Interferon‐α‐2a with or without 13‐cis retinoic acid in patients with progressive, measurable metastatic renal cell carcinoma

BACKGROUND In patients with metastatic renal cell carcinoma (MRCC), interferon‐α (IFN) monotherapy leads to response rates of 5–15%, dependent on the selection of patients. In 1995, preclinical and clinical data indicated an improvement of these results if IFN was combined with 13‐cis retinoic acid (CRA). METHODS In a randomized Phase II study, patients with measurable MRCC received either subcutaneous IFN (9 MU daily; Arm A) or the same daily subcutaneous dose of IFN plus oral CRA (1 mg/kg; Arm B). A central expert panel reviewed the X‐ray documentation of objective responses. RESULTS In the 50 eligible patients from Arm A, the objective, expert‐reviewed response rate was 6% (95% confidence interval [95% CI], 1.3–16.6%; 2 complete responses [CRs] and 1 partial response [PR]). A 19% response rate (95% CI, 9.4–32.0%) was stated for 53 eligible patients from Arm B (2 CRs and 8 PRs). Only one of the four CRs claimed by the clinical investigator was confirmed by the central review committee. Conversely, the expert committee deemed that 3 of 12 investigator‐stated PRs were CRs. Constitutional toxicity (flu‐like symptoms) and/or side effects from skin, mucosa, or eyes led to discontinuation of treatment in 22% of nonprogressing patients, more often in Arm B than in Arm A. CONCLUSIONS The results from this randomized Phase II study support expansion of the trial into a Phase III study to evaluate the effect of IFN‐CRA combination therapy on the survival of patients who undergo nephrectomy prior to IFN‐based immunotherapy. The considerable interobserver variability of response evaluation (individual investigator vs. expert panel) indicates the necessity of a central review of claimed responses in future Phase II studies involving patients with MRCC. Cancer 2004. © 2004 American Cancer Society. Based on the results from this randomized Phase II study, the survival‐prolonging efficacy of the combination of interferon α with 13‐cis retinoic acid should be assessed in a Phase III trial. Considerable interobserver variability of objective response evaluation warrants central review of claimed responses in patients with metastatic renal cell carcinoma.