Cancer Treatment Reviews
Volume 36, Issue 5 , Pages 416-424 , August 2010

Plethora of agents, plethora of targets, plethora of side effects in metastatic renal cell carcinoma

  • Manuela Schmidinger

      Affiliations

    • Department of Medicine I, Clinical Division of Oncology and Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
    • Corresponding Author InformationCorresponding author. Tel.: +43 1 40400 4429; fax: +43 1 40400 4498.
  • ,
  • Joaquim Bellmunt

      Affiliations

    • Solid Tumor Oncology (Genitourinary and Gastrointestinal), Medical Oncology Service, Hospital Del Mar, Paseo Maritimo 25–29, Barcelona 08003, Spain

Received 23 October 2009 ,Revised 13 January 2010 ,Accepted 18 January 2010.

References 

  1. Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev. 2005;CD001425
  2. Jonasch E, Haluska FG. Interferon in oncological practice: review of interferon biology, clinical applications, and toxicities. Oncologist. 2001;6:34–55
  3. Schwartz RN, Stover L, Dutcher J. Managing toxicities of high-dose interleukin-2. Oncology (Williston Park). 2002;16(Suppl. 13):11–20
  4. Sablin MP, Bouaita L, Balleyguier C, et al. Sequential use of sorafenib and sunitinib in renal cancer: Retrospective analysis in 90 patients. J Clin Oncol. 2007;25(June 20 Suppl.):244s;[Abstract 5038]
  5. Rini BI, Wilding G, Hudes G, et al. Axitinib (AG-013736; AG) in patients (pts) with metastatic renal cell cancer (RCC) refractory to sorafenib. J Clin Oncol. 2007;25(June 20 Suppl.):242s;[Abstract 5032]
  6. 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
  7. Escudier BJ, Bellmunt J, Negrier S, et al. Final results of the phase III, randomized, double-blind AVOREN trial of first-line bevacizumab (BEV)+interferon-α2a (IFN) in metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2009;27(May 20 Suppl.):239s;[Abstract 5020]
  8. Rini BI, Halabi S, Rosenberg J, et al. Bevacizumab plus interferon-alpha versus interferon-alpha monotherapy in patients with metastatic renal cell carcinoma: results of overall survival for CALGB 90206. J Clin Oncol. 2009;27(June 20 Suppl.):798s;[Abstract LBA5019]
  9. 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
  10. Sternberg CN, Szczylik C, Lee E, et al. A randomized, double-blind phase III study of pazopanib in treatment-naive and cytokine-pretreated patients with advanced renal cell carcinoma (RCC). J Clin Oncol. 2009;27(May 20 Suppl.):240s;[Abstract 5021]
  11. Escudier B, Eisen T, Stadler WM, et al. Sorafenib for treatment of renal cell carcinoma: final efficacy and safety results of the phase III treatment approaches in renal cancer global evaluation trial. J Clin Oncol. 2009;27:3312–3318
  12. 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
  13. 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
  14. Herbst C, Kosmehl H, Stiller KJ, et al. Evaluation of microvessel density by computerised image analysis in human renal cell carcinoma. Correlation to pT category, nuclear grade, proliferative activity and occurrence of metastasis. J Cancer Res Clin Oncol. 1998;124:141–147
  15. Jacobsen J, Grankvist K, Rasmuson T, Bergh A, Landberg G, Ljungberg B. Expression of vascular endothelial growth factor protein in human renal cell carcinoma. BJU Int. 2004;93:297–302
  16. Kaelin WG. The von Hippel–Lindau tumor suppressor protein and clear cell renal carcinoma. Clin Cancer Res. 2007;13:680s–684s
  17. Kaelin WG. The von Hippel–Lindau protein, HIF hydroxylation, and oxygen sensing. Biochem Biophys Res Commun. 2005;338:627–638
  18. Folkman J. Antiangiogenesis agents. In:  DeVita VT,  Helmann S,  Rosenberg SA editor. Cancer principles and practice of oncology. 7th ed.. Philadelphia: Lippincott Williams and Wilkins; 2005;p. 2865–2882
  19. Verheul HM, Pinedo HM. The role of vascular endothelial growth factor (VEGF) in tumor angiogenesis and early clinical development of VEGF-receptor kinase inhibitors. Clin Breast Cancer. 2000;1(Suppl. 1):S80–S84
  20. Jain RK, Duda DG, Clark JW, Loeffler JS. Lessons from phase III clinical trials on anti-VEGF therapy for cancer. Nat Clin Pract Oncol. 2006;3:24–40
  21. Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009;10:165–177
