Phase I clinical and pharmacokinetic study of high-dose mitoxantrone combined with carboplatin, cyclophosphamide, and autologous bone marrow rescue: high response rate for refractory ovarian carcinoma.

Abstract

This regimen was well tolerated at the MTD and appears promising for relapsed/refractory ovarian carcinoma, with mitoxantrone levels achieved that are active in vitro against platinum-resistant ovarian carcinoma cells.

High-dose mitoxantrone with peripheral blood progenitor cell rescue: toxicity, pharmacokinetics and implications for dosage and schedule

“…Doselimiting cardiac toxicity with a maximum tolerated dose as low as 50 mg m-2 was found when NOV was administered with high-dose thiotepa (Bowers et al, 1993). However, although decreases in LVEF or clinical signs of heart failure have been noticed, a doselimiting heart toxicity has not been found in several studies using doses of NOV up to 80 mg m-2 in combination with other potentially cardiotoxic agents such as CY and Ara-C (Mulder et al, 1989;Wallerstein et al, 1990;Feldman et al, 1993;Attal et al, 1994;Stiff et al, 1994). The single event observed in our study does not allow a conclusion to be made on the possible correlation between NOV dose levels and cardiotoxicity.…”

“…Contrary to what was previously reported, we were also able to confirm this observation in long-term exposure tests, that is a 7-day incubation, which might be considered a cytotoxicity assay that is more suitable for drugs with prolonged plasma half-life (Fountzilas et al, 1986). The absence of graft toxicity with 96 h earlier NOV administration has been recently reported by Stiff et al (1994) in ovarian cancer patients exposed to high-dose NOV, 75 mg m-2 in three divided doses, and reinfused with autologous bone marrow.…”

“…Mucositis is a frequent and important complication of high-dose NOV and L-PAM (Mulder et al, 1989;Ellis et al, 1990;Wallerstein et al, 1990;Bowers et al, 1993;Attal et al, 1994;Stiff et al, 1994;Patrone et al, 1995). Nonhaematological toxicity was observed in 76% of patients in our series, and in a third (33%) of them it was of intermediate-high grade requiring parenteral nutrition and some analgesic treatment.…”

“…In fact, NOV has haematological dose-limiting toxicity with reportedly limited cardiotoxicity compared with other anthracyclines, can be escalated at least five times above the conventional dose and clearly exhibits a steep dose-response curve in vitro (Von Hoff et al, 1986). Thus, it has been included in several high-dose regimens delivered with haematopoietic rescue (Mulder et al, 1989;Ellis et al, 1990;Wallerstein et al, 1990;Bowers et al, 1993;Attal et al, 1994;Stiff et al, 1994;Patrone et al, 1995). However, it has been claimed that very high dosages imply haematological toxicity that cannot be adequately rescued even by haematopoietic progenitor cell reinfusion (Attal et al, 1994).…”

A phase I dose escalation study of high-dose thiotepa, melphalan and carboplatin (TMCb) followed by autologous peripheral blood stem cell transplantation (PBSCT) in patients with solid tumors and hematologic malignancies

“…1,2 Because of the success which is seen in the treatment of hematologic malignancies, high-dose chemotherapy (HDC) and autologous peripheral blood stem cell transplantation (PBSCT) is being used increasingly in patients with solid tumors where a dose-response relationship is thought to exist. [3][4][5][6][7][8] High-dose chemotherapy with autologous PBSCT has been demonstrated to produce prolonged disease-free survival in some patients with advanced breast and ovarian cancer as well as refractory testicular cancer. [9][10][11][12][13][14] Reasons for poor outcome in some studies following HDC and autologous PBSCT using currently available treatment regimens include relapse and transplant-related mortality.…”