局部进展性肾癌术后靶向治疗的研究进展
|
摘要
靶向治疗作为一种新型治疗模式,在肾癌的姑息性治疗和术前辅助治疗方面均获得了显著的疗效,因此人们对其填补局部进展性肾癌术后辅助治疗的空白给予了新的期望。本文对局部进展性肾癌的特点及靶向药物的相关作用机制作简要介绍,并通过比较分析相关临床试验差异,找出影响靶向药物术后辅助治疗疗效的可能因素,进而探讨靶向药物用于局部进展性肾癌术后辅助治疗的价值和前景。
Targeted therapy,as a novel treatment modality,has achieved significant progress in both palliative and preoperative adjuvant treatment of renal cell carcinoma(RCC),new expectations have been given for its application in postoperative adjuvant treatment of locally advanced RCC.This article briefly introduces the characteristics of locally advanced RCC and the mechanism of targeted drugs,and analyzes the factors affecting the efficacy of targeted-drugs in postoperative adjuvant therapy from relevant clinical trials. The value and prospects of targeted drugs in postoperative therapy for locally advanced RCC are also discussed.
Targeted therapy,as a novel treatment modality,has achieved significant progress in both palliative and preoperative adjuvant treatment of renal cell carcinoma(RCC),new expectations have been given for its application in postoperative adjuvant treatment of locally advanced RCC.This article briefly introduces the characteristics of locally advanced RCC and the mechanism of targeted drugs,and analyzes the factors affecting the efficacy of targeted-drugs in postoperative adjuvant therapy from relevant clinical trials. The value and prospects of targeted drugs in postoperative therapy for locally advanced RCC are also discussed.
引文
[1]Brookman MS,Langenhuijsen JF,Volpe A,et al.Management of localized and locally advanced renal tumors.Acontemporary review of current treatment options[J].Minerva Med,2013,104(3):237-259.
[2]Vano YA,Tartour E,Fournier LS,et al.Prognostic factors in patients with advanced renal cell carcinoma treated with VEGF-targeted agents[J].Expert Rev Anticancer Ther,2014,14(5):523-542.
[3]Tobert CM,Uzzo RG,Wood CG,et al.Adjuvant and neoadjuvant therapy for renal cell carcinoma:a survey of the Society of Urologic Oncology[J].Urol Oncol,2013,31(7):1316-1320.
[4]Moch H,Cubilla AL,Humphrey PA,et al.The 2016 WHOClassification of Tumours of the Urinary System and Male Genital Organs-Part A:Renal,Penile,and Testicular Tumours[J].Eur Urol,2016,70(1):93-105.
[5]Adeniran AJ,Shuch B,Humphrey PA.Hereditary renal cell carcinoma syndromes clinical,pathologic,and genetic features[J].Am J Surg Pathol,2015,39(12):e1-e18.
[6]Maher ER.Hereditary renal cell carcinoma syndromes:diagnosis,surveillance and management[J].World J Urol,2018,36(12):1891-1898.
[7]Kallinikas G,Habib H,Tsimiliotis D,et al.Renal cell cancers:unveiling the hereditary ones and saving lives-a tailored diagnostic approach[J].Int Urol Nephrol,2017,49(9):1507-1512.
[8]Zhang HM,Yang FQ,Chen SJ,et al.Upregulation of long non-coding RNA MALAT1 correlates with tumor progression and poor prognosis in clear cell renal cell carcinoma[J].Tumor Biol,2015,36(4):2947-2955.
[9]Li W,Liu M,Feng Y,et al.Downregulated miR-646 in clear cell renal carcinoma correlated with tumour metastasis by targeting the nin one binding protein(NOB1)[J].Br J Cancer,2014,111(6):1188-1200.
[10]Yang FQ,Zhang HM,Chen SJ,et al.MiR-506 is downregulated in clear cell renal cell carcinoma and inhibits cell growth and metastasis via targeting FLOT1[J].PLoSOne,2015,10(3):e0120258.
[11]Gu W,Sun W,Guo C,et al.Culture and characterization of circulating endothelial progenitor cells in patients with renal cell carcinoma[J].J Urol,2015,194(1):214-222.
