A phase I/II study of 4 monthly courses of high-dose cyclophosphamide and thiotepa for metastatic breast cancer patients

Abstract

This pilot phase I/II study intended to determine the maximum tolerated dose of cyclophosphamide and thiotepa administered on four consecutive courses with peripheral blood progenitor cell and granulocyte-colony stimulating factor support, as firstline therapy for hormone-refractory metastatic breast cancer patients. Twenty-eight patients were entered in the study. After two courses of epirubicin (120 mg m 72 ) and cyclophosphamide (2 g m 72 ) followed by granulocyte-colony stimulating factor injection and leukaphereses, patients received four cycles of cyclophosphamide and thiotepa. Each cycle was followed by peripheral blood progenitor cell and granulocyte-colony stimulating factor supports, then repeated every 28 to 35 days. Six escalating dose levels of cyclophosphamide and thiotepa were planned, beginning at cyclophosphamide 1.5 g m 72 and thiotepa 200 mg m 72 . At least three patients were enrolled for each dose level. Eighteen patients completed the study. The maximum tolerated dose was 3000 mg m 72 cyclophosphamide and 400 mg m 72 thiotepa per course. Haematological toxicity was manageable on an outpatient basis and did not increase significantly with dose escalation. Dose-limiting toxicity was chemotherapy-induced immuno-suppression, which resulted in one toxic death and two life-threatening infections. Median times to treatment failure and survival were 11 and 26 months, respectively. Three patients were alive, free of disease 30 months after completion of the study. Such therapy allows for high-dose intensity and high cumulative doses on a short period of time with manageable toxicity.

Chemotherapy for metastatic breast cancer. Comparison of clinical practice and cost of drugs in two cohorts of patients: 1994–1998 and 2003–2006

“…Most of these patients received hormone therapies when indicated or palliative care. Second, in the 1990s, several clinical trials testing HDCSCT were ongoing at the Centre Léon Bérard [8][9][10] and these trials included only young patients (younger than 50 years). In our study, 27 patients treated in group 1 received HDCSCT and their median age was 37 years.…”

Pegase 03: a prospective randomized phase III trial of FEC with or without high-dose thiotepa, cyclophosphamide and autologous stem cell transplantation in first-line treatment of metastatic breast cancer

“…Results from another study investigating the feasibility of four cycles of ablative HDC (cyclophosphamide and thiotepa) with PBSC support are also encouraging but show that high toxicity may preclude the development of such treatments. 36 Another approach to potentially increasing the efficacy of HDC is to give it very soon after the start of treatment, rather than later as a consolidation therapy. We attempted to evaluate such an approach in a phase II randomized trial (in three centers) comparing the use of very high-dose intensification before or after two sequential cycles of HDC, but a high toxicity rate in the second option necessitated premature termination of randomization.…”