甲磺酸阿帕替尼治疗晚期食管鳞癌临床观察
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摘要
目的甲磺酸阿帕替尼是一种新型小分子酪氨酸激酶抑制剂,是治疗晚期胃癌有效靶向药物,本研究探讨甲磺酸阿帕替尼用于二线或二线以上化疗失败的晚期食管鳞癌临床疗效、不良反应及预后危险因素。方法研究对象为聊城市人民医院2015-06-10-2017-06-25接受过二线或二线以上化疗且病情进展或复发的60例ⅢB～Ⅳ期食管鳞癌患者,均经病理确诊,给予口服甲磺酸阿帕替尼500mg/次,1次/d。28d为1个周期,1个周期后观察并分析其临床疗效、预后影响因素及不良反应发生情况。所有入选患者治疗前1d行循环肿瘤细胞(circulating tumor cells,CTCs)检测,研究CTCs检测与患者预后关系。采用Kaplan-Meier法计算生存率及制作生存曲线图,Log-rank法进行生存率曲线统计学检验,Cox回归模型分析多因素对总生存期(overall survival,OS)影响。结果 60例ⅢB～Ⅳ期食管鳞癌患者均完成疗效评价,其中完全缓解(complete response,CR)0例,部分缓解(partial response,PR)14例(23.3%),疾病稳定(stable disease,SD)32例(53.3%),疾病进展(progressive disease,PD)14例(23.3%),客观缓解率(overall response rate,ORR)和疾病控制率(disease control rate,DCR)分别为23.3%和76.6%。不良反应主要有高血压35例(58.3%),蛋白尿28例(46.7%),手足综合征27例(45.0%),腹泻9例(15.0%),骨髓抑制12例(20.0%),反应程度主要为轻度反应。中位总生存期(median overall survival time,MOS)为215d。单因素分析显示患者ECOG体力状况评分(χ2=13.237,P<0.001)、CTCs计数分层(χ2=47.476,P<0.001)与患者OS有关联。Cox多因素回归分析显示,CTCs计数分层2～5(HR=3.446,95%CI=1.480～8.025,P=0.004)、CTCs计数分层≥5(HR=13.15,95%CI=8.75～20.56,P<0.001)和ECOG体力状况评分(HR=2.319,95%CI=1.188～4.526,P=0.014)是患者预后OS危险因素。结论甲磺酸阿帕替尼用于二线或二线以上化疗失败的ⅢB～Ⅳ期食管鳞癌仍具有一定临床疗效,不良反应轻。CTCs计数、ECOG体力状况评分与患者OS有关联,可以提示患者预后。
OBJECTIVE Apatinib mesylate is a novel small molecule tyrosine kinase inhibitor that was an effective targeted drug for the treatment of advanced gastric cancer.The aim of this study was to investigate the clinical efficacy,adverse reactions and prognostic factors of apatinil mesylate in the treatment for advanced esophageal squamous cell carcinoma who had failed in second-line or further-line chemotherapy.METHODS Sixty patients with stageⅢB-Ⅳesophageal squamous cell carcinoma were choosed from June 10,2015 to June 25,2017 in Liaocheng People's Hospital who had received second-line or further-line chemotherapy and whose condition had progressed or relapsed.All patients were diagnosed with pathology and were given oral apatinil mesylate 500 mg one day.The one cycle was 28 days and began to evaluate the efficacy,prognostic factors and adverse reactions after one cycle.The circulating tumor cells(CTCs)were detected one day before treatment in all selected patients.The relationship between CTCs and prognosis,clinical efficacy,prognostic factors and adverse reactions were observed and analyzed in time.Kaplan meier method was used to calculate the survival rate and the survival curve chart.The log rank method was used to test the survival curve and the Cox regression model was used to analyze the effect of multiple factors on the overall survival(OS).RESULTS The efficacy was evaluated in all sixty patients who with stageⅢB-Ⅳesophageal squamous cell carcinoma,including complete response(CR)in 0,partial response(PR)in 14(23.3%),stable disease(SD)32 cases(53.3%),progressive disease(PD)in 14 cases(23.3%),objective response rate(ORR)and disease control rate(DCR)were 23.3%and 76.6%.The main adverse reactions were 35 cases of hypertension(58.3%),28 cases of proteinuria(46.7%),27 cases of hand-foot syndrome(45.0%),9 cases of diarrhea(15.0%)and 12 cases of myelosuppression(20.0%).The degree is mainly mild reaction.The median overall survival time(MOS)was 215 days.Univariate analysis showed that patients with OS were associated with ECOG physical status scores(χ~2=13.237,P<0.001)and CTCs count stratification(χ~2=47.476,P<0.001).Cox multivariate regression analysis showed that CTCs counted stratification 2-5(HR=3.446,95%CI=1.480-8.025,P=0.004),CTCs counted stratification≥5(HR=13.15,95%CI= 8.75-20.56,P<0.001),ECOG physical status score 2(HR=2.319,95%CI=1.188-4.526,P=0.014)were risk factors for OS prognosis.CONCLUSIONS Apatinib mesylate for stageⅢB-Ⅳ esophageal cancer patients who failed in second-line or further-line chemotherapy still has a certain clinical effect and the adverse reactions are mild.CTCs count,ECOG physical status scores are associated with patient's OS and can indicate prognosis.
