Robert B. Livingston

I have continued to focus on two major themes in the treatment of breast cancer: dose dense or fractionated chemotherapy, and the development of new drug regimens based on an understanding of the mechanisms of drug action.

The principle of fractionated chemotherapy is that frequent (weekly or even daily) exposure to an agent will result in greater effective tumor cell kill, either by providing a tumor cytotoxic concentration for a greater length of time or by antiangiogenic mechanisms. This is analogous to the principle of fractionation long recognized in radiation therapy, that net efficacy is improved by the administration of small doses more frequently. We have applied this concept to breast cancer in the neoadjuvant setting (for locally advanced disease) and in adjuvant setting (for high risk, node positive patients). Our regimen was based on the weekly administration of doxorubicin and daily, oral administration of cyclophosphamide. In order to maintain adequate dose intensity in these regimens,filgrastim (GCSF) has been administered concurrent with cyclophosphamide. This AC+G combination produced a doubling in the expected pathologic complete response rate for locally advanced disease (from 13 to 26%), and a five year disease-free survival of 85% in the adjuvant setting, compared to the results of 60-65% expected for the standard AC program given every 3 weeks. The former observation has been confirmed in a group-wide, phase II trial by the Southwest Oncology Group (SWOG), chaired by my colleague, Dr. Ellis. We are about to open a Phase III, randomized trial in SWOG, which compares AC+G to standard AC as neoadjuvant therapy. A similar design has been proposed in the adjuvant setting.

Two new drug combinations have been pioneered by our group based on molecular mechanisms of interaction, which may be favorably interactive. The first involves combinations of antitubulins: the vinca alkaloid, vinorelbine, which inhibits polymerization of microtubules, has been coupled with paclitaxel or docetaxel, taxane compounds which block the takedown or depolymerization of microtubules in the mitotic spindle. Our phase II clinical data appear to confirm preclinical evidence of synergy for these combinations, possibly due to complimentary effects on mitotic spindle formation, but also possibly related to p53-independent mechanisms of apoptosis whish are common to both drug families. We have observed an overall response rate above 50%, and complete response rates in the 25% range, among women with antharacycline-pretreated breast cancer who received paclitaxel/vinorelbine (Ellis et al) or docetaxel/vinorelbine (Gralow at al). These regimens have also applied the principles of fractionation for dose density and GCSF administration for dose intensity. The docetaxel/vinorelbine combination is now undergoing a group-wide phase II trial in SWOG.

A second combination involves mitomycin C, and older polyfunctional alkylating agent, and irinotecan, a newer agent which interacts with topisomerse I. The latter is an enzyme whose function may be critical for the repair of mitomycin C-induced lesions. As fourth line chemotherapy, this combination has produced a 38% response rate in our group’s hands (Rinn et al). Our next step will be to combine this regimen with an antiangiogenic compound.