Renal cell carcinoma medical therapy: Difference between revisions

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{{Renal cell carcinoma}}
{{Renal cell carcinoma}}
==Overview==
==Overview==
==Medical Therapy==
Medical therapy is generally reserved for patients with metastatic disease when surgical management is not feasible. The goal of medical therapy is to achieve a favorable overall quality of life and to control tumor burdenMost patients who require systemic medical therapy continue treatment chronically.
===Immunotherapy===
Immunotherapy is considered the mainstay of therapy for patients with metastatic renal cell carcinoma.
====Aldesleukin (IL2)====
It is considered as a preferable option for patients with good cardiovascular performance status. Aldesleukin is associated with "capillary leak syndrome". Response to aldeleukin remains unpredictable, but recent evidence has shown that specific pathological features of the tumor and the expression of carbonic anhydrase 9 protein in von Hippel-Lindau syndrome may be associated with increased response to aldesleukin.<ref name="pmid15897568">{{cite journal| author=Atkins M, Regan M, McDermott D, Mier J, Stanbridge E, Youmans A et al.| title=Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. | journal=Clin Cancer Res | year= 2005 |volume= 11 | issue= 10 | pages= 3714-21 | pmid=15897568 | doi=10.1158/1078-0432.CCR-04-2019 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15897568  }} </ref><ref name="pmid12576453">{{cite journal| author=Bui MH, Seligson D, Han KR, Pantuck AJ, Dorey FJ, Huang Y et al.| title=Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. |journal=Clin Cancer Res | year= 2003 | volume= 9 | issue= 2 | pages= 802-11 |pmid=12576453 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12576453  }} </ref><ref name="pmid16113605">{{cite journal| author=Upton MP, Parker RA, Youmans A, McDermott DF, Atkins MB| title=Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy. | journal=J Immunother | year= 2005 | volume= 28 | issue= 5 | pages= 488-95 | pmid=16113605 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16113605  }}</ref> Although considered as first line agent, the true advantage of aldesleukin in metastatic renal cell carcinoma is still debatable.<ref name="pmid15625368">{{cite journal| author=McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF et al.| title=Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. |journal=J Clin Oncol | year= 2005 | volume= 23 | issue= 1 | pages= 133-41 |pmid=15625368 | doi=10.1200/JCO.2005.03.206 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15625368  }} </ref><ref name="pmid12915604">{{cite journal| author=Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P et al.| title=Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. | journal=J Clin Oncol | year= 2003 | volume= 21 | issue= 16 | pages= 3127-32 | pmid=12915604 |doi=10.1200/JCO.2003.02.122 | pmc=PMC2275327 |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12915604  }}</ref> Response to aldesleukin is believed to increase when combined with interferon alfa.<ref name="pmid9562581">{{cite journal| author=Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C et al.| title=Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d'Immunothérapie. | journal=N Engl J Med | year= 1998 | volume= 338 | issue= 18| pages= 1272-8 | pmid=9562581 | doi=10.1056/NEJM199804303381805 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9562581  }} </ref>


===Small Renal Masses===
====Interferon Alfa====
Interferon alfa has been shown to also be beneficial in renal cell carcinoma, particularly when combined with aldesleukin.<ref name="pmid9562581">{{cite journal|author=Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C et al.|title=Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d'Immunothérapie. | journal=N Engl J Med | year= 1998 | volume= 338 | issue= 18 | pages= 1272-8 | pmid=9562581 |doi=10.1056/NEJM199804303381805 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9562581  }} </ref>


