title: High-dose tamoxifen added to concurrent biochemotherapy with decrescendo interleukin-2 in patients with metastatic melanoma.
abstract: BACKGROUND
  In vitro cell culture data and preclinical models suggest that tamoxifen modulates tumor cell sensitivity to a wide range of therapeutic agents. In the current study, the authors examined whether high-dose tamoxifen (HDT) improved the overall and complete response in patients with metastatic melanoma who were treated with concurrent biochemotherapy.
  
  
  METHODS
  Forty-nine patients were treated with a biochemotherapy regimen of dacarbazine, vinblastine, cisplatin, decrescendo interleukin-2, interferon-alpha-2b, and tamoxifen. The study had a 2-step design, beginning with a tamoxifen dose escalation from 40 mg to 320 mg (17 subjects) to evaluate safety and tolerability, followed by Phase II accrual of 32 patients to HDT (320 mg) to assess clinical efficacy. Efficacy was compared with a similar modified biochemotherapy regimen with low-dose tamoxifen (LDT). Pharmacokinetic studies were performed to determine in vivo tamoxifen levels.
  
  
  RESULTS
  Tamoxifen dose escalation was completed without any reported dose-limiting toxicity. The overall response rate in the HDT group was 50% (95% confidence interval, 33.2%-66.8%), with a complete response rate of 6% and a median survival of 9.5 months. The overall response rate was not improved and the complete response and survival appeared inferior compared with that of patients recently treated with concurrent biochemotherapy and LDT. Serum tamoxifen levels were found to correlate with the dose administered, with a mean of 0.9 microM at the 40-mg dose to 4.6 microM at the 320-mg dose. Ultrafiltered protein-free sera demonstrated low (< 0.01 microM) concentrations of tamoxifen.
  
  
  CONCLUSIONS
  The addition of HDT to a regimen of concurrent biochemotherapy did not appear to improve response rates or overall survival, despite reaching the targeted plasma concentration. Unknown drug interactions or high protein binding of tamoxifen may account for the lack of clinical effectiveness.
authors.affiliation: Division of Medical Oncology, John Wayne Cancer Institute at Saint John's Health Center, 2001 Santa Monica Blvd., Santa Monica, CA 90404, USA. odays@jwci.org
authors.forename: S J
authors.initials: SJ
authors.lastname: O'Day
authors.forename: P D
authors.initials: PD
authors.lastname: Boasberg
authors.forename: T S
authors.initials: TS
authors.lastname: Kristedja
authors.forename: M
authors.initials: M
authors.lastname: Martin
authors.forename: H J
authors.initials: HJ
authors.lastname: Wang
authors.forename: P
authors.initials: P
authors.lastname: Fournier
authors.forename: M
authors.initials: M
authors.lastname: Cabot
authors.forename: M W
authors.initials: MW
authors.lastname: DeGregorio
authors.forename: G
authors.initials: G
authors.lastname: Gammon
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D008875:Middle Aged; D015996:Survival Rate; D013629:Tamoxifen / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018931:Antineoplastic Agents, Hormonal; D007376:Interleukin-2; D013629:Tamoxifen