title: A phase I-II study of cyclophosphamide, thiotepa, and carboplatin with autologous bone marrow transplantation in solid tumor patients.
abstract: The principles of dose-response and combination chemotherapy were basic to the design of the initial curative standard-dose treatment regimens for leukemias, lymphomas, and testis cancer. Agents were selected with different dose-limiting toxicities, resulting in subadditive toxicity in combination. A fourth principle in the design of curative regimens was to combine agents with different mechanisms of action to avoid cross-resistance. Based on these principles, combinations of the highest tolerated doses of active noncross-resistant agents are required to decrease the emergence of drug resistance and achieve optimum cytotoxicity. Hematopoietic stem-cell support provides a mechanism for significantly increasing the doses of active agents, a strategy that has resulted in the cure of 10% to 50% of selected patients with lymphoma who could not be cured with standard-dose therapy. The lack of sufficiently effective cytoreductive conditioning regimens remains the major impediment to improving the high-dose therapy of patients with solid tumors. In this study, 27 patients with solid tumors were treated with a combination of cyclophosphamide, thiotepa, and carboplatin (CTCb) in a phase I-II study. Severe mucositis and neurotoxicity were dose-limiting. The maximum-tolerated dose (MTD) of the combination was 6.0 g/m2 of cyclophosphamide, 500 mg/m2 of thiotepa, and 800 mg/m2 of carboplatin. There were two deaths (7%) of sepsis, and an overall response rate of 72% in refractory tumors (81% in breast cancer). CTCb is a combination with low morbidity and high cytoreductive efficacy designed to exploit the principles of curative cancer chemotherapy.
authors.affiliation: Department of Medicine, Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: J P
authors.initials: JP
authors.lastname: Eder
authors.forename: A
authors.initials: A
authors.lastname: Elias
authors.forename: T C
authors.initials: TC
authors.lastname: Shea
authors.forename: S M
authors.initials: SM
authors.lastname: Schryber
authors.forename: B A
authors.initials: BA
authors.lastname: Teicher
authors.forename: M
authors.initials: M
authors.lastname: Hunt
authors.forename: J
authors.initials: J
authors.lastname: Burke
authors.forename: R
authors.initials: R
authors.lastname: Siegel
authors.forename: L E
authors.initials: LE
authors.lastname: Schnipper
authors.forename: E
authors.initials: E
authors.lastname: Frei
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation; D001943:Breast Neoplasms / Q000188:drug therapy; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000008:administration & dosage; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D012512:Sarcoma, Ewing / Q000188:drug therapy; D013852:Thiotepa / Q000008:administration & dosage
chemical_list: D009944:Organoplatinum Compounds; D003520:Cyclophosphamide; D013852:Thiotepa; D016190:Carboplatin