====Partial Nephrectomy====
Small renal masses are defined as masses that are less than or equal to 4 cm on CT scan enhancement. Optimal management of small renal masses includes open or laparoscopic partial nephrectomy.<ref name="pmid17574056">{{cite journal| author=Gill IS, Kavoussi LR, Lane BR, Blute ML, Babineau D, Colombo JR et al.| title=Comparison of 1,800 laparoscopic and open partial nephrectomies for single renal tumors. | journal=J Urol | year= 2007 | volume= 178 | issue= 1 | pages= 41-6 | pmid=17574056 | doi=10.1016/j.juro.2007.03.038 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17574056  }} </ref><ref name="pmid18221958">{{cite journal| author=Lane BR, Novick AC, Babineau D, Fergany AF, Kaouk JH, Gill IS| title=Comparison of laparoscopic and open partial nephrectomy for tumor in a solitary kidney. | journal=J Urol | year= 2008 | volume= 179 | issue= 3 | pages= 847-51; discussion 852 | pmid=18221958 | doi=10.1016/j.juro.2007.10.050 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18221958  }} </ref><ref name="pmid19269025">{{cite journal| author=Rini BI, Campbell SC, Escudier B| title=Renal cell carcinoma. | journal=Lancet | year= 2009 | volume= 373 | issue= 9669 | pages= 1119-32 | pmid=19269025 | doi=10.1016/S0140-6736(09)60229-4 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19269025  }} </ref> Partial nephrectomy is characterized by a low-complication rate. Most common complications include urinary leak and hemorrhage that occur in 3-5% and 1%, respectively.<ref name="pmid17574056">{{cite journal| author=Gill IS, Kavoussi LR, Lane BR, Blute ML, Babineau D, Colombo JR et al.|title=Comparison of 1,800 laparoscopic and open partial nephrectomies for single renal tumors. | journal=J Urol | year= 2007 | volume= 178 | issue= 1 |pages= 41-6 | pmid=17574056 | doi=10.1016/j.juro.2007.03.038 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17574056  }}</ref><ref name="pmid18221958">{{cite journal| author=Lane BR, Novick AC, Babineau D, Fergany AF, Kaouk JH, Gill IS| title=Comparison of laparoscopic and open partial nephrectomy for tumor in a solitary kidney. | journal=J Urol| year= 2008 | volume= 179 | issue= 3 | pages= 847-51; discussion 852 |pmid=18221958 | doi=10.1016/j.juro.2007.10.050 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18221958  }}</ref><ref name="pmid19269025">{{cite journal| author=Rini BI, Campbell SC, Escudier B| title=Renal cell carcinoma. | journal=Lancet | year= 2009 | volume= 373 | issue= 9669 | pages= 1119-32 | pmid=19269025 | doi=10.1016/S0140-6736(09)60229-4 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19269025  }} </ref> Partial nephrectomy is associated with less chronic renal failure (CRF) than with radical nephrectomy, with a rate of CRF ranging between 5-20% and 36-65%, respectively.<ref name="pmid16945768">{{cite journal| author=Huang WC, Levey AS, Serio AM, Snyder M, Vickers AJ, Raj GV et al.| title=Chronic kidney disease after nephrectomy in patients with renal cortical tumours: a retrospective cohort study. | journal=Lancet Oncol | year= 2006 | volume= 7 | issue= 9 | pages= 735-40 | pmid=16945768 | doi=10.1016/S1470-2045(06)70803-8 | pmc=PMC2239298 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16945768  }} </ref>


Special consideration must be made for patient subgroups, including the elderly and those with high surgical risk. Because the average growth rate of small renal tumors is considered slow - approaching 0.28 cm/year and a 1% rate of metastasis - partial nephrectomy may be spared in these patients.<ref name="pmid16406965">{{cite journal| author=Chawla SN, Crispen PL, Hanlon AL, Greenberg RE, Chen DY, Uzzo RG| title=The natural history of observed enhancing renal masses: meta-analysis and review of the world literature. | journal=J Urol | year= 2006 | volume= 175 | issue= 2 | pages= 425-31 | pmid=16406965 | doi=10.1016/S0022-5347(05)00148-5 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16406965 }} </ref><ref name="pmid19269025">{{cite journal| author=Rini BI, Campbell SC, Escudier B| title=Renal cell carcinoma. | journal=Lancet | year= 2009 | volume= 373 | issue= 9669 | pages= 1119-32 | pmid=19269025 | doi=10.1016/S0140-6736(09)60229-4 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19269025 }} </ref>
===Targeted Therapy===
====VEGF Inhibiting Drugs====
=====Sunitinib=====
Sunitinib is a tyrosine kinase inhibitor of VEGF receptors considered as first line therapy.<ref name="pmid12538485">{{cite journal| author=Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G et al.| title=In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. | journal=Clin Cancer Res | year= 2003 |volume= 9 | issue= 1 | pages= 327-37 | pmid=12538485 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12538485  }}</ref>Sunitinib has been studied vs. interferon and has shown advantage in both survival and response rate.<ref name="pmid16330672">{{cite journal| author=Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA et al.| title=Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. |journal=J Clin Oncol | year= 2006 | volume= 24 | issue= 1 | pages= 16-24 | pmid=16330672| doi=10.1200/JCO.2005.02.2574 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16330672  }} </ref><ref name="pmid16757724">{{cite journal| author=Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR et al.| title=Sunitinib in patients with metastatic renal cell carcinoma. | journal=JAMA | year= 2006 | volume= 295 | issue= 21 | pages= 2516-24 |pmid=16757724 | doi=10.1001/jama.295.21.2516 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16757724  }} </ref><ref name="pmid17215529">{{cite journal| author=Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O et al.| title=Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. | journal=N Engl J Med | year= 2007 | volume= 356 | issue= 2 |pages= 115-24 | pmid=17215529 | doi=10.1056/NEJMoa065044 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17215529 }}</ref> Associated toxicity include: fatigue, hand-foot syndrome, diarrhea, hypertension, hypothyroidism, and decreased left ventricular function.<ref name="pmid17202116">{{cite journal| author=Rini BI, Tamaskar I, Shaheen P, Salas R, Garcia J, Wood L et al.|title=Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. | journal=J Natl Cancer Inst | year= 2007 | volume= 99 | issue= 1 | pages= 81-3 | pmid=17202116 | doi=10.1093/jnci/djk008 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17202116  }} </ref><ref name="pmid18083403">{{cite journal| author=Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, Nguyen L et al.| title=Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. | journal=Lancet | year= 2007 | volume= 370 | issue= 9604 | pages= 2011-9 | pmid=18083403 | doi=10.1016/S0140-6736(07)61865-0 | pmc=PMC2643085 |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18083403  }} </ref><ref name="pmid18386829">{{cite journal| author=Khakoo AY, Kassiotis CM, Tannir N, Plana JC, Halushka M, Bickford C et al.| title=Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor. | journal=Cancer | year= 2008 |volume= 112 | issue= 11 | pages= 2500-8 | pmid=18386829 | doi=10.1002/cncr.23460 | pmc=| url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18386829 }} </ref>


