All-trans retinoic acid and interferon-α-2a in patients with metastatic or recurrent carcinoma of the uterine cervix: Clinical and pharmacokinetic studies

Scott Wadler, Edward L. Schwartz, Hilda Haynes, Ronalde Rameau, Astrid Quish, John Mandeli, Robert Gallagher, Steven Hallam, Abbie Fields, Gary Goldberg, Frances McGill, Scott Jennings, Robert C. Wallach, Carolyn D. Runowicz, Allen Jacobs, Patrick Anderson, James F. Holland, Carmel Cohen, Peter Dottino, James SpeyerHoward Hochster, Thomas Caputo, Gregory Berk, Mark Pasmantier, Herbert F. Gretz, Katherine Economos, Linus Chuang

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22 Scopus citations

Abstract

BACKGROUND. Recent clinical trials with a combination of interferon (IFNα) and 13 cis-retinoic acid resulted in high response rates among 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 IFNα. METHODS. Sequential clinical trials were initiated by the New York Gynecologic Oncology Group to test the combination of tRA and IFNα in women with metastatic or recurrent carcinoma of the cervix who had failed primary therapy. IFNα was administered at 6 MU subcutaneously 3 times per week. In the first trial, tRA was administered at 50 mg/m 2 orally 3 tithes per day on a daily schedule (daily regimen), whereas in the second trial, tRA was administered at the same dose 3 times per day, but only on Days 1-3 each week [intermittent schedule). Clinical outcomes included response to therapy and survival. Plasma pharmacokinetic studies of tRA were performed in both trials to assess the effects of different schedules on plasma levels of the drug. RESULTS. Fourteen women with metastatic or recurrent squamous cell carcinoma of the cervix were enrolled in the daily trial and 12 women in the intermittent trial. There was no clinical activity for either regimen, and both studies were terminated according to an early stopping rule. Because tRA has been reported to induce its own 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 (AUC) was significantly different between the two groups. The average AUC on 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 treatment group. In 6 of 8 patients studied in the daily trial, the AUC decreased at least 60% by either Week 2 or Week 4. In contrast, in the intermittent trial, only 3 of 9 patients experienced >60% decrease in plasma levels of the drug at either Day 8 or Day 28. CONCLUSIONS. The combination of tRA+ IFNα was inactive in patients with advanced carcinoma of the cervix when employed at these doses on either the daily or intermittent schedule. The failure of activity of this regimen did not result from induction of metabolism of tRA, suggesting that intrinsic mechanisms of resistance to tRA at the cellular level may be of greater importance.

Original languageEnglish (US)
Pages (from-to)1574-1580
Number of pages7
JournalCancer
Volume79
Issue number8
DOIs
StatePublished - Apr 15 1997

Keywords

  • cervical carcinoma
  • interferon
  • pharmacokinetic trial
  • retinoic acid

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Wadler, S., Schwartz, E. L., Haynes, H., Rameau, R., Quish, A., Mandeli, J., Gallagher, R., Hallam, S., Fields, A., Goldberg, G., McGill, F., Jennings, S., Wallach, R. C., Runowicz, C. D., Jacobs, A., Anderson, P., Holland, J. F., Cohen, C., Dottino, P., ... Chuang, L. (1997). All-trans retinoic acid and interferon-α-2a in patients with metastatic or recurrent carcinoma of the uterine cervix: Clinical and pharmacokinetic studies. Cancer, 79(8), 1574-1580. https://doi.org/10.1002/(SICI)1097-0142(19970415)79:8<1574::AID-CNCR20>3.0.CO;2-U