转移性肾细胞癌的全身性治疗 - NEJM医学前沿
提示: 手机请竖屏浏览!

转移性肾细胞癌的全身性治疗
Systemic Therapy for Metastatic Renal-Cell Carcinoma


Toni K. Choueiri ... 肿瘤 • 2017.01.26
相关阅读
• 转移性肾癌的肿瘤细胞减灭性肾切除术 • 纳武利尤单抗联合伊匹单抗与舒尼替尼治疗晚期肾细胞癌的比较研究 • ASCO 2017报告——泌尿生殖系统癌症

晚期肾癌的药物选择:中国患者仍需等待

 

刘天舒

复旦大学附属中山医院


肾癌在中国的发病率较西方国家低。据统计,2011年中国新发病例45,096例,发病率为3.35/10万,占所有肿瘤的第15位1。在晚期肾细胞癌的治疗中,手术治疗的地位仍然很高。所有体力状况耐受,肾脏病灶能切除者均推荐减瘤性肾切除术,孤立性转移灶也推荐行切除术。转移性肾癌对放疗和化疗不敏感。放疗仅用于减轻症状,以及针对骨转移及脑转移进行局部治疗。过去,转移性肾癌主要的药物治疗方式为细胞因子治疗(IFN-α及IL-2)。由于IL-2制剂的毒副反应大,国内一直没有批准该类药物。而国内唯一可用的IFN-α,在转移性肾透明细胞癌中的客观缓解率仅为15%2。随着靶向药物以及免疫治疗的不断发展,晚期肾癌的治疗迎来了天翻地覆的变化。

查看更多

直到最近,对于肾癌仍缺乏有效的全身性治疗方法。从1975年到2008年,肾癌的发病率稳步增高,2008年后趋于平稳1-3。目前,它是美国男性和女性中最常诊断的10种癌症之一,2016年估计有超过62,000新病例4。它的预后一直不佳,目前5年的总体生存率为74%,局部疾病(三期)患者的生存率则降到53%,而转移性疾病患者的生存率只有8%1,3。肾癌是中老年疾病:91%的患者在≥45岁确诊,48%的患者在≥65岁确诊1。肾细胞癌作为最常见的肾癌类型,发生于90%的病例,且男性患病率接近女性的两倍3

肾癌患者的5年生存率从1987~1989年的57%提高至2006~2012年的74%1;生存率的提高部分归功于早期检测技术的进步,诊断出的无痛性和低级别肿瘤占更大的比例5。然而1/3的肾癌患者表现为局部或远处转移1,在为局限性肾细胞癌患者实施根治性肾脏切除术治疗后,大约1/4的患者出现远处复发6-8。远处转移最常发生于肺、淋巴结、肝、骨和脑9。尽管每年有超过14,000例患者死于肾癌4,但我们仍然看到转移性肾细胞癌的全身性治疗在过去20年中取得相当大的进步10。研究者对最常见的肾细胞癌类型,即肾透明细胞癌的发病机制有了更好的理解,从而带来了新的药物、更多的治疗选择以及患者生存率的提高。





作者信息

Toni K. Choueiri, M.D., and Robert J. Motzer, M.D.
From the Lank Center for Genitourinary Oncology, Dana–Farber Cancer Institute, Boston (T.K.C.); and the Department of Medicine, Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York (R.J.M.). Address reprint requests to Dr. Choueiri at the Dana–Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02215, or at toni_choueiri@dfci.harvard.edu; or to Dr. Motzer at the Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065-6094, or at motzerr@mskcc.org.

 

参考文献

1. Surveillance, Epidemiology, and End Results Program. SEER stat fact sheets: kidney and renal pelvis cancer. Bethesda, MD: National Cancer Institute (http://seer.cancer.gov/statfacts/html/kidrp.html).

2.  Surveillance, Epidemiology and End Results Program. SEER fast stats: compare statistics by cancer site — kidney and renal pelvis, 1975-2013. Bethesda, MD: National Cancer Institute, 2016 (http://seer.cancer.gov/faststats/selections.php?series=cancer).