====Probe-Based Thermal Ablation====
Percutaneous or laparoscopic probe-based thermal ablation is a new management method for patients with small renal masses. The technique utilizes extreme temperatures, such as cryoablation or radiofrequency ablation.<ref name="pmid11068292">{{cite journal| author=Gill IS, Novick AC, Meraney AM, Chen RN, Hobart MG, Sung GT et al.| title=Laparoscopic renal cryoablation in 32 patients. | journal=Urology | year= 2000 | volume= 56 | issue= 5 | pages= 748-53 | pmid=11068292 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11068292  }} </ref><ref name="pmid15879772">{{cite journal| author=Gill IS, Remer EM, Hasan WA, Strzempkowski B, Spaliviero M, Steinberg AP et al.| title=Renal cryoablation: outcome at 3 years. | journal=J Urol | year= 2005 | volume= 173 | issue= 6 | pages= 1903-7 | pmid=15879772 | doi=10.1097/01.ju.0000158154.28845.c9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15879772  }} </ref> Thermal ablation is still considered inferior to partial nephrectomy due to the following considerations:
*Difficulty in ablation of large (>3.5 cm) tumors<ref name="pmid19269025">{{cite journal| author=Rini BI, Campbell SC, Escudier B| title=Renal cell carcinoma. | journal=Lancet | year= 2009 | volume= 373 | issue= 9669 | pages= 1119-32 | pmid=19269025 | doi=10.1016/S0140-6736(09)60229-4 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19269025  }} </ref>


*Higher local recurrence rate in thermal ablation<ref name="pmid18280512">{{cite journal| author=Kunkle DA, Egleston BL, Uzzo RG| title=Excise, ablate or observe: the small renal mass dilemma--a meta-analysis and review. | journal=J Urol | year= 2008 | volume= 179 | issue= 4 | pages= 1227-33; discussion 1233-4 | pmid=18280512 | doi=10.1016/j.juro.2007.11.047 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18280512 }} </ref>
=====Sorafenib=====
Sorafenib is a raf kinase inhibitor of VEGF receptor, often regarded as a weaker inhibitor than sunitinib. Sorafenib has shown approximately a significant additional 3 month progression free survival and similarly, a significant additional median overall survival of approximately 3.4 months.<ref name="pmid17215530">{{cite journal|author=Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M et al.|title=Sorafenib in advanced clear-cell renal-cell carcinoma. | journal=N Engl J Med |year= 2007 | volume= 356 | issue= 2 | pages= 125-34 | pmid=17215530 |doi=10.1056/NEJMoa060655 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17215530  }}</ref>Associated toxicity includes those of sunitinib but at a lesser rate.
=====Bevacizumab=====
Monoclonal antibody against VEGF considered first line therapy in Europe.<ref name="pmid9377574">{{cite journal| author=Presta LG, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L et al.| title=Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. |journal=Cancer Res | year= 1997 | volume= 57 | issue= 20 | pages= 4593-9 | pmid=9377574| doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9377574  }} </ref><ref name="pmid19269025">{{cite journal| author=Rini BI, Campbell SC, Escudier B| title=Renal cell carcinoma. | journal=Lancet | year= 2009 | volume= 373 | issue= 9669 | pages= 1119-32 | pmid=19269025 | doi=10.1016/S0140-6736(09)60229-4 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19269025  }}</ref> Response rate and progression free survival are both increased with combination with inferferon.<ref name="pmid18156031">{{cite journal| author=Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C et al.| title=Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. | journal=Lancet | year= 2007 | volume= 370 | issue= 9605 | pages= 2103-11 | pmid=18156031 | doi=10.1016/S0140-6736(07)61904-7 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18156031  }}</ref>Toxicity includes fatigue, anorexia, hypertension, and proteinuria.<ref name="pmid19269025">{{cite journal| author=Rini BI, Campbell SC, Escudier B| title=Renal cell carcinoma. | journal=Lancet | year= 2009 | volume= 373 | issue= 9669 | pages= 1119-32 | pmid=19269025 | doi=10.1016/S0140-6736(09)60229-4 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19269025 }} </ref>


