Original Study| Volume 15, ISSUE 6, e943-e954, December 2017

Evaluation of the Clinical Utility of Renin-Angiotensin System Inhibitors in Patients Undergoing Radical Surgery for Urothelial Carcinoma of the Upper Urinary Tract



      Renin-angiotensin system (RAS) inhibitors are effective for treating patients with cancer. The present study evaluated the impact of RAS inhibitors, including angiotensin-2 converting enzyme inhibitors and angiotensin 2 receptor blockers, after patients underwent radical surgery for upper urinary tract urothelial carcinoma (UTUC).


      This retrospective study included 312 patients with nonmetastatic UTUC who underwent radical surgery. The oncological outcomes of patients treated or not treated with RAS inhibitors following surgery were evaluated. Recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) were assessed using the Kaplan-Meier method and Cox regression analysis.


      The median follow-up duration after radical surgery was 44.7 months. The 5-year RFS, CSS, and OS rates of patients who did or did not receive RAS inhibitors were 82.3% versus 68.9% (P = .018), 88.9% versus 71.8% (P = .0044), and 68.7% versus 61.8% (P = .047), respectively. Multivariable analyses revealed that the use of RAS inhibitors was an independent prognostic factor for RFS, CSS, and OS (hazard ratio [HR] 0.48, P = .013; HR 0.31, P = .002; and HR 0.52, P = .01, respectively). Moreover, patients treated with RAS inhibitors versus untreated patients had better 5-year RFS compared with those in the pT2 and < pN1 subgroups (pT2: 100.0% vs. 62.2%, P = .014 and < pN1: 87.2% vs. 74.7%, P = .034).


      RAS inhibitors significantly improved RFS, CSS, and OS of patients with UTUC who underwent radical surgery. These agents may be particularly beneficial for patients with stage pT2 or < pN1 disease.


