[1]
Yeung KT, Cohen EE. Lenvatinib in advanced, radioactive iodine-refractory, differentiated thyroid carcinoma. Clin Cancer Res 2015; 21: 5420-6.
[2]
Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 2011; 364: 501-13.
[3]
Masaki C, Sugino K, Saito N, et al. Lenvatinib induces early tumour shrinkage in patients with advanced thyroid carcinoma. Endocr J 2017; 64: 819-26.
[4]
Blumenthal GM, Cortazar P, Zhang JJ, et al. FDA approval summary: Sunitinib for the treatment of progressive well-differentiated locally advanced or metastatic pancreatic neuroendocrine tumors. Oncologist 2012; 17: 1108-13.
[5]
Goodman VL, Rock EP, Dagher R, et al. Approval summary: Sunitinib for the treatment of imatinib refractory or intolerant gastrointestinal stromal tumors and advanced renal cell carcinoma. Clin Cancer Res 2007; 13: 1367-73.
[6]
Haas NB, Manola J, Uzzo RG, et al. Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): A double-blind, placebo-controlled, randomised, phase 3 trial. Lancet 2016; 387: 2008-16.
[7]
Gore ME, Szczylik C, Porta C, et al. Final results from the large sunitinib global expanded-access trial in metastatic renal cell carcinoma. Br J Cancer 2015; 113: 12-9.
[8]
Rini BI, Cohen DP, Lu DR, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2011; 103: 763-73.
[9]
Lamarca A, Abdel-Rahman O, Salu I, McNamara MG, Valle JW, Hubner RA. Identification of clinical biomarkers for patients with advanced hepatocellular carcinoma receiving sorafenib. Clin Transl Oncol 2017; 19: 364-72.
[10]
Di Costanzo GG, Casadei Gardini A, Marisi G, et al. Validation of a simple scoring system to predict sorafenib effectiveness in patients with hepatocellular carcinoma. Target Oncol 2017; 12: 795-803.
[11]
Ancker OV, Wehland M, Bauer J, Infanger M, Grimm D. The adverse effect of hypertension in the treatment of thyroid cancer with multi-kinase inhibitors. Int J Mol Sci 2017; 18: 625.
[12]
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000; 100: 57-70.
[13]
Leung DW, Cachianes G, Kuang WJ, Goeddel DV, Ferrara N. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 1989; 246: 1306-9.
[14]
Brown LF, Berse B, Jackman RW, et al. Expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in adenocarcinomas of the gastrointestinal tract. Cancer Res 1993; 53: 4727-35.
[15]
Brown LF, Berse B, Jackman RW, et al. Increased expression of vascular permeability factor (vascular endothelial growth factor) and its receptors in kidney and bladder carcinomas. Am J Pathol 1993; 143: 1255-62.
[16]
Greb RR, Maier I, Wallwiener D, Kiesel L. Vascular endothelial growth factor A (VEGF-A) mRNA expression levels decrease after menopause in normal breast tissue but not in breast cancer lesions. Br J Cancer 1999; 81: 225-31.
[17]
Ferrara N. VEGF as a therapeutic target in cancer. Oncology 2005; 69: 11-6.
[18]
Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993; 362: 841-4.
[19]
Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med 2003; 9: 669-76.
[20]
Lemmon MA, Schlessinger J. Cell signalling by receptor tyrosine kinases. Cell 2010; 141: 1117-34.
[21]
Gotink KJ, Verheul HM. Anti-angiogenic tyrosine kinase inhibitors: What is their mechanism of action? Angiogenesis 2010; 13: 1-14.
[22]
Kowanetz M, Ferrara N. Vascular endothelial growth factor signalling pathways: Therapeutic perspective. Clin Cancer Res 2006; 12: 5018-22.
[23]
Frandsen S, Kopp S, Wehland M, Pietsch J, Infanger M, Grimm D. Latest Results for Anti-Angiogenic Drugs in Cancer Treatment. Curr Pharm Des 2016; 22: 5927-42.
