Although the improvements in local control may benefit overall survival, this form of targeted therapy is still a locoregional treatment, and a high proportion of distant failures and second primary cancers occur. Given that adjuvant systemic therapy has not generally been found to improve outcomes, significant advances in survival improvement are only likely to be achieved if systemic disease can similarly be targeted. Drug delivery systems that are selectively taken up and retained by tumor cells will be required. Such methods are not yet available but are the subject of intensive research. Drugs to reduce the incidence of second primary cancers are also being investigated. Numerous agents have been investigated, and the most successful to date have been retinoic acid and its derivatives. Concerns of toxicity and the temporary nature of the responses have prevented the widespread use of chemopreventive agents. No standard approach exists for control of high-risk premalignant lesions. New treatments using agents such as cyclooxygenase inhibitors and biomodulation of retinoids are under investigation.
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