ALL-TRANS-RETINOIC ACID AND INTERFERON-ALPHA-2A IN PATIENTS WITH METASTATIC OR RECURRENT CARCINOMA OF THE UTERINE CERVIX - CLINICAL AND PHARMACOKINETIC STUDIES

BACKGROUND. Recent clinical trials with a combination of interferon (I FN alpha) and 13 cis-retinoic acid resulted in high response rates amo ng women with locally advanced and metastatic carcinoma of the uterine cervix. The authors sought to amplify these observations by employing the isomer of 13 cis-retinoic acid, all-trans retinoic acid (tRA), in combination with IFN alpha. METHODS. Sequential clinical trials were initiated by the New York Gynecologic Oncology Group to test the combi nation of tRA and IFN alpha in women with metastatic or recurrent carc inoma of the cervix who had failed primary therapy. IFN alpha was admi nistered at 6 MU subcutaneously 3 times per week. In the first trial, tRA was administered at 50 mg/m(2) orally 3 times per day on a daily s chedule (daily regimen), whereas in the second trial, tRA was administ ered at the same dose 3 times per day, but only on Days 1-3 each week (intermittent schedule). Clinical outcomes included response to therap y and survival. Plasma pharmacokinetic studies of tRA were performed i n both trials to assess the effects of different schedules on plasma l evels of the drug. RESULTS. Fourteen women with metastatic or recurren t squamous cell carcinoma of the cervix were enrolled in the daily tri al and 12 women in the intermittent trial. There was no clinical activ ity for either regimen, and both studies were terminated according to an early stopping rule. Because tRA has been reported to induce its ow n metabolism, plasma levels of tRA were measured on Days 1, 8, and 28. The change in the area under the time versus tRA concentration curve (AUG) was significantly different between the two groups. The average AUC an Day 8 was 14% of that observed on Day 1 for the daily treatment group; in contrast, it was 107% on Day 1 in the intermittent treatmen t group. In 6 of 8 patients studied in the daily trial, the AUC decrea sed at least 60% by either Week 2 or Week 4. In contrast, in the inter mittent trial, only 3 of 9 patients experienced >60% decrease in plasm a levels of the drug at either Day 8 Or Day 28. CONCLUSIONS. The combi nation of tRA + IFN alpha was inactive in patients with advanced carci noma of the cervix when employed at these doses on either the daily or intermittent schedule. The failure of activity of this regimen did no t result from induction of metabolism of tRA, suggesting that intrinsi c mechanisms of resistance to tRA at the cellular level may be of grea ter importance. (C) 1997 American Cancer Society.