Metastatic renal cell carcinoma: Current scenario and future trends

Anubha Bharthuar

doi:10.4103/2278-330X.96505

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Review Article

01 (

); 30-35

doi:

10.4103/2278-330X.96505

Metastatic renal cell carcinoma: Current scenario and future trends

Anubha Bharthuar^1,

1 Department of Medical Oncology and Hematology, Patel Cancer and Superspeciality Hospital, Jalandhar City, Punjab, India

*Corresponding author: Dr. Anubha Bharthuar. anubhabharthuar@gmail.com

Published: 2020-11-09

MedIntel Services Pvt Ltd. This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/.)

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Abstract

An improved understanding of the biology of renal cell carcinoma (RCC) has led to the development of a number of targeted agents, which has resulted in a paradigm shift in the management of metastatic RCC. We review the current therapeutic strategies for metastatic RCC and present a synopsis of the novel agents in use today with a discussion of the phase III trials that demonstrated their clinical benefit. The management of RCC continues to evolve. The introduction of VEGF and mTOR inhibitors has markedly expanded our drug armamentarium and improved the outcome of a disease that has always been challenging to treat. Knowledge from upcoming trials will help us utilize these drugs for maximum clinical efficacy with optimal dosing and sequencing, either individually or in combination therapy.

Keywords

References

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Lam JS, Shvarts O, Leppert JT, Figlin RA, Belldegrun AS. Renal cell carcinoma 2005: New frontiers in staging, prognostication and targeted molecular therapy. J Urol 2005;173:1853-62.
Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001;345:1655-9.
Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. Radical nephrectomy plus interferon alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: A randomised trial. Lancet 2001;358:966-70.
Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. Cytoreductive nephrectomy in patients with metastatic renal cancer: A combined analysis. J Urol 2004;171:1071-6.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125-34.
Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: A randomised, double-blind phase III trial. Lancet 2007;370:2103-11.
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: A double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449-56.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-24.
Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 2008;26:5422-8.
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Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 2000;6 Suppl 1:S55-7.
Neidhart JA. Interferon therapy for the treatment of renal cancer. Cancer 1986;57:1696-9.
Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev 2005;1:CD001425.
Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002;20:289-96.
Shuin T, Kondo K, Torigoe S, Kishida T, Kubota Y, Hosaka M, et al. Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res 1994;54:2852-5.
Ferrara N. Vascular endothelial growth factor: Basic science and clinical progress. Endocr Rev 2004;25:581-611.
George DJ, Kaelin WG. The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer. N Engl J Med 2003;349:419-21.
Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: Implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 2001;17:615-75.
Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: A randomised, double-blind phase III trial. Lancet 2007;370:2103-11.
Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): Final analysis of overall survival. J Clin Oncol 2010;28:2144-50.
Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: Final results of CALGB 90206. J Clin Oncol 2010;28:2137-43.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-24.
Motzer RJ, Hutson TE, Olsen MR, Hudes GR, Burke JM, Edenfield WJ, et al. Randomized phase II multicenter study of the efficacy and safety of sunitinib on the 4/2 versus continuous dosing schedule as first-line therapy of metastatic renal cell carcinoma: Renal EFFECT Trial. J Clin Oncol 2011;29 Suppl 7:abstr 308.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, 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;27:3312-8.
Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:1280-9.
Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomized phase III trial. J Clin Oncol 2010;28:1061-8.
Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial. Lancet 2011;378:1931-9.
Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2011;103:763-73.
Bhargava P, Esteves B, Nosov DA, Nosov DA, Lyulko AA, Anischenkoet AO, 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 2008;26 Suppl 1:35403.
Available from: http://www.clinicaltrials.gov/ct2/show/NCT01030783. [Last cited in 2012].
Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007;12:9-22.
Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, et al. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 2006;66:5549-54.
Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-81.
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma : Final results and analysis of prognostic factors. Cancer 2010;116:4256-65.
Escudier BJ, Negrier S, Gravis G, Chevreau C, Delva R, Bay J, et al. Can the combination of temsirolimus and bevacizumab improve the treatment of metastatic renal cell carcinoma (mRCC)? Results of the randomized TORAVA phase II trial. J Clin Oncol 2010;15s:abstr 4516.
Available from: http://clinicaltrials.gov/ct2/show/NCT00631371. [Last cited in 2012].
Hainsworth JD, Spigel D, Burris HA, Waterhouse D, Clark BL, Whorf R. Phase II trial of bevacizumab and everolimus in patients with advanced renal cell carcinoma. J Clin Oncol 2010;28:2131-6.
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[1] Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.

[2] Lam JS, Shvarts O, Leppert JT, Figlin RA, Belldegrun AS. Renal cell carcinoma 2005: New frontiers in staging, prognostication and targeted molecular therapy. J Urol 2005;173:1853-62.

[3] Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med 2001;345:1655-9.

[4] Mickisch GH, Garin A, van Poppel H, de Prijck L, Sylvester R. Radical nephrectomy plus interferon alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: A randomised trial. Lancet 2001;358:966-70.

[5] Flanigan RC, Mickisch G, Sylvester R, Tangen C, Van Poppel H, Crawford ED. Cytoreductive nephrectomy in patients with metastatic renal cancer: A combined analysis. J Urol 2004;171:1071-6.

[6] Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125-34.

