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Metastatic Renal Cell Cancer—Systemic Therapy

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Abstract

Management of metastatic renal cell carcinoma (mRCC) has evolved considerably in the past 10 years due to better understanding of tumor biology. This development has changed mRCC to a chronic progressive disease with several lines of treatment options. The introduction of several new targeted therapies including immunotherapy has improved median overall survival of approximately 1 year to >2 years in mRCC.

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References

  1. Escudier B, Eisen T, Porta C, Patard JJ, Khoo V, Algaba F et al (2012) Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 23(suppl 7):vii65–vii71

    Article  PubMed  Google Scholar 

  2. Karumanchi SA, Merchan J, Sukhatme VP (2002) Renal cancer: molecular mechanisms and newer therapeutic options. Curr Opin Nephrol Hypertens 11(1):37–42

    Article  PubMed  Google Scholar 

  3. Ljungberg B, Campbell SC, Choi HY, Cho HY, Jacqmin D, Lee JE et al (2011) The epidemiology of renal cell carcinoma. Eur Urol 60(4):615–621. https://doi.org/10.1016/j.eururo.2011.06.049

    Article  PubMed  Google Scholar 

  4. Lekanidi K, Vlachou PA, Morgan B, Vasanthan S (2007) Spontaneous regression of metastatic renal cell carcinoma: case report. J Med Case Rep 1(1):89. https://doi.org/10.1186/1752-1947-1-89

    Article  PubMed  PubMed Central  Google Scholar 

  5. Lokich J (1997) Spontaneous regression of metastatic renal cancer. Case report and literature review. Am J Clin Oncol 20(4):416–418. https://doi.org/10.1097/00000421-199708000-00020

    Article  CAS  PubMed  Google Scholar 

  6. Attig S, Hennenlotter J, Pawelec G, Klein G, Koch SD, Pircher H, Feyerabend S, Wernet D, Stenzl A, Rammensee HG, Gouttefangeas C (2009) Simultaneous infiltration of polyfunctional effector and suppressor T cells into renal cell carcinomas. Cancer Res 69(21):8412–8419. https://doi.org/10.1158/0008-5472.CAN-09-0852

    Article  CAS  PubMed  Google Scholar 

  7. Schendel DJ, Gansbacher B, Oberneder R, Kriegmair M, Hofstetter A, Riethmüller G et al (1993) Tumor-specific lysis of human renal cell carcinomas by tumor-infiltrating lymphocytes. I. HLA-A2-restricted recognition of autologous and allogeneic tumor lines. J Immunol Baltim Md 1950 151(8):4209–4220

    CAS  Google Scholar 

  8. Fisher RI, Rosenberg SA, Fyfe G (2000) Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 6(Suppl 1):S55–S57

    PubMed  Google Scholar 

  9. Rosenberg SA, Yang JC, Topalian SL, Schwartzentruber DJ, Weber JS, Parkinson DR, Seipp CA, Einhorn JH, White DE (1994) Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 271(12):907–913. https://doi.org/10.1001/jama.1994.03510360033032

    Article  CAS  PubMed  Google Scholar 

  10. Sd F (2000) Interferon in metastatic renal cell carcinoma. Semin Oncol. 27(2):187–193

    Google Scholar 

  11. Rj A (2000) Chemotherapy for renal cell carcinoma. Semin Oncol 27(2):177–186

    Google Scholar 

  12. Yagoda A, Petrylak D, Thompson S (1993) Cytotoxic chemotherapy for advanced renal cell carcinoma. Urol Clin North Am 20(2):303–321

    CAS  PubMed  Google Scholar 

  13. Latif F, Tory K, Gnarra J, Yao M, Duh FM, Orcutt ML et al (1993) Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 260(5112):1317–1320. https://doi.org/10.1126/science.8493574

    Article  CAS  PubMed  Google Scholar 

  14. Maher ER, Neumann HP, von Richard S (2011) Hippel–Lindau disease: a clinical and scientific review. Eur J Hum Genet 19(6):617–623. https://doi.org/10.1038/ejhg.2010.175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Leung SK, Ohh M (2002) Playing tag with HIF: the VHL story. J Biomed Biotechnol 2(3):131–135. https://doi.org/10.1155/S1110724302205057

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Kim WY, Kaelin WG (2004) Role of VHL gene mutation in human cancer. J Clin Oncol Off J Am Soc Clin Oncol 22(24):4991–5004. https://doi.org/10.1200/JCO.2004.05.061

