PHASE-I TRIAL OF SEQUENTIAL HIGH-DOSE CHEMOTHERAPY WITH ESCALATING DOSE PACLITAXEL, MELPHALAN, AND CYCLOPHOSPHAMIDE, THIOTEPA, AND CARBOPLATIN WITH PERIPHERAL-BLOOD PROGENITOR SUPPORT IN WOMEN WITH RESPONDING METASTATIC BREAST-CANCER

A single high-dose cycle of chemotherapy with stem cell support can pr oduce disease-free survival of 15-20% for at least 3 years in women wi th responding stage IV breast cancer. North American Autologous Bone M arrow Transplant Registry data suggest that a complete response (CR) i s the single most important prognostic factor associated with prolonge d disease-free survival. Therefore, if sequential high-dose chemothera py can increase the CR rate, then perhaps an increased proportion of p atients will remain disease free. Women with at least a partial respon se (PR) to induction chemotherapy received three separate high-dose cy cles of chemotherapy with peripheral blood progenitor support and gran ulocyte colony-stimulating factor. The first intensification was a dos e escalation of paclitaxel (400-825 mg/ m(2)), the second intensificat ion was melphalan (180 mg/m(2)), and the third intensification consist ed of 6000 mg/m(2) cyclophosphamide (1500 mg/m(2)/day), 500 mg/m(2) th iotepa (125 mg/m(2)/day), and 800 mg/m(2) carboplatin (200 mg/m(2)/day ; CTCb). Thirty-six women were enrolled and 31 completed all three cyc les. After the paclitaxel infusion most patients developed reversible predominantly sensory neuropathy. Of the 19 patients with measurable d isease, 6 converted to CR, 7 converted to a PR (the complete resoluti on of all soft tissue or visceral disease with sclerosis of prior lyti c bone lesions), and 2 had a further PR for an overall response rate o f 79%. Two patients had no further response and disease in two patient s progressed, and thus they were taken off the study before CTCb. Seve nty-eight percent are progression-free at a median follow-up of 14 mon ths (range, 3-24+). Three sequential cycles of high-dose chemotherapy are feasible and were administered in this study with no mortality. Si ngle agent paclitaxel at doses up to 825 mg/m(2) were well tolerated w ith moderate reversible toxicity.