Selecting dose-intense drug combinations: metastatic breast cancer

A mathematical model previously described is applied to the problem of selecting drug combinations for metastatic breast cancer. The model accounts for the differing single-agent activities of the drugs as well as their differing profiles of toxicity. With no bone marrow protection, combinations with cisplatin offer a small improvement in total equivalent dose over therapy with the more active single-agents. Restricting consideration to the four most commonly used agents, single-agent doxorubicin has the greatest equivalent dose. With protection for leukopenia or willingness to accept a higher incidence of severe leukopenia, a combination with large doses of cyclophosphamide, doxorubicin, and fluorouracil, and a small dose of cisplatin has greatest equivalent dose. The doublets cyclophosphamide/fluorouracil or fluorouracil/cisplatin at higher doses are almost as good. With protection for leukopenia and thrombocytopenia, a cyclophosphamide/thiotepa combination at very high doses maximizes total equivalent dose. This approach can be used to identify regimens worthy of prospective evaluation.