NCCN task force report: Optimizing treatment of advanced renal cell carcinoma with molecular targeted therapy

JNCCN Journal of the National Comprehensive Cancer Network

Volumn 9, Issue SUPPL. 1, 2011, Pages

  Hudes, Gary R ^a   Carducci, Michael A ^a   Choueiri, Toni K ^a   Esper, Peg ^a   Jonasch, Eric ^a   Kumar, Rashmi ^a   Margolin, Kim A ^a   Michaelson, M Dror ^a   Motzer, Robert J ^a   Pili, Roberto ^a   Roethke, Susan ^a   Srinivas, Sandy ^a  

^a NONE

Author keywords

Molecular targeted therapy; mTOR; NCCN; Patient outcomes; Renal cell carcinoma; TKI; VEGF

Indexed keywords

AFLIBERCEPT; ALPHA INTERFERON; AMG 386; AMG 836; AXITINIB; BEVACIZUMAB; CEDIRANIB; DOVITINIB; DOXORUBICIN; ENTINOSTAT; EVEROLIMUS; FORETINIB; GEMCITABINE; INTERLEUKIN 2; ISPINESIB; PANOBINOSTAT; PAZOPANIB; PERIFOSINE; PLACEBO; PROTEIN TYROSINE KINASE INHIBITOR; RAMUCIRUMAB; RAPAMYCIN; RILOTUMUMAB; RX 0201; SORAFENIB; SUNITINIB; TEMSIROLIMUS; TIVOZANIB; UNCLASSIFIED DRUG; UNINDEXED DRUG; VASCULOTROPIN RECEPTOR; VORINOSTAT;

ANEMIA; ANOREXIA; ARTERY THROMBOSIS; ARTICLE; ASCITES; ASTHENIA; CENTRAL NERVOUS SYSTEM DISEASE; CHEMOTHERAPY INDUCED EMESIS; CYTOPENIA; DIARRHEA; DRUG EFFICACY; DRUG MECHANISM; DRUG MEGADOSE; DRUG SAFETY; ENDOCRINE DISEASE; FATIGUE; GASTROINTESTINAL DISEASE; GENE MUTATION; GENETIC ANALYSIS; HAND FOOT SYNDROME; HEART DISEASE; HEART INFARCTION; HEART LEFT VENTRICLE EJECTION FRACTION; HUMAN; HYPERGLYCEMIA; HYPERLIPIDEMIA; HYPERTENSION; HYPOGLYCEMIA; HYPOPHOSPHATEMIA; HYPOTHYROIDISM; KIDNEY CARCINOMA; KIDNEY DYSFUNCTION; LIVER DYSFUNCTION; LIVER TOXICITY; LUNG CONGESTION; LUNG TOXICITY; MOLECULAR BIOLOGY; MOLECULARLY TARGETED THERAPY; MUCOSA INFLAMMATION; NAUSEA; NEPHRECTOMY; NEUTROPENIA; PERIPHERAL EDEMA; PLEURA EFFUSION; PROTEINURIA; QT PROLONGATION; QUALITY OF LIFE; RASH; SIDE EFFECT; SINGLE NUCLEOTIDE POLYMORPHISM; STOMATITIS; TREATMENT RESPONSE; CLINICAL TRIAL (TOPIC); GENETICS; KIDNEY TUMOR; METABOLISM; METHODOLOGY; TREATMENT OUTCOME;

CARCINOMA, RENAL CELL; CLINICAL TRIALS AS TOPIC; HUMANS; KIDNEY NEOPLASMS; MOLECULAR TARGETED THERAPY; TREATMENT OUTCOME;

EID: 79952784860     PISSN: 15401405     EISSN: 15401413     Source Type: Journal    
DOI: 10.6004/jnccn.2011.0124     Document Type: Article

References (167)

1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-300.
2. Motzer RJ, Agarwal N, Beard C, et al. NCCN Clinical Practice Guidelines in Oncology for Kidney Cancer, version 1.2011. Available at: www.NCCN.org/professionals/physician-gls/PDF/kidney.pdf. Accessed January 5, 2011.
3. Brannon AR, Reddy A, Seiler M, et al. Molecular stratification of clear cell renal cell carcinoma by consensus clustering reveals distinct subtypes and survival patterns. Genes Cancer 2010;1:152-163.
4. Eble J, Sauter G, Epstein JI, Sesterhenn IA. World Health Organization Classification of Tumours: Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon, France: IARC Press; 2004.
5. Lopez-Beltran A, Scarpelli M, Montironi R, Kirkali Z. 2004 WHO classification of the renal tumors of the adults. Eur Urol 2006;49:798-805.