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        • Margulis V.
        • Shariat S.F.
        • Matin S.F.
        • et al.
        Outcomes of radical nephroureterectomy: a series from the Upper Tract Urothelial Carcinoma Collaboration.
        Cancer. 2009; 115: 1224-1233
        • Abouassaly R.
        • Alibhai S.M.
        • Shah N.
        • Timilshina N.
        • Fleshner N.
        • Finelli A.
        Troubling outcomes from population-level analysis of surgery for upper tract urothelial carcinoma.
        Urology. 2010; 76: 895-901
        • Lughezzani G.
        • Burger M.
        • Margulis V.
        • et al.
        Prognostic factors in upper urinary tract urothelial carcinomas: a comprehensive review of the current literature.
        Eur Urol. 2012; 62: 100-114
        • Rouprêt M.
        • Babjuk M.
        • Compérat E.
        • et al.
        European Association of Urology guidelines on upper urinary tract urothelial cell carcinoma: 2015 update.
        Eur Urol. 2015; 68: 868-879
        • Mazzola C.R.
        • Chin J.
        Targeting the VEGF pathway in metastatic bladder cancer.
        Expert Opin Investig Drugs. 2015; 24: 913-927
        • Kosugi M.
        • Miyajima A.
        • Kikuchi E.
        • Horiguchi Y.
        • Murai M.
        Angiotensin II type 1 receptor antagonist candesartan as an angiogenic inhibitor in a xenograft model of bladder cancer.
        Clin Cancer Res. 2006; 12: 2888-2893
        • Kosugi M.
        • Miyajima A.
        • Kikuchi E.
        • Kosaka T.
        • Horiguchi Y.
        • Murai M.
        Effect of angiotensin II type 1 receptor antagonist on tumor growth and angiogenesis in a xenograft model of human bladder cancer.
        Hum Cell. 2007; 20: 1-9
        • Tanaka N.
        • Miyajima A.
        • Kosaka T.
        • et al.
        Acquired platinum resistance enhances tumour angiogenesis through angiotensin II type 1 receptor in bladder cancer.
        Br J Cancer. 2011; 105: 1331-1337
        • Shirotake S.
        • Miyajima A.
        • Kosaka T.
        • et al.
        Angiotensin II type 1 receptor expression and microvessel density in human bladder cancer.
        Urology. 2011; 77: 1009.e19-1009.e25
        • Tanaka N.
        • Miyajima A.
        • Kikuchi E.
        • et al.
        Prognostic impact of renin-angiotensin system blockade in localised upper-tract urothelial carcinoma.
        Br J Cancer. 2012; 106: 290-296
        • Yoshida T.
        • Kinoshita H.
        • Shimada S.
        • Sugi M.
        • Matsuda T.
        Preoperative pyuria is a poor prognostic factor in patients with urothelial carcinoma of the upper urinary tract after surgery [e-pub ahead of print].
        Clin Genitourin Cancer. 2016;
        • Leask A.
        Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation.
        Circ Res. 2010; 106: 1675-1680
        • Cavalera M.
        • Wang J.
        • Frangogiannis N.G.
        Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities.
        Transl Res. 2014; 164: 323-335
        • McGowan T.A.
        • Zhu Y.
        • Sharma K.
        Transforming growth factor-beta: a clinical target for the treatment of diabetic nephropathy.
        Curr Diab Rep. 2004; 4: 447-454
        • Neo J.H.
        • Malcontenti-Wilson C.
        • Muralidharan V.
        • Christophi C.
        Effect of ACE inhibitors and angiotensin II receptor antagonists in a mouse model of colorectal cancer liver metastases.
        J Gastroenterol Hepatol. 2007; 22: 577-584
        • Huang H.
        • Zhou J.
        • Cui Z.
        • Wang B.
        • Hu Y.
        Angiotensin II type 1 receptor-associated protein plays a role in regulating the local renin-angiotensin system in HSC-T6 cells.
        Mol Med Rep. 2015; 12: 3763-3768
        • Miyajima A.
        • Kikuchi E.
        • Kosaka T.
        • Oya M.
        Angiotensin II type 1 receptor antagonist as an angiogenic inhibitor in urogenital cancer.
        Rev Recent Clin Trials. 2009; 4: 75-78
        • Zhao Y.
        • Chen X.
        • Cai L.
        • Yang Y.
        • Sui G.
        • Fu S.
        Angiotensin II/angiotensin II type I receptor (AT1R) signaling promotes MCF-7 breast cancer cells survival via PI3-kinase/Akt pathway.
        J Cell Physiol. 2010; 225: 168-173
        • Miyajima A.
        • Kosaka T.
        • Kikuchi E.
        • Oya M.
        Renin-angiotensin system blockade: its contribution and controversy.
        Int J Urol. 2015; 22: 721-730
        • Lever A.F.
        • Hole D.J.
        • Gillis C.R.
        • et al.
        Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer?.
        Lancet. 1998; 352: 179-184
        • Song T.
        • Choi C.H.
        • Kim M.K.
        • Kim M.L.
        • Yun B.S.
        • Seong S.J.
        The effect of angiotensin system inhibitors (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers) on cancer recurrence and survival: a meta-analysis.
        Eur J Cancer Prev. 2017; 26: 78-85
        • Yuge K.
        • Miyajima A.
        • Tanaka N.
        • et al.
        Prognostic value of renin-angiotensin system blockade in non-muscle-invasive bladder cancer.
        Ann Surg Oncol. 2012; 19: 3987-3993
        • Blute M.L.
        • Rushmer T.J.
        • Shi F.
        • et al.
        Renin-angiotensin inhibitors decrease recurrence after transurethral resection of bladder tumor in patients with nonmuscle invasive bladder cancer.
        J Urol. 2015; 194: 1214-1219
        • Yoshida T.
        • Kinoshita H.
        • Fukui K.
        • et al.
        Prognostic impact of renin-angiotensin inhibitors in patients with bladder cancer undergoing radical cystectomy.
        Ann Surg Oncol. 2017; 24: 823-831
        • Seisen T.
        • Krasnow R.E.
        • Bellmunt J.
        • et al.
        Effectiveness of adjuvant chemotherapy after radical nephroureterectomy for locally advanced and/or positive regional lymph node upper tract urothelial carcinoma.
        J Clin Oncol. 2017; 35: 852-860