Double dose-intensive chemotherapy with autologous stem-cell support for metastatic breast cancer: No improvement in progression-free survival by the sequence of high-dose melphalan followed by cyclophosphamide, thiotepa, and carboplatin

Purpose: Twenty-one percent of responding metastatic breast cancer patients remain progression-free a median 50 months following one intensification cycle of cyclophosphamide (6,000 mg/m(2)), thiotepa (500 mg/m(2)), and carboplatin (800 mg/m(2)) (CTCb) with autologous bone marrow transplantation (ABMT). This trial studied whether the sequence of high-dose melphalan followed by CTCb resulted in improved disease response and duration. Methods: Women with at least partial responses (PRs) to induction received melphalan (140 or 180 mg/m(2)) with peripheral-blood progenitor cell (PBPC) and granulocyte colony-stimulating factor (G-CSF) support. They were monitored as outpatients. After recovery, patients were hospitalized for CTCb with marrow, PBPC, and G-CSF support. Results: Data on 67 women, at a median of 25 months from CTCb, were examined. After melphalan, 49 (73%) required admission for fever (89%), mucositis (35%), or infection (15%) (median stay, 8 days). All received CTCb. For the first 33 patients, the median days from start of melphalan to CTCb was 24. After liver toxicity (one death from venoocclusive disease [VOD]) developed in 11 patients during CTCb, the interval between intensifications was increased to 35 days without incident. Twenty-three patients (34%) are progression-free a median of 16 months post-CTCb. The median progression-free survival (PFS) and survival rimes for the whole group are estimated at 11 and 20 months, respectively. Conclusion: Treatment with this sequence of high-dose melphalan followed by CTCb has not resulted in superior PFS to date, when compared with single-intensification CTCb. This report discusses factors related to patient selection, the role of induced drug resistance, and the schedule of administration of alkylating agents that may adversely influence outcome. (C) 1996 by American Society of Clinical Oncology.