6. Linehan WM, Walther MM, Zbar B. The genetic basis of cancer of the kidney. J Urol 2003;170:2163-2172. (Pubitemid 37413950)
7. Pei J, Feder MM, Al-Saleem T, et al. Combined classical cytogenetics and microarray-based genomic copy number analysis reveal frequent 3;5 rearrangements in clear cell renal cell carcinoma. Genes Chromosomes Cancer 2010;49:610-619.
8. Gunawan B, Huber W, Holtrup M, et al. Prognostic impacts of cytogenetic findings in clear cell renal cell carcinoma: gain of 5q31-qter predicts a distinct clinical phenotype with favorable prognosis. Cancer Res 2001;61:7731-7738. (Pubitemid 33049357)
9. Kardas I, Mrozek K, Babinska M, et al. Cytogenetic and molecular findings in 75 clear cell renal cell carcinomas. Oncol Rep 2005;13:949-956.
10. Klatte T, Rao PN, de Martino M, et al. Cytogenetic profile predicts prognosis of patients with clear cell renal cell carcinoma. J Clin Oncol 2009;27:746-753.
11. Beroukhim R, Brunet J, Napoli A, et al. Patterns of gene expression and copy number alterations in von-Hippel Lindau disease-associated and sporadic clear cell carcinoma of the kidney. Cancer Res 2009;69:4674-4681.
12. Young AP, Schlisio S, Minamishima YA, et al. VHL loss actuates a HIF-independent senescence programme mediated by Rb and p400. Nat Cell Biol 2008;10:361-369. (Pubitemid 351331024)
13. Dalgliesh GL, Furge K, Greenman C, et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 2010;463:360-363.
14. Brunelli M, Eccher A, Gobbo S, et al. Loss of chromosome 9p is an independent prognostic factor in patients with clear cell renal cell carcinoma. Mod Pathol 2008;21:1-6.
15. Moch H, Presti JC Jr, Sauter G, et al. Genetic aberrations detected by comparative genomic hybridization are associated with clinical outcome in renal cell carcinoma. Cancer Res 1996;56:27-30. (Pubitemid 26010380)
16. Yoshimoto T, Matsuura K, Karnan S, et al. High-resolution analysis of DNA copy number alterations and gene expression in renal clear cell carcinoma. J Pathol 2007;213:392-401. (Pubitemid 350206511)
17. Monzon FA, Hagenkord JM, Lyons-Weiler MA, et al. Whole genome SNP arrays as a potential diagnostic tool for the detection of characteristic chromosomal aberrations in renal epithelial tumors. Mod Pathol 2008;21:599-608. (Pubitemid 351589654)
18. Gordan JD, Lal P, Dondeti VR, et al. HIF-alpha effects on c-Myc distinguish two subtypes of sporadic VHL-deficient clear cell renal carcinoma. Cancer Cell 2008;14:435-446.
19. Sarbassov DD, Guertin DA, Ali SM, Sabatini DM. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005;307:1098-1101. (Pubitemid 40262113)
20. Toschi A, Lee E, Gadir N, et al. Differential dependence of hypoxia- inducible factors 1 alpha and 2 alpha on mTORC1 and mTORC2. J Biol Chem 2008;283:34495-34499.
21. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990;61:759-767.
22. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 2007;370:2103-2111. (Pubitemid 350296300)
23. Rini BI, Halabi S, Rosenberg JE, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 2008;26:5422-5428.
24. Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427-434. (Pubitemid 36910021)
25. Gordon MS, Margolin K, Talpaz M, et al. Phase I safety and pharmacokinetic study of recombinant human anti-vascular endothelial growth factor in patients with advanced cancer. J Clin Oncol 2001;19:843-850. (Pubitemid 32119100)
26. Kim KJ, Li B, Winer J, et al. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature 1993;362:841-844. (Pubitemid 23132159)
27. Fabian MA, Biggs WH III, Treiber DK, et al. A small moleculekinase interaction map for clinical kinase inhibitors. Nat Biotechnol 2005;23:329-336. (Pubitemid 41094421)
28. Eskens F, de Jonge M, Esteves B, et al. Updated results from a phase I study of AV-951 (KRN951), a potent and selective VEGFR-1, -2 and -3 tyrosine kinase inhibitor, in patients with advanced solid tumors [abstract]. Presented at 2008 AACR Annual Meeting; April 12-16, 2008; San Diego, California. Abstract LB-201.
29. Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol 2007;25:884-896. (Pubitemid 350002890)
30. Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med 2005;353:2477-2490. (Pubitemid 41770167)
31. Motzer RJ, Russo P. Systemic therapy for renal cell carcinoma. J Urol 2000;163:408-417. (Pubitemid 30060482)
32. Rini BI, Bukowski RM. Targeted therapy for metastatic renal cell carcinoma: a home run or a work in progress? Oncology 2008;22:388-396.
33. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125-134. (Pubitemid 46089673)
34. Dhanasekaran DN, Johnson GL. MAPKs: function, regulation, role in cancer and therapeutic targeting. Oncogene 2007;26:3097-3099. (Pubitemid 46763009)
35. Motzer RJ, Michaelson MD, Redman BG, et al. 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 2006;24:16-24. (Pubitemid 46630489)
36. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-124. (Pubitemid 46089672)
37. Schutz FA, Choueiri TK, Sternberg CN. Pazopanib: clinical development of a potent anti-angiogenic drug. Crit Rev Oncol Hematol 2010; in press.
38. Nicklin P, Bergman P, Zhang B, et al. Bidirectional transport of amino acids regulates mTOR and autophagy. Cell 2009;136:521-534.
39. Seeliger H, Guba M, Kleespies A, et al. Role of mTOR in solid tumor systems: a therapeutical target against primary tumor growth, metastases, and angiogenesis. Cancer Metastasis Rev 2007;26:611-621. (Pubitemid 350115107)
40. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell 2006;124:471-484.
41. Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007;12:9-22. (Pubitemid 47001784)
42. Robb VA, Karbowniczek M, Klein-Szanto AJ, Henske EP. Activation of the mTOR signaling pathway in renal clear cell carcinoma. J Urol 2007;177:346-352. (Pubitemid 44879483)
43. Youssif TA, Fahmy MA, Koumakpayi IH, et al. The mammalian target of rapamycin pathway is widely activated without PTEN deletion in renal cell carcinoma metastases. Cancer 2011;15:290-300.
44. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-2281. (Pubitemid 46849157)
45. Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d'Immunotherapie. N Engl J Med 1998;338:1272-1278. (Pubitemid 28216581)
46. Fyfe G, Fisher RI, Rosenberg SA, et al. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol 1995;13:688-696.
47. Dutcher JP, Fisher RI, Weiss G, et al. Outpatient subcutaneous interleukin- 2 and interferon-alpha for metastatic renal cell cancer: five-year follow-up of the Cytokine Working Group Study. Cancer J Sci Am 1997;3:157-162.
48. Rosenberg SA, Mule JJ, Spiess PJ, et al. Regression of established pulmonary metastases and subcutaneous tumor mediated by the systemic administration of high-dose recombinant interleukin 2. J Exp Med 1985;161:1169-1188. (Pubitemid 15011332)
49. van Boxel-Dezaire AH, Rani MR, Stark GR. Complex modulation of cell type-specific signaling in response to type I interferons. Immunity 2006;25:361-372. (Pubitemid 44354225)
50. Yagoda A, Abi-Rached B, Petrylak D. Chemotherapy for advanced renal-cell carcinoma: 1983-1993. Semin Oncol 1995;22:42-60.
51. Yagoda A, Petrylak D, Thompson S. Cytotoxic chemotherapy for advanced renal cell carcinoma. Urol Clin North Am 1993;20:303-321. (Pubitemid 23154480)
52. Mickisch G, Bier H, Bergler W, et al. P-170 glycoprotein, glutathione and associated enzymes in relation to chemoresistance of primary human renal cell carcinomas. Urol Int 1990;45:170-176. (Pubitemid 20172046)
53. Dutcher JP, Nanus D. Long-term survival of patients with sarcomatoid renal cell cancer treated with chemotherapy. Med Oncol 2010; in press.
54. Haas N, Manola J, Pins M, et al. ECOG 8802: phase II trial of doxorubicin (Dox) and gemcitabine (Gem) in metastatic renal cell carcinoma (RCC) with sarcomatoid features [abstract]. Presented at the 2009 ASCO Genitourinary Cancers Symposium; February 26-28, 2009; Orlando, Florida. Abstract 285
55. McDermott DF, Regan MM, Clark JI, et al. 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 2005;23:133-141. (Pubitemid 41702632)
56. Motzer RJ, Hutson TE, Tomczak P, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584-3590.
57. McDermott DF. Update on the application of interleukin-2 in the treatment of renal cell carcinoma. Clin Cancer Res 2007;13:716s-720s.
58. Yang JC, Sherry RM, Steinberg SM, et al. Randomized study of high-dose and low-dose interleukin-2 in patients with metastatic renal cancer. J Clin Oncol 2003;21:3127-3132. (Pubitemid 46606294)
59. Rosenberg SA, Yang JC, Topalian SL, et al. Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin 2. JAMA 1994;271:907-913.
