Treatment of Metastatic Renal Cell Carcinoma
Authors:
Richter Igor 1,2; Dvořák Josef 2
Authors‘ workplace:
Onkologické oddělení, Krajská nemocnice Liberec
1; Onkologická klinika 1. LF UK a Thomayerova nemocnice, Praha
2
Published in:
Klin Onkol 2018; 31(2): 110-116
Category:
Review
doi:
https://doi.org/10.14735/amko2018110
Overview
Introduction:
Renal cell cancer accounts for approximately 2–3% of all cases of malignancy. The incidence of kidney cancer in the Czech Republic is the highest in the world. Approximately 70% of renal cell carcinomas are clear-cell renal cancer. Various treatment options for metastatic renal cell cancer (mRCC) have been developed. Treatment regimens comprise antiangiogenic drugs in combination with vascular endothelial growth factor receptor inhibitors, mTOR inhibitors, and immunotherapy.
Aim:
This review provides an overview of the current treatment options for mRCC. Patients with a good performance status and a low systemic disease burden are candidates for cytoreductive nephrectomy. Ablative methods, such as stereotactic radiotherapy, can be used in patients with oligometastatic disease. Sunitinib and pazopanib are preferred first-line treatments for mRCC and provide similar outcomes. Second-line and higher line treatments markedly changed with the development of new drugs, such as cabozantinib and the immunotherapy nivolumab. The optimal treatment sequence for mRCC is discussed. Ongoing studies are evaluating combined treatments and searching for potential biomarkers. However, the tumor heterogeneity of renal cell cancer complicates the use of biomarkers.
Conclusion:
The results of clinical trials have markedly changed the treatment guidelines for mRCC. New strategies include combinatorial approaches, which mainly incorporate immunotherapy.
Key words:
renal cancer – targeted therapy – immunotherapy – metastases – biomarkers
The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.
The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.
Submitted:
19. 12. 2017
Accepted:
7. 1. 2018
Sources
1. Marenčák J, Ondrušová M, Ondruš D. Súčasný pohľad na diagnostiku a liečbu karcinómu obličky. Klin Onkol 2017; 30 (3): 175–181. doi: 10.14735/amko2017175.
2. Dušek L, Mužík J, Kubásek M et al. Epidemiologie zhoubných nádorů v České republice. [online]. Dostupné z: www: http: //www.svod.cz.
3. Dušek L, Mužík J, Malúšková D et al. Incidence a mortalita nádorových onemocnění v České republice. Klin Onkol 2014; 27 (6): 406–423. doi: 10.14735/amko2014406.
4. Srigley JR, Delahunt B, Eble JN et al. The International Society of Urological Pathology (ISUP) Vancouver classification of renal neoplasma. Am J Surg Pathol 2013; 37 (10): 1469–1489. doi: 10.1097/PAS.0b013e318299f2d1.
5. Moch H, Cubilla AL, Humprey PA et al. The 2016 WHO classification of tumours of the urinary system and male genital organs – port A: renal, penile, and testicular tumours. Eur Urol 2016; 70 (1): 93–105. doi: 10.1016/j.eururo.2016.02.029.
6. Kaelin WG Jr. The von Hippel-Lindau tumour suppressors protein: O2 sensing and cancer. Nat Rev Cancer 2008; 8 (11): 865–873. doi: 10.1038/nrc2502.
7. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal carcinoma. Nature 2013; 499 (7456): 43–49. doi: 10.1038/nature12222.
8. Sabatiny DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 2006; 6 (9): 729–734. doi: 10.1038/nrc1974.
9. Büchler T. Imunoterapie renálního karcinomu. Klin Onkol 2015; 28 (Suppl 4): 4S64–4S68. doi: 10.14735/amko20154S64.
10. Motzer RJ, Bacik BA, Russi P 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. doi: 10.1200/JCO.2002.20.1.289.
11. 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. doi: 10.1056/NEJMoa066838.
12. Heng DY, Xie W, Regan MM et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results form a large, multicenter study. J Clin Oncol 2009; 27 (34): 5794–5799. doi: 10.1200/JCO.2008.21.4809.
13. Heng DY, Xie W, Regan MM et al. External validation and comparison with other models of the International Database Consortium Prognostic Model: a population-based study. Lancet Oncol 2013; 14 (2): 141–148. doi: 10.1016/S1470-2045 (12) 70559-4.
