title: Clinical phase I dose escalation and pharmacokinetic study of high-dose chemotherapy with treosulfan and autologous peripheral blood stem cell transplantation in patients with advanced malignancies.
abstract: A Phase I dose escalation and pharmacokinetic study of the alkylating cytotoxic agent treosulfan was conducted to evaluate the maximum tolerated dose and the dose-limiting toxicities in patients with advanced malignancies rescued by autologous peripheral blood stem cell transplantation. Twenty-two patients (15 ovarian and 7 other carcinomas/lymphomas) with a median age of 48 years were treated with 28 high-dose courses. Treosulfan was infused over 2 h at escalating doses from 20 to 56 g/m2, and pharmacokinetic parameters were analyzed. At 56 g/m2, three of six patients experienced dose-limiting toxicities: diarrhea grade III/IV in three patients; mucositis/stomatitis grade III in one patient; toxic epidermal necrolysis in one patient; and grade III acidosis in one patient. Other low-grade side effects, including erythema, pain, fatigue, and nausea/vomiting, were recorded. Two patients died within 4 weeks after treatment because of rapid tumor progression and fungal infection, respectively. Plasma half-life, distribution volume, and renal elimination of treosulfan were independent of dose, whereas the increase in area under the curve was linear up to 56 g/m2 treosulfan. The maximum tolerated dose of high-dose treosulfan is 47 g/m2. A split-dose or continuous infusion regimen is recommended for future high-dose trials. In consideration of antineoplastic activity and limited organ toxicity, inclusion of high-dose treosulfan in combination protocols with autologous peripheral blood stem cell transplantation seems worthwhile.
authors: Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Essen Medical School. max.scheulen@uni-essen.de
authors: M E
authors: ME
authors: Scheulen
authors: R A
authors: RA
authors: Hilger
authors: C
authors: C
authors: Oberhoff
authors: J
authors: J
authors: Casper
authors: M
authors: M
authors: Freund
authors: K M
authors: KM
authors: Josten
authors: M
authors: M
authors: Bornhäuser
authors: G
authors: G
authors: Ehninger
authors: W E
authors: WE
authors: Berdel
authors: J
authors: J
authors: Baumgart
authors: A
authors: A
authors: Harstrick
authors: P
authors: P
authors: Bojko
authors: H H
authors: HH
authors: Wolf
authors: A E
authors: AE
authors: Schindler
authors: S
authors: S
authors: Seeber
mesh_terms: D000328:Adult; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use*; D002066:Busulfan / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D014182:Transplantation, Autologous
chemical_list: D018906:Antineoplastic Agents, Alkylating; C018404:treosulfan; D002066:Busulfan