60. Negrier S, Perol D, Ravaud A, et al. Medroxyprogesterone, interferon alfa-2a, interleukin 2, or combination of both cytokines in patients with metastatic renal carcinoma of intermediate prognosis: results of a randomized controlled trial. Cancer 2007;110:2468-2477. (Pubitemid 350174932)
61. Cho DC, Puzanov I, Regan MM, et al. Retrospective analysis of the safety and efficacy of interleukin-2 after prior VEGF-targeted therapy in patients with advanced renal cell carcinoma. J Immunother 2009;32:181-185.
62. Bui MH, Seligson D, Han KR, et al. Carbonic anhydrase IX is an independent predictor of survival in advanced renal clear cell carcinoma: implications for prognosis and therapy. Clin Cancer Res 2003;9:802-811. (Pubitemid 36182618)
63. Leibovich BC, Blute ML, Cheville JC, et al. Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 2003;97:1663-1671. (Pubitemid 36350710)
64. Leibovich BC, Han KR, Bui MH, et al. Scoring algorithm to predict survival after nephrectomy and immunotherapy in patients with metastatic renal cell carcinoma: a stratification tool for prospective clinical trials. Cancer 2003;98:2566-2575. (Pubitemid 37509519)
65. Upton M, Parker RA, Youmans A, et al. Histologic predictors of renal cell carcinoma response to interleukin-2-based therapy. J Immunother 2005;28:488-495. (Pubitemid 41232570)
66. Atkins M, Regan M, McDermott D, et al. Carbonic anhydrase IX expression predicts outcome of interleukin 2 therapy for renal cancer. Clin Cancer Res 2005;11:3714-3721. (Pubitemid 40685588)
67. National Institutes of Health. The high-dose aldesleukin (IL-2) "SELECT" trial for patients with metastatic renal cell carcinoma (SELECT). ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/show/ NCT00554515. Accessed January 7, 2011.
68. McDermott D, Ghebremichael M, Signoretti S, et al. The highdose aldesleukin (HD IL-2) SELECT trial in patients with metastatic renal cell carcinoma (mRCC): preliminary assessment of clinical benefit [abstract]. Presented at the 2010 ASCO Genitourinary Cancers Symposium; March 5-7, 2010; San Francisco, California. Abstract 321.
69. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002;20:289-296. (Pubitemid 34032623)
70. Dutcher JP, de Souza P, McDermott D, et al. Effect of temsirolimus versus interferon-alpha on outcome of patients with advanced renal cell carcinoma of different histologies. Med Oncol 2009;26:202-209.
71. Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006;295:2516-2524. (Pubitemid 43854967)
72. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010;28:1061-1068.
73. Dudek AZ, Zolnierek J, Dham A, et al. Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. Cancer 2009;115:61-67.
74. Heuer R, Eichelberg C, Zacharias M, Heinzer H. Sequential use of the tyrosine kinase inhibitors sorafenib and sunitinib [abstract]. Eur Urol 2009;8(Suppl 4):183. Abstract 251.
75. Porta C, Procopio G, Sabbatini R, et al. Retrospective analysis of the sequential use of sorafenib and sunitinib in patients with advanced renal cell carcinoma (RCC) [abstract]. Eur Urol 2009;8(Suppl 4):183. Abstract 252.
76. Sablin MP, Bouaita L, Balleyguier C, et al. Sequential use of sorafenib and sunitinib in renal cancer: retrospective analysis in 90 patients [abstract]. J Clin Oncol 2007;25(Suppl 18S):Abstract 5038.
77. Shepard DR, Rini BI, Garcia JA, et al. A multicenter prospective trial of sorafenib in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC) refractory to prior sunitinib or bevacizumab [abstract]. J Clin Oncol 2008;26(Suppl 18S):Abstract 5123.
78. Tamaskar I, Pili R. Update on novel agents in renal cell carcinoma. Expert Rev Anticancer Ther 2009;9:1817-1827.
79. Zimmermann K, Schmittel A, Steiner U, et al. Sunitinib treatment for patients with advanced clear-cell renal-cell carcinoma after progression on sorafenib. Oncology 2009;76:350-354.
80. Eichelberg C, Heuer R, Chun FK, et al. Sequential use of the tyrosine kinase inhibitors sorafenib and sunitinib in metastatic renal cell carcinoma: a retrospective outcome analysis. Eur Urol 2008;54:1373-1378.
81. Sablin MP, Negrier S, Ravaud A, et al. Sequential sorafenib and sunitinib for renal cell carcinoma. J Urol 2009;182:29-34.
82. Rini BI, Wilding G, Hudes G, et al. Phase II study of axitinib in sorafenib-refractory metastatic renal cell carcinoma. J Clin Oncol 2009;27:4462-4468.
83. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449-456.
84. Gerullis H, Bergmann L, Maute L, et al. Feasibility of sequential use of sunitinib and temsirolimus in advanced renal cell carcinoma. Med Oncol 2010;27:373-378.