[7] Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: A randomised, double-blind phase III trial. Lancet 2007;370:2103-11.

[8] Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Efficacy of everolimus in advanced renal cell carcinoma: A double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449-56.

[9] Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-24.

[10] Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, et al. Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 2008;26:5422-8.

[11] Available from: http://www.clinicaltrials.gov/ct2/show/NCT00930033. [Last cited in 2012].

[12] Available from: http://www.clinicaltrials.gov/ct2/show/NCT00626509. [Last cited in 2012].

[13] Available from: http://www.clinicaltrials.gov/ct2/show/NCT00717587. [Last cited in 2012].

[14] Available from: http://www.clinicaltrials.gov/ct2/show/NCT00113217. [Last cited in 2012].

[15] Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am 2000;6 Suppl 1:S55-7.

[16] Neidhart JA. Interferon therapy for the treatment of renal cancer. Cancer 1986;57:1696-9.

[17] Coppin C, Porzsolt F, Awa A, Kumpf J, Coldman A, Wilt T. Immunotherapy for advanced renal cell cancer. Cochrane Database Syst Rev 2005;1:CD001425.

[18] Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol 2002;20:289-96.

[19] Shuin T, Kondo K, Torigoe S, Kishida T, Kubota Y, Hosaka M, et al. Frequent somatic mutations and loss of heterozygosity of the von Hippel-Lindau tumor suppressor gene in primary human renal cell carcinomas. Cancer Res 1994;54:2852-5.

[20] Ferrara N. Vascular endothelial growth factor: Basic science and clinical progress. Endocr Rev 2004;25:581-611.

[21] George DJ, Kaelin WG. The von Hippel-Lindau protein, vascular endothelial growth factor, and kidney cancer. N Engl J Med 2003;349:419-21.

[22] Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: Implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol 2001;17:615-75.

[23] Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: A randomised, double-blind phase III trial. Lancet 2007;370:2103-11.

[24] Escudier B, Bellmunt J, Négrier S, Bajetta E, Melichar B, Bracarda S, et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): Final analysis of overall survival. J Clin Oncol 2010;28:2144-50.

[25] Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Archer L, et al. Phase III trial of bevacizumab plus interferon alfa versus interferon alfa monotherapy in patients with metastatic renal cell carcinoma: Final results of CALGB 90206. J Clin Oncol 2010;28:2137-43.

[26] Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007;356:115-24.

[27] Motzer RJ, Hutson TE, Olsen MR, Hudes GR, Burke JM, Edenfield WJ, et al. Randomized phase II multicenter study of the efficacy and safety of sunitinib on the 4/2 versus continuous dosing schedule as first-line therapy of metastatic renal cell carcinoma: Renal EFFECT Trial. J Clin Oncol 2011;29 Suppl 7:abstr 308.

[28] Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Staehler M, 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;27:3312-8.

[29] Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:1280-9.

[30] Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomized phase III trial. J Clin Oncol 2010;28:1061-8.

[31] Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial. Lancet 2011;378:1931-9.

[32] Rini BI, Cohen DP, Lu DR, Chen I, Hariharan S, Gore ME, et al. Hypertension as a biomarker of efficacy in patients with metastatic renal cell carcinoma treated with sunitinib. J Natl Cancer Inst 2011;103:763-73.

[33] Bhargava P, Esteves B, Nosov DA, Nosov DA, Lyulko AA, Anischenkoet AO, 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 2008;26 Suppl 1:35403.

[34] Available from: http://www.clinicaltrials.gov/ct2/show/NCT01030783. [Last cited in 2012].

[35] Guertin DA, Sabatini DM. Defining the role of mTOR in cancer. Cancer Cell 2007;12:9-22.

[36] Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G, et al. Antiangiogenic potential of the Mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 2006;66:5549-54.

[37] Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med 2007;356:2271-81.

[38] Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma : Final results and analysis of prognostic factors. Cancer 2010;116:4256-65.

[39] Escudier BJ, Negrier S, Gravis G, Chevreau C, Delva R, Bay J, et al. Can the combination of temsirolimus and bevacizumab improve the treatment of metastatic renal cell carcinoma (mRCC)? Results of the randomized TORAVA phase II trial. J Clin Oncol 2010;15s:abstr 4516.

[40] Available from: http://clinicaltrials.gov/ct2/show/NCT00631371. [Last cited in 2012].

[41] Hainsworth JD, Spigel D, Burris HA, Waterhouse D, Clark BL, Whorf R. Phase II trial of bevacizumab and everolimus in patients with advanced renal cell carcinoma. J Clin Oncol 2010;28:2131-6.

[42] Available from: http://clinicaltrials.gov/ct2/show/NCT01198158. [Last cited in 2012].

[43] Available from: http://clinicaltrials.gov/ct2/show/NCT00719264. [Last cited in 2012].

[44] Available from: http://clinicaltrials.gov/ct2/show/NCT00378703. [Last cited in 2012].

[45] Available from: http://clinicaltrials.gov/ct2/show/NCT00903175. [Last cited in 2012].

[46] Available from: http://clinicaltrials.gov/ct2/show/NCT00720941. [Last cited in 2012].

[47] Available from: http://clinicaltrials.gov/ct2/show/NCT01064310. [Last cited in 2012].

Metastatic renal cell carcinoma: Current scenario and future trends

Abstract

Abstract

Keywords

References

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