[24]
Grimm D, Bauer J, Schoenberger J. Blockade of neoangiogenesis, a new and promising technique to control the growth of malignant tumors and their metastases. Curr Vasc Pharmacol 2009; 7: 347-57.
[25]
Kristensen TB, Knutsson MLT, Wehland M, et al. Anti-vascular endothelial growth factor therapy in breast cancer. Int J Mol Sci 2014; 15: 23024-41.
[26]
Holash J, Davis S, Papadopoulos N, et al. VEGF-Trap: A VEGF blocker with potent antitumor effects. Proc Natl Acad Sci USA 2002; 99: 11393-8.
[27]
Wehland M, Bauer J, Infanger M, Grimm D. Target-based anti-angiogenic therapy in breast cancer. Curr Pharm Des 2012; 18: 4244-57.
[28]
Wang Y, Fei D, Vanderlaan M, Song A. Biological activity of bevacizumab, a humanised anti-VEGF antibody in vitro. Angiogenesis 2004; 7: 335-45.
[29]
Soltau J, Drevs J. Mode of action and clinical impact of VEGF signalling inhibitors. Expert Rev Anticancer Ther 2009; 9: 649-62.
[30]
Laursen R, Wehland M, Kopp S, et al. Effects and role of multikinase inhibitors in thyroid cancer. Curr Pharm Des 2016; 22: 5915-26.
[31]
Hartmann JT, Haap M, Kopp HG, Lipp HP. Tyrosine kinase inhibitors - a review on pharmacology, metabolism and side effects. Curr Drug Metab 2009; 10: 470-81.
[33]
Wilhelm SM, Carter C, Tang L, et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 2004; 64: 7099-109.
[34]
Kane RC, Farrell AT, Saber H, et al. Sorafenib for the treatment of advanced renal cell carcinoma. Clin Cancer Res 2006; 12: 7271-8.
[35]
Randrup Hansen C, Grimm D, Bauer J, Wehland M, Magnusson NE. Effects and side effects of using sorafenib and sunitinib in the treatment of metastatic renal cell carcinoma. Int J Mol Sci 2017; 18: 461.
[36]
Grimm MO, Wolff I, Zastrow S, Frohner M, Wirth M. Advances in renal cell carcinoma treatment. Ther Adv Urol 2010; 2: 11-7.
[37]
Kane RC, Farrell AT, Madabushi R, et al. Sorafenib for the treatment of unrespectable hepatocellular carcinoma. Oncologist 2009; 14: 95-100.
[38]
Brose MS, Nutting CM, Sherman SI, et al. Rationale and design of decision: a double-blind, randomized, placebo-controlled phase III trial evaluating the efficacy and safety of sorafenib in patients with locally advanced or metastatic radioactive iodine (RAI)-refractory, differentiated thyroid cancer. BMC Cancer 2011; 11: 349.
[39]
Brose MS, Nutting CM, Jarzab B, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: A randomised, double-blind, phase 3 trial. Lancet 2014; 384: 319-28.
[40]
Escudier B, Chevreau C, Lasset C, et al. Cytokines in metastatic renal cell carcinoma: Is it useful to switch to interleukin-2 or interferon after failure of a first treatment? Groupe Francais d’Immunotherape. J Clin Oncol 1999; 17: 2039-43.
[41]
Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: 115-24.
[42]
Okamoto K, Ikemori-Kawada M, Jestel A, et al. Distinct binding mode of multikinase inhibitor lenvatinib revealed by biochemical characterization. ACS Med Chem Lett 2015; 6: 89-94.
[43]
Nair A, Lemery SJ, Yang J, et al. FDA approval summary: Lenvatinib for progressive, radio-iodine-refractory differentiated thyroid cancer. Clin Cancer Res 2015; 21: 5205-8.
