Concepts for treatment of micrometastases developed in murine systems

Small tumor cell foci, whether left in situ during primary surgical excision or escaping lethal radiation damage, as well as distant metastases, are the primary reason for treatment failure in man and are the proper targets for the chemotherapist and immunotherapist. Since cure probably requires reduction of the total body burden of tumor cells to very small numbers (possibly to less than one cell), and since first-order kinetics of tumor cell kill by drugs appears to be a natural law in cancer chemotherapy, drug treatment should be started as soon as possible after likely noncurative primary treatment with surgery or radiation. Current knowledge of tumor cell population growth kinetics indicates that the growth fraction (viable tumor cells undergoing active cell replication) is inversely related to population size. Tumor cells in micrometastases should, therefore, be more sensitive to anticancer drugs active against anabolizing cells than are tumor cells in the larger, grossly apparent primary tumor from which they were derived. This indicates the probability that micrometastases will be effectively responsive to more drugs than is the primary and clinically apparent tumor from which they came. Studies with at least four metastatic and uniformly fatal murine solid tumors (lung, breast, colon, and melanoma) have demonstrated significantly improved cure rates with drug treatment following surgical removal of the grossly apparent primary tumor than can be obtained with either surgery or drug treatment when used alone. Further, both disease staging and drug dosage have been shown to influence cure rates of combined-modality treatment. With several mouse tumors, a significantly smaller number of viable tumor cells can establish lethal tumors in the presence of radiation-inactivated tumor cells than in their absence. This suggests that small numbers of residual viable tumor cells in radiation-treated tumor sites may be a greater threat to clinical cure than smaller tumor cell populations remaining in situ after surgery.