title: Phase I trial of high-dose tamoxifen in combination with cisplatin in patients with lung cancer and other advanced malignancies.
abstract: BACKGROUND
  Tamoxifen has been reported to enhance the antitumor activity of cisplatin in preclinical models by modulation of protein kinase C signal transduction and apoptosis-related pathways.
  
  
  METHODS
  We conducted a phase I study of high-dose oral tamoxifen in combination with intravenous cisplatin, with two objectives: 1) to determine tolerability, and 2) to determine the daily tamoxifen dose required to achieve serum levels equivalent to in vitro concentrations reported to enhance cisplatin cytotoxicity in preclinical models. Tamoxifen was administered days one through seven at escalating daily doses of 160 mg/m2 (n = 5), 200 mg/m2 (n = 6), and 250 mg/m2 (n = 4) by patient cohort, followed by cisplatin at 100 mg/m2 on day eight. Serum concentrations of tamoxifen and its hydroxylated metabolite N-desmethyltamoxifen were determined by high-performance liquid chromatography (HPLC) on day eight of the first treatment cycle in seven patients.
  
  
  RESULTS
  Fifteen patients with advanced malignancies received treatment with tamoxifen at 160 mg/m2, 200 mg/m2, and 250 mg/m2 per cycle, respectively. Serum concentrations of tamoxifen and N-desmethyltamoxifen on day eight of the first cycle ranged from 1.75-8.22 microM (mean 4.72 microM) and 3.62-10.85 microM (mean 3.87 microM), respectively. Toxicity analysis demonstrated that grade 3/4 nonhematological toxicity occurred in 0/5 at a tamoxifen dose of 160 mg/m2, 1/6 at a tamoxifen dose of 200 mg/m2, and in 1/4 patients at the 250 mg/m2 dose level. No grade 4 hematological toxicity occurred. Classic dose-limiting toxicity was not observed; the trial was closed to further accrual after documentation that targeted tamoxifen levels (around 5 microM) were achieved with daily tamoxifen doses > or = 160 mg/m2 in combination with cisplatin.
  
  
  CONCLUSIONS
  This regimen of high-dose tamoxifen in combination with cisplatin can be safely administered. Serum tamoxifen levels comparable to concentrations required for enhancement of cisplatin sensitivity in vitro are clinically achievable with acceptable toxicity. The level of antitumor activity in nonsmall cell lung cancer NSCLC is encouraging (partial response in 4/10 patients). Based on these data, a Phase II study of high-dose tamoxifen in combination with cisplatin in patients with metastatic NSCLC is being conducted through the Southwest Oncology Group.
authors.affiliation: Division of Hematology/Oncology, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA. perez.edith@mayo.edu
authors.forename: Edith A
authors.initials: EA
authors.lastname: Perez
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Edelman
authors.forename: Robert
authors.initials: R
authors.lastname: O'Donnell
authors.forename: Ignacio J
authors.initials: IJ
authors.lastname: Lauder
authors.forename: Michael
authors.initials: M
authors.lastname: DeGregorio
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002945:Cisplatin / Q000008:administration & dosage / Q000009:adverse effects; D004334:Drug Administration Schedule; D004379:Duodenal Neoplasms / Q000188:drug therapy; D005260:Female; D006402:Hematologic Diseases / Q000139:chemically induced; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D013945:Thymoma / Q000188:drug therapy; D013953:Thymus Neoplasms / Q000188:drug therapy; D013964:Thyroid Neoplasms / Q000188:drug therapy; D016896:Treatment Outcome
chemical_list: D013629:Tamoxifen; D002945:Cisplatin