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.
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.
Conley
B
B
Greenebaum Cancer Center, Divisions of Hematology and Oncology, Department of Medicine, University of Maryland School of Medicine, Baltimore, USA.
O'Shaughnessy
J
J
Prindiville
S
S
Lawrence
J
J
Chow
C
C
Jones
E
E
Merino
M J
MJ
Kaiser-Kupfer
M I
MI
Caruso
R C
RC
Podgor
M
M
Goldspiel
B
B
Venzon
D
D
Danforth
D
D
Wu
S
S
Noone
M
M
Goldstein
J
J
Cowan
K H
KH
Zujewski
J
J
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
D016588:Anticarcinogenic Agents; D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D017313:Fenretinide