[44]
Scott LJ. Lenvatinib: first global approval. Drugs 2015; 75: 553-60.
[45]
Schlumberger M, Tahara M, Wirth LJ, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015; 372: 621-30.
[46]
Brinda BJ, Viganego F, Vo T, Dolan D, Fradley MG. Anti-VEGF-induced hypertension: A review of pathophysiology and treatment options. Curr Treat Options Cardiovasc Med 2016; 18: 33.
[47]
Finn RS, Cheng A-L, Ikeda K, et al. A multicenter, open-label, phase 3 trial to compare the efficacy and safety of lenvatinib (E7080) versus sorafenib in first-line treatment of subjects with unresectable hepatocellular carcinoma. J Clin Oncol 2014; 32: 4153.
[48]
Cheng A-L, Finn RS, Qin S, et al. Phase III trial of lenvatinib (LEN) vs. sorafenib (SOR) in first-line treatment of patients (pts) with unresectable hepatocellular carcinoma (uHCC). J Clin Oncol 2017; 35: 4001.
[49]
Raoul JL, Gilabert M, Adhoute X, Edeline J. An in-depth review of chemical angiogenesis inhibitors for treating hepatocellular carcinoma. Expert Opin Pharmacother 2017; 18: 1467-76.
[50]
Srinivas S, Stein D, Teltsch DY, Tao S, Cisar L, Ramaswamy K. Real-world chart review study of adverse events management in patients taking tyrosine kinase inhibitors to treat metastatic renal cell carcinoma. J Oncol Pharm Pract 2018; 24: 574-83.
[51]
Zhu C, Ma X, Hu Y, et al. Safety and efficacy profile of lenvatinib in cancer therapy: A systematic review and meta-analysis. Oncotarget 2016; 7: 44545-57.
[52]
Noize P, Grelaud A, Bay JO, et al. Real-life patterns of use, safety and effectiveness of sunitinib in first-line therapy of metastatic renal cell carcinoma: The SANTORIN cohort study. Pharmacoepidemiol Drug Saf 2017; 26: 1561-9.
[53]
Schmid TA, Gore ME. Sunitinib in the treatment of metastatic renal cell carcinoma. Ther Adv Urol 2016; 8: 348-71.
[54]
Sica DA. Angiogenesis inhibitors and hypertension: An emerging issue. J Clin Oncol 2006; 24: 1329-31.
[56]
Bendtsen MAF, Grimm D, Bauer J, et al. Hypertension caused by lenvatinib and everolimus in the treatment of metastatic renal cell carcinoma. Int J Mol Sci 2017; 18: 1736.
[57]
de Jesus-Gonzalez N, Robinson E, Moslehi J, Humphreys BD. Management of anti-angiogenic therapy-induced hypertension. Hypertension 2012; 60: 607-15.
[58]
Wasserstrum Y, Kornowski R, Raanani P, Leader A, Pasvolsky O, Iakobishvili Z. Hypertension in cancer patients treated with anti-angiogenic based regimens. Cardiooncology 2015; 1: 6.
[59]
Bair SM, Choueiri TK, Moslehi J. Cardiovascular complications associated with novel angiogenesis inhibitors: Emerging evidence and evolving perspectives. Trends Cardiovasc Med 2013; 23: 104-13.
[60]
Semeniuk-Wojtas A, Lubas A, Stec R, Szczylik C, Niemczyk S. Influence of tyrosine kinase inhibitors on hypertension and nephrotoxicity in metastatic renal cell cancer patients. Int J Mol Sci 2016; 17: 2073.
[61]
Bohm F, Pernow J. The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovasc Res 2007; 76: 8-18.
[62]
Kappers MHW. Hypertension induced by the tyrosine kinase inhibitor sunitinib is associated with increased circulating endothelin-1 levels. Hypertension 2010; 56: 675-81.
