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04-08-2016 | Renal cell carcinoma | Article

Medical treatment of renal cancer: new horizons

Authors: Basma Greef, Tim Eisen

Abstract

Renal cell carcinoma (RCC) makes up 2–3% of adult cancers. The introduction of tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin inhibitors in the mid-2000s radically changed the management of RCC. These targeted treatments superseded immunotherapy with interleukin-2 and interferon. The pendulum now appears to be shifting back towards immunotherapy, with the evidence of prolonged overall survival of patients with metastatic RCC on treatment with the anti-programmed cell death 1 ligand monoclonal antibody, nivolumab. Clinical prognostic criteria aid prediction of relapse risk for resected localised disease. Unfortunately, for patients at high risk of relapse, no adjuvant treatment has yet shown benefit, although further trials are yet to report. Clinical prognostic models also have a role in the management of advanced disease; now there is a pressing need for predictive biomarkers to direct therapy. Treatment selection for metastatic disease is currently based on histology, prognostic group and patient preference based on side effect profile. In this article, we review the current medical and surgical management of localised, oligometastatic and advanced RCC, including side effect management and the evidence base for management of poor-risk and non-clear cell disease. We discuss recent results from clinical trials and how these are likely to shape future practice and a renaissance of immunotherapy for renal cell cancer.

Br J Cancer 2016; 115: 505–516. doi:10.1038/bjc.2016.230

Keywords: systemic therapy; metastatic renal cell carcinoma; T-cell checkpoint inhibitors; tyrosine kinase inhibitors

Renal cell carcinoma (RCC) represents 2–3% of all adult cancers (Rini et al, 2009a). It is the seventh most common malignancy in men, and the ninth in women (Rini et al, 2009a) with 10 144 new cases and 4252 deaths in the United Kingdom per year (Cancer Research UK, 2016). Risk factors include hypertension, smoking, obesity and end-stage renal disease. With increasing use of radiological investigations, there has been a steady increase in the rate of incidental diagnosis, which now accounts for half of all new RCC cases. A third of cases present with metastatic disease at diagnosis (Gupta et al, 2008) and a third of those undergoing surgery for early stage disease will relapse, after a median of 1.9 years (Stewart et al, 2014).

Literature

Al-Marrawi MY, Rini BI, Harshman LC, Bjarnason G, Wood L, Vaishampayan U, MacKenzie M, Knox JJ, Agarwal N, Al-Harbi H, Kollmannsberger C, Tan M-H, Rha SY, Donskov FN, North S, Choueiri TK, Heng DY (2013) The association of clinical outcome to first-line VEGF-targeted therapy with clinical outcome to second-line VEGF-targeted therapy in metastatic renal cell carcinoma patients. Target Oncol 8: 203–209. | Article | PubMed |

Albiges L, Fay AP, Xie W, Krajewski K, McDermott DF, Heng DYC, Dariane C, DeVelasco G, Lester R, Escudier B, Choueiri TK (2015) Efficacy of targeted therapies after PD-1/PD-L1 blockade in metastatic renal cell carcinoma. Eur J Cancer 51: 2580–2586. | Article | PubMed |

Amin A, Plimack ER, Infante JR, Ernstoff MS, Rini BI, McDermott DF, Knox JJ, Pal SK, Henner Voss M, Sharma P, Kollmannsberger CK, Heng DYC, Spratlin JL, Shen Y, Kurland JF, Gagnier P, Hammers HJ (2014) Nivolumab (anti-PD-1; BMS-936558, ONO-4538) in combination with sunitinib or pazopanib in patients (pts) with metastatic renal cell carcinoma (mRCC). J Clin Oncol 32(5s Suppl): (abstract 5010).

