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Maintenance Therapy to Suppress Micrometastasis: The New Challenge for Adjuvant Cancer Treatment

Author's Affiliation: Department of Medicine, University of Hong Kong, Professorial Block, Queen Mary Hospital, Pokfulam, Hong Kong

Requests for reprints: Richard J. Epstein, Department of Medicine, University of Hong Kong, Professorial Block, Queen Mary Hospital, Pokfulam, Hong Kong. Phone: 852-2855-3994; Fax: 852-2816-2863; E-mail: repstein{at}hku.hk.

The palliative efficacy of cytotoxic drugs is routinely assessed using tumor shrinkage (response) rates shown in clinical trials. Although adjuvant drug therapy has a goal distinct from that of palliative therapy (i.e., to prolong survival by inhibiting progression of micrometastatic disease), it is widely assumed that the adjuvant efficacy of a drug will parallel its response rate ("activity") in advanced stages of the disease. Reconsideration of this assumption seems timely in view of recent developments: the realization that many predictors of short-term tumor response correlate inversely with long-term survival outcomes; the characterization of tumor progression as a discontinuous process that may include dormant phases; the understanding that micrometastasis is therapeutically suppressible by a variety of mechanisms including direct tumor cell kill, cytotoxic disruption of paracrine growth signals from normal tissues, and targeted inhibition of prometastatic pathways; the recognition that tumor dormancy not only blocks the antimetastatic efficacy of cytotoxic drugs but also represents a therapeutic end point for metastasis-suppressive noncytotoxic drugs such as hormone inhibitors; and the insight that optimal adjuvant drug therapy is likely to include both induction and maintenance components. The traditional view of cytoreductive response as a prerequisite for adjuvant drug efficacy thus merits reappraisal, with a view to accelerating incorporation of novel noncytotoxic maintenance therapies into controlled studies.

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