[63]
Kappers MHW. Sunitinib-induced systemic vasoconstriction in swine is endothelin mediated and does not involve nitric oxide or oxidative stress. Hypertension 2012; 59: 151-7.
[64]
Mayer EL, Dallabrida SM, Rupnick MA, et al. Contrary effects of the receptor tyrosine kinase inhibitor vandetanib on constitutive and flow-stimulated nitric oxide elaboration in humans. Hypertension 2011; 58: 85-92.
[65]
van der Veldt AA, de Boer MP, Boven E, et al. Reduction in skin microvascular density and changes in vessel morphology in patients treated with sunitinib. Anticancer Drugs 2010; 21: 439-46.
[66]
Thijs AM, van Herpen CM, Verweij V, et al. Impaired endothelium-dependent vasodilation does not initiate the development of sunitinib-associated hypertension. J Hypertens 2015; 33: 2075-82.
[67]
Mourad JJ, des Guetz G, Debbabi H, Levy BI. Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol 2008; 19: 927-34.
[68]
Robinson ES, Khankin EV, Karumanchi SA, Humphreys BD. Hypertension induced by VEGF signalling pathway inhibition: Mechanisms and potential use as a biomarker. Semin Nephrol 2010; 30: 591-601.
[69]
Gonzalez-Pacheco FR, Deudero JJ, Castellanos MC, et al. Mechanisms of endothelial response to oxidative aggression: Protective role of autologous VEGF and induction of VEGFR2 by H2O2. Am J Physiol Heart Circ Physiol 2006; 291: 1395-401.
[70]
Veronese ML, Mosenkis A, Flaherty KT, et al. Mechanisms of hypertension associated with BAY 43-9006. J Clin Oncol 2006; 24: 1363-9.
[71]
Chrisoulidou A, Mandanas S, Margaritidou E, et al. Treatment compliance and severe adverse events limit the use of tyrosine kinase inhibitors in refractory thyroid cancer. OncoTargets Ther 2015; 8: 2435-42.
[72]
Larochelle P, Kollmannsberger C, Feldman RD, et al. Hypertension management in patients with renal cell cancer treated with anti-angiogenic agents. Curr Oncol 2012; 19: 202-8.
[73]
Leon-Mateos L, Mosquera J, Anton Aparicio L. Treatment of sunitinib-induced hypertension in solid tumour by nitric oxide donors. Redox Biol 2015; 6: 421-5.
[74]
Bamias A, Lainakis G, Manios E, et al. Diagnosis and management of hypertension in advanced renal cell carcinoma: Prospective evaluation of an algorithm in patients treated with sunitinib. J Chemother 2009; 21: 347-50.
[75]
Maitland ML, Bakris GL, Black HR, et al. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signalling pathway inhibitors. J Natl Cancer Inst 2010; 102: 596-604.
[76]
James PA, Oparil S, Carter BL, et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311: 507-20.
[77]
Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2013; 31: 1281-357.
[78]
Zamorano JL, Lancellotti P, Rodriguez Munoz D, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 2016; 37: 2768-801.
[79]
Resteghini C, Cavalieri S, Galbiati D, et al. Management of tyrosine kinase inhibitors (TKI) side effects in differentiated and medullary thyroid cancer patients. Best Pract Res Clin Endocrinol Metab 2017; 31: 349-61.
[80]
McKay RR, Rodriguez GE, Lin X, et al. Angiotensin system inhibitors and survival outcomes in patients with metastatic renal cell carcinoma. Clin Cancer Res 2015; 21: 2471-9.
[81]
Penttila P, Rautiola J, Poussa T, Peltola K, Bono P. Angiotensin Inhibitors as Treatment of Sunitinib/Pazopanib-induced Hypertension in Metastatic Renal Cell Carcinoma. Clin Genitourin Cancer 2017; 15: 384-90.