  22. Lobov IB, Brooks PC, Lang RA. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proc Natl Acad Sci USA. 2002;99:11205–11210
  23. Baluk P, Hashizume H, McDonald DM. Cellular abnormalities of blood vessels as targets in cancer. Curr Opin Genet Dev. 2005;15:102–111
  24. Willett CG, Boucher Y, di Tomaso E, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med. 2004;10:145–147
  25. Presta LG, Chen H, O’Connor SJ, et al. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res. 1997;57:4593–4599
  26. Kim KJ, Li B, Houck K, Winer J, Ferrara N. The vascular endothelial growth factor proteins: identification of biologically relevant regions by neutralizing monoclonal antibodies. Growth Factors. 1992;7:53–64
  27. 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
  28. Bukowski RM, Kabbinavar FF, Figlin RA, et al. Randomized phase II study of erlotinib combined with bevacizumab compared with bevacizumab alone in metastatic renal cell cancer. J Clin Oncol. 2007;25:4536–4541
  29. 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
  30. Rini B, Halabi S, Rosenberg J, et al. CALGB 90206: a phase III trial of bevacizumab plus interferon-alpha monotherapy in metastatic renal cell carcinoma. In: Presented at Genitourinary Cancers Symposium; 2008. p. 267 [Abstract 350].
  31. Avastin Summary of Product Characteristics (SmPC). 2008. Available from: http://www.emea.europa.eu/humandocs/Humans/EPAR/avastin/avastin.htm.
  32. Besse B, Lasserre S, Compton P, et al. Bevacizumab Safety in Patients with Central Nervous System Metastases. Clin Cancer Res. 2010;16:269–278
  33. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666–2676
  34. Sandler A, Gray R, Perry MC, et al. Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542–2550
  35. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–2342
  36. Carmeliet P, Ferreira V, Breier G, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature. 1996;380:435–439
  37. Ferrara N, Chen H, vis-Smyth T, et al. Vascular endothelial growth factor is essential for corpus luteum angiogenesis. Nat Med. 1998;4:336–340
  38. Wedge SR, Kendrew J, Hennequin LF, et al. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibitor for the treatment of cancer. Cancer Res. 2005;65:4389–4400
  39. Rousseau S, Houle F, Huot J. Integrating the VEGF signals leading to actin-based motility in vascular endothelial cells. Trends Cardiovasc Med. 2000;10:321–327
  40. Koolwijk P, Peters E, Van dV, et al. Involvement of VEGFR-2 (kdr/flk-1) but not VEGFR-1 (flt-1) in VEGF-A and VEGF-C-induced tube formation by human microvascular endothelial cells in fibrin matrices in vitro. Angiogenesis. 2001;4:53–60
  41. Gerber HP, McMurtrey A, Kowalski J. Et al. Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. Requirement for Flk-1/KDR activation. J Biol Chem. 1998;273:30336–30343
  42. Bates DO, Heald RI, Curry FE, Williams B. Vascular endothelial growth factor increases Rana vascular permeability and compliance by different signalling pathways. J Physiol. 2001;533:263–272
  43. Porta C, Szczylik C. Tolerability of first-line therapy for metastatic renal cell carcinoma. Cancer Treat Rev. 2009;35:297–307
  44. Kamba T, McDonald DM. Mechanisms of adverse effects of anti-VEGF therapy for cancer. Br J Cancer. 2007;96:1788–1795
  45. Izzedine H, Rixe O, Billemont B, Baumelou A, Deray G. Angiogenesis inhibitor therapies: focus on kidney toxicity and hypertension. Am J Kidney Dis. 2007;50:203–218
  46. Bates DO, Jones RO. The role of vascular endothelial growth factor in wound healing. Int J Low Extrem Wounds. 2003;2:107–120
  47. Witzenbichler B, Asahara T, Murohara T, et al. Vascular endothelial growth factor-C (VEGF-C/VEGF-2) promotes angiogenesis in the setting of tissue ischemia. Am J Pathol. 1998;153:381–394
  48. Shay-Salit A, Shushy M, Wolfovitz E, et al. VEGF receptor 2 and the adherens junction as a mechanical transducer in vascular endothelial cells. Proc Natl Acad Sci USA. 2002;99:9462–9467
  49. Vaughn C, Zhang L, Schiff D. Reversible posterior leukoencephalopathy syndrome in cancer. Curr Oncol Rep. 2008;10:86–91
