**8. Conclusion**

Despite great improvement in treatment outcomes with targeted agents in mRCC, the fact remains that complete remissions are rarely achieved and most patients progress and develop resistance to the treatment. Many questions are still open and at least some of them are expected to be solved with the on-going and future clinical trials. Intrinsic and extrinsic tumor resis‐ tances are major obstacles in successful long term tumor control and one of the major questions is the optimal sequencing of treatment. Use of sequential therapy with changing mechanisms of action is a rational approach to overcome this resistance.

[7] Guillot A, Levy A, Pacaut C, Collard O, Massard C, Merrouche Y, et.al. Reapprasal of the role of bevacisumab in the terapeutic strategy in advanced renal cell carcinoma.

Changing Mechanisms of Action as a Strategy for Sequential Targeted Therapy of Metastatic Renal-Cell Carcinoma

http://dx.doi.org/10.5772/55694

205

[8] Hsu T. Complex cellular functions of the von Hippel–Lindau tumor suppressor gene:

[9] Oudart S, Elaidi RT. Sequential therapy with targeted agents in patients with ad‐ vanced renal cell carcinoma: Optimizing patient benefit. Cancer treatments Review

[10] Porta C, Szczylik C, Escudier B. Combination or sequencing strategies to improve the outcome of metastatic renal cell carcinoma patients: a critical review. Critical Reviws

[11] NCCN clinical practice guidelines. Kidney cancer: http://www.nccn.org (accessed

[12] Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et.al. Su‐ nitinib versus interferon alfa in metastatic renal-cell carcinoma. New England Jour‐

[13] Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et.al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. Journal of Clinical Oncology 2009;

[14] Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et.al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III

[15] Guillot A, Levy A, Pecaut C, Collard O, Massard C, Merrouche Y et.al. Reappraisal of the reole of bevacisumab in the therapeutic strategy in advanced renal cell carcino‐

[16] Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et.al. Bev‐ acisumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a

[17] Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: final results of CALGB 90206. Journal of Clinical On‐

[18] Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et.al. Sorafenib in advanced clear-cell renal-cell carcinoma. New England Journal of Medicine 2007;

randomised, double-blind phase III trial. Lancet 2007; 370(9605): 2103-2111.

trial. Journal of Clinical Oncology 2010; 28(6): 1061-1068.

ma. Clinical Genitourinary Cancer 2012; 10(3): 147-152.

insights from model organisms. Oncogene. 2012; 31(18): 2247-2257.

Clinical Genitourinary Cancer 2012; 10(3): 147-152.

in Oncology/ Hematology 2012; 82(3): 323-337.

nal of Medicine 2007; 356(2): 115-124.

cology 2010; 28(13): 2137-2143.

356(2): 125-134.

2012; 38(8): 981-987.

November 2012)

27(22): 3584-3590.