[82]
Izzedine H, Ederhy S, Goldwasser F, et al. Management of hypertension in angiogenesis inhibitor-treated patients. Ann Oncol 2009; 20: 807-15.
[83]
Langenberg MH, van Herpen CM, De Bono J, et al. Effective strategies for management of hypertension after vascular endothelial growth factor signalling inhibition therapy: Results from a phase II randomized, factorial, double-blind study of Cediranib in patients with advanced solid tumors. J Clin Oncol 2009; 27: 6152-9.
[84]
Cho DC. Prognostic biomarkers for patients with advanced renal cell carcinoma treated with VEGF-targeted tyrosine kinase inhibitors. OncoTargets Ther 2013; 6: 679-84.
[85]
Wehland M, Bauer J, Magnusson NE, Infanger M, Grimm D. Biomarkers for anti-angiogenic therapy in cancer. Int J Mol Sci 2013; 14: 9338-64.
[86]
Shah DR. Tyrosine kinase inhibitors: Their on-target toxicities as potential indicators of efficacy. Drug Saf 2013; 36: 413-26.
[87]
Boursiquot BC, Zabor EC, Glezerman IG, Jaimes EA. Hypertension and VEGF (vascular endothelial growth factor) receptor tyrosine kinase inhibition: Effects on renal function. Hypertension 2017; 70: 552-8.
[88]
George S, Reichardt P, Lechner T, Li S, Cohen DP, Demetri GD. Hypertension as a potential biomarker of efficacy in patients with gastrointestinal stromal tumour treated with sunitinib. Ann Oncol 2012; 23: 3180-7.
[89]
Duffaud F, Sleijfer S, Litiere S, et al. Hypertension (HTN) as a potential biomarker of efficacy in pazopanib-treated patients with advanced non-adipocytic soft tissue sarcoma. A retrospective study based on European organisation for research and treatment of cancer (EORTC) 62043 and 62072 trials. Eur J Cancer 2015; 51: 2615-23.
[90]
Goldstein D, Rosenberg JE, Figlin RA, et al. Is change in blood pressure a biomarker of pazopanib and sunitinib efficacy in advanced/metastatic renal cell carcinoma? Eur J Cancer 2016; 53: 96-104.
[91]
Soerensen AV, Geertsen PF, Christensen IJ, et al. A five-factor biomarker profile obtained week 4-12 of treatment for improved prognostication in metastatic renal cell carcinoma: Results from DARENCA study 2. Acta Oncol 2016; 55: 341-8.
[92]
Rautiola J, Donskov F, Peltola K, Joensuu H, Bono P. Sunitinib-induced hypertension, neutropaenia and thrombocytopaenia as predictors of good prognosis in patients with metastatic renal cell carcinoma. BJU Int 2016; 117: 110-7.
[93]
Donskov F, Michaelson MD, Puzanov I, et al. Sunitinib-associated hypertension and neutropenia as efficacy biomarkers in metastatic renal cell carcinoma patients. Br J Cancer 2015; 113: 1571-80.
[94]
Howell J, Pinato DJ, Ramaswami R, et al. On-target sorafenib toxicity predicts improved survival in hepatocellular carcinoma: A multi-centre, prospective study. Aliment Pharmacol Ther 2017; 45: 1146-55.
[95]
Bono P, Elfving H, Utriainen T, et al. Hypertension and clinical benefit of bevacizumab in the treatment of advanced renal cell carcinoma. Ann Oncol 2009; 20: 393-4.
[96]
Dahlberg SE, Sandler AB, Brahmer JR, Schiller JH, Johnson DH. Clinical course of advanced non-small-cell lung cancer patients experiencing hypertension during treatment with bevacizumab in combination with carboplatin and paclitaxel on ECOG 4599. J Clin Oncol 2010; 28: 949-54.
[97]
Scartozzi M, Galizia E, Chiorrini S, et al. Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Ann Oncol 2009; 20: 227-30.
