Phase‐II trial of combination treatment of interferon‐α, cimetidine, cyclooxygenase‐2 inhibitor and renin‐angiotensin‐system inhibitor (I‐CCA therapy) for advanced renal cell carcinoma

Abstract

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....

Acquired platinum resistance enhances tumour angiogenesis through angiotensin II type 1 receptor in bladder cancer

“…Nakai et al (2010) reported that the use of angiotensin-converting enzyme inhibitors or ARBs with gemcitabine was an independent prognostic factor for both progression-free survival and overall survival in patients with advanced pancreatic cancer. Two prospective studies also proposed the potency of AT1R blockade in cancer treatment (Yoshiji et al , 2009; Tatokoro et al , 2011). Although an increasing body of evidence suggests the efficacy of ARBs may be promising, we examined the effect of combination therapy consisting of CDDP and olmesartan in T24PR tumours, and found no significant difference in tumour growth between the ARB-only group and CDDP+ARB-treated group (data not shown).…”

Prognonstic impact of renin-angiotensin system blockade in localised upper-tract urothelial carcinoma

“…On the other hand, with respect to cancer treatment, a few reports evaluated the efficacy of RAS inhibitor administration, and most reported positive outcomes, especially in combination with other anti-cancer agents (Uemura et al , 2005; Wilop et al , 2009; Nakai et al , 2010; Tatokoro et al , 2011). Wilop et al analysed retrospectively 287 patients with advanced non-small cell lung cancer undergoing first-line platinum-based chemotherapy, and reported that patients receiving either ACEIs or ARBs had a median survival that was 3.1 months longer than non-recipients (11.7 vs 8.6 months) (Wilop et al , 2009).…”

Role of C‐reactive protein in urological cancers: A useful biomarker for predicting outcomes

“…9 Recent investigations have revealed that external symptoms of systemic inflammation are significant predictors of poor outcome in many cancers. [10][11][12][13] To obtain a better understanding of the underlying mechanism of inflammation as it relates to cancer progression, some therapeutic approaches that target the cancer-associated inflammation have been shown to be effective, such as cyclooxygenase-2 inhibitor in combination with IFN-a for RCC, 14,15 and aspirin for colorectal cancer. 16 Quantification of the systemic inflammatory response is essential to adequately evaluate the activity or outcomes of inflammation-related diseases.…”