Armstrong AJ, Halabi S, Eisen T, Broderick S, Stadler WM, Jones RJ, Garcia JA, Vaishampayan UN, Picus J, Hawkins RE, Hainsworth JD, Kollmannsberger CK, Logan TF, Puzanov I, Pickering LM, Ryan CW, Protheroe A, Lusk CM, Oberg S, George DJ (2016) Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol 17: 378–388. | Article | PubMed |

Asimakopoulos AD, Miano R, Annino F, Micali S, Spera E, Iorio B, Vespasiani G, Gaston R (2014) Robotic radical nephrectomy for renal cell carcinoma: a systematic review. BMC Urol 14: 75. | Article | PubMed |

Batelli C, Cho DC (2011) mTOR inhibitors in renal cell carcinoma. Therapy 8: 359–367. | Article | PubMed | CAS |

Bjarnason GA, Khalil B, Hudson JM, Williams R, Milot LM, Atri M, Kiss A, Burns PN (2014) Outcomes in patients with metastatic renal cell cancer treated with individualized sunitinib therapy: correlation with dynamic microbubble ultrasound data and review of the literature. Urol Oncol 32: 480–487. | Article | PubMed | CAS |

Cancer Research UK (2016) Kidney Cancer Stastistics. Available at http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics-by-cancer-type/kidney-cancer (accessed on 05/04/2016).

Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee J-L, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DYC, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ (2015) Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373: 1814–1823. | Article | PubMed | CAS |

Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, Davies H, Edkins S, Hardy C, Latimer C, Teague J, Andrews J, Barthorpe S, Beare D, Buck G, Campbell PJ, Forbes S, Jia M, Jones D, Knott H, Kok CY, Lau KW, Leroy C, Lin M-L, McBride DJ, Maddison M, Maguire S, McLay K, Menzies A, Mironenko T, Mulderrig L, Mudie L, O’Meara S, Pleasance E, Rajasingham A, Shepherd R, Smith R, Stebbings L, Stephens P, Tang G, Tarpey PS, Turrell K, Dykema KJ, Khoo SK, Petillo D, Wondergem B, Anema J, Kahnoski RJ, Teh BT, Stratton MR, Futreal PA (2010) Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463: 360 363. | Article | PubMed | ISI | CAS |

Dickerson EC, Davenport MS, Liu PS (2015) Spontaneous regression of primary renal cell carcinoma following image-guided percutaneous biopsy. Clin Imaging 39: 520–524. | Article | PubMed |

Dudek A, Sica R, Sidani A, Gopalji Jha G, Xie H, Shivaram Alva A, Stein M, Singer E (2016) Phase Ib study of pembrolizumab in combination with bevacizumab for the treatment of metastatic renal cell carcinoma: Big Ten Cancer Research Consortium BTCRC-GU14-003. J Clin Oncol 34(2s Suppl): (abstract 559).

Duns G, van den Berg E, van Duivenbode I, Osinga J, Hollema H, Hofstra RM, Kok K (2010) Histone Methyltransferase Gene SETD2 is a Novel Tumor Suppressor Gene in Clear Cell Renal Cell Carcinoma. Cancer Res 70: 4287–4291. | Article | PubMed | ISI | CAS |

Dutcher JP, de Souza P, McDermott D, Figlin RA, Berkenblit A, Thiele A, Krygowski M, Strahs A, Feingold J, Hudes G (2009) Effect of temsirolimus versus interferon-alpha on outcome of patients with advanced renal cell carcinoma of different tumor histologies. Med Oncol 26: 202–209. | Article | PubMed | CAS |

Escudier B, Michaelson MD, Motzer RJ, Hutson TE, Clark JI, Lim HY, Porfiri E, Zalewski P, Kannourakis G, Staehler M, Tarazi J, Rosbrook B, Cisar L, Hariharan S, Kim S, Rini BI (2014a) Axitinib versus sorafenib in advanced renal cell carcinoma: subanalyses by prior therapy from a randomised phase III trial. Br J Cancer 110: 2821–2828. | Article | PubMed |

Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, Chevreau C, Filipek M, Melichar B, Bajetta E, Gorbunova V, Bay JO, Bodrogi I, Jagiello-Gruszfeld A, Moore N (2007) Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370: 2103–2111. | Article | PubMed | ISI |

Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Négrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D (2014b) Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol 32: 1412–1418. | Article | PubMed | ISI | CAS |

Escudier B, Porta C, Schmidinger M, Algaba F, Patard JJ, Khoo V, Eisen T, Horwich A (2014c) Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 25(S3): iii49–iii56. | Article | PubMed |