85. National Institutes of Health. Pazopanib versus sunitinib in the treatment of locally advanced and/or metastatic renal cell carcinoma (COMPARZ). ClinicalTrials.gov. Available at: www.clinicaltrials.gov/ct2/show/NCT00720941. Accessed January 7, 2011.
86. National Institutes of Health. Efficacy and safety comparison of RAD001 versus sunitinib in the first-line and second-line treatment of patients with metastatic renal cell carcinoma (RECORD-3). ClinicalTrials.gov. Available at: www.clinicaltrials.gov/ct2/show/NCT00903175. Accessed January 7, 2011.
87. National Institutes of Health. Temsirolimus versus sorafenib as second-line therapy in patients with advanced RCC who have failed first-line sunitinib. ClinicalTrials.gov. Available at: www.clinicaltrials.gov/ct2/show/ NCT00474786. Accessed January 7, 2011.
88. Pfizer announces positive phase 3 trial results for axitinib in patients with previously-treated metastatic renal cell carcinoma (mRCC) [news release]. New York, NY: PR Newswire; November 19, 2010. Available at: www.prnewswire.com/ news-releases/pfizer-announces-positive-phase-3-trial-results-for-axitinib-in- patients-with-previously-treated-metastatic-renal-cell-carcinomamrcc-109184544. html. Accessed January 7, 2011.
89. National Institutes of Health. Sequential two-agent assessment in renal cell carcinoma therapy. ClinicalTrials.gov. Available at: www.clinicaltrial.gov/ ct2/show/NCT01217931?term=START+trial&rank=2. Accessed January 7, 2011.
90. National Institutes of Health. Bevacizumab, sorafenib, and temsirolimus in treating patients with metastatic kidney cancer. ClinicalTrials.gov. Available at: www.clinicaltrial.gov/ct2/show/NCT00378703. Accessed January 7, 2011.
91. National Institutes of Health. Study comparing bevacizumab + temsirolimus vs. bevacizumab + interferon-alfa in advanced renal cell carcinoma subjects (INTORACT). ClinicalTrials.gov. Available at: www.clinicaltrials.gov/ct2/show/ NCT00631371. Accessed January 7, 2011.
92. National Institutes of Health. Safety and efficacy of bevacizumab plus RAD001 versus interferon alfa-2a and bevacizumab in adult patients with kidney cancer (L2201). ClinicalTrials.gov. Available at: www.clinicaltrials.gov/ct2/ show/NCT00719264. Accessed January 7, 2011.
93. Flanigan RC, Mickisch G, Sylvester R, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol 2004;171:1071-1076. (Pubitemid 38327529)
94. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001;345:1655-1659. (Pubitemid 33126820)
95. Mickisch GH, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet 2001;358:966-970. (Pubitemid 32913522)
96. National Institutes of Health. Clinical trial to assess the importance of nephrectomy (CARMENA). ClinicalTrials.gov. Available at: www.clinicaltrials. gov/ct2/show/NCT00930033. Accessed January 7, 2011.
97. National Institutes of Health. Immediate surgery or surgery after sunitinib malate in treating patients with metastatic kidney cancer. ClinicalTrials.gov. Available at: www.clinicaltrials.gov/ct2/show/NCT01099423. Accessed January 7, 2011.
98. National Institutes of Health. Sunitinib or sorafenib in treating patients with kidney cancer that was removed by surgery. ClinicalTrials.gov. Available at: www.clinicaltrials.gov/ct2/show/NCT00326898. Accessed January 7, 2011.
99. National Institutes of Health. A clinical trial comparing ef- ficacy and safety of sunitinib versus placebo for thetreatment of patients at high risk of recurrent renal cell cancer (S-TRAC). ClinicalTrials.gov. Available at: www.clinicaltrials.gov/ct2/show/NCT00375674. Accessed January 7, 2011.
100. National Institutes of Health. Sorafenib in treating patients at risk of relapse after undergoing surgery to remove kidney cancer. ClinicalTrials.gov. Available at: www.clinicaltrials.gov/ct2/show/NCT00492258. Accessed January 7, 2011.
101. Rixe O, Bukowski RM, Michaelson MD, et al. Axitinib treatment in patients with cytokine-refractory metastatic renal-cell cancer: a phase II study. Lancet Oncol 2007;8:975-984. (Pubitemid 47629888)
102. Sane DC, Anton L, Brosnihan KB. Angiogenic growth factors and hypertension. Angiogenesis 2004;7:193-201.
103. Tang JR, Markham NE, Lin YJ, et al. Inhaled nitric oxide attenuates pulmonary hypertension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor. Am J Physiol Lung Cell Mol Physiol 2004;287:L344-351.