*Ill-defined radiographic parameters for success in thermal ablation<ref name="pmid18280507">{{cite journal| author=Weight CJ, Kaouk JH, Hegarty NJ, Remer EM, O'Malley CM, Lane BR et al.| title=Correlation of radiographic imaging and histopathology following cryoablation and radio frequency ablation for renal tumors. | journal=J Urol | year= 2008 | volume= 179 | issue= 4 | pages= 1277-81; discussion 1281-3 | pmid=18280507 | doi=10.1016/j.juro.2007.11.075 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18280507 }} </ref>
====mTOR Inhibitors====
=====Temsirolimus=====
Temsirolimus is often reserved only for high risk patients with metastatic disease. Temsirolimus monotherapy is regarded as superior to interferon monotherapy with no additional advantage in combination therapy of both drugs.<ref name="pmid10561319">{{cite journal| author=Motzer RJ, Mazumdar M, Bacik J, Berg W, Amsterdam A, Ferrara J|title=Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma. | journal=J Clin Oncol | year= 1999 | volume= 17 | issue= 8 | pages= 2530-40| pmid=10561319 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10561319  }} </ref><ref name="pmid15681528">{{cite journal| author=Mekhail TM, Abou-Jawde RM, Boumerhi G, Malhi S, Wood L, Elson P et al.| title=Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. | journal=J Clin Oncol | year= 2005 | volume= 23 |issue= 4 | pages= 832-41 | pmid=15681528 | doi=10.1200/JCO.2005.05.179 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15681528  }}</ref> Toxicity includes anemia, asthenia, dyspnea, dyslipidemia, and hyperglycemia. New studies have shown added benefit when temsirolimus is combined with everolimus.<ref name="pmid18653228">{{cite journal| author=Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S et al.| title=Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. |journal=Lancet | year= 2008 | volume= 372 | issue= 9637 | pages= 449-56 | pmid=18653228| doi=10.1016/S0140-6736(08)61039-9 | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18653228 }} </ref>


*Post-ablation surgery may be compromised due to presence of ablation fibrotic reactions<ref name="pmid19269025">{{cite journal| author=Rini BI, Campbell SC, Escudier B| title=Renal cell carcinoma. | journal=Lancet | year= 2009 | volume= 373 | issue= 9669 | pages= 1119-32 | pmid=19269025 | doi=10.1016/S0140-6736(09)60229-4 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19269025 }} </ref>
===Chemotherapy===
*Unavailable long-term data on patients undergoing ablation
====Medroxyprogesterone====
Large randomized trials did not yield high responses as anti-tumor effects when used alone or when used with other medications.(95,96) Their role is reserved for palliative care.<ref name="pmid10023944">{{cite journal| author=| title=Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators. | journal=Lancet | year= 1999 |volume= 353 | issue= 9146 | pages= 14-7 | pmid=10023944 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10023944  }} </ref><ref name="pmid7855619">{{cite journal| author=Yagoda A, Abi-Rached B, Petrylak D|title=Chemotherapy for advanced renal-cell carcinoma: 1983-1993. | journal=Semin Oncol |year= 1995 | volume= 22 | issue= 1 | pages= 42-60 | pmid=7855619 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7855619  }} </ref><ref name="pmid10647643">{{cite journal| author=Motzer RJ, Russo P| title=Systemic therapy for renal cell carcinoma. | journal=J Urol | year= 2000 | volume= 163 | issue= 2 |pages= 408-17 | pmid=10647643 | doi= | pmc= |url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=10647643 }} </ref>


