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Yasuhisa Fujii md phd, Department of Urology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-Ku, Tokyo 113-8519, Japan. Email: email@example.com
Abstract: We report three cases of metastatic renal cell carcinoma (RCC) in which combination treatment of cimetidine, cyclooxygenase-2 inhibitor and renin-angiotensin system inhibitor (angiotensin converting enzyme inhibitor or angiotensin II type 1 receptor antagonist) (CCA therapy) was effective. Case 1: A 47-year-old man who had a 12-cm right renal tumor with multiple pulmonary and hepatic metastases refused cytokine therapy for economic reasons and received CCA therapy. All of the metastases showed partial remission, which continued for 12 months. Case 2: A 62-year-old man with multiple pulmonary and mediastinal lymph node metastases from clear cell RCC refractory to interferon-α and interleukin-2 started CCA therapy. Partial remission has been maintained for 16 months. Case 3: A 64-year-old man with pulmonary metastases from clear cell RCC discontinued interferon-α treatment due to its side effects after six months and received CCA therapy. Pulmonary metastases showed partial remission for 31 months. The CCA therapy could be an alternative treatment for metastatic RCC patients unfit for cytokine therapy.
The prognosis of patients with metastatic renal cell carcinoma (RCC) is poor, with a median overall survival period of approximately one year and a five-year survival rate of less than 10%.1 Previously, the only effective agents for metastatic RCC were interferon-alpha (IFN-α) and interleukin-2 (IL-2). However, combined data for these agents resulted in an overall chance of partial or complete remission in just 10–20% of cases.2
Recently, novel molecularly targeted agents including sorafenib, sunitinib and temsirolimus have been shown as promising agents. Although sorafenib and sunitinib can produce tumor shrinkage in more patients and prolong the progression-free survival period for longer compared with cytokines, they have rarely been associated with complete remission. The long-term clinical benefits of these agents remain unclear. Furthermore, these new agents impose an enormous economic burden. Most importantly, significant side-effects sometimes make it impossible to continue these drugs. Therefore, there has remained a clear need for novel more effective therapies for advanced RCC.
The anti-tumor effects of cimetidine, cyclooxygenase-2 (COX-2) inhibitor and renin-angiotensin system (RAS) inhibitor (angiotensin converting enzyme [ACE] inhibitor or angiotensin II type 1 receptor [AT1R] antagonist) have been recognized in in vitro or in vivo studies.3–10 Herein we describe three cases of metastatic RCC in which a combination treatment of these three agents (CCA therapy) was effective.
A 47-year-old man presented with progressive gross hematuria, cough, bilateral lower extremity edema, severe abdominal pain and weight loss. Computed tomography (CT) revealed a 12-cm right renal mass invading the iliopsoas muscle with multiple pulmonary metastases, a large amount of pleural effusion and large hepatic metastases, providing a diagnosis of cT4N0M1 RCC. Serum corrected calcium level was 12 mg/dL (normal range, 8.5–10.5 mg/dL). We recommended IFN-α for him but he refused it for economic reasons. We proposed a combination therapy consisting of cimetidine 800 mg, etodolac, a selective COX-2 inhibitor, 10 mg and candesartan cilexetil, AT1R antagonist, 12 mg orally as an alternative treatment and then he consented to it. After he started CCA therapy, all the symptoms gradually disappeared and the serum corrected calcium level normalized. Eight months later, the metastatic lesions reduced markedly in size, achieving a partial remission (> 50% reduction in tumor size) (Fig. 1). After a year, metastatic lesions enlarged again and he died another year later.
A 62-year-old man presented with a metastatic left radial tumor from clear cell RCC. The patient, whose renal tumor was staged as T1bN0M1, underwent a left radical nephrectomy and resection of radial tumor followed by IFN-α subcutaneously for a year. The patient developed multiple pulmonary metastases eighteen months after the surgery. The metastatic lesion grew despite resumption of IFN-α for four months, and then the treatment was changed to intravenous administration of IL-2. Since pulmonary metastases enlarged and mediastinal lymph node metastases appeared, IL-2 was stopped. CCA therapy of cimetidine 800 mg, meloxicam, a selective COX-2 inhibitor, 10 mg and candesartan cilexetil 4 mg orally, was started. All of the metastatic lesions gradually reduced in size. A year after the initiation of CCA therapy, a nearly complete remission was achieved (Fig. 2). He has remained well without progression for 16 months.
