INTERFERON ALFA-2A AND 13-CIS-RETINOIC ACID IN RENAL-CELL CARCINOMA - ANTITUMOR-ACTIVITY IN A PHASE-II TRIAL AND INTERACTIONS IN-VITRO

Purpose: A phase 11 trial of interferon alfa-2 alpha (IFN) and 13-cis-retinoic acid (CRA) was conducted in patients with renal cell carcinoma (RCC), In vitro studies were performed to investigate potential mechanisms of interaction. Patients and Methods: Forty-four patients were treated. IFN was given daily at 3 MU and escalated to 6 and 9 MU if tolerated. The dose of CRA was 1 mg/kg/d, The effects of combining CRA and IFN on the proliferation of five RCC cell lines were examined, and retinoid sensitivity was correlated to the expression of retinoic acid receptors. Results: Thirteen (30%) of 43 assessable patients achieved a major response (three complete and 10 partial), Responding sites included bone metastases and renal primary tumors, Seven responding patients remain progression-free at 10+ to 19+ months, The response proportion was higher then in our prior experience with IFN, which was 10% in 149 patients. Eleven of 12 renal cancer cell lines were resistant to CRA alone; one, SK-RC-06, showed 90% inhibition of cell growth. CRA augmented the antiproliferative effect of IFN in several IFN-sensitive cell lines, but not in IFN-resistant lines, Northern blot analysis showed that expression of retinoic acid receptor-beta (RAR-beta) was repressed and not induced by retinoic acid in retinoic acid-insensitive RCC lines. However, RAR-beta expression wets induced by retinoic acid in SK-RC-06 cells, Conclusion: IFN and CRA showed antitumor activity in patients with advanced RCC, and the proportion and nature of response suggested CRA added therapeutic benefit to IFN. A phase III randomised trial of IFN plus CRA versus IFN alone and a phase II trial of single-agent CRA have been initiated. J Clin Oncol 13:1950-1957. (C) 1995 by American Society of Clinical Oncology.