===Locally Advanced Renal Tumors===
The chances of malignancy generally increase with the size of the tumor (> 7 cm) and with the extent of local invasion, especially along the inferior vena cava.<ref name="pmid19269025">{{cite journal| author=Rini BI, Campbell SC, Escudier B| title=Renal cell carcinoma. | journal=Lancet | year= 2009 | volume= 373 | issue= 9669 | pages= 1119-32 | pmid=19269025 | doi=10.1016/S0140-6736(09)60229-4 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19269025  }} </ref>


====Radical Nephrectomy====
In summary, the following table shows the response rate of various treatment options for renal cell carcinoma:
Total nephrectomy should always be considered as first line of cure in patients with locally advanced renal cell carcinoma. Radical nephrectomy is curative in 40-60% of all renal cell carcinoma cases.<ref name="pmid15217427">{{cite journal| author=Blute ML, Leibovich BC, Lohse CM, Cheville JC, Zincke H| title=The Mayo Clinic experience with surgical management, complications and outcome for patients with renal cell carcinoma and venous tumour thrombus. | journal=BJU Int | year= 2004 | volume= 94 | issue= 1 | pages= 33-41 | pmid=15217427 | doi=10.1111/j.1464-410X.2004.04897.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15217427  }} </ref><ref name="pmid12655523">{{cite journal| author=Leibovich BC, Blute ML, Cheville JC, Lohse CM, Frank I, Kwon ED et al.| title=Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. | journal=Cancer | year= 2003 | volume= 97 | issue= 7 | pages= 1663-71 | pmid=12655523 | doi=10.1002/cncr.11234 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12655523  }} </ref> Following resection of the tumor with no evidence of metastasis, observation has been shown to be the optimal management plan with insufficient evidence to support the use of adjuvant medical or radiation therapy.<ref name="pmid8640706">{{cite journal| author=Galligioni E, Quaia M, Merlo A, Carbone A, Spada A, Favaro D et al.| title=Adjuvant immunotherapy treatment of renal carcinoma patients with autologous tumor cells and bacillus Calmette-Guèrin: five-year results of a prospective randomized study. | journal=Cancer | year= 1996 | volume= 77 | issue= 12 | pages= 2560-6 | pmid=8640706 | doi=10.1002/(SICI)1097-0142(19960615)77:12<2560::AID-CNCR20>3.0.CO;2-P | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8640706  }} </ref><ref name="pmid12663707">{{cite journal| author=Messing EM, Manola J, Wilding G, Propert K, Fleischmann J, Crawford ED et al.| title=Phase III study of interferon alfa-NL as adjuvant treatment for resectable renal cell carcinoma: an Eastern Cooperative Oncology Group/Intergroup trial. | journal=J Clin Oncol | year= 2003 | volume= 21 | issue= 7 | pages= 1214-22 | pmid=12663707 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12663707  }} </ref><ref name="pmid11208835">{{cite journal| author=Pizzocaro G, Piva L, Colavita M, Ferri S, Artusi R, Boracchi P et al.| title=Interferon adjuvant to radical nephrectomy in Robson stages II and III renal cell carcinoma: a multicentric randomized study. | journal=J Clin Oncol | year= 2001 | volume= 19 | issue= 2 | pages= 425-31 | pmid=11208835 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11208835  }} </ref><ref name="pmid12810695">{{cite journal| author=Clark JI, Atkins MB, Urba WJ, Creech S, Figlin RA, Dutcher JP et al.| title=Adjuvant high-dose bolus interleukin-2 for patients with high-risk renal cell carcinoma: a cytokine working group randomized trial. | journal=J Clin Oncol | year= 2003 | volume= 21 | issue= 16 | pages= 3133-40 | pmid=12810695 | doi=10.1200/JCO.2003.02.014 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12810695  }} </ref><ref name="pmid15756254">{{cite journal| author=Atzpodien J, Schmitt E, Gertenbach U, Fornara P, Heynemann H, Maskow A et al.| title=Adjuvant treatment with interleukin-2- and interferon-alpha2a-based chemoimmunotherapy in renal cell carcinoma post tumour nephrectomy: results of a prospectively randomised trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). | journal=Br J Cancer | year= 2005 | volume= 92 | issue= 5 | pages= 843-6 | pmid=15756254 | doi=10.1038/sj.bjc.6602443 | pmc=PMC2361915 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15756254  }} </ref><ref name="pmid12597146">{{cite journal| author=Gez E, Libes M, Bar-Deroma R, Rubinov R, Stein M, Kuten A| title=Postoperative irradiation in localized renal cell carcinoma: the Rambam Medical Center experience. | journal=Tumori | year= 2002 | volume= 88 | issue= 6 | pages= 500-2 | pmid=12597146 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12597146  }} </ref><ref name="pmid3553111">{{cite journal| author=Kjaer M, Frederiksen PL, Engelholm SA| title=Postoperative radiotherapy in stage II and III renal adenocarcinoma. A randomized trial by the Copenhagen Renal Cancer Study Group. | journal=Int J Radiat Oncol Biol Phys | year= 1987 | volume= 13 | issue= 5 | pages= 665-72 | pmid=3553111 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3553111  }} </ref><ref name="pmid9932477">{{cite journal| author=Valentini V, Rosetto ME, Fares C, Mantini G, Salvi G, Turriziani A| title=Radiotherapy and local control in rectal cancer. | journal=Rays | year= 1998 | volume= 23 | issue= 3 | pages= 580-5 | pmid=9932477 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9932477  }} </ref><ref name="pmid2824861">{{cite journal| author=Pizzocaro G, Piva L, Di Fronzo G, Giongo A, Cozzoli A, Dormia E et al.| title=Adjuvant medroxyprogesterone acetate to radical nephrectomy in renal cancer: 5-year results of a prospective randomized study. | journal=J Urol | year= 1987 | volume= 138 | issue= 6 | pages= 1379-81 | pmid=2824861 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2824861  }} </ref>


