title: Pilot trial of the safety, tolerability, and retinoid levels of N-(4-hydroxyphenyl) retinamide in combination with tamoxifen in patients at high risk for developing invasive breast cancer.
abstract: OBJECTIVE
  N-(4-hydroxyphenyl) retinamide (¿4-HPR, Fenretinide; R.W. Johnson Pharmaceutical Research Institute, Springhouse, PA) and tamoxifen (TAM) have synergistic antitumor and chemopreventive activity against mammary cancer in preclinical studies. We performed a pilot study of this combination in women at high risk for developing breast cancer.
  
  
  METHODS
  Thirty-two women were treated with four cycles of 4-HPR, 200 mg orally (PO) for 25 days of each 28-day cycle, and TAM, 20 mg PO once daily for 23 months beginning after 1 month of 4-HPR alone. Tolerability, dark adaptometry, tissue biopsies, and retinoid plasma concentrations (Cp) were evaluated.
  
  
  RESULTS
  Symptomatic reversible nyctalopia developed in two patients (6%) on 4-HPR, but 16 (73%) of 22 patients had reversible changes in dark adaptation, which correlated with relative decrease in Cp retinol (P </=.01). Four patients stopped treatment for side effects, and 84% of patients had hot flashes. Other commonly reported (grade </= 2) reversible toxicities included skin and ocular dryness, fatigue, and mood changes. Serum high-density lipoprotein increased and cholesterol decreased from baseline to month 4. Baseline mean +/- SD Cp retinol was 708 +/- 280 ng/mL. Mean +/- SD Cp of 4-HPR, N-(4-methoxyphenyl) retinamide (4-MPR), and retinol after 1 month of 4-HPR were 0.34 +/- 0.21 micromol/L, 0.28 +/- 0.21 micromol/L, and 282 +/- 127 ng/mL, respectively. Mean retinoid Cps did not change after 3 months of 4-HPR + TAM.
  
  
  CONCLUSIONS
  TAM administration did not affect Cp 4-HPR or 4-MPR. Reversible nyctalopia correlated with relative decrease in Cp retinol but was not symptomatic for most patients. TAM + 4-HPR has acceptable tolerability for this high-risk cohort.
authors.affiliation: Greenebaum Cancer Center, Divisions of Hematology and Oncology, Department of Medicine, University of Maryland School of Medicine, Baltimore, USA.
authors.forename: B
authors.initials: B
authors.lastname: Conley
authors.forename: J
authors.initials: J
authors.lastname: O'Shaughnessy
authors.forename: S
authors.initials: S
authors.lastname: Prindiville
authors.forename: J
authors.initials: J
authors.lastname: Lawrence
authors.forename: C
authors.initials: C
authors.lastname: Chow
authors.forename: E
authors.initials: E
authors.lastname: Jones
authors.forename: M J
authors.initials: MJ
authors.lastname: Merino
authors.forename: M I
authors.initials: MI
authors.lastname: Kaiser-Kupfer
authors.forename: R C
authors.initials: RC
authors.lastname: Caruso
authors.forename: M
authors.initials: M
authors.lastname: Podgor
authors.forename: B
authors.initials: B
authors.lastname: Goldspiel
authors.forename: D
authors.initials: D
authors.lastname: Venzon
authors.forename: D
authors.initials: D
authors.lastname: Danforth
authors.forename: S
authors.initials: S
authors.lastname: Wu
authors.forename: M
authors.initials: M
authors.lastname: Noone
authors.forename: J
authors.initials: J
authors.lastname: Goldstein
authors.forename: K H
authors.initials: KH
authors.lastname: Cowan
authors.forename: J
authors.initials: J
authors.lastname: Zujewski
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000473:pathology / Q000517:prevention & control*; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D008875:Middle Aged; D009755:Night Blindness / Q000139:chemically induced; D010865:Pilot Projects; D018570:Risk Assessment; D013629:Tamoxifen / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D016588:Anticarcinogenic Agents; D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D017313:Fenretinide