  50. Patel TV, Morgan JA, Demetri GD, et al. A preeclampsia-like syndrome characterized by reversible hypertension and proteinuria induced by the multitargeted kinase inhibitors sunitinib and sorafenib. J Natl Cancer Inst. 2008;100:282–284
  51. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–134
  52. Scappaticci FA, Skillings JR, Holden SN, et al. Arterial thromboembolic events in patients with metastatic carcinoma treated with chemotherapy and bevacizumab. J Natl Cancer Inst. 2007;99:1232–1239
  53. Fabbro D, Ruetz S, Buchdunger E, et al. Protein kinases as targets for anticancer agents: from inhibitors to useful drugs. Pharmacol Ther. 2002;93:79–98
  54. Christensen JG. A preclinical review of sunitinib, a multitargeted receptor tyrosine kinase inhibitor with anti-angiogenic and antitumour activities. Ann Oncol. 2007;18(Suppl. 10):x3–x10
  55. Chow LQ, Eckhardt SG. Sunitinib: from rational design to clinical efficacy. J Clin Oncol. 2007;25:884–896
  56. Wilhelm SM, Carter C, Tang L, et al. BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 2004;64:7099–7109
  57. Bhargava P, Esteves B, Nosov DA, et al. Updated activity and safety results of a phase II randomized discontinuation trial (RDT) of AV-951, a potent and selective VEGFR1, 2, and 3 kinase inhibitor, in patients with renal cell carcinoma (RCC). J Clin Oncol. 2009;27(May 20 Suppl.):242s;[Abstract 5032]
  58. Sloan B, Scheinfeld NS. Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. Curr Opin Invest Drugs. 2008;9:1324–1335
  59. Sonpavde G, Hutson TE, Sternberg CN. Pazopanib, a potent orally administered small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma. Expert Opin Invest Drugs. 2008;17:253–261
  60. Kumar R, Knick VB, Rudolph SK, et al. Pharmacokinetic–pharmacodynamic correlation from mouse to human with pazopanib, a multikinase angiogenesis inhibitor with potent antitumor and antiangiogenic activity. Mol Cancer Ther. 2007;6:2012–2021
  61. Hu-Lowe DD, Zou HY, Grazzini ML, et al. Nonclinical antiangiogenesis and antitumor activities of axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endothelial growth factor receptor tyrosine kinases 1, 2, 3. Clin Cancer Res. 2008;14:7272–7283
  62. Tsai KY, Yang CH, Kuo TT, Hong HS, Chang JWC. Hand–foot syndrome and seborrheic dermatitis-like rash induced by sunitinib in a patient with advanced renal cell carcinoma. J Clin Oncol. 2006;24:5786–5788
  63. Erber R, Thurnher A, Katsen AD, et al. Combined inhibition of VEGF and PDGF signaling enforces tumor vessel regression by interfering with pericyte-mediated endothelial cell survival mechanisms. FASEB J. 2004;18:338–340
  64. Botchkareva NV, Khlgatian M, Longley BJ, Botchkarev VA, Gilchrest BA. SCF/c-kit signaling is required for cyclic regeneration of the hair pigmentation unit. FASEB J. 2001;15:645–658
  65. Force T, Krause DS, Van Etten RA. Molecular mechanisms of cardiotoxicity of tyrosine kinase inhibition. Nat Rev Cancer. 2007;7:3324
  66. 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
  67. Gerber HP, Malik AK, Solar GP, et al. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature. 2002;417:954–958
  68. Ramsden JD. Angiogenesis in the thyroid gland. J Endocrinol. 2000;166:475–480
  69. Chu TF, Rupnick MA, Kerkela R, et al. Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet. 2007;370:2011–2019
  70. Yang JC. Bevacizumab for patients with metastatic renal cancer: an update. Clin Cancer Res. 2004;10:6367S–6370S
  71. Giantonio BJ, Catalano PJ, Meropol NJ, et al. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the eastern cooperative oncology group study E3200. J Clin Oncol. 2007;25:1539–1544
  72. Tamaskar I, Bukowski R, Elson P, et al. Thyroid function test abnormalities in patients with metastatic renal cell carcinoma treated with sorafenib. Ann Oncol. 2008;19:265–268
  73. Houk HE, Bello CL, Michaelson MD, et al. Exposure-response of sunitinib in metastatic renal cell carcinoma (mRCC): A population pharmacokinetic/pharmacodynamic (PKPD) approach. J Clin Oncol. 2007;25(June 20 Suppl.):241s;[Abstract 5027]
  74. Mendel DB, Laird AD, Xin XH, et al. 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. 2003;9:327–337
  75. Humar R, Kiefer FN, Berns H, Resink TJ, Battegay EJ. Hypoxia enhances vascular cell proliferation and angiogenesis in vitro via rapamycin (mTOR)-dependent signaling. FASEB J. 2002;16:771–780