3.  American Cancer Society. Kidney cancer (adult) — renal cell carcinoma (http://www.cancer.org/cancer/kidneycancer/detailedguide/).

4. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:7-30

5. Gill IS, Aron M, Gervais DA, Jewett MA. Small renal mass. N Engl J Med 2010;362:624-634

6. Dabestani S, Thorstenson A, Lindblad P, Harmenberg U, Ljungberg B, Lundstam S. Renal cell carcinoma recurrences and metastases in primary non-metastatic patients: a population-based study. World J Urol 2016;34:1081-1086

7. Rabinovitch RA, Zelefsky MJ, Gaynor JJ, Fuks Z. Patterns of failure following surgical resection of renal cell carcinoma: implications for adjuvant local and systemic therapy. J Clin Oncol 1994;12:206-212

8. Sandock DS, Seftel AD, Resnick MI. A new protocol for the followup of renal cell carcinoma based on pathological stage. J Urol 1995;154:28-31

9. McKay RR, Kroeger N, Xie W, et al. Impact of bone and liver metastases on patients with renal cell carcinoma treated with targeted therapy. Eur Urol 2014;65:577-584

10. Motzer RJ, Bander NH, Nanus DM. Renal-cell carcinoma. N Engl J Med 1996;335:865-875

11. Srigley JR, Delahunt B, Eble JN, et al. The International Society of Urological Pathology (ISUP) Vancouver Classification of Renal Neoplasia. Am J Surg Pathol 2013;37:1469-1489

12. Latif F, Tory K, Gnarra J, et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993;260:1317-1320

13. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013;499:43-49

14. Kaelin WG Jr. The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat Rev Cancer 2008;8:865-873

15. Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, et al. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet 2012;44:751-759

16. Varela I, Tarpey P, Raine K, et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 2011;469:539-542

17. Hakimi AA, Ostrovnaya I, Reva B, et al. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin Cancer Res 2013;19:3259-3267

18. Sabatini DM. mTOR and cancer: insights into a complex relationship. Nat Rev Cancer 2006;6:729-734

19. Kwiatkowski DJ, Manning BD. Molecular basis of giant cells in tuberous sclerosis complex. N Engl J Med 2014;371:778-780

20. Heng DY, Choueiri TK. Non-clear cell renal cancer: features and medical management. J Natl Compr Canc Netw 2009;7:659-665

21. The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of papillary renal-cell carcinoma. N Engl J Med 2016;374:135-145

22. Sankin A, Hakimi AA, Hsieh JJ, Molina AM. Metastatic non-clear cell renal cell carcinoma: an evidence based review of current treatment strategies. Front Oncol 2015;5:67-67

23. Davis CF, Ricketts CJ, Wang M, et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell 2014;26:319-330

24. Wang J, Papanicolau-Sengos A, Chintala S, et al. Collecting duct carcinoma of the kidney is associated with CDKN2A deletion and SLC family gene up-regulation. Oncotarget 2016;7:29901-29915

25. Calderaro J, Moroch J, Pierron G, et al. SMARCB1/INI1 inactivation in renal medullary carcinoma. Histopathology 2012;61:428-435

26. Malouf GG, Monzon FA, Couturier J, et al. Genomic heterogeneity of translocation renal cell carcinoma. Clin Cancer Res 2013;19:4673-4684

27. Harshman LC, Drake CG, Choueiri TK. PD-1 blockade in renal cell carcinoma: to equilibrium and beyond. Cancer Immunol Res 2014;2:1132-1141

28. Thompson RH, Dong H, Lohse CM, et al. PD-1 is expressed by tumor-infiltrating immune cells and is associated with poor outcome for patients with renal cell carcinoma. Clin Cancer Res 2007;13:1757-1761

29. Choueiri TK, Fay AP, Gray KP, et al. PD-L1 expression in nonclear-cell renal cell carcinoma. Ann Oncol 2014;25:2178-2184