[12]Park JY,Lee JL,Baek S,et al.Sarcomatoid features,necrosis,and grade are prognostic factors in metastatic clear cell renal cell carcinoma with vascular endothelial growth factor-targeted therapy[J].Hum Pathol,2014,45(7):1437-1444.
[13]Ruiz JN,Belum VR,Creel P,et al.Current practices in the management of adverse events associated with targeted therapies for advanced renal cell carcinoma:a national survey of oncologists[J].Clin Genitour Cancer,2014,12(5):341-347.
[14]Hansen CR,Grimm D,Bauer J,et al.Effects and side effects of using sorafenib and sunitinib in the treatment of metastatic renal cell carcinoma[J].Int J Mol Sci,2017,18(2):206-211.
[15]Fisher R,Gore M,Larkin J.Current and future systemic treatments for renal cell carcinoma[J].Semin Cancer Biol,2013,23(1):38-45.
[16]Escudier B,Eisen T,Stadler WM,et al.Sorafenib for treatment of renal cell carcinoma:final efficacy and safety results of the phaseⅢtreatment approaches in renal cancer global evaluation trial[J].J Clin Oncol,2009,27(20):3312-3318.
[17]Beck J,Procopio G,Bajetta E,et al.Final results of the European Advanced Renal Cell Carcinoma Sorafenib(EU-ARCCS)expanded-access study:a large open-label study in diverse community settings[J].Ann Oncol,2011,22(8):1812-1823.
[18]Zhou AP,He ZS,Yu SY,et al.Clinical study of sorafenib in the treatment of metastatic renal cancer[J].Chinese Journal of Urology,2009,30(1):10-14.[周爱萍,何志嵩,于世英,等.索拉非尼治疗转移性肾癌的临床研究[J].中华泌尿外科杂志,2009,30(1):10-14.]
[19]Motzer RJ,Hutson TE,Tomczak P,et al.Sunitinib versus interferon alfa in metastatic renal-cell carcinoma[J].N Engl J Med,2007,356(2):115-124.
[20]Van Cutsem E,Hamamoto Y,Lee J,et al.Prognostic factors of overall survival(os)in previously treated advanced gastric cancer(agc):analysis of the phase 3 granite-1 trial[J].Ann Oncol,2012,23:9.
[21]Motzer RJ,Jonasch E,Agarwal N,et al.Kidney cancer,version 2.2017 clinical practice guidelines in oncology[J].J Nati Compr Canc Netw,2017,15(6):804-834.
[22]Powles T,Albiges L,Staehler M,et al.Updated european association of urology guidelines:recommendations for the treatment of first-line metastatic clear cell renal cancer[J].Eur Urol,2018,73(3):311-315.
[23]Lane BR,Derweesh IH,Kim HL,et al.Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma[J].Urol Oncol,2015,33(3):112.e15-e21.
[24]Lin CH,Yuan HJ,Wang K,et al.Initial experience of sorafenib neoadjuvant therapy combined with retroperitoneoscopy in treating T2 large renal carcinoma[J].Biomed Res Int,2015,2015:609549.
[25]Bex A,Powles T,Karam JA.Role of targeted therapy in combination with surgery in renal cell carcinoma[J].Int JUrol,2016,23(1):5-12.
[26]Chuang JC,Liang Y,Wakelee HA.Neoadjuvant and adjuvant therapy for non-small cell lung cancer[J].Hematol Oncol Clin North Am,2017,31(1):31-44.
[27]Milleron B,Westeel V,Gounant V,et al.Pathological complete response:a predictive survival factor after neoadjuvant chemotherapy in lung cancer[J].Bull Cancer,2016,103(1):66-72.
[28]Terakawa T,Hussein AA,Bando Y,Guru KA,et al.Presurgical pazopanib for renal cell carcinoma with inferior vena caval thrombus:a single-institution study[J].Anticancer Drugs,2018,29(6):565-571.