  76. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell. 2006;124:471–484
  77. Abraham RT, Gibbons JJ. The mammalian target of rapamycin signaling pathway: twists and turns in the road to cancer therapy. Clin Cancer Res. 2007;13:3109–3114
  78. Crouthamel MC, Kahana JA, Korenchuk S, et al. Mechanism and management of AKT inhibitor-induced hyperglycemia. Clin Cancer Res. 2009;15:217–225
  79. Aggarwal D, Fernandez ML, Soliman GA. Rapamycin, an mTOR inhibitor, disrupts triglyceride metabolism in guinea pigs. Metabolism. 2006;55:794–802
  80. Albiges L, Caramella C, Ferte C, et al. Interstitial pneumonitis during RAD-001 treatment: incidence by blinded radiological analysis. Eur J Cancer Suppl. 2009;7:427;[Abstract 7114]
  81. Pablo M, Hudes G, Dutcher J, et al. Radiographic findings of drug-induced pneumonitis and clinical correlation in patients with advanced renal cell carcinoma treated with temsirolimus. Eur J Cancer Suppl. 2009;7:426;[Abstract 7113]
  82. Pastore S, Mascia F, Mariani V, Girolomoni G. The epidermal growth factor receptor system in skin repair and inflammation. J Invest Dermatol. 2008;128:1365–1374
  83. Klein S, Levitzki A. Targeting the EGFR and the PKB pathway in cancer. Curr Opin Cell Biol. 2009;21:185–193
  84. Letavernier E, Legendre C. MToR inhibitors-induced proteinuria: mechanisms, significance, and management. Transplant Rev (Orlando). 2008;22:125–130
  85. Anderson R, Jatoi A, Robert C, Wood LS, Keating KN, Lacouture ME. Search for evidence-based approaches for the prevention and palliation of hand–foot skin reaction (HFSR) caused by the multikinase inhibitors (MKIs). Oncologist. 2009;14:291–302
  86. 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
  87. 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
  88. 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. J Clin Oncol. 2007;25(June 20 Suppl.):141s;Abstract 3512
  89. Cen P, Daleiden A, Doshi G, Amato R. A phase I study of everolimus plus sorafenib in patients with metastatic renal cell carcinoma (mRCC). J Clin Oncol. 2009;27(May 20 Suppl.):[Abstract e16056]
  90. Kroog GS, Feldman DR, Kondagunta GV, et al. Phase I trial of RAD001 (everolimus) plus sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27(May 20 Suppl.):243s;[Abstract 5037]
  91. Harzstark AL, Rosenberg JE, Weinberg V, et al. A phase I study of sorafenib and RAD001 for metastatic clear cell renal cell carcinoma. J Clin Oncol. 2009;27(May 20 Suppl.):259s;[Abstract 5104]
  92. Ryan CW, Curti BD, Pattee KJ, Besaw L, Beer TM, Fisher B. A dose-escalation phase II study of sunitinib (S) plus erlotinib (E) in advanced renal carcinoma (RCC). In: Presented at 2008 Genitourinary Cancers Symposium, San Francisco, CA; 2008. p. 267 [Abstract 361].
  93. Whorf RC, Hainsworth J, Spigel DR, et al. Phase II study of bevacizumab and everolimus (RAD001) in the treatment of advanced renal cell carcinoma (RCC). J Clin Oncol. 2008;26(May 20 Suppl.):252s;[Abstract 5010]
  94. 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. J Clin Oncol. 2009;27(May 20 Suppl.):244s;[Abstract 5039]
  95. 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). J Clin Oncol. 2008;26(May 20 Suppl.):252s;[Abstract 5011]
  96. 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
  97. Clinical study results – Genentech. http://clinicalstudyresults.gene.com/avf4167g.pdf [serial online] 2009.
  98. Cooney MM, Garcia J, Elson P, et al. Sunitinib and bevacizumab in advanced solid tumors: a phase I trial. J Clin Oncol. 2008;26(May 20 Suppl.):160s;[Abstract 3530]
  99. Sablin MP, Negrier S, Ravaud A, et al. Sequential sorafenib and sunitinib for renal cell carcinoma. J Urol. 2009;182:29–34
  100. Rini BI, Michaelson MD, Rosenberg JE, et al. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol. 2008;26:3743–3748
  101. Dudek AZ, Zolnierek J, Dham A, Lindgren BR, Szczylik C. Sequential therapy with sorafenib and sunitinib in renal cell carcinoma. Cancer. 2009;115:61–67

PII: S0305-7372(10)00018-6

doi: 10.1016/j.ctrv.2010.01.003

Cancer Treatment Reviews
Volume 36, Issue 5 , Pages 416-424 , August 2010