30. Rosenblatt J, McDermott DF. Immunotherapy for renal cell carcinoma. Hematol Oncol Clin North Am 2011;25:793-812

31. Klapper JA, Downey SG, Smith FO, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma: a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer 2008;113:293-301

32. 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;33:496.e11-496.e16

33. McDermott DF, Cheng SC, Signoretti S, et al. The high-dose aldesleukin “select” trial: a trial to prospectively validate predictive models of response to treatment in patients with metastatic renal cell carcinoma. Clin Cancer Res 2015;21:561-568

34. 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;20:289-296

35. 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

36. 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 from a large, multicenter study. J Clin Oncol 2009;27:5794-5799

37. Heng DY, Xie W, Regan MM, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol 2013;14:141-148

38. 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

39. 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

40. 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

41. Sternberg CN, Hawkins RE, Wagstaff J, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer 2013;49:1287-1296

42. 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

43. 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 overall survival. J Clin Oncol 2010;28:2144-2150

44. 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

45. 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;28:2137-2143

46. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722-731

47. Motzer RJ, Hutson TE, McCann L, Deen K, Choueiri TK. Overall survival in renal-cell carcinoma with pazopanib versus sunitinib. N Engl J Med 2014;370:1769-1770

48. Wyeth Pharmaceuticals, 2016 Prescribing information: Torisel — temsirolimus. (http://labeling.pfizer.com/showlabeling.aspx?id=490).

49.  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

50. 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;116:4256-4265

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. 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

53. 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;378:1931-1939

54. 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;16:1473-1482

55. Motzer RJ, Hutson TE, Ren M, Dutcus C, Larkin J. Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. Lancet Oncol 2016;17:e4-e5

56. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1814-1823

57. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma (METEOR): final results from a randomised, open-label, phase 3 trial. Lancet Oncol 2016;17:917-927

58. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med 2015;373:1803-1813

59. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: kidney cancer, version 2. 2017 (https://www.nccn.org/professionals/physician_gls/pdf/kidney.pdf).

60.  Négrier S, Gravis G, Pérol D, et al. Temsirolimus and bevacizumab, or sunitinib, or interferon alfa and bevacizumab for patients with advanced renal cell carcinoma (TORAVA): a randomised phase 2 trial. Lancet Oncol 2011;12:673-680

61. Ravaud A, Barrios CH, Alekseev B, et al. RECORD-2: phase II randomized study of everolimus and bevacizumab versus interferon α-2a and bevacizumab as first-line therapy in patients with metastatic renal cell carcinoma. Ann Oncol 2015;26:1378-1384

62. Rini BI, Bellmunt J, Clancy J, et al. Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol 2014;32:752-759

63. Rini BI, Atkins MB. Resistance to targeted therapy in renal-cell carcinoma. Lancet Oncol 2009;10:992-1000

64. Zhou L, Liu XD, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene 2016;35:2687-2697

65. Choueiri TK, Fishman M, Escudier B, et al. Immunomodulatory activity of nivolumab in metastatic renal cell carcinoma. Clin Cancer Res 2016 May 11 (Epub ahead of print)

66.  Motzer RJ, Rini BI, McDermott DF, et al. Nivolumab for metastatic renal cell carcinoma: results of a randomized phase II trial. J Clin Oncol 2015;33:1430-1437

67. Cella D, Grünwald V, Nathan P, et al. Quality of life in patients with advanced renal cell carcinoma given nivolumab versus everolimus in CheckMate 025: a randomised, open-label, phase 3 trial. Lancet Oncol 2016;17:994-1003

68. Valenca LB, Hirsch MS, Choueiri TK, Harshman LC. Non-clear cell renal cell carcinoma, part 2: therapy. Clin Adv Hematol Oncol 2015;13:383-391

69. Vera-Badillo FE, Templeton AJ, Duran I, et al. Systemic therapy for non-clear cell renal cell carcinomas: a systematic review and meta-analysis. Eur Urol 2015;67:740-749