104. Izzedine H, Rixe O, Billemont B, et al. Angiogenesis inhibitor therapies: focus on kidney toxicity and hypertension. Am J Kidney Dis 2007;50:203-218. (Pubitemid 47095077)
105. Zhu X, Wu S, Dahut WL, Parikh CR. Risks of proteinuria and hypertension with bevacizumab, an antibody against vascular endothelial growth factor: systematic review and meta-analysis. Am J Kidney Dis 2007;49:186-193. (Pubitemid 46178407)
106. Gordon MS, Cunningham D. Managing patients treated with bevacizumab combination therapy. Oncology 2005;69(Suppl 3):25-33. (Pubitemid 41680950)
107. Kim CY, Chu D, Baer L, Wu S. High-grade proteinuria associated with bevacizumab in patients with renal cell cancer and non-renal cell cancer [abstract]. J Clin Oncol 2009;27(Suppl 18S):Abstract e16089.
108. Billemont B, Thibault F, Ropert S, et al. Association between acute severe renal toxicity (ASRT) and survival in patients (pts) with metastatic renal cell carcinoma (mRCC) receiving sunitinib [abstract]. Presented at the 2009 ASCO Genitourinary Cancers Symposium; February 26-28, 2009; Orlando, Florida. Asbtract 307.
109. Patel PH, Senico PL, Curiel RE, Motzer RJ. Phase I study combining treatment with temsirolimus and sunitinib malate in patients with advanced renal cell carcinoma. Clin Genitourin Cancer 2009;7:24-27.
110. Sleijfer S, Ray-Coquard I, Papai Z, et al. Pazopanib, a multikinase angiogenesis inhibitor, in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the European Organisation for Research and Treatment of Cancer-soft tissue and bone sarcoma group (EORTC study 62043). J Clin Oncol 2009;27:3126-3132.
111. Kamba T, McDonald DM. Mechanisms of adverse effects of anti- VEGF therapy for cancer. Br J Cancer 2007;96:1788-1795. (Pubitemid 46912024)
112. Ranpura V, Hapani S, Chuang J, Wu S. Risk of cardiac ischemia and arterial thromboembolic events with the angiogenesis inhibitor bevacizumab in cancer patients: a meta-analysis of randomized controlled trials. Acta Oncol 2010;49:287-297.
113. Choueiri TK, Schutz FA, Je Y, et al. Risk of arterial thromboembolic events with sunitinib and sorafenib: a systematic review and meta-analysis of clinical trials. J Clin Oncol 2010;28:2280-2285.
114. Sutent [package insert]. New York, NY: Pfizer, Inc.; 2010.
115. Schmidinger M, Zielinski CC, Vogl UM, et al. Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 2008;26:5204-5212.
116. Telli ML, Witteles RM, Fisher GA, Srinivas S. Cardiotoxicity associated with the cancer therapeutic agent sunitinib malate. Ann Oncol 2008;19:1613-1618.
117. Joensuu H. Cardiac toxicity of sunitinib. Lancet 2007;370:1978-1980. (Pubitemid 350236322)
118. Lacouture ME, Wu S, Robert C, et al. Evolving strategies for the management of hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and sunitinib. Oncologist 2008;13:1001-1011.
119. Chu D, Lacouture ME, Fillos T, Wu S. Risk of hand-foot skin reaction with sorafenib: a systematic review and meta-analysis. Acta Oncol 2008;47:176-186.
120. Chu D, Lacouture ME, Weiner E, Wu S. Risk of hand-foot skin reaction with the multitargeted kinase inhibitor sunitinib in patients with renal cell and non-renal cell carcinoma: a meta-analysis. Clin Genitourin Cancer 2009;7:11-19.
121. Basson MD. Gut mucosal healing: is the science relevant? Am J Pathol 2002;161:1101-1105.
122. Baatar D, Jones MK, Tsugawa K, et al. Esophageal ulceration triggers expression of hypoxia-inducible factor-1 alpha and activates vascular endothelial growth factor gene: implications for angiogenesis and ulcer healing. Am J Pathol 2002;161:1449-1457.
123. Jones MK, Kawanaka H, Baatar D, et al. Gene therapy for gastric ulcers with single local injection of naked DNA encoding VEGF and angiopoietin-1. Gastroenterology 2001;121:1040-1047. (Pubitemid 33022082)
124. Xu CF, Reck BH, Xue Z, et al. Pazopanib-induced hyperbilirubinemia is associated with Gilbert's syndrome UGT1A1 polymorphism. Br J Cancer 2010;102:1371-1377.
125. Rini BI, Tamaskar I, Shaheen P, et al. Hypothyroidism in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2007;99:81-83.
126. Hapani S, Chu D, Wu S. Risk of gastrointestinal perforation in patients with cancer treated with bevacizumab: a meta-analysis. Lancet Oncol 2009;10:559-568.