[29]Zhao JP.Targeted adjuvant therapy for locally advanced renal cancer[J].Journal of Clinical Urology,2011,26(8):132-136.[赵菊平.局部进展期肾癌术后靶向辅助治疗的初步研究[J].临床泌尿外科杂志,2011,26(8):132-136.]
[30]Zhang K,Lu MJ,Da J,et al.Retroperitoneal laparoscopic surgery combined with targeted drug therapy for synchronous bilateral multiple renal cell carcinoma:experience summary and literature review[J].Chinese Journal of Clinicians(Electronic Edition),2015,9(2):206-209.[张克,卢慕峻,达骏,等.后腹腔镜手术结合靶向药物治疗同时性双侧多发肾癌的经验总结及文献回顾分析[J].中华临床医师杂志(电子版),2015,9(2):206-209.]
[31]Zhang ZX.Efficacy of low-dose sunitinib adjuvant therapy for high-risk renal cancer after surgery[J].Zhejiang Clinical Medicine,2014,16(3):62-68.[张振兴.低剂量舒尼替尼辅助治疗高危肾癌术后的疗效观察[J].浙江临床医学,2014,16(3):62-68.]
[32]Liu F.Adjuvant therapy with two targeted drugs for locally advanced renal cell carcinoma[J].Chinese Journal of Modern Medicine,2018,20(2):60-62.[刘峰.局部进展期肾癌术后应用两种靶向药物辅助治疗疗效分析[J].中国现代医药杂志,2018,20(2):60-62.]
[33]Zhao J,Zhu Y,Zhang C,et al.Sorafenib or sunitinib as postoperative adjuvant therapy for Chinese patients with locally advanced clear cell renal cell carcinoma at high risk for disease recurrence[J].Urol Oncol,2013,31(8):1800-1805.
[34]Gu L,Li H,Chen L,et al.Postoperative adjuvant sorafenib or sunitinib for nonmetastatic renal cell carcinoma with venous tumor thrombus:a prospective cohort study[J].Transl Oncol,2017,10(6):949-955.
[35]Bai Y,Li S,Jia Z,et al.Adjuvant therapy for locally advanced renal cell carcinoma:a meta-analysis and systematic review[J].Urol Oncol,2018,36(2):79.e1-e79.
[36]Haas NB,Manola J,Dutcher JP,et al.Adjuvant treatment for high-risk clear cell renal cancer updated results of a high-risk subset of the assure randomized trial[J].JAMAOncol,2017,3(9):1249-1252.
[37]Motzer RJ,Ravaud A,Patard JJ,et al.Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy:subgroup analyses and updated overall survival results[J].Eur Urol,2018,73(1):62-68.
[38]Blinman PL,Davis ID,Martin A,et al.Patients’preferences for adjuvant sorafenib after resection of renal cell carcinoma in the SORCE trial:what makes it worthwhile?[J].Ann Oncol,2018,29(2):370-376.
[39]Motzer RJ,Haas NB,Donskov F,et al.Randomized phaseⅢtrial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma[J].J Clin Oncol,2017,35(35):3916-3923.
[40]Synold TW,Plets M,Tangen CM,et al.Everolimus(EVE)exposure as a predictor of toxicity(Tox)in renal cell cancer(RCC)patients(Pts)in the adjuvant setting:results of a pharmacokinetic analysis for SWOG 50931(EVEREST)a phaseⅢstudy(NCT01120249)[J].J Clin Oncol,2017,35(2):849-855.
[41]Gross-Goupil M,Kwon TG,Eto M,et al.Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma:results from the phaseⅢ,randomized ATLAS trial[J].Ann Oncol,2018,29(12):2371-2378.
[42]Bandini M,Smith A,Marchioni M,et al.Adjuvant therapies in nonmetastatic renal-cell carcinoma:a review of the literature[J].Clin Genitourin Cancer,2018,16(3):176-183.
[43]Bandini M,Smith A,Zaffuto E,et al.Effect of pathological high-risk features on cancer-specific mortality in nonmetastatic clear cell renal cell carcinoma:a tool for optimizing patient selection for adjuvant therapy[J].World JUrol,2018,36(1):51-57.
