A phase I-II preoperative biomarker trial of fenretinide in ascitic ovarian cancer.
OBJECTIVE
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 micromol/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 micromol/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.
Colombo
Nicoletta
N
Division of Gynecologic Oncology, European Institute of Oncology, Milan, Italy.
Formelli
Franca
F
Cantù
Maria Grazia
MG
Parma
Gabriella
G
Gasco
Milena
M
Argusti
Alessandra
A
Santinelli
Alfredo
A
Montironi
Rodolfo
R
Cavadini
Elena
E
Baglietto
Laura
L
Guerrieri-Gonzaga
Aliana
A
Viale
Giuseppe
G
Decensi
Andrea
A
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D001202:Ascitic Fluid / Q000737:chemistry / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000097:blood; D018394:CA-125 Antigen / Q000097:blood / Q000187:drug effects; D002276:Carcinoid Tumor / Q000097:blood / Q000188:drug therapy / Q000473:pathology / Q000601:surgery; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D005240:Feasibility Studies; D005260:Female; D017313:Fenretinide / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism / Q000627:therapeutic use*; D005354:Fibrosarcoma / Q000097:blood / Q000188:drug therapy / Q000473:pathology / Q000601:surgery; D006801:Humans; D019394:Ki-67 Antigen / Q000097:blood / Q000187:drug effects; D016014:Linear Models; D008875:Middle Aged; D009367:Neoplasm Staging; D009375:Neoplasms, Glandular and Epithelial / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*; D010051:Ovarian Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery*; D010052:Ovariectomy; D016896:Treatment Outcome; D014801:Vitamin A / Q000097:blood
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D018394:CA-125 Antigen; D019394:Ki-67 Antigen; D014801:Vitamin A; D017313:Fenretinide