127. Maroto JP, Hudes G, Dutcher JP, et al. Drug-related pneumonitis in patients with advanced renal cell carcinoma treated with temsirolimus. J Clin Oncol 2011;in press.
128. Esper P, Gale D, Muehlbauer P. What kind of rash is it: deciphering the dermatologic toxicities of biologic and targeted therapies. Clin J Oncol Nurs 2007;11:659-666.
129. Balagula Y, Lacouture ME, Cotliar JA. Dermatologic toxicities of targeted anticancer therapies. J Support Oncol 2010;8:149-161.
130. Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. National Cancer Institute. Available at: http://evs.nci.nih.gov/ftp1/CTCAE/ CTCAE-4.03-2010-06-14-QuickReference-8.5x11.pdf. Accessed January 7, 2011.
131. Maitland ML, Bakris GL, Black HR, et al. Initial assessment, surveillance, and management of blood pressure in patients receiving vascular endothelial growth factor signaling pathway inhibitors. J Natl Cancer Inst 2010;102:596-604.
132. White DA, Camus P, Endo M, et al. Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma. Am J Respir Crit Care Med 2010;182:396-403.
133. Hutson TE, Figlin RA, Kuhn JG, Motzer RJ. Targeted therapies for metastatic renal cell carcinoma: an overview of toxicity and dosing strategies. Oncologist 2008;13:1084-1096.
134. Ravaud A. How to optimise treatment compliance in metastatic renal cell carcinoma with targeted agents. Ann Oncol 2009;20(Suppl 1):i7-12.
135. Billemont B, Medioni J, Taillade L, et al. Blood glucose levels in patients with metastatic renal cell carcinoma treated with sunitinib. Br J Cancer 2008;99:1380-1382.
136. Nexavar [package insert]. Montville, NJ; Bayer HealthCare Pharmaceuticals Inc.; 2010.
137. Avastin [package insert]. South San Francisco, CA; Genentech, Inc.; 2009.
138. Torisel [package insert]. Charlotte, NC; Wyeth Pharmaceuticals Inc.; 2010.
139. Votrient [package insert]. Research Triangle Park, NC; GlaxoSmithKline; 2009.
140. Afinitor [package insert]. East Hanover, NJ; Novartis Pharmaceuticals Corporation; 2010.
141. Shepard DR, Garcia JA. Toxicity associated with the long-term use of targeted therapies in patients with advanced renal cell carcinoma. Expert Rev Anticancer Ther 2009;9:795-805.
142. Berger AM, Abernethy AP, Atkinson A, et al. NCCN Clinical Practice Guidelines in Oncology: Cancer-Related Fatigue, version 1.2011. Available at: http://www.nccn.org/professionals/physician-gls/PDF/fatigue.pdf. Accessed January 7, 2011.
143. National Institutes of Health. Axitinib (AG 013736) as second line therapy for metastatic renal cell cancer. ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT00678392. Accessed January 7, 2011.
144. National Institutes of Health. a study to compare tivozanib (AV-951) to sorafenib in subjects with advanced renal cell carcinoma (TIVO-1). ClinicalTrials.gov. Available at: www.clinicaltrials.gov/ct2/show/NCT01030783. Accessed January 7, 2011.
145. Shi M, Kim KB, Chesney J, et al. Effect of TKI258 in plasma biomarkers and pharmacokinetics in patients with advanced melanoma [abstract]. J Clin Oncol 2009;27(Suppl 18S):Abstract 9020.
146. Casanovas O, Hicklin DJ, Bergers G, Hanahan D. Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in latestage pancreatic islet tumors. Cancer Cell 2005;8:299-309. (Pubitemid 41443415)
147. Angevin E, Lin C, Pande AU, et al. A phase I/II study of dovitinib (TKI258), a FGFR and VEGFR inhibitor, in patients (pts) with advanced or metastatic renal cell cancer: phase I results [abstract]. J Clin Oncol 2010;28(Suppl 18S):Abstract 3057.
148. Angevin E. A phase I/II study of TKI258 (dovitinib), a FGFR and VEGFR inhibitor, in patients (pts) with advanced or metastatic renal cell cancer (mRCC): preliminary phase II results [abstract]. Presented at the 35th European Society for Medical Oncology (ESMO) Congress; October 8-12, 2010; Milan, Italy. Abstract 507P.
149. National Institutes of Health. Study of TKI258 versus sorafenib in patients with metastatic renal cell carcinoma. ClinicalTrials.gov. Available at: www.clinicaltrials.gov/ct2/show/NCT01223027. Accessed January 7, 2011.
150. Garcia JA, Hudes GR, Choueiri TK, et al. Phase II study of IMC-1121B in patients with metastatic renal cancer (mRCC) following VEGFR-2 tyrosine kinase inhibitor (TKI) therapy (IMCL CP12-0605/NCT00515697) [abstract]. Presented at the 2010 ASCO Genitourinary Cancers Symposium; March 5-7, 2010; San Francisco, California. Abstract 326.
