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

• Published in: Cancer epidemiology, biomarkers & prevention biomarkers & prevention, 2006-10, Vol.15 (10), p.1914-1919
• Main Authors: COLOMBO, Nicoletta, FORMELLI, Franca, GUERRIERI-GONZAGA, Aliana, VIALE, Giuseppe, DECENSI, Andrea, CANTU, Maria Grazia, PARMA, Gabriella, GASCO, Milena, ARGUSTI, Alessandra, SANTINELLI, Alfredo, MONTIRONI, Rodolfo, CAVADINI, Elena, BAGLIETTO, Laura
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - adverse effects; Antineoplastic Agents - metabolism; Antineoplastic Agents - therapeutic use; Ascitic Fluid - chemistry; Ascitic Fluid - cytology; Ascitic Fluid - drug effects; Ascitic Fluid - metabolism; Biological and medical sciences; biological markers; Biomarkers, Tumor - blood; CA-125 Antigen - blood; CA-125 Antigen - drug effects; Carcinoid Tumor - blood; Carcinoid Tumor - drug therapy; Carcinoid Tumor - pathology; Carcinoid Tumor - surgery; Case-Control Studies; Cell Proliferation - drug effects; chemoprevention; Chromatography, High Pressure Liquid; clinical trial; Dose-Response Relationship, Drug; Feasibility Studies; Female; Female genital diseases; fenretinide; Fenretinide - administration & dosage; Fenretinide - adverse effects; Fenretinide - metabolism; Fenretinide - therapeutic use; Fibrosarcoma - blood; Fibrosarcoma - drug therapy; Fibrosarcoma - pathology; Fibrosarcoma - surgery; Gynecology. Andrology. Obstetrics; Humans; Ki-67 Antigen - blood; Ki-67 Antigen - drug effects; Linear Models; Medical sciences; Middle Aged; Neoplasm Staging; Neoplasms, Glandular and Epithelial - blood; Neoplasms, Glandular and Epithelial - drug therapy; Neoplasms, Glandular and Epithelial - pathology; Neoplasms, Glandular and Epithelial - surgery; ovarian neoplasms; Ovarian Neoplasms - blood; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - pathology; Ovarian Neoplasms - surgery; Ovariectomy; Treatment Outcome; Tumors; Vitamin A - blood
• ISSN: 1055-9965; 1538-7755
• DOI: 10.1158/1055-9965.EPI-06-0183

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)