Finke JH, Rini B, Ireland J, Rayman P, Richmond A, Golshayan A, Wood L, Elson P, Garcia J, Dreicer R, Bukowski R (2008) Sunitinib reverses type-1 immune suppression and decreases T-regulatory cells in renal cell carcinoma patients. Clin Cancer Res 14: 6674–6682. | Article | PubMed | CAS |

Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED (2004) Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol 171: 1071–1076. | Article | PubMed | ISI |

Fyfe GA, Risher RI, Rosenberg SA, Sznol M, Parkinson DR (1996) Long-term response data for 255 patients with metastatic renal cell carcinoma treated with high-dose recombinant interleukin-2 therapy. J Clin Oncol 14: 2410–2411. | PubMed | ISI | CAS |

Gerety EL, Lawrence EM, Wason J, Yan H, Hilborne S, Buscombe J, Cheow HK, Shaw AS, Bird N, Fife K, Heard S, Lomas DJ, Matakidou A, Soloviev D, Eisen T, Gallagher FA (2015) Prospective study evaluating the relative sensitivity of 18F-NaF PET/CT for detecting skeletal metastases from renal cell carcinoma in comparison to multidetector CT and 99m Tc-MDP bone scintigraphy, using an adaptive trial design. Ann Oncol 26: 2113–2118. | Article | PubMed |

Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore M, Szallasi Z, Downward J, Futreal PA, Swanton C (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 366: 883–892. | Article | PubMed | ISI | CAS |

Gibney GT, Aziz S a., Camp RL, Conrad P, Schwartz BE, Chen CR, Kelly WK, Kluger HM (2013) C-Met is a prognostic marker and potential therapeutic target in clear cell renal cell carcinoma. Ann Oncol 24: 343–349. | Article | PubMed |

Gossage L, Eisen T, Maher ER (2015) VHL, the story of a tumour suppressor gene. Nat Rev Cancer 15: 55–64. | Article | PubMed | CAS |

Gossage L, Murtaza M, Slatter AF, Lichtenstein CP, Warren A, Haynes B, Marass F, Roberts I, Shanahan SJ, Claas A, Dunham A, May AP, Rosenfeld N, Forshew T, Eisen T (2014) Clinical and pathological impact of VHL, PBRM1, BAP1 SETD2, KDM6A and JARIDIc cell renal cell carcinoma. Genes Chromosomes Cancer53: 38–51. | Article | PubMed | ISI | CAS |

Gupta K, Miller JD, Li JZ, Russell MW, Charbonneau C (2008) Epidemiologic and socioeconomic burden of metastatic renal cell carcinoma (mRCC): a literature review. Cancer Treat Rev 34: 193–205. | Article | PubMed | ISI |

Haas NB, Manola J, Uzzo RG, Atkins MB, Wilding G, Pins M, Jewett MAS, Kane CJ, Cella D, Wagner LI, Coomes B, Wood CG, Dutcher JP, Flaherty K, DiPaola RS (2015) Initial results from ASSURE (E2805): adjuvant sorafenib or sunitinib for unfavourable renal carcinoma, an ECOG-ACRIN-led, NCTN phase III trial. J Clin Oncol 33(Suppl 7): (abstract 403).

Haas NB, Nathanson KL (2014) Hereditary kidney cancer syndromes. Adv Chronic Kidney Dis 21: 81–90. | Article | PubMed |

Hakimi AA, Chen Y-B, Wren J, Gonen M, Abdel-Wahab O, Heguy A, Liu H, Takeda S, Tickoo SK, Reuter VE, Voss MH, Motzer RJ, Coleman JA, Cheng EH, Russo P, Hsieh JJ (2013) Clinical and pathologic impact of select chromatin-modulating tumor suppressors in clear cell renal cell carcinoma. Eur Urol 63: 848–854. | Article | PubMed | ISI |

Hammers HJ, Plimack ER, Infante JR, Rini BI, McDermott DF, Ernstoff MS, Henner Voss M, Sharma P, Kumar Pal S, Razak AR, Kollmannsberger CK, Heng DYC, Spratlin JL, Shen Y, Gagnier P, Amin A (2015) Expanded cohort results from CheckMate016: a phase I study of nivolumab in combination with ipilimumab in metastatic renal cell carcinoma (mRCC). J Clin Oncol 33(Suppl): (abstract 4516).

