阿昔替尼剂量滴定在治疗晚期转移性肾癌中的临床应用及疗效评价
摘要
目的评价阿昔替尼及其剂量滴定治疗晚期转移性肾癌的疗效及安全性。方法回顾性分析2014年9月至2017年12月间四川大学华西医院使用阿昔替尼系统治疗晚期转移肾癌患者的临床及病理资料,根据采用阿昔替尼治疗方法的不同,分为剂量滴定(n=26)与标准剂量(n=24)阿昔替尼治疗,其中剂量滴定使用2种策略:策略1(主动滴定,n=7)为根据患者在治疗中未出现严重不良反应而进行滴定,策略2(被动滴定,n=19)为患者在治疗过程中出现疾病进展后进行剂量滴定。统计其基线及后续随访信息,患者疗效评估根据RECIST 1.1标准及Choi标准进行,不良反应评价按照CTCAE 4.0标准分为1～5级,其中3～5级定义为严重不良反应。结果共纳入晚期转移肾癌患者58例,中位无疾病进展生存(PFS)时间及总生存(OS)时间分别为8.0月和29.0月。Choi标准下,客观缓解率(ORR)较RECIST 1.1标准提高(43.1%vs. 15.5%,P=0.001),而疾病控制率(DCR)基本一致(87.9%vs. 86.2%,P=0.782)。剂量滴定患者26例,与配对的24例标准剂量治疗患者比较,前者PFS时间较长(P=0.027),而两组间OS时间差异无统计学意义(P=0.072)。被动滴定者19例,主动滴定者7例,两组间PFS及OS时间差异均无统计学意义(P=0.338和P=0.470)。阿昔替尼治疗总体不良反应由高到低分别为乏力(67.2%,39例)、高血压(56.9%,33例)、淋巴细胞减少(53.4.%,31例)及高血脂(53.4%,31例)等,以1～2级不良反应为主;滴定前后患者不良反应种类及发生率无明显变化。结论阿昔替尼作为晚期转移性肾癌的标准二线治疗药物,具有可靠的安全性及疗效。剂量滴定可为患者带来生存获益,主动及被动滴定策略均可采用。
引文
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[2] MENNITTO A,VERZONI E,GRASSI P,et al.Multimodal treatment of advanced renal cancer in 2017.Expert Rev Clin Pharmacol,2017,10(12):1395-1402.
[3] MOTZER RJ,BANDER NH,NANUS DM.Renal-cell carcinoma.N Engl J Med,1996,335(12):865-875.
[4] 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.
[5] 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.
[6] ALT AL,BOORJIAN SA,LOHSE CM,et al.Survival after complete surgical resection of multiple metastases from renal cell carcinoma.Cancer,2011,117(13):2873-2882.
[7] RUGO HS,HERBST RS,LIU G,et al.Phase Ⅰ trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors:pharmacokinetic and clinical results.J Clin Oncol,2005,23(24):5474-5483.
[8] 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.
[9] RINI BI,GARRETT M,POLAND B,et al.Axitinib in metastatic renal cell carcinoma:results of a pharmacokinetic and pharmacodynamic analysis.J Clin Pharmacol,2013,53(5):491-504.
[10] RINI BI,MELICHAR B,UEDA T,et al.Axitinib with or without dose titration for first-line metastatic renal-cell carcinoma:a randomised double-blind phase 2 trial.Lancet Oncol,2013,14(12):1233-1242.
[11] RINI BI,TOMITA Y,MELICHAR B,et al.Overall survival analysis from a randomized phase ii study of axitinib with or without dose titration in first-line metastatic renal cell carcinoma.Clin Genitourin Cancer,2016,14(6):499-503.
[12] EISENHAUER EA,THERASSE P,BOGAERTS J,et al.New response evaluation criteria in solid tumours:revised RECIST guideline (version 1.1).Eur J Cancer,2009,45(2):228-247.
[13] CHOI H,CHARNSANGAVEJ C,FARIA SC,et al.Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate:proposal of new computed tomography response criteria.J Clin Oncol,2007,25(13):1753-1759.
[14] DUECK AC,MENDOZA TR,MITCHELL SA,et al.Validity and reliability of the us national cancer institute’s patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE).JAMA Oncol,2015,1(8):1051-1059.
[15] UMEYAMA Y,SHIBASAKI Y,AKAZA H.Axitinib in metastatic renal cell carcinoma:beyond the second-line setting.Future Oncol,2017,13(21):1839-1852.
[16] MOTZER R J,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.
[17] SHERMAN S,AMZAL B,CALVO E,et al.An indirect comparison of everolimus versus axitinib in us patients with advanced renal cell carcinoma in whom prior sunitinib therapy failed.Clin Ther,2015,37(11):2552-2559[2018-08-22].https://doi.org/10.1016/j.clinthera.2015.09.013.
[18] MATIAS M,LE TEUFF G,ALBIGES L,et al.Real world prospective experience of axitinib in metastatic renal cell carcinoma in a large comprehensive cancer centre.Eur J Cancer,2017,79:185-192[2018-08-22].https://doi.org/10.1016/j.ejca.2017.04.015.
[19] MIYAKE H,HARADA K,OZONO S,et al.Efficacy and safety of axitinib in elderly patients with metastatic renal cell carcinoma.Med Oncol,2016,33(8):95[2018-08-22].https://link.springer.com/article/10.1007%2Fs12032-016-0813-1.doi:10.1007/s12032-016-0813-1.
[20] D’ANIELLO C,VITALE M G,FARNESI A,et al.Axitinib after sunitinib in metastatic renal cancer:preliminary results from Italian “Real-World” sax study.Front Pharmacol,2016,7:331[2018-08-22].https://doi.org/10.3389/fphar.2016.00331.
[21] HUTSON TE,DAVIS ID,MACHIELS JP,et al.Efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma.J Clin Oncol,2010,28(3):475-480.
[22] HUTSON TE,LESOVOY V,AL-SHUKRI S,et al.Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma:a randomised open-label phase 3 trial.Lancet Oncol,2013,14(13):1287-1294.
[23] ORNSTEIN MC,WOOD L,ELSON P,et al.Clinical effect of dose escalation after disease progression in patients with metastatic renal cell carcinoma.Clin Genitourin Cancer,2017,15(2):e275-e280[2018-08-22].https://doi.org/10.1016/j.clgc.2016.08.014.
[24] RINI BI,MELICHAR B,FISHMAN MN,et al.Axitinib dose titration:analyses of exposure,blood pressure and clinical response from a randomized phase Ⅱ study in metastatic renal cell carcinoma.Ann Oncol,2015,26(7):1372-1377.
[25] QIN SK,JIN J,GUO J,et al.Efficacy and safety of first-line sunitinib in Chinese patients with metastatic renal cell carcinoma.Future Oncol,2018,14(18):1835-1845.