70. Armstrong AJ, Halabi S, Eisen T, et al. Everolimus versus sunitinib for patients with metastatic non-clear cell renal cell carcinoma (ASPEN): a multicentre, open-label, randomised phase 2 trial. Lancet Oncol 2016;17:378-388

71. 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;32:2765-2772

72. Tannir NM, Jonasch E, Albiges L, et al. Everolimus versus sunitinib prospective evaluation in metastatic non-clear cell renal cell carcinoma (ESPN): a randomized multicenter phase 2 trial. Eur Urol 2016;69:866-874

73. Choueiri TK, Vaishampayan U, Rosenberg JE, et al. Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. J Clin Oncol 2013;31:181-186

74. Diamond E, Molina AM, Carbonaro M, et al. Cytotoxic chemotherapy in the treatment of advanced renal cell carcinoma in the era of targeted therapy. Crit Rev Oncol Hematol 2015;96:518-526

75. 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;29:761-767

76. Jonasch E, Lal LS, Atkinson BJ, et al. Treatment of metastatic renal carcinoma patients with the combination of gemcitabine, capecitabine and bevacizumab at a tertiary cancer centre. BJU Int 2011;107:741-747

77. Michaelson MD, McKay RR, Werner L, et al. Phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid and/or poor-risk metastatic renal cell carcinoma. Cancer 2015;121:3435-3443

78. Nanus DM, Garino A, Milowsky MI, Larkin M, Dutcher JP. Active chemotherapy for sarcomatoid and rapidly progressing renal cell carcinoma. Cancer 2004;101:1545-1551

79. Oudard S, Banu E, Vieillefond A, et al. Prospective multicenter phase II study of gemcitabine plus platinum salt for metastatic collecting duct carcinoma: results of a GETUG (Groupe d’Etudes des Tumeurs Uro-Génitales) study. J Urol 2007;177:1698-1702

80. 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

81. 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;358:966-970 

82. 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 Cancer Data Base study. J Clin Oncol 2016;34:3267-3275

83. 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;66:704-710

84. Kavolius JP, Mastorakos DP, Pavlovich C, Russo P, Burt ME, Brady MS. Resection of metastatic renal cell carcinoma. J Clin Oncol 1998;16:2261-2266

85. Shaikh T, Handorf EA, Murphy CT, et al. Contemporary trends in the utilization of radiotherapy in patients with renal cell carcinoma. Urology 2015;86:1165-1173

86. Straka C, Kim DW, Timmerman RD, Pedrosa I, Jacobs C, Brugarolas J. Ablation of a site of progression with stereotactic body radiation therapy extends sunitinib treatment from 14 to 22 months. J Clin Oncol 2013;31:e401-e403

87. Lipton A, Colombo-Berra A, Bukowski RM, Rosen L, Zheng M, Urbanowitz G. Skeletal complications in patients with bone metastases from renal cell carcinoma and therapeutic benefits of zoledronic acid. Clin Cancer Res 2004;10:6397S-6403S

88. McKay RR, Lin X, Perkins JJ, Heng DY, Simantov R, Choueiri TK. Prognostic significance of bone metastases and bisphosphonate therapy in patients with renal cell carcinoma. Eur Urol 2014;66:502-509

89. Sonpavde G, Choueiri TK. Biomarkers: the next therapeutic hurdle in metastatic renal cell carcinoma. Br J Cancer 2012;107:1009-1016

90. 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;22:2445-2452

91. 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;20:1955-1964

92. Iyer G, Hanrahan AJ, Milowsky MI, et al. Genome sequencing identifies a basis for everolimus sensitivity. Science 2012;338:221-221

93. 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

94. Di Napoli A, Signoretti S. Tissue biomarkers in renal cell carcinoma: issues and solutions. Cancer 2009;115:Suppl:2290-2297

95. Gerlinger M, Rowan AJ, Horswell S, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366:883-892

96. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib (CABOSUN) as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol 2016 November 14 (Epub ahead of print).

服务条款 | 隐私政策 | 联系我们