Quantitative histopathology and chromosome 9 polysomy in a clinical trial of 4-HPR.
OBJECTIVE
This trial examined the use of 4-hydroxyphenyl-retinamide (4-HPR), demonstrated to be a potent inhibitor of carcinogenesis in vitro and in animal models, in patients with cervical intraepithelial neoplasia (CIN) grades 2 to 3. Quantitative pathology and chromosome 9 polysomy were used to understand the biology and quantify the clinical histopathologic changes observed.


METHODS
Patients were randomized to 4-HPR or placebo for 6 months and followed for six more months. Cervical biopsies were obtained at baseline, 6 months, and 12 months; the biopsies were read blinded three times by the study pathologist. Feulgen-stained sections were also obtained and analyzed using computer-assisted image cytometry. Chromosome 9 polysomy was performed on tissue slices using in situ hybridization and measured quantitatively. Statistical analyses were carried out in S-Plus (Insightful Corporation, Seattle, WA) and R.


RESULTS
The interim analysis, planned for 40 patients, was carried out on 39. The 6- and 12-month analyses showed a statistically significant difference between the two study arms. When code was broken, the 4-HPR-treatment arm was found to have fared less well than placebo. Analyses of Feulgen-stained sections provided a quantitative measure of the increase of DNA content and texture features. Chromosome 9 polysomy was also measured using image analysis. The changes observed were consistent with those of cells displaying cancerous changes, indicating a lack of response.


CONCLUSIONS
4-HPR is not active at 200 mg/day. The interim analysis was helpful in directing the study; and, in this case, ending it. The intermediate endpoint biomarkers of quantitative histomorphometry and chromosome 9 polysomy yielded quantitative and repeatable results consistent with the findings of the clinical pathologist.
Yamal
Jose-Miguel
JM
Center for Biomedical Engineering, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Cox
Dennis
D
Hittelman
Walter N
WN
Boiko
Iouri
I
Malpica
Anais
A
Guillaud
Martial
M
MacAulay
Calum
C
Follen
Michele
M
Vlastos
Anne-Therese
AT
D016588:Anticarcinogenic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D002869:Chromosome Aberrations; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D005260:Female; D017313:Fenretinide / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D017313:Fenretinide