We have recently reported favorable responses to a combination treatment comprising cimetidine, a cyclooxygenase-2 inhibitor and a renin-angiotensin-system inhibitor in metastatic renal cell carcinoma (RCC). In view of the potential synergistic effects of these three agents and interferon-a (I-CCA therapy), we conducted a phase-II trial to examine the efficacy and toxicity of I-CCA as firstline treatment. Fifty-one patients with advanced RCC received natural interferon-a (3-6 million U thrice/week) and cimetidine (800 mg), cyclooxygenase-2 inhibitor meloxicam (10 mg), and renin-angiotensin-system inhibitor candesartan (4 mg) or perindopril (4 mg) orally daily. Memorial Sloan-Kettering Cancer Center prognostic categories were favorable, intermediate and poor in 10 (20%), 31 (61%) and 10 (20%) patients, respectively. The primary end-point was the objective response rate (ORR) and the secondary end-points included clinical benefit, progression-free survival (PFS), overall survival (OS) and safety. Median follow-up was 19 months. Complete response (CR) was observed in four patients (8%) and partial response in seven (14%), yielding an ORR of 22%. None of the four patients who achieved CR relapsed during the 16-to 81-month follow up. The ORR were 17% in the favorable-or intermediate-risk group and 40% in the poor-risk group. The other 24 patients (45%) had stable disease for at least 6 months, resulting in a clinical benefit rate of 67%. The median PFS and OS were 12 and 30 months, respectively. Grade 3/4 toxicities were never observed. The I-CCA therapy, providing favorable responses and low toxicity profiles, is worthy of further consideration as a firstline therapy for metastatic RCC. (Cancer Sci 2011; 102: 137-143) R enal cell carcinoma (RCC) is the most common renal malignancy and accounts for approximately 2% of all cancers.(1) Metastatic disease is present in around 30% of RCC patients when diagnosed, and 30-40% of patients with earlystage disease relapse with metastases following nephrectomy. Renal cell carcinoma is highly resistant to conventional cytotoxic chemotherapy and the prognoses in patients with metastatic RCC (mRCC) are poor, (2) with a median overall survival (OS) period of approximately 1 year (3) and a 5-year survival rate of <10%. Immunoreactive cytokines, interferon-a (IFN-a) and interleukin-2 (IL-2) were the treatment mainstay for mRCC.(5) Interferon-a offers a small but significant advantage in OS. (6) However, cases of complete remission (CR) by IFN-a are rare and progression-free survival (PFS) is reported to be approximately 5 months. (7,8) High-dose immunotherapy with intravenous IL-2 results in generally durable CR in approximately 6% of patients, but significant toxicities can occur with this regimen, making it applicable to a limited number of patients. Based on a better understanding of the biology and genetics of RCC, targeted agents have been developed and shown to have significant antitumor activities against RCC, resulting in dramatic paradigm shifts in the management of mRCC....