Dysplasia of the uterine cervix is a recognized preneoplastic condition. Because of the observed ability of retinoids to reverse other dysplastic conditions in vitro and in vivo, a number of clinical studies have been carried out of the effect of these agents on cervical dysplasia, with the object of developing a means of chemoprevention of cervical malignancies in women at risk. We have conducted phase I and II trials of topical tretinoin (retinoic acid and Retin-A) delivered by means of a cervical cap and inert collagen sponge system. The results of these studies warranted a phase III trial, which is now underway. The outcome of the latter investigation will have important implications, not only for the management of patients with cervical dysplasia but also for therapeutic approaches to other precancerous conditions.

The present study was undertaken to evaluate the systemic absorption and cervical tissue uptake of all-trans-retinoic acid (TRA), delivered via a collagen spongecervical cap delivery device in patients with intraepithelial cervical dysplasia. Ten patients with histologically proven mild or moderate cervical dysplasia were included in this pharmacologic study. The two TRA concentrations (0.05% and 0.372%) selected for study represent the starting and maximally tolerated doses used in phase I clinical trial. All-trans-retinoic-11-3H acid (3H-TRA, 500 mu Ci) was used to facilitate cervical tissue uptake studies. Cervical biopsies and post-treatment blood samples were obtained from each patient after TRA exposure. The uptake of TRA into cervical tissues four hours after drug administration was significantly increased at the maximally tolerated TRA dose. There was a rapid decrease in cervical tissue concentration of TRA at the 0.372% dose between 4 and 24 h after drug exposure, suggesting a relatively short elimination half-life of TRA in cervical tissues. HPLC analysis of post-treatment blood samples indicate that there was no systemic absorption of TRA after local cervical administration.

Forty-two patients were entered into a phase I trial to evaluate the vitamin A derivative, trans-retinoic acid, in cervical intraepithelial neoplasia. Treatment consisted of four consecutive 24-h applications of retinoids via an inert collagen sponge in a cervical cap. Patients were followed for response at 3-month intervals using cytology, colposcopy, and selected biopsies. Thirty-six patients were evaluable (mild dysplasia, 13; moderate dysplasia, 17; severe dysplasia, 6) with follow-up from 5 to 18 months. Complete regression was seen in 2/14 (14%) patients treated with concentrations of 0.05%----0.1167% and in 10/22 (45%) patients treated with concentrations of 0.1583%----0.484% (p less than 0.05). One patient with negative biopsies at 12 months has subsequently recurred at 18 months.

Background

Purpose

Methods

Results

Conclusions

Implications

Retinoids are effective suppressors of the phenotypic development of cancer in many animal systems, whether the process is initiated by chemical, physical or viral carcinogens. Cases of cervical intraepithelial neoplasia are excellent for studying the effectiveness of retinoids as chemopreventive agents because the process can be closely followed by serial colposcopic and pathologic (cytology or biopsy) means and changes in the condition safely monitored. We have previously conducted a phase I study of trans-retinoic acid (Tretinoin) given topically by a collagen sponge and cervical cap. A dose of 0.372% was selected for phase II trial. We have treated 20 patients with topical retinoic acid, and a complete response with total regression of disease was obtained in 50%. Systemic and cervical side effects were mild and vaginal side effects moderate but tolerable. These results provide a clinical basis for a randomized, double-blind phase III study to definitely answer the question of whether retinoic acid is an effective chemopreventive agent for cervical cancer.

The human tumor stem cell assay (HTSCA) has been used to study the in vitro sensitivity rates of anticancer drugs used in the treatment of 115 patients with previously untreated and relapsing ovarian cancer. The data from these studies have identified patterns of cross resistance and residual sensitivity between these agents, and have allowed the prospective selection of single agents possessing in vitro activity for the treatment of 32 patients with relapsing disease. cis-Platinum and vinblastine were the most active agents in vitro against ovarian TCFUs from both previously untreated and relapsing patients. Prior therapy with even one drug was associated with the acquisition of resistance to several classes of compounds (e.g., melphalan resistance was almost always associated with in vitro adriamycin resistance, P less than 0.001). A clinical trial yielding similar data would have required nearly 450 evaluable ovarian cancer patients. In 11 of 32 patients in vitro testing predicted sensitivity to single agents: eight of these had partial remissions for a predictive accuracy of 73%. In 33 instances the HTSCA had 100% accuracy in predicting the lack of clinical response. Thus, the HTSCA for advanced ovarian cancer appears to have a similar predictive accuracy rate to the estrogen receptor assay for predicting the response to hormonal therapy for disseminated breast cancer.