[98]
Friberg G, Kasza K, Vokes EE, Kindler HL. Early hypertension (HTN) as a potential pharmacodynamic (PD) marker for survival in pancreatic cancer (PC) patients (pts) treated with bevacizumab (B) and gemcitabine (G). J Clin Oncol 2005; 23: 3020.
[99]
Tocci G, Presta V, Figliuzzi I, et al. Prevalence and clinical outcomes of white-coat and masked hypertension: Analysis of a large ambulatory blood pressure database. J Clin Hypertens 2018; 20: 297-305.
[100]
Manolis AA, Manolis TA, Mikhailidis DP, Manolis AS. Cardiovascular safety of oncologic agents: A double-edged sword even in the era of targeted therapies - part 1. Expert Opin Drug Saf 2018; 17: 875-92.
[101]
Manolis AA, Manolis TA, Mikhailidis DP, Manolis AS. Cardiovascular safety of oncologic agents: A double-edged sword even in the era of targeted therapies - Part 2. Expert Opin Drug Saf 2018; 17: 893-915.
[102]
Donskov F, Heng DY, Rini BI. On-treatment biomarkers in metastatic renal cell carcinoma: towards individualization of prognosis? Expert Rev Anticancer Ther 2017; 17: 97-9.
[103]
Ko JJ, Xie W, Kroeger N, et al. The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: A population-based study. Lancet Oncol 2015; 16: 293-300.
[104]
Agarwal M, Thareja N, Benjamin M, Akhondi A, Mitchell GD. Tyrosine Kinase Inhibitor-Induced Hypertension. Curr Oncol Rep 2018; 20: 65.
[105]
Small HY, Montezano AC, Rios FJ, Savoia C, Touyz RM. Hypertension due to antiangiogenic cancer therapy with vascular endothelial growth factor inhibitors: Understanding and managing a new syndrome. Can J Cardiol 2014; 30: 534-43.
[106]
Tew WP, Colombo N, Ray-Coquard I, et al. Intravenous aflibercept in patients with platinum-resistant, advanced ovarian cancer: results of a randomized, double-blind, phase 2, parallel-arm study. Cancer 2014; 120: 335-43.
[107]
Ranpura V, Pulipati B, Chu D, Zhu X, Wu S. Increased risk of high-grade hypertension with bevacizumab in cancer patients: A meta-analysis. Am J Hypertens 2010; 23: 460-8.
[108]
Fuso Nerini I, Cesca M, Bizzaro F, Giavazzi R. Combination therapy in cancer: Effects of angiogenesis inhibitors on drug pharmacokinetics and pharmacodynamics. Chin J Cancer 2016; 35: 61.
[109]
Yang B, Wang C, Xie Y, Xu L, Wu X, Wu D. Monitoring tyrosine kinase inhibitor therapeutic responses with a panel of metabolic biomarkers in chronic myeloid leukaemia patients. Cancer Sci 2018; 109: 777-84.
[110]
Voss MH, Chen D, Marker M, et al. Circulating biomarkers and outcome from a randomised phase II trial of sunitinib vs. everolimus for patients with metastatic renal cell carcinoma. Br J Cancer 2016; 114: 642-9.
[111]
Jain RK, Duda DG, Willett CG, et al. Biomarkers of response and resistance to antiangiogenic therapy. Nat Rev Clin Oncol 2009; 6: 327-38.
[112]
Li J, Lin B, Li X, Tang X, He Z, Zhou K. Biomarkers for predicting response to tyrosine kinase inhibitors in drug-sensitive and drug-resistant human bladder cancer cells. Oncol Rep 2015; 33: 951-7.
[113]
Dornbusch J, Walter M, Gottschalk A, et al. Evaluation of polymorphisms in angiogenesis-related genes as predictive and prognostic markers for sunitinib-treated metastatic renal cell carcinoma patients. J Cancer Res Clin Oncol 2016; 142: 1171-82.