===Metastatic Renal Tumors===
According to two phase III studies, radical nephrectomy or debulking, along with use of interferon alfa, is also used as part of a more aggressive management plan in cases with positive metastasis.<ref name="pmid14767273">{{cite journal| author=Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED| title=Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. | journal=J Urol | year= 2004 | volume= 171 | issue= 3 | pages= 1071-6 | pmid=14767273 | doi=10.1097/01.ju.0000110610.61545.ae | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14767273  }} </ref><ref name="pmid11759643">{{cite journal| author=Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC et al.| title=Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. | journal=N Engl J Med | year= 2001 | volume= 345 | issue= 23 | pages= 1655-9 | pmid=11759643 | doi=10.1056/NEJMoa003013 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11759643  }} </ref><ref name="pmid11583750">{{cite journal| author=Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R, European Organisation for Research and Treatment of Cancer (EORTC) Genitourinary Group| title=Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. | journal=Lancet | year= 2001 | volume= 358 | issue= 9286 | pages= 966-70 | pmid=11583750 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11583750  }} </ref> However, radical nephrectomy in such cases is not curative and should be performed only when benefits outweigh the procedure's risks. Thus, radical nephrectomy in metastatic cases is reserved only for those with the following tumor features<ref name="pmid17509276">{{cite journal| author=Rini BI, Campbell SC| title=The evolving role of surgery for advanced renal cell carcinoma in the era of molecular targeted therapy. | journal=J Urol | year= 2007 | volume= 177 | issue= 6 | pages= 1978-84 | pmid=17509276 | doi=10.1016/j.juro.2007.01.136 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17509276  }} </ref>:
*Tumor invading > 75% of the involved kidney
*Good cardiopulmonary function
*Absent CNS or liver metastasis
*Procedural difficulty and tumor proximity to other organs and anatomic structures
Several factors play an important role in increasing risk of recurrence of renal cell carcinoma following radical nephrectomy. Risk factors are listed below<ref name="pmid11435824">{{cite journal| author=Kattan MW, Reuter V, Motzer RJ, Katz J, Russo P| title=A postoperative prognostic nomogram for renal cell carcinoma. | journal=J Urol | year= 2001 | volume= 166 | issue= 1 | pages= 63-7 | pmid=11435824 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11435824  }} </ref><ref name="pmid12655523">{{cite journal| author=Leibovich BC, Blute ML, Cheville JC, Lohse CM, Frank I, Kwon ED et al.| title=Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. | journal=Cancer | year= 2003 | volume= 97 | issue= 7 | pages= 1663-71 | pmid=12655523 | doi=10.1002/cncr.11234 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12655523  }} </ref><ref name="pmid11250993">{{cite journal| author=Zisman A, Pantuck AJ, Dorey F, Said JW, Shvarts O, Quintana D et al.| title=Improved prognostication of renal cell carcinoma using an integrated staging system. | journal=J Clin Oncol | year= 2001 | volume= 19 | issue= 6 | pages= 1649-57 | pmid=11250993 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11250993  }} </ref>:
*Stage of tumor
*Grade of tumor
*Performance status
*Presence of tumor-related symptoms
===Resection of Metastasis===
Metastasectomy is rarely performed in less than 5% of all cases.<ref name="pmid19269025">{{cite journal| author=Rini BI, Campbell SC, Escudier B| title=Renal cell carcinoma. | journal=Lancet | year= 2009 | volume= 373 | issue= 9669 | pages= 1119-32 | pmid=19269025 | doi=10.1016/S0140-6736(09)60229-4 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19269025  }} </ref> Generally, the procedure is to be considered only in the following cases, with a 5-year survival of 30% of all cases<ref name="pmid15734422">{{cite journal| author=Murthy SC, Kim K, Rice TW, Rajeswaran J, Bukowski R, DeCamp MM et al.| title=Can we predict long-term survival after pulmonary metastasectomy for renal cell carcinoma? | journal=Ann Thorac Surg | year= 2005 | volume= 79 | issue= 3 | pages= 996-1003 | pmid=15734422 | doi=10.1016/j.athoracsur.2004.08.034 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15734422  }} </ref><ref name="pmid12440625">{{cite journal| author=Pfannschmidt J, Hoffmann H, Muley T, Krysa S, Trainer C, Dienemann H| title=Prognostic factors for survival after pulmonary resection of metastatic renal cell carcinoma. | journal=Ann Thorac Surg | year= 2002 | volume= 74 | issue= 5 | pages= 1653-7 | pmid=12440625 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12440625  }} </ref>:
*Isolated metastasis
*Chance of complete resection
*Indolent course of metastasis


