Progress in the treatment of metastatic renal cell carcinoma_West China Medical Journal

Authors：

ZENG Yuanyuan ,  LIU Lei

Department of Head and Neck Oncology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding author：

LIU Lei, Email: liuleihx@gmail.com

Keywords：

Metastatic renal cell carcinoma; Cytoreductive nephrectomy; Cytokine; Targeted therapy; Immunotherapy

DOI：

10.7507/1002-0179.201907153

Video：

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Metastatic renal cell carcinoma accounts for 20%-30% of newly diagnosed renal cell carcinoma and its prognosis is poor. It is not sensitive to radiotherapy or chemotherapy, and traditional cytokine therapy has limited efficacy in patient with metastatic renal cell carcinoma. In recent years, with the emergence of targeted drugs and immune checkpoint inhibitors, the survival of patients with metastatic renal cancer has been greatly improved. This article reviews treatment and research progress of metastatic renal cell carcinoma. It mainly introduces the medical treatment, including cytokine therapy, targeted therapy and emerging immunotherapy, and further analyzes the value of cytoreductive nephrectomy in the context of targeted therapy. The purpose of this article is to provide evidence for reasonable choices of treatment regimens in order to better guide clinical treatment.

Citation： ZENG Yuanyuan, LIU Lei. Progress in the treatment of metastatic renal cell carcinoma. West China Medical Journal, 2019, 34(9): 1068-1074. doi: 10.7507/1002-0179.201907153 Copy

1.	Aydin H, Chen L, Cheng L, et al. Clear cell tubulopapillary renal cell carcinoma: a study of 36 distinctive low-grade epithelial tumors of the kidney. Am J Surg Pathol, 2010, 34(11): 1608-1621.
2.	Gobbo S, Eble JN, Maclennan GT, et al. Renal cell carcinomas with papillary architecture and clear cell components: the utility of immunohistochemical and cytogenetical analyses in differential diagnosis. Am J Surg Pathol, 2008, 32(12): 1780-1786.
3.	Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med, 2005, 353(23): 2477-2490.
4.	Cairns P. Renal cell carcinoma. Cancer Biomark, 2010, 9(1/2/3/4/5/6): 461-473.
5.	Flanigan RC, Mickisch G, Sylvester R, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol, 2004, 171(3): 1071-1076.
6.	Conti SL, Thomas IC, Hagedorn JC, et al. Utilization of cytoreductive nephrectomy and patient survival in the targeted therapy era. Int J Cancer, 2014, 134(9): 2245-2252.
7.	Choueiri TK, Xie W, Kollmannsberger C, et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J Urol, 2011, 185(1): 60-66.
8.	Heng DY, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol, 2014, 66(4): 704-710.
9.	Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med, 2018, 379(5): 417-427.
10.	Ljungberg B, Albiges L, Abu-Ghanem Y, et al. European Association of Urology guidelines on renal cell carcinoma: the 2019 update. Eur Urol, 2019, 75(5): 799-810.
11.	Sathianathen NJ, Krishna S, Anderson JK, et al. The current status of immunobased therapies for metastatic renal-cell carcinoma. Immunotargets Ther, 2017, 6: 83-93.
12.	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(1): 133-141.
13.	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-S57.
14.	Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med, 2007, 356(2): 115-124.
15.	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(1): 289-296.
16.	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(9605): 2103-2111.
17.	Vachhani P, George S. VEGF inhibitors in renal cell carcinoma. Clin Adv Hematol Oncol, 2016, 14(12): 1016-1028.
18.	Thomas GV, Tran C, Mellinghoff IK, et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med, 2006, 12(1): 122-127.
19.	Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med, 2007, 356(2): 125-134.
20.	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(20): 3312-3318.
21.	Escudier B, Szczylik C, Hutson TE, 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(8): 1280-1289.
22.	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(22): 3584-3590.
23.	秦叔逵, Pan S, 金杰, 等. 舒尼替尼一线治疗中国晚期转移性肾细胞癌患者的多中心临床研究//第十五届全国临床肿瘤学大会暨2012年CSCO学术年会论文集. 北京: 中国抗癌协会, 北京市希思科临床肿瘤学研究基金会, 2013: 569-570.
24.	Porta C, Gore ME, Rini BI, et al. Long-term safety of sunitinib in metastatic renal cell carcinoma. Eur Urol, 2016, 69(2): 345-351.
25.	Inoue R, Kitamura H, Shindo T, et al. Dosing schedules and outcomes in patients treated with first-line sunitinib for advanced renal cell carcinoma. Hinyokika Kiyo, 2016, 62(4): 173-177.
26.	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(6): 1061-1068.
27.	Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med, 2013, 369(8): 722-731.
28.	Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med, 2015, 373(19): 1814-1823.
29.	Schmidt L, Duh FM, Chen F, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet, 1997, 16(1): 68-73.
30.	Martínez Chanzá N, Xie W, Asim Bilen M, et al. Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study. Lancet Oncol, 2019, 20(4): 581-590.
31.	Rini BI, Halabi S, Rosenberg JE, 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(13): 2137-2143.
32.	Murugan AK, Liu R, Xing M. Identification and characterization of two novel oncogenic mTOR mutations. Oncogene, 2019, 38(26): 5211-5226.
33.	Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med, 2007, 356(22): 2271-2281.
34.	Hutson TE, Escudier B, Esteban E, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol, 2014, 32(8): 760-767.
35.	Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer, 2010, 116(18): 4256-4265.
36.	Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol, 2014, 32(25): 2765-2772.
37.	Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med, 2015, 373(19): 1803-1813.
38.	Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol, 2015, 16(15): 1473-1482.
39.	Motzer RJ, Hutson TE, Ren M, et al. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol, 2016, 17(1): e4-e5.
40.	Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med, 2018, 378(14): 1277-1290.
41.	Bunt SK, Yang L, Sinha P, et al. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res, 2007, 67(20): 10019-10026.
42.	Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med, 2019, 380(12): 1116-1127.
43.	Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med, 2019, 380(12): 1103-1115.