    Article  CAS  Google Scholar 

  17. Pugh CW, Ratcliffe PJ (2003) Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med 9(6):677–684. https://doi.org/10.1038/nm0603-677

    Article  CAS  PubMed  Google Scholar 

  18. Kaelin WG (2002) Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer 2(9):673–682. https://doi.org/10.1038/nrc885

    Article  CAS  PubMed  Google Scholar 

  19. Sufan RI, Jewett MAS, Ohh M (2004) The role of von Hippel-Lindau tumor suppressor protein and hypoxia in renal clear cell carcinoma. Am J Physiol Renal Physiol 287(1):F1–F6. https://doi.org/10.1152/ajprenal.00424.2003

    Article  CAS  PubMed  Google Scholar 

  20. Barry RE, Krek W (2004) The von Hippel-Lindau tumour suppressor: a multi-faceted inhibitor of tumourigenesis. Trends Mol Med 10(9):466–472. https://doi.org/10.1016/j.molmed.2004.07.008

    Article  CAS  PubMed  Google Scholar 

  21. Maxwell PH, Pugh CW, Ratcliffe PJ (2001) Activation of the HIF pathway in cancer. Curr Opin Genet Dev 11(3):293–299

    Article  CAS  PubMed  Google Scholar 

  22. de Paulsen N, Brychzy A, Fournier MC, Klausner RD, Gnarra JR, Pause A et al (2001) Role of transforming growth factor-alpha in von Hippel--Lindau (VHL)(-/-) clear cell renal carcinoma cell proliferation: a possible mechanism coupling VHL tumor suppressor inactivation and tumorigenesis. Proc Natl Acad Sci U S A 98(4):1387–1392

    PubMed  PubMed Central  Google Scholar 

  23. Lolkema MP, Gervais ML, Snijckers CM, Hill RP, Giles RH, Voest EE, Ohh M (2005) Tumor suppression by the von Hippel-Lindau protein requires phosphorylation of the acidic domain. J Biol Chem 280(23):22205–22211. https://doi.org/10.1074/jbc.M503220200

    Article  CAS  PubMed  Google Scholar 

  24. Kurban G, Hudon V, Duplan E, Ohh M, Pause A (2006) Characterization of a von Hippel Lindau pathway involved in extracellular matrix remodeling, cell invasion, and angiogenesis. Cancer Res 66(3):1313–1319. https://doi.org/10.1158/0008-5472.CAN-05-2560

    Article  CAS  PubMed  Google Scholar 

  25. Simons M, Walz G (2006) Polycystic kidney disease: cell division without a c(l)ue? Kidney Int 70(5):854–864. https://doi.org/10.1038/sj.ki.5001534

    Article  CAS  PubMed  Google Scholar 

  26. Thoma CR, Frew IJ, Hoerner CR, Montani M, Moch H, Krek W (2007) pVHL and GSK3beta are components of a primary cilium-maintenance signalling network. Nat Cell Biol 9(5):588–595. https://doi.org/10.1038/ncb1579

    Article  CAS  PubMed  Google Scholar 

  27. Frew IJ, Thoma CR, Georgiev S, Minola A, Hitz M, Montani M, Moch H, Krek W (2008) pVHL and PTEN tumour suppressor proteins cooperatively suppress kidney cyst formation. EMBO J 27(12):1747–1757. https://doi.org/10.1038/emboj.2008.96

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hergovich A, Lisztwan J, Barry R, Ballschmieter P, Krek W (2003) Regulation of microtubule stability by the von Hippel-Lindau tumour suppressor protein pVHL. Nat Cell Biol 5(1):64–70. https://doi.org/10.1038/ncb899

    Article  CAS  PubMed  Google Scholar 

  29. Hergovich A, Lisztwan J, Thoma CR, Wirbelauer C, Barry RE, Krek W (2006) Priming-dependent phosphorylation and regulation of the tumor suppressor pVHL by glycogen synthase kinase 3. Mol Cell Biol 26(15):5784–5796. https://doi.org/10.1128/MCB.00232-06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Thoma CR, Toso A, Gutbrodt KL, Reggi SP, Frew IJ, Schraml P, Hergovich A, Moch H, Meraldi P, Krek W (2009) VHL loss causes spindle misorientation and chromosome instability. Nat Cell Biol 11(8):994–1001. https://doi.org/10.1038/ncb1912

