title: High-dose melphalan, misonidazole, and autologous bone marrow transplantation for the treatment of metastatic colorectal carcinoma. A phase I study.
abstract: To augment the antitumor effect of high-dose melphalan and determine pharmacokinetics we conducted a phase I trial of escalating doses of high-dose IV melphalan with the chemosensitizer misonidazole for patients with advanced colorectal carcinoma. Fourteen patients with modified Dukes D adenocarcinoma of the colorectum were treated with a single course of melphalan (40-60 mg/m2 i.v. bolus q.d. X 3 days) and misonidazole (1-3 g/m2 p.o. q.d. X 3 days) followed by autologous bone marrow transplantation. Toxicity consisted of severe myelosuppression, moderate nausea and vomiting, and mild mucositis and diarrhea. One patient developed unexplained renal tubular acidosis, and a diffuse encephalopathy occurred in another patient. Three patients died within the first 30 days after the start of treatment, two due to tumor progression and one due to sepsis and disseminated intravascular coagulation-induced intracerebral hemorrhage. Six of 14 patients achieved a partial response, and the median response duration was 4 months (range 3-10 months). Analysis of misonidazole serum concentrations showed similar pharmacokinetics to those previously reported, suggesting no significant drug interaction with intravenous melphalan. Mean peak serum concentrations ranged from 81.8 micrograms/ml to 115.2 micrograms/ml at the second and third misonidazole dose levels, which approximate those known to provide effective chemosensitization with melphalan in animal models. In this phase I study, we showed that maximally tolerated doses of intravenous melphalan can safely be combined with oral misonidazole. In view of the large volumes of oral misonidazole required at the highest dose level, subsequent studies to determine the maximally tolerated dose of misonidazole should employ the intravenous form.
authors.affiliation: Department of Medicine, Ireland Cancer Center of University Hospitals of Cleveland, Ohio.
authors.forename: T R
authors.initials: TR
authors.lastname: Spitzer
authors.forename: H M
authors.initials: HM
authors.lastname: Lazarus
authors.forename: R J
authors.initials: RJ
authors.lastname: Creger
authors.forename: N A
authors.initials: NA
authors.lastname: Berger
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000601:surgery; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000601:surgery; D004334:Drug Administration Schedule; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D008297:Male; D008558:Melphalan / Q000008:administration & dosage*; D008875:Middle Aged; D008920:Misonidazole / Q000008:administration & dosage* / Q000493:pharmacokinetics; D009362:Neoplasm Metastasis; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000601:surgery; D012074:Remission Induction
chemical_list: D008920:Misonidazole; D008558:Melphalan