[44]Wolff I,May M,Hoschke B,et al.Do we need new highrisk criteria for surgically treated renal cancer patients to improve the outcome of future clinical trials in the adjuvant setting?Results of a comprehensive analysis based on the multicenter CORONA database[J].Eur J Surg Oncol,2016,42(5):744-750.
[45]Wei C,Wang S,Ye Z,et al.Efficacy of targeted therapy for advanced renal cell carcinoma:a systematic review and meta-analysis of randomized controlled trials[J].Int Braz JUrol,2018,44(2):219-237.
[46]Kovacova J,Juracek J,Poprach A,et al.Candidate microrna biomarkers of therapeutic response to sunitinib in metastatic renal cell carcinoma:a validation study in patients with extremely good and poor response[J].Anticancer Res,2018,38(5):2961-2965.
[2]Vano YA,Tartour E,Fournier LS,et al.Prognostic factors in patients with advanced renal cell carcinoma treated with VEGF-targeted agents[J].Expert Rev Anticancer Ther,2014,14(5):523-542.
[3]Tobert CM,Uzzo RG,Wood CG,et al.Adjuvant and neoadjuvant therapy for renal cell carcinoma:a survey of the Society of Urologic Oncology[J].Urol Oncol,2013,31(7):1316-1320.
[4]Moch H,Cubilla AL,Humphrey PA,et al.The 2016 WHOClassification of Tumours of the Urinary System and Male Genital Organs-Part A:Renal,Penile,and Testicular Tumours[J].Eur Urol,2016,70(1):93-105.
[5]Adeniran AJ,Shuch B,Humphrey PA.Hereditary renal cell carcinoma syndromes clinical,pathologic,and genetic features[J].Am J Surg Pathol,2015,39(12):e1-e18.
[6]Maher ER.Hereditary renal cell carcinoma syndromes:diagnosis,surveillance and management[J].World J Urol,2018,36(12):1891-1898.
[7]Kallinikas G,Habib H,Tsimiliotis D,et al.Renal cell cancers:unveiling the hereditary ones and saving lives-a tailored diagnostic approach[J].Int Urol Nephrol,2017,49(9):1507-1512.
[8]Zhang HM,Yang FQ,Chen SJ,et al.Upregulation of long non-coding RNA MALAT1 correlates with tumor progression and poor prognosis in clear cell renal cell carcinoma[J].Tumor Biol,2015,36(4):2947-2955.
[9]Li W,Liu M,Feng Y,et al.Downregulated miR-646 in clear cell renal carcinoma correlated with tumour metastasis by targeting the nin one binding protein(NOB1)[J].Br J Cancer,2014,111(6):1188-1200.
[10]Yang FQ,Zhang HM,Chen SJ,et al.MiR-506 is downregulated in clear cell renal cell carcinoma and inhibits cell growth and metastasis via targeting FLOT1[J].PLoSOne,2015,10(3):e0120258.
[11]Gu W,Sun W,Guo C,et al.Culture and characterization of circulating endothelial progenitor cells in patients with renal cell carcinoma[J].J Urol,2015,194(1):214-222.
[12]Park JY,Lee JL,Baek S,et al.Sarcomatoid features,necrosis,and grade are prognostic factors in metastatic clear cell renal cell carcinoma with vascular endothelial growth factor-targeted therapy[J].Hum Pathol,2014,45(7):1437-1444.
[13]Ruiz JN,Belum VR,Creel P,et al.Current practices in the management of adverse events associated with targeted therapies for advanced renal cell carcinoma:a national survey of oncologists[J].Clin Genitour Cancer,2014,12(5):341-347.
[14]Hansen CR,Grimm D,Bauer J,et al.Effects and side effects of using sorafenib and sunitinib in the treatment of metastatic renal cell carcinoma[J].Int J Mol Sci,2017,18(2):206-211.
[15]Fisher R,Gore M,Larkin J.Current and future systemic treatments for renal cell carcinoma[J].Semin Cancer Biol,2013,23(1):38-45.
