title: Escalating doses of carboplatin with high-dose ifosfamide using autologous bone marrow as support: a phase I study.
abstract: In this phase I study, 16 adult cancer patients were treated with concurrent 4-day continuous infusions of ifosfamide at 12 g/m2 and escalating doses of carboplatin (400-1600 mg/m2) to determine the major non-haematological dose-limiting toxicity of the combination. Mesna was given by continuous infusion over 5 days for uroprotection (total dose per course = 15 g/m2). Autologous bone marrow support, which was mandated for subsequent dose levels once granulocytes remained below 500/microliters for more than 14 days in at least 2 patients entered at a given dose level, was used at dose levels above 400 mg/m2 carboplatin. Renal toxicity became dose-limiting at the maximum tolerated dose level of 1600 mg/m2 carboplatin. Temporary creatinine elevations above 2 mg/dl (median peak 2.6 mg/dl) were observed in 3 and irreversible renal toxicity occurred in 1 (peak creatinine 6.9 mg/dl, chronic creatinine 5-6 mg/dl) of the 5 patients entered at this dose level. Severe confusion and lethargy associated with rising creatinine developed in 2 patients. Two complete and four partial responses were documented in 14 heavily pretreated evaluable patients. The complete responses continue at 14+ and 20+ months in a patient with germ cell carcinoma and Ewing's sarcoma, respectively. Carboplatin appears to contribute to the renal toxicity of ifosfamide. Nevertheless, the combination of carboplatin and ifosfamide at 80% and 75% of the single-agent maximal tolerated doses respectively produced acceptable non-haematological toxicity. Further studies in the treatment of sarcoma, germ cell, ovarian and lung carcinomas with this combination are warranted.
authors.affiliation: Division of Clinical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115.
authors.forename: A D
authors.initials: AD
authors.lastname: Elias
authors.forename: L J
authors.initials: LJ
authors.lastname: Ayash
authors.forename: J P
authors.initials: JP
authors.lastname: Eder
authors.forename: C
authors.initials: C
authors.lastname: Wheeler
authors.forename: J
authors.initials: J
authors.lastname: Deary
authors.forename: L
authors.initials: L
authors.lastname: Weissman
authors.forename: M
authors.initials: M
authors.lastname: Hunt
authors.forename: J
authors.initials: J
authors.lastname: Critchlow
authors.forename: L
authors.initials: L
authors.lastname: Schnipper
authors.forename: E
authors.initials: E
authors.lastname: Frei
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D016026:Bone Marrow Transplantation; D016190:Carboplatin / Q000008:administration & dosage; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage; D009369:Neoplasms / Q000188:drug therapy*; D012074:Remission Induction; D014182:Transplantation, Autologous
chemical_list: D016190:Carboplatin; D007069:Ifosfamide