    Article  CAS  PubMed  Google Scholar 

  31. Pause A, Lee S, Lonergan KM, Klausner RD (1998) The von Hippel-Lindau tumor suppressor gene is required for cell cycle exit upon serum withdrawal. Proc Natl Acad Sci U S A 95(3):993–998. https://doi.org/10.1073/pnas.95.3.993

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Kim J, Jonasch E, Alexander A, Short JD, Cai S, Wen S et al (2009) Cytoplasmic sequestration of p27 via AKT phosphorylation in renal cell carcinoma. Clin Cancer Res Off J Am Assoc Cancer Res 15(1):81–90

    Article  CAS  Google Scholar 

  33. Roe J-S, Kim H-R, Hwang I-Y, Cho E-J, Youn H-D (2011) von Hippel-Lindau protein promotes Skp2 destabilization on DNA damage. Oncogene 30(28):3127–3138. https://doi.org/10.1038/onc.2011.40

    Article  CAS  PubMed  Google Scholar 

  34. Roe J-S, Kim H, Lee S-M, Kim S-T, Cho E-J, Youn H-D (2006) p53 stabilization and transactivation by a von Hippel-Lindau protein. Mol Cell 22(3):395–405. https://doi.org/10.1016/j.molcel.2006.04.006

    Article  CAS  PubMed  Google Scholar 

  35. Lai Y, Song M, Hakala K, Weintraub ST, Shiio Y (2011) Proteomic dissection of the von Hippel-Lindau (VHL) interactome. J Proteome Res 10(11):5175–5182. https://doi.org/10.1021/pr200642c

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Li M, Fang X, Baker DJ, Guo L, Gao X, Wei Z, Han S, van Deursen JM, Zhang P (2010) The ATM-p53 pathway suppresses aneuploidy-induced tumorigenesis. Proc Natl Acad Sci U S A 107(32):14188–14193. https://doi.org/10.1073/pnas.1005960107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, Rolland F, Demkow T, Hutson TE, Gore M, Freeman S, Schwartz B, Shan M, Simantov R, Bukowski RM, TARGET Study Group (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356(2):125–134. https://doi.org/10.1056/NEJMoa060655

    Article  CAS  PubMed  Google Scholar 

  38. Eisen T, Oudard S, Szczylik C, Gravis G, Heinzer H, Middleton R, Cihon F, Anderson S, Shah S, Bukowski R, Escudier B, for the TARGET Study Group (2008) Sorafenib for older patients with renal cell carcinoma: subset analysis from a randomized trial. J Natl Cancer Inst 100(20):1454–1463. https://doi.org/10.1093/jnci/djn319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, Shah S, Bukowski RM (2009) Randomized phase II trial of first-line treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol 27(8):1280–1289. https://doi.org/10.1200/JCO.2008.19.3342

    Article  CAS  Google Scholar 

  40. Amato R, Zhai J, Willis J, Saxena S, DeFoe MA (2012) Phase II trial of intrapatient dose-escalated sorafenib in patients with metastatic renal cell carcinoma. Clin Genitourin Cancer 10(3):153–158

    Article  PubMed  Google Scholar 

  41. Hutson TE (2011) Targeted therapies for the treatment of metastatic renal cell carcinoma: clinical evidence. Oncologist 16(Suppl 2):14–22. https://doi.org/10.1634/theoncologist.2011-S2-14

    Article  PubMed  PubMed Central  Google Scholar 

  42. Logan JE, Rampersaud EN, Sonn GA, Chamie K, Belldegrun AS, Pantuck AJ, Slamon DJ, Kabbinavar FF (2012) Systemic therapy for metastatic renal cell carcinoma: a review and update. Rev Urol 14(3–4):65–78

    PubMed  PubMed Central  Google Scholar 

  43. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM (2003) SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther 2(5):471–478

    Article  CAS  PubMed  Google Scholar 

  44. 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(2):115–124. https://doi.org/10.1056/NEJMoa065044

    Article  CAS  PubMed  Google Scholar 

  45. Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, Garcia-del-Muro X, Sosman JA, Solska E, Wilding G, Thompson JA, Kim ST, Chen I, Huang X, Figlin RA (2009) Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol 27(22):3584–3590. https://doi.org/10.1200/JCO.2008.20.1293

    Article  CAS  Google Scholar 

  46. Motzer RJ, Hutson TE, Olsen MR, Hudes GR, Burke JM, Edenfield WJ, Wilding G, Agarwal N, Thompson JA, Cella D, Bello A, Korytowsky B, Yuan J, Valota O, Martell B, Hariharan S, Figlin RA (2012) Randomized phase II trial of sunitinib on an intermittent versus continuous dosing schedule as first-line therapy for advanced renal cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol 30(12):1371–1377. https://doi.org/10.1200/JCO.2011.36.4133