[16]Escudier B,Eisen T,Stadler WM,et al.Sorafenib for treatment of renal cell carcinoma:final efficacy and safety results of the phaseⅢtreatment approaches in renal cancer global evaluation trial[J].J Clin Oncol,2009,27(20):3312-3318.
[17]Beck J,Procopio G,Bajetta E,et al.Final results of the European Advanced Renal Cell Carcinoma Sorafenib(EU-ARCCS)expanded-access study:a large open-label study in diverse community settings[J].Ann Oncol,2011,22(8):1812-1823.
[18]Zhou AP,He ZS,Yu SY,et al.Clinical study of sorafenib in the treatment of metastatic renal cancer[J].Chinese Journal of Urology,2009,30(1):10-14.[周爱萍,何志嵩,于世英,等.索拉非尼治疗转移性肾癌的临床研究[J].中华泌尿外科杂志,2009,30(1):10-14.]
[19]Motzer RJ,Hutson TE,Tomczak P,et al.Sunitinib versus interferon alfa in metastatic renal-cell carcinoma[J].N Engl J Med,2007,356(2):115-124.
[20]Van Cutsem E,Hamamoto Y,Lee J,et al.Prognostic factors of overall survival(os)in previously treated advanced gastric cancer(agc):analysis of the phase 3 granite-1 trial[J].Ann Oncol,2012,23:9.
[21]Motzer RJ,Jonasch E,Agarwal N,et al.Kidney cancer,version 2.2017 clinical practice guidelines in oncology[J].J Nati Compr Canc Netw,2017,15(6):804-834.
[22]Powles T,Albiges L,Staehler M,et al.Updated european association of urology guidelines:recommendations for the treatment of first-line metastatic clear cell renal cancer[J].Eur Urol,2018,73(3):311-315.
[23]Lane BR,Derweesh IH,Kim HL,et al.Presurgical sunitinib reduces tumor size and may facilitate partial nephrectomy in patients with renal cell carcinoma[J].Urol Oncol,2015,33(3):112.e15-e21.
[24]Lin CH,Yuan HJ,Wang K,et al.Initial experience of sorafenib neoadjuvant therapy combined with retroperitoneoscopy in treating T2 large renal carcinoma[J].Biomed Res Int,2015,2015:609549.
[25]Bex A,Powles T,Karam JA.Role of targeted therapy in combination with surgery in renal cell carcinoma[J].Int JUrol,2016,23(1):5-12.
[26]Chuang JC,Liang Y,Wakelee HA.Neoadjuvant and adjuvant therapy for non-small cell lung cancer[J].Hematol Oncol Clin North Am,2017,31(1):31-44.
[27]Milleron B,Westeel V,Gounant V,et al.Pathological complete response:a predictive survival factor after neoadjuvant chemotherapy in lung cancer[J].Bull Cancer,2016,103(1):66-72.
[28]Terakawa T,Hussein AA,Bando Y,Guru KA,et al.Presurgical pazopanib for renal cell carcinoma with inferior vena caval thrombus:a single-institution study[J].Anticancer Drugs,2018,29(6):565-571.
[29]Zhao JP.Targeted adjuvant therapy for locally advanced renal cancer[J].Journal of Clinical Urology,2011,26(8):132-136.[赵菊平.局部进展期肾癌术后靶向辅助治疗的初步研究[J].临床泌尿外科杂志,2011,26(8):132-136.]
[30]Zhang K,Lu MJ,Da J,et al.Retroperitoneal laparoscopic surgery combined with targeted drug therapy for synchronous bilateral multiple renal cell carcinoma:experience summary and literature review[J].Chinese Journal of Clinicians(Electronic Edition),2015,9(2):206-209.[张克,卢慕峻,达骏,等.后腹腔镜手术结合靶向药物治疗同时性双侧多发肾癌的经验总结及文献回顾分析[J].中华临床医师杂志(电子版),2015,9(2):206-209.]
[31]Zhang ZX.Efficacy of low-dose sunitinib adjuvant therapy for high-risk renal cancer after surgery[J].Zhejiang Clinical Medicine,2014,16(3):62-68.[张振兴.低剂量舒尼替尼辅助治疗高危肾癌术后的疗效观察[J].浙江临床医学,2014,16(3):62-68.]