A 64-year-old man presented with a 10-cm left renal tumor with multiple pulmonary metastases. The patient underwent a left radical nephrectomy followed by IFN-α subcutaneously. Pathological examination demonstrated clear cell RCC staged as pT3aN0M1. Six months later, he required the discontinuation of IFN-α because of general fatigue, appetite loss and liver dysfunction. Since metastatic sites grew, CCA therapy of cimetidine 400 mg, meloxicam 10 mg and perindopril, ACE inhibitors, 4 mg orally was commenced. Metastatic lesions gradually reduced in size over two years, thus achieving a partial remission (Fig. 3). Brain metastases appeared 31 months later, however, and he died 41 months after the commencement of CCA therapy.
None of the three patients experienced any appreciable side effects associated with CCA therapy.
Here we report three cases in which a favorable response to a combination treatment of cimetidine, cyclooxygenase-2 inhibitor and renin-angiotensin system inhibitor in metastatic renal cell carcinoma was achieved (Table 1). The duration of the effects was relatively long, at least one year to progression.
Table 1. Summary of clinical presentations and results of combination treatment of cimetidine, cyclooxygenase-2 inhibitor and renin-angiotensin system inhibitor (CCA therapy)
TNM stage at start of CCA
Sites of Metastases
Prior cytokine therapies
Response to CCA
Time to Progression (Months)
Survival from initiation of CCA (Months)
AWD, alive with the disease ; CCA, combination treatment of cimetidine, cyclooxygenase-2 inhibitor and renin-angiotensin system inhibitor; DOD, dead of the disease; HEP, hepatic; IFN-α, interferon-alpha; IL-2, interleukin-2; LYM, lymph node; OSS, osseous; PR, partial remission; PUL, pulmonary.
OSS, PUL, LYM
COX-2 is expressed in the majority of RCC and correlates with stage, grade, and microvessel density and may promote RCC angiogenesis and tumor growth.3 Inhibition of COX-2 has been shown in both preclinical and clinical studies to inhibit angiogenesis and carcinogenesis in solid tumors including metastatic RCC.4
Cimetidine demonstrated anti-tumor activity in vitro because it inhibits the activity of suppressor T cells bearing a histamine type 2 receptor.5 The Hoosier Oncology Group evaluated high-dose cimetidine in 42 patients with metastatic RCC. There were two complete remissions in 38 evaluable patients.6 Nagano et al. reported two cases of metastatic renal carcinoma that were successfully treated with an ordinary dose of cimetidine against distant metastases, where one patient was refractory to IFN-α, and the other one had discontinued IFN-α because of side effects.7
Angiotensin-II plays a fundamental role not only as a vasoconstrictor but also as a mitogenic factor through the AT1R in cardiovascular cells. Interestingly, there is increasing evidence that RAS is implicated in the development of various cancers.8 There have been several reports that angiotensin II can induce neovascularization in experimental systems via the AT1R.9 Uemura et al. reported that the AT1R antagonist has the potential to inhibit the growth of prostate cancer cells and tumors through the AT1 receptor.8 The AT1R antagonist prevented lung metastatic nodules of RCC in mice along with the inhibition of neovascularization and vascular endothelial growth factor expression.10
Although the anti-tumor effects of these agents to several cancer cells including RCC cell lines have been demonstrated in in vitro and in vivo animal studies, there have been few cases reported in which actual antitumorigenic effects were shown in the clinical setting.4,6,7
It is highly unlikely that these tumor shrinkages in our cases were spontaneous regression of RCC. The reported incidence of spontaneous tumor regressions in RCC is extremely low (less than 1%), and most spontaneous regressions have been observed following the treatment of the primary tumors such as surgical removal, radiotherapy, or embolization.11
To date, it has been unclear which agent of the three contributes most. Concomitant use of more than one compound may allow interruption of an important cancer pathway at more than one point or the synchronous inhibition of a separate but cross-communicating system. We believe this approach holds more promise than the sequential use of monotherapy. The efficacy of CCA therapy for metastatic RCC and other cancers should be verified by future trials. We have conducted a prospective trial of combination therapy with IFN-α plus cimetidine, COX-2 inhibitor and AT1R blocker (ICCA therapy) in patients with advanced RCC as a front line approach. We believe that the present cases are encouraging and clinically important because they support the addition of CCA therapy to IFN-α for the treatment of advanced RCC. In conclusion, CCA therapy could be considered as a valid treatment option for patients with metastatic RCC who, for various reasons, cannot receive cytokine therapies or molecularly targeted agents.