    Article  CAS  Google Scholar 

  47. Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, Barrios CH, Salman P, Gladkov OA, Kavina A, Zarbá 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 Oncol Off J Am Soc Clin Oncol 28(6):1061–1068. https://doi.org/10.1200/JCO.2009.23.9764

    Article  CAS  Google Scholar 

  48. 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(8):722–731. https://doi.org/10.1056/NEJMoa1303989

    Article  CAS  PubMed  Google Scholar 

  49. 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 (2014) 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 Off J Am Soc Clin Oncol 32(14):1412–1418. https://doi.org/10.1200/JCO.2013.50.8267

    Article  CAS  Google Scholar 

  50. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, Hammers H, Hutson TE, Lee JL, Peltola K, Roth BJ, Bjarnason GA, Géczi L, Keam B, Maroto P, Heng DY, Schmidinger M, Kantoff PW, Borgman-Hagey A, Hessel C, Scheffold C, Schwab GM, Tannir NM, Motzer RJ, METEOR Investigators (2015) Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19):1814–1823. https://doi.org/10.1056/NEJMoa1510016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Rini BI, Melichar B, Ueda T, Grünwald V, Fishman MN, Arranz JA, Bair AH, Pithavala YK, Andrews GI, Pavlov D, Kim S, Jonasch E (2013) Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma: a randomised double-blind phase 2 trial. Lancet Oncol 14(12):1233–1242. https://doi.org/10.1016/S1470-2045(13)70464-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Motzer RJ, Escudier B, Tomczak P, Hutson TE, Michaelson MD, Negrier S, Oudard S, Gore ME, Tarazi J, Hariharan S, Chen C, Rosbrook B, Kim S, Rini BI (2013) Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 14(6):552–562. https://doi.org/10.1016/S1470-2045(13)70093-7

    Article  CAS  PubMed  Google Scholar 

  53. Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, Rosbrook B, Chen C, Kim S, Vogelzang NJ (2013) Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: a randomised open-label phase 3 trial. Lancet Oncol 14(13):1287–1294. https://doi.org/10.1016/S1470-2045(13)70465-0

    Article  CAS  PubMed  Google Scholar 

  54. 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 IG, Barbarash O, Gokmen E, O'Toole T, Lustgarten S, Moore L, Motzer RJ, Global ARCC Trial (2007) Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 356(22):2271–2281. https://doi.org/10.1056/NEJMoa066838

    Article  CAS  PubMed  Google Scholar 

  55. Flaherty KT, Manola JB, Pins M, McDermott DF, Atkins MB, Dutcher JJ et al (2015) BEST: a randomized phase II study of vascular endothelial growth factor, RAF kinase, and mammalian target of rapamycin combination targeted therapy with bevacizumab, sorafenib, and temsirolimus in advanced renal cell carcinoma—a trial of the ECOG-ACRIN Cancer Research Group (E2804). J Clin Oncol Off J Am Soc Clin Oncol 33(21):2384–2391

    Article  CAS  Google Scholar 

  56. Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, Motzer RJ (2014) Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol 32(8):760–767. https://doi.org/10.1200/JCO.2013.50.3961

    Article  CAS  Google Scholar 

  57. Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, Srimuninnimit V, Pittman K, Sabbatini R, Rha SY, Flaig TW, Page R, Bavbek S, Beck JT, Patel P, Cheung F, Yadav S, Schiff EM, Wang X, Niolat J, Sellami D, Anak O, Knox JJ (2014) Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol 32(25):2765–2772. https://doi.org/10.1200/JCO.2013.54.6911

    Article  CAS  Google Scholar 

  58. 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 LA, Waxman IM, Sharma P, CheckMate 025 Investigators (2015) Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 373(19):1803–1813. https://doi.org/10.1056/NEJMoa1510665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Oncology, Tata Memorial Hospital, Mumbai, India

    Amit Joshi, Arvind Sahu, Vanita Noronha, Vijay Patil & Kumar Prabhash

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  1. Amit Joshi
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  2. Arvind Sahu
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Joshi, A., Sahu, A., Noronha, V. et al. Metastatic Renal Cell Cancer—Systemic Therapy. Indian J Surg Oncol 9, 97–104 (2018). https://doi.org/10.1007/s13193-018-0721-2

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