title: 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.
abstract: The purpose of this study was to determine the maximum tolerated dose of carboplatin administered with 500 mg/m2 thiotepa and 100 mg/m2 melphalan followed by autologous peripheral blood stem cell (PBSC) infusion in patients with refractory malignancies. Twenty-eight patients with refractory malignancies received high-dose thiotepa (500 mg/m2, melphalan (100 mg/m2) and escalating doses of carboplatin 900-1500 mg/m2) followed by infusion of cryopreserved autologous PBSCs. The maximum tolerated doses were determined to be 500 mg/m2 thiotepa, 100 mg/m2 melphalan and 1350 mg/m2 carboplatin. Two consecutive patients receiving 1500 mg/m2 carboplatin experienced grade 3 mucositis and colitis. Ten patients were enrolled at the maximum tolerated dose and none had grade 3-4 regimen-related toxicity and mortality. All patients at this level experienced grade 1-2 mucositis, 90% grade 1-2 gastrointestinal toxicity, 30% grade 1-2 cardiac and renal toxicity, and 10% experienced grade 1 hepatic toxicity. The median time to achieve a granulocyte count of 0.5x10(9)/l was 9 days (range 7-12 days) and platelet count of 20x10(9)/l was 10 days (range 7-15 days). Of eight patients with stage IV refractory breast cancer, even were evaluable for response, one patient on day 75 will be evaluated soon. Five of seven (71.5%) evaluable patients achieved a complete remission (CR) and two had no response. Of seven patients with non-Hodgkin's lymphoma (n = 4) or Hodgkin's disease (n = 3), five achieved a CR (71.5%). Thiotepa, melphalan and carboplatin can be administered in high doses with tolerable mucositis as the major side-effect. This combination has significant activity in patients with breast cancer, and phase II studies in patients with breast cancer and other chemotherapy-sensitive malignancies are warranted.
authors.affiliation: Ankara University Medical School, Ibni Sina Hospital, Department of Hematology/Oncology and Bone Marrow Transplant Unit, Ankara, Turkey.
authors.forename: T
authors.initials: T
authors.lastname: Demirer
authors.forename: O
authors.initials: O
authors.lastname: Ilhan
authors.forename: N M
authors.initials: NM
authors.lastname: Mandel
authors.forename: M
authors.initials: M
authors.lastname: Arat
authors.forename: N
authors.initials: N
authors.lastname: Günel
authors.forename: H
authors.initials: H
authors.lastname: Celebi
authors.forename: C
authors.initials: C
authors.lastname: Ustün
authors.forename: H
authors.initials: H
authors.lastname: Akan
authors.forename: S
authors.initials: S
authors.lastname: Demirer
authors.forename: S
authors.initials: S
authors.lastname: Aydintuğ
authors.forename: A
authors.initials: A
authors.lastname: Uysal
authors.forename: H
authors.initials: H
authors.lastname: Koç
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D016190:Carboplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D005260:Female; D019337:Hematologic Neoplasms / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D008875:Middle Aged; D009369:Neoplasms / Q000628:therapy*; D013852:Thiotepa / Q000008:administration & dosage; D014182:Transplantation, Autologous
chemical_list: D013852:Thiotepa; D016190:Carboplatin; D008558:Melphalan