14. Vyzula R, Adámková Krákorová D, Arenberger P et al. Zhoubný novotvar ledviny (C64). In: Modrá kniha České onkologické společnosti. Brno: Masarykův onkologický ústav 2017: 116–119.
15. Hanna N, Sun M, Meyer CP et al. Survival analyses of patients with metastatic renal cancer treated with targeted therapy with or without cytoreductive nephrectomy: a national vancer data base study. J Clin Oncol 2016; 34 (27): 3267–3275. doi: 10.1200/JCO.2016.66.7931.
16. 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. doi: 10.1016/j.eururo.2014.05.034.
17. Bex A, Mulders P, Jewett M et al. Immediate versus deferred cytoreductive nephrectomy (CN) in patients with synchronous metastatic renal cell carcinoma (mRCC) receiving sunitinib (EORTC 30073 SURTIME). Ann Oncol 2017; 28 (Suppl 5): v605–v649. doi: 10.1093/annonc/mdx 440.
18. Allard CB, Gelpi-Hammerschmidt F, Harshman LC et al. Contemporary trends in high-dose interleukin-2 use for metastatic renal cell carcinoma in the United States. Urol Oncol 2015; 33 (11): 496. e11–e16. doi: 10.1016/j.urolonc.2015.06.014.
19. Motzer RJ, Hutson TE, Tomczak P et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Eng J Med 2007; 356 (2): 115–124. doi: 10.1056/NEJMoa065044.
20. 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. doi: 10.1200/JCO.2008.20.1293.
21. Sternberg CN, Davis ID, Mardiak J et al. Pazopanib in locally advanced or metstatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010; 28 (6): 1061–1068. doi: 10.1200/JCO.2009.23.9764.
22. Escudier B, Bellmunt J, Négrier S et al. Phase III trial of bevacizumab plus interferon alfa-2a in patients with metastatic renal cell carcinoma (AVOREN): final analysis of overal survival. J Clin Oncol 2010; 28 (13): 2144–2150. doi: 10.1200/JCO.2009.26.7849.
23. 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. doi: 10.1200/JCO.2009.26.5561.
24. Motzer RJ, Hutson TE, Cella D et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013; 369: 722–731. doi: 10.1056/NEJMoa1303989.
25. Motzer RJ, Hutson TE, McCann L et al. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med 2014; 370 (18): 1769–1770. doi: 10.1056/NEJMc1400731.
26. Escudier B, Porta C, Bono P et al. Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol 2014; 32 (14): 1412–1418. doi: 10.1200/JCO.2013.50.8267.
27. Najjar YG, Mittal K, Elson P et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer 2014; 50 (6): 1084–1089. doi: 10.1016/j.ejca.2014.01.025.
28. Atkinson BJ, Kalra S, Wang X et al. Clinical outcomes for patients with metastatic renal cell carcinoma treated with alternative sunitinib schedules. J Urol 2014; 191 (3): 611–618. doi: 10.1016/j.juro.2013.08.090.
29. Bracarda S, Iacovelli R, Boni L et al. Sunitinib administered on 2/1 schedule in patients with metastatic renal cell carcinoma: the RAINBOW analysis. Ann Oncol 2015; 26 (10): 2107–2113. doi: 10.1093/annonc/mdv315.
30. Lee JL, Kim MK, Park I et al. Randomized phase II trial of sunitinib four weeks on and two weeks off versus two weeks on and one week off in metastatic clear-cell type renal cell carcinoma: RESTORE trial. Ann Oncol 2015; 26 (11): 2300–2305. doi: 10.1093/annonc/mdv357.
31. 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. doi: 10.1056/NEJMoa066838.
32. Choueiri TK, Halabi S, Sanford BL et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: The alliance A031203 CABOSUN trial. J Clin Oncol 2017; 35 (6): 591–597. doi: 10.1200/JCO.2016.70.7398.
33. 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 (9637): 449–456. doi: 10.1016/S0140-6736 (08) 61039-9.
34. 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 evaluation trial. J Clin Oncol 2009; 27 (20): 3312–3318. doi: 10.1200/JCO.2008.19.5511.
35. Rini BI, Escudier B, Tomczak P et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378 (9807): 1931–1939. doi: 10.1016/S0140-6736 (11) 61613-9.
36. Motzer RJ, Escudier B, Tomczak P et al. Axitinib versus sorafenib as second-line treatment for advanced renal cell carcinoma: overall survival analysis and updated results from a randomised phase 3 trial. Lancet Oncol 2013; 14 (6): 552–562. doi: 10.1016/S1470-2045 (13) 700 93-7.
