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

PURPOSE:

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.

PATIENTS AND 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: B Conley, J O'Shaughnessy, S Prindiville, J Lawrence, C Chow, E Jones, M J Merino, M I Kaiser-Kupfer, R C Caruso, M Podgor, B Goldspiel, D Venzon, D Danforth, S Wu, M Noone, J Goldstein, K H Cowan, J Zujewski
• Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology (J Clin Oncol) Vol. 18 Issue 2 Pg. 275-83 (Jan 2000) ISSN: 0732-183X [Print] United States
• PMID: 10637240 (Publication Type: Clinical Trial, Journal Article)

Chemical References

• Anticarcinogenic Agents
• Antineoplastic Agents, Hormonal
• Tamoxifen
• Fenretinide

Topics

• Administration, Oral
• Adult
• Aged
• Anticarcinogenic Agents (administration & dosage, adverse effects, pharmacokinetics)
• Antineoplastic Agents, Hormonal (administration & dosage, pharmacology, therapeutic use)
• Breast Neoplasms (pathology, prevention & control)
• Female
• Fenretinide (administration & dosage, adverse effects, pharmacokinetics)
• Humans
• Middle Aged
• Night Blindness (chemically induced)
• Pilot Projects
• Risk Assessment
• Tamoxifen (administration & dosage, pharmacology, therapeutic use)