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A Phase I-II Preoperative Biomarker Trial of Fenretinide in Ascitic Ovarian Cancer

Divisions of ¹ Gynecologic Oncology, ² Chemoprevention, ³ Pathology, European Institute of Oncology; ⁴ Chemoprevention Unit, National Cancer Institute, Milan, Italy; ⁵ University of Milan Bicocca, Clinic of Obstetrics and Gynecology, S. Gerardo Hospital, Monza, Italy; ⁶ Cancer Epidemiology Centre, The Cancer Council of Victoria, Melbourne, Australia; ⁷ Division of Medical Oncology, E.O. Ospedali Galliera, Genoa, Italy; and ⁸ Institute of Pathology, University of Ancona, Ancona, Italy

Requests for reprints: Andrea Decensi, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Phone: 39-0257489861; Fax: 39-0257489809. E-mail: andrea.decensi{at}ieo.it

Purpose: To evaluate study feasibility, toxicity, drug concentrations, and activity of escalating doses of the synthetic retinoid fenretinide [N-(4-hydroxyphenyl)retinamide (4-HPR)] in ovarian cancer by measuring serum CA125 and cytomorphometric biomarkers in cancer cells collected from ascitic fluid before and after treatment.

Methods: Twenty-two naive patients with ascitic ovarian cancer were treated with escalating doses of 4-HPR at 0, 400, 600, and 800 mg/d for 1 to 4 weeks before surgery. Changes in the proportion of proliferating cells expressed by Ki67 and computer-assisted cytomorphometric variables (nuclear area, DNA index, and chromatin texture) were determined in ascitic cells. Drug levels were measured by high-performance liquid chromatography.

Results: Doses up to 800 mg/d were well tolerated, and no adverse reactions occurred. There was no effect of 4-HPR on changes in serum CA125, Ki67 expression, which were assessed in 75% of subjects, and cytomorphometric variables, which were assessed in 80% of subjects. Plasma retinol levels were significantly lower in affected women than healthy donors. 4-HPR plasma concentrations increased slightly with increasing doses and attained a 1.4 µmol/L concentration with 800 mg/d. Drug levels in malignant ascitic cells and tumor tissue were higher than in plasma but were 50 and 5 times lower, respectively, than in carcinoma cells treated in vitro with 1 µmol/L 4-HPR.

Conclusions: Cell biomarkers can be measured in ascitic cells to assess drug activity. Under our experimental conditions, 4-HPR did not show activity in advanced ovarian cancer cells. However, clinical evidence supports further investigation of fenretinide for ovarian cancer prevention. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1914–9)

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