37. 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. doi: 10.1056/NEJMoa1510016.
38. Choueiri TK, Escudier B, Powles T et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomized, open-label, phase 3 trial. Lancet Oncol 2016; 17 (7): 917–927. doi: 10.1016/S1470-2045 (16) 30107-3.
39. Motzer RJ, Escudier B, McDermott DF et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015; 373 (19): 1903–1813. doi: 10.1056/NEJMoa1510665.
40. 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. doi: 10.1200/JCO.2013.50.3961.
41. 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 (22): 7272–7283. doi: 10.1158/1078-0432.CCR-08-0652.
42. Zhou L, Liu XD, Sun M et al. Targeting MET and AXL overcomes resistence to sunitinib therapy in renal cell carcinoma. Oncogene 2016; 35 (21): 2687–2697. doi: 10.1038/onc.2015.343.
43. The Cancer Genome Atlas Research Network. Comprehensive molecular characterisation of papilary renal-cell carcinoma. N Engl J Med 2016; 374 (2): 135–145. doi: 10.1056/NEJMoa1505917.
44. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer, version 2. 2018. [online]. Available from: https: //www.nccn.org/professionals/physician_gls/default.aspx¨.
45. Armstrong AJ, Halabi S, Eisen T et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol 2016; 17 (3): 378–388. doi: 10.1016/S1470-2045 (15) 00515-X.
46. 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. doi: 10.1200/JCO.2013.54.6911.
47. Tannir NM, Jonasch E, Albiges L et al. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol 2016; 69 (5): 866–874. doi: 10.1016/j.eururo.2015.10.049.
48. Haas NB, Lin X, Manola J et al. A phase II trial of doxorubicin and gemcitabine in renal cell carcinoma with sarcomatoid features. ECOG 8802. Med Oncol 2012; 29 (2): 761–767. doi: 10.1007/s12032-011-9829-8.
49. Nanus DM, Garino A, Miowsky MI et al. Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma. Cancer 2004; 101 (7): 1545–1551. doi: 10.1002/cncr.20541.
50. 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. doi: 10.1016/S1470-2045 (15) 00290-9.
51. Escudier B. Tannir N, McDermott DF et al. CheckMate 214: Efficacy and safety of nivolumab + ipilimumab v sunitinib for treatment-naive advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. Ann Oncol 2017; 28 (Suppl 5): abstr. LBA5. doi: 10.1093/annonc/mdx440.029.
52. Amin A, Dudek AZ, Logan TF et al. Survival with AGS-003, an autologous dendritic cell-based immunotherapy, in combination with sunitinib in unfavorable risk patients with advanced renal cell carcinoma (RCC): phase 2 study results. J Immunother Cancer 2015; 3: 14. doi: 10.1186/s40425-015-0055-3.
53. Cancer Genome Atlas Research Network Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013; 499 (7456): 43–49. doi: 10.1038/nature12222.
54. Hsieh J, Chen D, Wang P et al. Identification of efficacy biomarkers in a large metastatic renal cell carcinoma (mRCC) cohort through next generation sequencing (NGS): results from RECORD-3. J Clin Oncol 2015; 33 (Suppl 15): abstr. 4509. doi: 10.1200/jco.2015.33.15_suppl.4509.
55. Kwiatkowski DJ, Choueiri TK, Fay AP et al. Mutations in TSC1, TSC2 and mTOR are associated with response to rapalogs in patients with metastatic renal cell carcinoma. Clin Cancer Res 2016; 22 (10): 2445–2452. doi: 10.1158/ 1078-0432.CCR-15-2631.
56. Voss MH, Hakimi AA, Pham CG et al. Tumor genetic analyses of patients with metastatic renal cell carcinoma and extended benefit from mTOR inhibitor therapy. Clin Cancer Res 2014; 20 (7): 1955–1964. doi: 10.1158/1078-0432.CCR-13-2345.
57. Choueiri TK, Figueroa DJ, Fay AP et al. Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib: results from COMPARZ, a randomized controlled trial. Clin Cancer Res 2015; 21: 1071–1077. doi: 10.1158/1078-0432.CCR-14-1993.
58. Poprach A, Lakomý R, Büchler T. Imunoterapie zhoubného nádoru ledviny. Klin Onkol 2017; 30 (Suppl 3): 3S55–3S61. doi: 10.14735/amko20173S55.
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Clinical Oncology
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