==References==
==References==

Revision as of 22:46, 11 January 2014

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

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Overview

Medical Therapy

Medical therapy is generally reserved for patients with metastatic disease when surgical management is not feasible. The goal of medical therapy is to achieve a favorable overall quality of life and to control tumor burdenMost patients who require systemic medical therapy continue treatment chronically.

Immunotherapy

Immunotherapy is considered the mainstay of therapy for patients with metastatic renal cell carcinoma.

Aldesleukin (IL2)

It is considered as a preferable option for patients with good cardiovascular performance status. Aldesleukin is associated with "capillary leak syndrome". Response to aldeleukin remains unpredictable, but recent evidence has shown that specific pathological features of the tumor and the expression of carbonic anhydrase 9 protein in von Hippel-Lindau syndrome may be associated with increased response to aldesleukin.[1][2][3] Although considered as first line agent, the true advantage of aldesleukin in metastatic renal cell carcinoma is still debatable.[4][5] Response to aldesleukin is believed to increase when combined with interferon alfa.[6]

Interferon Alfa

Interferon alfa has been shown to also be beneficial in renal cell carcinoma, particularly when combined with aldesleukin.[6]


Targeted Therapy

VEGF Inhibiting Drugs

Sunitinib

Sunitinib is a tyrosine kinase inhibitor of VEGF receptors considered as first line therapy.[7]Sunitinib has been studied vs. interferon and has shown advantage in both survival and response rate.[8][9][10] Associated toxicity include: fatigue, hand-foot syndrome, diarrhea, hypertension, hypothyroidism, and decreased left ventricular function.[11][12][13]


Sorafenib

Sorafenib is a raf kinase inhibitor of VEGF receptor, often regarded as a weaker inhibitor than sunitinib. Sorafenib has shown approximately a significant additional 3 month progression free survival and similarly, a significant additional median overall survival of approximately 3.4 months.[14]Associated toxicity includes those of sunitinib but at a lesser rate.

Bevacizumab

Monoclonal antibody against VEGF considered first line therapy in Europe.[15][16] Response rate and progression free survival are both increased with combination with inferferon.[17]Toxicity includes fatigue, anorexia, hypertension, and proteinuria.[16]

mTOR Inhibitors

Temsirolimus

Temsirolimus is often reserved only for high risk patients with metastatic disease. Temsirolimus monotherapy is regarded as superior to interferon monotherapy with no additional advantage in combination therapy of both drugs.[18][19] Toxicity includes anemia, asthenia, dyspnea, dyslipidemia, and hyperglycemia. New studies have shown added benefit when temsirolimus is combined with everolimus.[20]

Chemotherapy

Medroxyprogesterone

Large randomized trials did not yield high responses as anti-tumor effects when used alone or when used with other medications.(95,96) Their role is reserved for palliative care.[21][22][23]


In summary, the following table shows the response rate of various treatment options for renal cell carcinoma:


References

  1. ↑ Atkins M, Regan M, McDermott D, Mier J, Stanbridge E, Youmans A; et al. (2005). "Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer". Clin Cancer Res. 11 (10): 3714–21. doi:10.1158/1078-0432.CCR-04-2019. PMID 15897568.
  2. ↑ Bui MH, Seligson D, Han KR, Pantuck AJ, Dorey FJ, Huang Y; et al. (2003). "Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy". Clin Cancer Res. 9 (2): 802–11. PMID 12576453.
  3. ↑ Upton MP, Parker RA, Youmans A, McDermott DF, Atkins MB (2005). "Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy". J Immunother. 28 (5): 488–95. PMID 16113605.
  4. ↑ McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF; et al. (2005). "Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma". J Clin Oncol. 23 (1): 133–41. doi:10.1200/JCO.2005.03.206. PMID 15625368.
  5. ↑ Yang JC, Sherry RM, Steinberg SM, Topalian SL, Schwartzentruber DJ, Hwu P; et al. (2003). "Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer". J Clin Oncol. 21 (16): 3127–32. doi:10.1200/JCO.2003.02.122. PMC 2275327. PMID 12915604.
  6. ↑ 6.0 6.1 Negrier S, Escudier B, Lasset C, Douillard JY, Savary J, Chevreau C; et al. (1998). "Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Français d'Immunothérapie". N Engl J Med. 338 (18): 1272–8. doi:10.1056/NEJM199804303381805. PMID 9562581.
  7. ↑ Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G; et al. (2003). "In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship". Clin Cancer Res. 9 (1): 327–37. PMID 12538485.
  8. ↑ Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA; et al. (2006). "Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma". J Clin Oncol. 24 (1): 16–24. doi:10.1200/JCO.2005.02.2574. PMID 16330672.
  9. ↑ Motzer RJ, Rini BI, Bukowski RM, Curti BD, George DJ, Hudes GR; et al. (2006). "Sunitinib in patients with metastatic renal cell carcinoma". JAMA. 295 (21): 2516–24. doi:10.1001/jama.295.21.2516. PMID 16757724.
  10. ↑ Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O; et al. (2007). "Sunitinib versus interferon alfa in metastatic renal-cell carcinoma". N Engl J Med. 356 (2): 115–24. doi:10.1056/NEJMoa065044. PMID 17215529.
  11. ↑ Rini BI, Tamaskar I, Shaheen P, Salas R, Garcia J, Wood L; et al. (2007). "Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib". J Natl Cancer Inst. 99 (1): 81–3. doi:10.1093/jnci/djk008. PMID 17202116.
  12. ↑ Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, Nguyen L; et al. (2007). "Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib". Lancet. 370 (9604): 2011–9. doi:10.1016/S0140-6736(07)61865-0. PMC 2643085. PMID 18083403.
  13. ↑ Khakoo AY, Kassiotis CM, Tannir N, Plana JC, Halushka M, Bickford C; et al. (2008). "Heart failure associated with sunitinib malate: a multitargeted receptor tyrosine kinase inhibitor". Cancer. 112 (11): 2500–8. doi:10.1002/cncr.23460. PMID 18386829.
  14. ↑ Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M; et al. (2007). "Sorafenib in advanced clear-cell renal-cell carcinoma". N Engl J Med. 356 (2): 125–34. doi:10.1056/NEJMoa060655. PMID 17215530.
  15. ↑ Presta LG, Chen H, O'Connor SJ, Chisholm V, Meng YG, Krummen L; et al. (1997). "Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders". Cancer Res. 57 (20): 4593–9. PMID 9377574.
  16. ↑ 16.0 16.1 Rini BI, Campbell SC, Escudier B (2009). "Renal cell carcinoma". Lancet. 373 (9669): 1119–32. doi:10.1016/S0140-6736(09)60229-4. PMID 19269025.
  17. ↑ Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C; et al. (2007). "Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial". Lancet. 370 (9605): 2103–11. doi:10.1016/S0140-6736(07)61904-7. PMID 18156031.
  18. ↑ 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 (8): 2530–40. PMID 10561319.
  19. ↑ Mekhail TM, Abou-Jawde RM, Boumerhi G, Malhi S, Wood L, Elson P; et al. (2005). "Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma". J Clin Oncol. 23 (4): 832–41. doi:10.1200/JCO.2005.05.179. PMID 15681528.
  20. ↑ Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S; et al. (2008). "Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial". Lancet. 372 (9637): 449–56. doi:10.1016/S0140-6736(08)61039-9. PMID 18653228.
  21. ↑ "Interferon-alpha and survival in metastatic renal carcinoma: early results of a randomised controlled trial. Medical Research Council Renal Cancer Collaborators". Lancet. 353 (9146): 14–7. 1999. PMID 10023944.
  22. ↑ Yagoda A, Abi-Rached B, Petrylak D (1995). "Chemotherapy for advanced renal-cell carcinoma: 1983-1993". Semin Oncol. 22 (1): 42–60. PMID 7855619.
  23. ↑ Motzer RJ, Russo P (2000). "Systemic therapy for renal cell carcinoma". J Urol. 163 (2): 408–17. PMID 10647643.
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