Hemal AK, Kumar A (2009) A prospective comparison of laparoscopic and robotic radical nephrectomy for T1-2N0M0 renal cell carcinoma. World J Urol 27: 89–94. | Article | PubMed |

Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, Eigl BJ, Ruether JD, Cheng T, North S, Venner P, Knox JJ, Chi KN, Kollmannsberger C, McDermott DF, Oh WK, Atkins MB, Bukowski RM, Rini BI, Choueiri TK (2009) Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol 27: 5794–5799. | Article | PubMed | ISI | CAS |

Heng DYC, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, Rha SY, Agarwal N, Kollmannsberger C, Rini BI, Choueiri TK (2013) External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: A population-based study. Lancet Oncol 14: 141–148. | Article | PubMed | ISI |

Hollingsworth JM, Miller DC, Daignault S, Hollenbeck BK (2007) Five-year survival after surgical treatment for kidney cancer: A population-based competing risk analysis. Cancer 109: 1763–1768. | Article | PubMed | ISI |

Hu M, Sun X-J, Zhang Y-L, Kuang Y, Hu C-Q, Wu W-L, Shen S-H, Du T-T, Li H, He F, Xiao H-S, Wang Z-G, Liu T-X, Lu H, Huang Q-H, Chen S-J, Chen Z (2010) Histone H3 lysine 36 methyltransferase Hypb/Setd2 is required for embryonic vascular remodeling. Proc Natl Acad Sci USA 107: 2956–2961. | Article | PubMed |

Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, Staroslawska E, Sosman J, Mcdermott D, Bodrogi I, Kovacevic Z, Lesovoy V, Schmidt-Wolf IGH, Barbarash O, Gokmen E, Toole TO, Lustgarten S, Moore L, Motzer RJ (2007) Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma. N Engl J Med 356: 2271–2281. | Article | PubMed | ISI | CAS |

Izzedine H, Derosa L, Le Teuff G, Albiges L, Escudier B (2015) Hypertension and angiotensin system inhibitors: impact on outcome in sunitinib-treated patients for metastatic renal cell carcinoma. Ann Oncol26: 1128–1133. | Article | PubMed |

Joseph RW, Kapur P, Serie DJ, Parasramka M, Ho TH, Cheville JC, Frenkel E, Parker AS, Brugarolas J (2016) Clear cell renal cell carcinoma subtypes identified by BAP1 and PBRM1 expression. J Urol 195: 180–187. | Article | PubMed |

Kapur P, Peña-Llopis S, Christie A, Zhrebker L, Pavía-Jiménez A, Rathmell WK, Xie XJ, Brugarolas J (2013) Effects on survival of BAP1 and PBRM1 mutations in sporadic clear-cell renal-cell carcinoma: a retrospective analysis with independent validation. Lancet Oncol 14: 159–167. | Article | PubMed | ISI | CAS |

Kavolius JP, Mastorakos DP, Pavlovich C, Russo P, Burt ME, Brady MS (1998) Resection of metastatic renal cell carcinoma. J Clin Oncol 16: 2261–2266. | PubMed | ISI | CAS |

Ko JS, Zea AH, Rini BI, Ireland JL, Elson P, Cohen P, Golshayan A, Rayman PA, Wood L, Garcia J, Dreicer R, Bukowski R, Finke JH (2009) Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients. Clin Cancer Res 15: 2148–2157. | Article | PubMed | ISI | CAS |

Larkin J, Chiarion-Sileni V, Gonzalez R, Grob J, Cowey C, Lao C, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur G, Ascierto P, Long G, Callahan M, Postow M, Grossman K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin L, Horak C, Hodi F, Wolchok J (2015) Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 373: 23–34. | Article | PubMed | CAS |

Leibovich BC, Blute ML, Cheville JC, Lohse CM, Frank I, Kwon ED, Weaver AL, Parker AS, Zincke H (2003) Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 97: 1663–1671. | Article | PubMed | ISI |

