cisplatin, but the numbers treated and the improvement in overall survival (approximately 2 months) were small.5 Newer agents being investigated include the topoisomerase inhibitor, topotecan, and the pyrimidine antimetabolite, gemcitabine. Trials to date have reported modest response rates. Some encouraging results have been seen with the tax-anes, paclitaxel and docetaxel, with response rates reported as high as 50%. These drugs may prove useful in combination therapies or as adjuncts to radiotherapy.

It was hoped that the use of drugs in combination would provide a better outcome. Numerous phase II and III trials have been performed using a variety of combinations, but the results have been disappointing. Four multi-institutional trials large enough to detect a significant difference between combi nation and single-agent chemotherapy have been reported.6-9 These were all able to demonstrate an improvement in response rates with multiagent treatments, but this was achieved at the cost of greater toxicity without any improvement in median survival. A meta-analysis of trials of combination chemotherapy conducted during the early 1990s found cisplatin to be the most effective single agent, and that the combination of cisplatin and 5-FU was more efficacious than any other single agent or combination.10 This combination remains the gold standard to which all new combinations are compared. However, even with this combination, responses are seen in about one-third of patients, no more than one-half of which are complete. What is still unknown is whether this group of patients with advanced disease would fare better with good supportive care than with toxic therapies producing responses that are infrequent and of brief duration. One subset of this group in which cisplatin-based combination chemotherapy has produced lasting responses is patients with recurrent undifferentiated nasopharyngeal carcinoma. Higher response rates than at other sites, both complete and partial, are usually reported, and long-term disease-free survival has been reported in a few.11-13 At most subsites of the head and neck, the role of chemotherapy cannot be considered part of standard management even in its traditional use in incurable disease, outside the context of trials designed to evaluate new therapies.

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