[32]Liu F.Adjuvant therapy with two targeted drugs for locally advanced renal cell carcinoma[J].Chinese Journal of Modern Medicine,2018,20(2):60-62.[刘峰.局部进展期肾癌术后应用两种靶向药物辅助治疗疗效分析[J].中国现代医药杂志,2018,20(2):60-62.]
[33]Zhao J,Zhu Y,Zhang C,et al.Sorafenib or sunitinib as postoperative adjuvant therapy for Chinese patients with locally advanced clear cell renal cell carcinoma at high risk for disease recurrence[J].Urol Oncol,2013,31(8):1800-1805.
[34]Gu L,Li H,Chen L,et al.Postoperative adjuvant sorafenib or sunitinib for nonmetastatic renal cell carcinoma with venous tumor thrombus:a prospective cohort study[J].Transl Oncol,2017,10(6):949-955.
[35]Bai Y,Li S,Jia Z,et al.Adjuvant therapy for locally advanced renal cell carcinoma:a meta-analysis and systematic review[J].Urol Oncol,2018,36(2):79.e1-e79.
[36]Haas NB,Manola J,Dutcher JP,et al.Adjuvant treatment for high-risk clear cell renal cancer updated results of a high-risk subset of the assure randomized trial[J].JAMAOncol,2017,3(9):1249-1252.
[37]Motzer RJ,Ravaud A,Patard JJ,et al.Adjuvant sunitinib for high-risk renal cell carcinoma after nephrectomy:subgroup analyses and updated overall survival results[J].Eur Urol,2018,73(1):62-68.
[38]Blinman PL,Davis ID,Martin A,et al.Patients’preferences for adjuvant sorafenib after resection of renal cell carcinoma in the SORCE trial:what makes it worthwhile?[J].Ann Oncol,2018,29(2):370-376.
[39]Motzer RJ,Haas NB,Donskov F,et al.Randomized phaseⅢtrial of adjuvant pazopanib versus placebo after nephrectomy in patients with localized or locally advanced renal cell carcinoma[J].J Clin Oncol,2017,35(35):3916-3923.
[40]Synold TW,Plets M,Tangen CM,et al.Everolimus(EVE)exposure as a predictor of toxicity(Tox)in renal cell cancer(RCC)patients(Pts)in the adjuvant setting:results of a pharmacokinetic analysis for SWOG 50931(EVEREST)a phaseⅢstudy(NCT01120249)[J].J Clin Oncol,2017,35(2):849-855.
[41]Gross-Goupil M,Kwon TG,Eto M,et al.Axitinib versus placebo as an adjuvant treatment of renal cell carcinoma:results from the phaseⅢ,randomized ATLAS trial[J].Ann Oncol,2018,29(12):2371-2378.
[42]Bandini M,Smith A,Marchioni M,et al.Adjuvant therapies in nonmetastatic renal-cell carcinoma:a review of the literature[J].Clin Genitourin Cancer,2018,16(3):176-183.
[43]Bandini M,Smith A,Zaffuto E,et al.Effect of pathological high-risk features on cancer-specific mortality in nonmetastatic clear cell renal cell carcinoma:a tool for optimizing patient selection for adjuvant therapy[J].World JUrol,2018,36(1):51-57.
[44]Wolff I,May M,Hoschke B,et al.Do we need new highrisk criteria for surgically treated renal cancer patients to improve the outcome of future clinical trials in the adjuvant setting?Results of a comprehensive analysis based on the multicenter CORONA database[J].Eur J Surg Oncol,2016,42(5):744-750.
[45]Wei C,Wang S,Ye Z,et al.Efficacy of targeted therapy for advanced renal cell carcinoma:a systematic review and meta-analysis of randomized controlled trials[J].Int Braz JUrol,2018,44(2):219-237.
[46]Kovacova J,Juracek J,Poprach A,et al.Candidate microrna biomarkers of therapeutic response to sunitinib in metastatic renal cell carcinoma:a validation study in patients with extremely good and poor response[J].Anticancer Res,2018,38(5):2961-2965.