Li H, Samawi H, Heng DYC (2015) The use of prognostic factors in metastatic renal cell carcinoma. Urol Oncol 33: 509–516. | Article | PubMed |

MacLennan S, Imamura M, Lapitan MC, Omar MI, Lam TBL, Hilvano-Cabungcal AM, Royle P, Stewart F, MacLennan G, MacLennan SJ, Canfield SE, McClinton S, Griffiths TRL, Ljungberg B, N’Dow J (2012) Systematic review of oncological outcomes following surgical management of localised renal cancer. Eur Urol 61: 972–993. | Article | PubMed | ISI |

McDermott DF, Cheng SC, Signoretti S, Margolin KA, Clark JI, Sosman JA, Dutcher JP, Logan TF, Curti BD, Ernstoff MS, Appleman L, Wong MKK, Khushalani NI, Oleksowicz L, Vaishampayan UN, Mier JW, Panka DJ, Bhatt RS, Bailey AS, Leibovich BC, Kwon ED, Kabbinavar FF, Belldegrun AS, Figlin RA, Pantuck AJ, Regan MM, Atkins MB (2015) The High-dose aldesleukin ‘select’ trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res 21: 561–568. | Article | PubMed | CAS |

McKay RR, Rodriguez GE, Lin X, Kaymakcalan MD, Hamnvik O-PR, Sabbisetti VS, Bhatt RS, Simantov R, Choueiri TK (2015) Angiotensin system inhibitors and survival outcomes in patients with metastatic renal cell carcinoma. Clin Cancer Res 21: 2471–2479. | Article | PubMed |

Michaelson MD, McKay RR, Werner L, Atkins MB, Van Allen EM, Olivier KM, Song J, Signoretti S, McDermott DF, Choueiri TK (2015) Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer 121: 3435–3443. | Article | PubMed |

Motzer BRJ, Bacik J, Murphy B a, Russo P, Mazumdar M (2002) Interferon-Alfa as a Comparative Treatment for Clinical. J Clin Oncol 20: 289–296. | Article | PubMed | ISI | CAS |

Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, Tykodi SS, Sosman JA, Procopio G, Plimack ER, Castellano D, Choueiri TK, Gurney H, Donskov F, Bono P, Wagstaff J, Gauler TC, Ueda T, Tomita Y, Schutz FA, Kollmannsberger C, Larkin J, Ravaud A, Simon JS, Xu L-A, Waxman IM, Sharma P CheckMate 025 Investigators (2015a) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373: 1803–1813. | Article | PubMed | CAS |

Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, Grünwald V, Thompson JA, Figlin RA, Hollaender N, Urbanowitz G, Berg WJ, Kay A, Lebwohl D, Ravaud A (2008) Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet372: 449–456. | Article | PubMed | ISI | CAS |

Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, Nathan P, Staehler M, de Souza P, Merchan JR, Boleti E, Fife K, Jin J, Jones R, Uemura H, De Giorgi U, Harmenberg U, Wang J, Sternberg CN, Deen K, McCann L, Hackshaw MD, Crescenzo R, Pandite LN, Choueiri TK (2013) Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 369: 722–731. | Article | PubMed | ISI | CAS |

Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, Jassem J, Zolnierek J, Maroto JP, Mellado B, Melichar B, Tomasek J, Kremer A, Kim H-J, Wood K, Dutcus C, Larkin J (2015b) Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol 16: 1473–1482. | Article | PubMed | CAS |

Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, Oudard S, Negrier S, Szczylik C, Kim ST, Chen I, Bycott PW, Baum CM, Figlin RA (2007) Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 356: 115–124. | Article | PubMed | ISI |

Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J (1999) Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. J Clin Oncol 17: 2530–2540. | PubMed | ISI | CAS |

Motzer RJ, Porta C, Vogelzang NJ, Sternberg CN, Szczylik C, Zolnierek J, Kollmannsberger C, Rha SY, Bjarnason GA, Melichar B, De Giorgi U, Grünwald V, Davis ID, Lee J, Esteban E, Sklodowska-curie M (2014) Dovitinib versus sorafenib for third-line targeted treatment of patients with metastatic renal cell carcinoma: an open-label, randomised phase 3 trial. Lancet Oncol 15: 286–296. | Article | PubMed |