151. Appleman LJ, Gordan MS, Samlowski W, et al. Open-label phase 1b study of AMG 386, a selective angiopoietin1/2-neutralizing peptibody, in combination with sorafenib or sunitinib in advanced renal cell carcinoma (RCC): interim results [abstract]. Presented at the 35th European Society for Medical Oncology (ESMO) Congress; October 8-12, 2010; Milan, Italy. Abstract 505P.
152. National Institutes of Health. AMG 386, 20060159 phase 2, RCC 1st line in combination with sorafenib. ClinicalTrials.gov. Available at: www.clinicaltrials.gov/ct2/show/NCT00467025. Accessed January 7, 2011.
153. Verheul HM, Hammers H, van Erp K, et al. Vascular endothelial growth factor trap blocks tumor growth, metastasis formation, and vascular leakage in an orthotopic murine renal cell cancer model. Clin Cancer Res 2007;13:4201-4208. (Pubitemid 47105984)
154. National Institutes of Health. VEGF trap in treating patients with metastatic or unresectable kidney cancer. ClinicalTrials.gov. Available at: www.clinicaltrials.gov/ct2/show/NCT00357760. Accessed January 7, 2011.
155. Qian DZ, Wang X, Kachhap SK, et al. The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ ZK222584. Cancer Res 2004;64:6626-6634. (Pubitemid 39297923)
156. Hammers HJ, Verheul H, Wilky B, et al. Phase I safety and pharmacokinetic/ pharmacodynamic results of the histone deacetylase inhibitor vorinostat in combination with bevacizumab in patients with kidney cancer [abstract]. J Clin Oncol 2008;26(Suppl 18S):Abstract 16094.
157. National Institutes of Health. Vorinostat and bevacizumab in treating patients with unresectable or metastatic kidney cancer. ClinicalTrials.gov. Available at: www.clinicaltrials.gov/ct2/show/NCT00324870. Accessed January 7, 2011.
158. Pili R, Lodge M, Verheul H, et al. Combination of the histone deacetylase inhibitor vorinostat with bevacizumab in pretreated patients with renal cell carcinoma: safety, efficacy, and pharmacodynamic results [abstract]. Presented at the 2010 ASCO Genitourinary Cancers Symposium; March 5-7, 2010; San Francisco, California. Abstract 350.
159. Brahmer JR, Drake CG, Wollner I, et al. Phase I study of singleagent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 2010;28:3167-3175.
160. Sznol M, Powderly JD, Smith DC, et al. Safety and antitumor activity of biweekly MDX-1106 (Anti-PD-1, BMS-936558/ ONO-4538) in patients with advanced refractory malignancies [abstract]. J Clin Oncol 2010;28(Suppl):Abstract 2506.
161. Kroog GS, Feldman DR, Kondagunta GV, et al. Phase I trial of RAD001 (everolimus) plus sunitinib in patients with metastatic renal cell carcinoma [abstract]. J Clin Oncol 2009;27(Suppl 15S):Abstract 5037.
162. Feldman DR, Baum MS, Ginsberg MS, et al. Phase I trial of bevacizumab plus escalated doses of sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:1432-1439.
163. Merchan JR, Pitot HC, Qin R, et al. Phase I/II trial of CCI 779 and bevacizumab in advanced renal cell carcinoma (RCC): safety and activity in RTKI refractory RCC patients [abstract]. J Clin Oncol 2009;27(Suppl 15S):Abstract 5039.
164. Hainsworth JD, Spigel DR, Burris HA III, et al. Phase II trial of bevacizumab and everolimus in patients with advanced renal cell carcinoma. J Clin Oncol 2010;28:2131-2136.
165. Sosman JA, Flaherty KT, Atkins MB, et al. Updated results of phase I trial of sorafenib (S) and bevacizumab (B) in patients with metastatic renal cell cancer (mRCC) [abstract]. J Clin Oncol 2008;26(Suppl 15S):Abstract 5011.
166. Patnaik A, Ricart A, Cooper J, et al. A phase I, pharmacokinetic and pharmacodynamic study of sorafenib (S), a multi-targeted kinase inhibitor in combination with temsirolimus (T), an mTOR inhibitor in patients with advanced solid malignancies [abstract]. J Clin Oncol 2007;25(Suppl 18S):Abstract 3512.
167. Cen P, Daleiden A, Doshi G, Amato R. A phase I study of everolimus plus sorafenib in patients with metastatic renal cell carcinoma (mRCC) [abstract]. J Clin Oncol 2009;27(Suppl 15S):Abstract e16056.