1. Aydin H, Chen L, Cheng L, et al. Clear cell tubulopapillary renal cell carcinoma: a study of 36 distinctive low-grade epithelial tumors of the kidney. Am J Surg Pathol, 2010, 34(11): 1608-1621.
2. Gobbo S, Eble JN, Maclennan GT, et al. Renal cell carcinomas with papillary architecture and clear cell components: the utility of immunohistochemical and cytogenetical analyses in differential diagnosis. Am J Surg Pathol, 2008, 32(12): 1780-1786.
3. Cohen HT, McGovern FJ. Renal-cell carcinoma. N Engl J Med, 2005, 353(23): 2477-2490.
4. Cairns P. Renal cell carcinoma. Cancer Biomark, 2010, 9(1/2/3/4/5/6): 461-473.
5. Flanigan RC, Mickisch G, Sylvester R, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol, 2004, 171(3): 1071-1076.
6. Conti SL, Thomas IC, Hagedorn JC, et al. Utilization of cytoreductive nephrectomy and patient survival in the targeted therapy era. Int J Cancer, 2014, 134(9): 2245-2252.
7. Choueiri TK, Xie W, Kollmannsberger C, et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J Urol, 2011, 185(1): 60-66.
8. Heng DY, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol, 2014, 66(4): 704-710.
9. Méjean A, Ravaud A, Thezenas S, et al. Sunitinib alone or after nephrectomy in metastatic renal-cell carcinoma. N Engl J Med, 2018, 379(5): 417-427.
10. Ljungberg B, Albiges L, Abu-Ghanem Y, et al. European Association of Urology guidelines on renal cell carcinoma: the 2019 update. Eur Urol, 2019, 75(5): 799-810.
11. Sathianathen NJ, Krishna S, Anderson JK, et al. The current status of immunobased therapies for metastatic renal-cell carcinoma. Immunotargets Ther, 2017, 6: 83-93.
12. 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(1): 133-141.
13. 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-S57.
14. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med, 2007, 356(2): 115-124.
15. 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(1): 289-296.
16. 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(9605): 2103-2111.
17. Vachhani P, George S. VEGF inhibitors in renal cell carcinoma. Clin Adv Hematol Oncol, 2016, 14(12): 1016-1028.
18. Thomas GV, Tran C, Mellinghoff IK, et al. Hypoxia-inducible factor determines sensitivity to inhibitors of mTOR in kidney cancer. Nat Med, 2006, 12(1): 122-127.
19. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med, 2007, 356(2): 125-134.
20. 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(20): 3312-3318.
21. Escudier B, Szczylik C, Hutson TE, 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(8): 1280-1289.
22. 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(22): 3584-3590.
23. 秦叔逵, Pan S, 金杰, 等. 舒尼替尼一线治疗中国晚期转移性肾细胞癌患者的多中心临床研究//第十五届全国临床肿瘤学大会暨2012年CSCO学术年会论文集. 北京: 中国抗癌协会, 北京市希思科临床肿瘤学研究基金会, 2013: 569-570.
24. Porta C, Gore ME, Rini BI, et al. Long-term safety of sunitinib in metastatic renal cell carcinoma. Eur Urol, 2016, 69(2): 345-351.
25. Inoue R, Kitamura H, Shindo T, et al. Dosing schedules and outcomes in patients treated with first-line sunitinib for advanced renal cell carcinoma. Hinyokika Kiyo, 2016, 62(4): 173-177.
26. 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(6): 1061-1068.
27. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med, 2013, 369(8): 722-731.
28. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med, 2015, 373(19): 1814-1823.
29. Schmidt L, Duh FM, Chen F, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet, 1997, 16(1): 68-73.
30. Martínez Chanzá N, Xie W, Asim Bilen M, et al. Cabozantinib in advanced non-clear-cell renal cell carcinoma: a multicentre, retrospective, cohort study. Lancet Oncol, 2019, 20(4): 581-590.
31. Rini BI, Halabi S, Rosenberg JE, 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(13): 2137-2143.
32. Murugan AK, Liu R, Xing M. Identification and characterization of two novel oncogenic mTOR mutations. Oncogene, 2019, 38(26): 5211-5226.
33. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med, 2007, 356(22): 2271-2281.
34. Hutson TE, Escudier B, Esteban E, et al. Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol, 2014, 32(8): 760-767.
35. Motzer RJ, Escudier B, Oudard S, et al. Phase 3 trial of everolimus for metastatic renal cell carcinoma: final results and analysis of prognostic factors. Cancer, 2010, 116(18): 4256-4265.
36. Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol, 2014, 32(25): 2765-2772.
37. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med, 2015, 373(19): 1803-1813.
38. Motzer RJ, Hutson TE, Glen H, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol, 2015, 16(15): 1473-1482.
39. Motzer RJ, Hutson TE, Ren M, et al. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol, 2016, 17(1): e4-e5.
40. Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med, 2018, 378(14): 1277-1290.
41. Bunt SK, Yang L, Sinha P, et al. Reduced inflammation in the tumor microenvironment delays the accumulation of myeloid-derived suppressor cells and limits tumor progression. Cancer Res, 2007, 67(20): 10019-10026.
42. Rini BI, Plimack ER, Stus V, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med, 2019, 380(12): 1116-1127.
43. Motzer RJ, Penkov K, Haanen J, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med, 2019, 380(12): 1103-1115.

West China Medical Journal

Progress in the treatment of metastatic renal cell carcinoma

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