Motzer RJ, Rini BI, McDermott DF, Redman BG, Kuzel TM, Harrison MR, Vaishampayan UN, Drabkin HA, George S, Logan TF, Margolin KA, Plimack ER, Lambert AM, Waxman IM, Hammers HJ (2015c) Nivolumab for metastatic renal cell carcinoma: results of a randomized phase ii trial. J Clin Oncol 33: 1430–1437. | Article | PubMed | CAS |

Pal SK, Haas NB (2014) Adjuvant therapy for renal cell carcinoma: past, present, and future. Oncologist19: 851–859. | Article | PubMed |

Pena-LLopis S, Christie A, Xie X-J, Brugarolas J (2013) Co-operation and antagonism among cancer genes: the renal cancer paradigm. Cancer Res 73: 4173–4179. | Article | PubMed |

Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, Leng N, Pavía-Jiménez A, Wang S, Yamasaki T, Zhrebker L, Sivanand S, Spence P, Kinch L, Hambuch T, Jain S, Lotan Y, Margulis V, Sagalowsky AI, Summerour PB, Kabbani W, Wong SWW, Grishin N, Laurent M, Xie X-J, Haudenschild CD, Ross MT, Bentley DR, Kapur P, Brugarolas J (2012) BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 44: 751–759. | Article | PubMed | CAS |

Pham A, Ye D-W, Pal S (2015) Overview and management of toxicities associated with systemic therapies for advanced renal cell carcinoma. Urol Oncol 33: 517–527. | Article | PubMed |

Raman R, Vaena D (2015) Immunotherapy in metastatic renal cell carcinoma: a comprehensive review. Biomed Res Int 2015: 367354. | Article | PubMed |

Rini B, Goddard A, Knezevic D, Maddala T, Zhou M, Aydin H, Campbell S, Elson P, Koscielny S, Lopatin M, Svedman C, Martini J-F, Williams JA, Verkarre V, Radulescu C, Neuzillet Y, Hemmerlé I, Timsit MO, Tsiatis AC, Bonham M, Lebret T, Mejean A, Escudier B (2015a) A 16-gene assay to predict recurrence after surgery in localised renal cell carcinoma: development and validation studies. Lancet Oncol 16: 676–685. | Article | PubMed | CAS |

Rini B, Stenzl A, Zdrojowy R, Kogan M, Shkolnik M, Oudard S, Weikert S, Bracarda S, Crabb S, Bedke J, Ludwig J, Maurer D, Mendrzyk R, Mahr A, Fritsch J, Weinschenk T, Singh H, Kirner A, Reindhardt C, Eisen T (2015b) Results from an open-label, randomized, controlled Phase 3 study investigating IMA901 multipeptide cancer vaccine in patients receiving sunitinib as first-line therapy for advanced/metastatic RCC. Eur J Cancer 51(Suppl 3): S718 (abstract 17LBA). | Article |

Rini BI, Campbell SC, Escudier B (2009a) Renal cell carcinoma. Lancet 373: 1119–1132. | Article | PubMed | ISI | CAS |

Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, Figlin R a., Baum MS, Motzer RJ (2011a) Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 103: 763–773. | Article | PubMed | ISI | CAS |

Rini BI, Dorff TB, Elson P, Suarez C, Humbert J, Pyle L, Larkin J, Plimack ER (2014) A prospective observational study of metastatic renal cell carcinoma (mRCC) prior to initiation of systemic therapy. J Clin Oncol 32(5s Suppl): (abstract 4520).

Rini BI, Escudier B, Hariharan S, Roberts WG, Tarazi J, Rosbrook B, Askerova Z, DeAnnuntis LL, Motzer RJ (2015c) Long-term safety with axitinib in previously treated patients with metastatic renal cell carcinoma. Clin Genitourin Cancer 13: 540–547. | Article | PubMed |

Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, Michaelson MD, Gorbunova VA, Gore ME, Rusakov IG, Negrier S, Ou Y-C, Castellano D, Lim HY, Uemura H, Tarazi J, Cella D, Chen C, Rosbrook B, Kim S, Motzer RJ (2011b) Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 378: 1931–1939. | Article | PubMed | ISI | CAS |

Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou S-S, Archer L, Atkins JN, Picus J, Czaykowski P, Dutcher J, Small EJ (2008) Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 26: 5422–5428. | Article | PubMed | ISI | CAS |

Rini BI, Quinn DI, Baum M, Wood LS, Tarazi J, Rosbrook B, Arruda LS, Cisar L, Roberts WG, Kim S, Motzer RJ (2015d) Hypertension among patients with renal cell carcinoma receiving axitinib or sorafenib: analysis from the randomized phase III AXIS trial. Target Oncol 10: 45–53. | Article | PubMed |

Robson CJ, Churchill BM, Anderson W (1969) The results of radical nephrectomy for renal cell carcinoma. J Urol 101: 297–301. | PubMed | ISI | CAS |

Russo P, Jang TL, Pettus JA, Huang WC, Eggener SE, O’Brien MF, Karellas ME, Karanikolas NT, Kagiwada MA (2008) Survival rates after resection for localized kidney cancer: 1989 to 2004. Cancer 113: 84–96. | Article | PubMed | ISI |

Sacré A, Barthélémy P, Korenbaum C, Burgy M, Wolter P, Dumez H, Lerut E, Loyson T, Joniau S, Oyen R, Debruyne PR, Schöffski P, Beuselinck B, Sacré A, Barthélémy P, Korenbaum C, Burgy M, Wolter P, Dumez H, Lerut E, Loyson T, Joniau S, Oyen R, Debruyne PR, Schöffski P, Beuselinck B, Korenbaum C, Burgy M, Wolter P, Dumez H, Sacre A (2016) Prognostic factors in second-line targeted therapy for metastatic clear-cell renal cell carcinoma after progression on an anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor receptor tyrosine kinase inhibitor. Acta Oncol. 55(3): 329–340. | Article | PubMed |

Shablak A, Sikand K, Shanks JH, Thistlethwaite F, Spencer-Shaw A, Hawkins RE (2011) High-dose interleukin-2 can produce a high rate of response and durable remissions in appropriately selected patients with metastatic renal cancer. J Immunother 34: 107–112. | Article | PubMed |

Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarba JJ, Chen M, McCann L, Pandite L, Roychowdhury DF, Hawkins RE (2010) Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol28: 1061–1068. | Article | PubMed | ISI | CAS |

Stewart SB, Thompson RH, Psutka SP, Cheville JC, Lohse CM, Boorjian SA, Leibovich BC (2014) Evaluation of the National Comprehensive Cancer Network and American Urological Association renal cell carcinoma surveillance guidelines. J Clin Oncol 32: 4059–4065. | Article | PubMed | ISI |

Tunuguntla HSGR, Jorda M (2008) Diagnostic and prognostic molecular markers in renal cell carcinoma. J Urol 179: 2096–2102. | Article | PubMed |

Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, Davies H, Jones D, Lin M-L, Teague J, Bignell G, Butler A, Cho J, Dalgliesh GL, Galappaththige D, Greenman C, Hardy C, Jia M, Latimer C, Lau KW, Marshall J, McLaren S, Menzies A, Mudie L, Stebbings L, Largaespada DA, Wessels LFA, Richard S, Kahnoski RJ, Anema J, Tuveson DA, Perez-Mancera PA, Mustonen V, Fischer A, Adams DJ, Rust A, Chan-on W, Subimerb C, Dykema K, Furge K, Campbell PJ, Teh BT, Stratton MR, Futreal PA (2011) Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature469: 539–542. | Article | PubMed | ISI | CAS |

Wolter P, Dumez H, Schoffski P (2007) Suntinib and Hypothyroidism. N Engl J Med 356: 1580. | Article | PubMed | CAS |

Young AC, Craven RA, Cohen D, Taylor C, Booth C, Harnden P, Cairns DA, Astuti D, Gregory W, Maher ER, Knowles MA, Joyce A, Selby PJ, Banks RE (2009) Analysis of VHL gene alterations and their relationship to clinical parameters in sporadic conventional renal cell carcinoma. Clin Cancer Res 15: 7582–7592. | Article | PubMed | ISI | CAS |

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