OBJECTIVE Apatinib mesylate is a novel small molecule tyrosine kinase inhibitor that was an effective targeted drug for the treatment of advanced gastric cancer.The aim of this study was to investigate the clinical efficacy,adverse reactions and prognostic factors of apatinil mesylate in the treatment for advanced esophageal squamous cell carcinoma who had failed in second-line or further-line chemotherapy.METHODS Sixty patients with stageⅢB-Ⅳesophageal squamous cell carcinoma were choosed from June 10,2015 to June 25,2017 in Liaocheng People's Hospital who had received second-line or further-line chemotherapy and whose condition had progressed or relapsed.All patients were diagnosed with pathology and were given oral apatinil mesylate 500 mg one day.The one cycle was 28 days and began to evaluate the efficacy,prognostic factors and adverse reactions after one cycle.The circulating tumor cells(CTCs)were detected one day before treatment in all selected patients.The relationship between CTCs and prognosis,clinical efficacy,prognostic factors and adverse reactions were observed and analyzed in time.Kaplan meier method was used to calculate the survival rate and the survival curve chart.The log rank method was used to test the survival curve and the Cox regression model was used to analyze the effect of multiple factors on the overall survival(OS).RESULTS The efficacy was evaluated in all sixty patients who with stageⅢB-Ⅳesophageal squamous cell carcinoma,including complete response(CR)in 0,partial response(PR)in 14(23.3%),stable disease(SD)32 cases(53.3%),progressive disease(PD)in 14 cases(23.3%),objective response rate(ORR)and disease control rate(DCR)were 23.3%and 76.6%.The main adverse reactions were 35 cases of hypertension(58.3%),28 cases of proteinuria(46.7%),27 cases of hand-foot syndrome(45.0%),9 cases of diarrhea(15.0%)and 12 cases of myelosuppression(20.0%).The degree is mainly mild reaction.The median overall survival time(MOS)was 215 days.Univariate analysis showed that patients with OS were associated with ECOG physical status scores(χ~2=13.237,P<0.001)and CTCs count stratification(χ~2=47.476,P<0.001).Cox multivariate regression analysis showed that CTCs counted stratification 2-5(HR=3.446,95%CI=1.480-8.025,P=0.004),CTCs counted stratification≥5(HR=13.15,95%CI= 8.75-20.56,P<0.001),ECOG physical status score 2(HR=2.319,95%CI=1.188-4.526,P=0.014)were risk factors for OS prognosis.CONCLUSIONS Apatinib mesylate for stageⅢB-Ⅳ esophageal cancer patients who failed in second-line or further-line chemotherapy still has a certain clinical effect and the adverse reactions are mild.CTCs count,ECOG physical status scores are associated with patient's OS and can indicate prognosis.
引文
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[13]曹恒,王静,纪媛媛,等.甲磺酸阿帕替尼治疗晚期非小细胞肺癌临床观察[J].中华肿瘤防治杂志,2017,24(7):468-476.
[14]李春杏,高玲燕,郑丽,等.阿帕替尼对晚期实体恶性肿瘤疗效[J].中华肿瘤防治杂志,2018,25(15):1113-1122.
[15]Li J,Qin S,Xu J,et al.Randomized,double-blind,placebo-controlled phaseⅢtrial of apatinib in patients with chemotherapyrefractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction[J].J Clin Oncol,2016,34(13):1448-1454.
[16]Qin SK,Li J.Experts consensus on the clinical application of apatinib in gastric cancer treatment[J].Chin Clin Oncol,2015,20(9):841-847.
[17]Li J,Wang L.Efficacy and safety of apatinib treatment for advanced esophageal squamous cell carcinoma[J].Onco Targets T-her,2017,7(10):3965-3969.
[18]Song Z,Yu X,Lou G,et al.Salvage treatment with apatinib for advanced non-small-cell lung cancer[J].Onco Targets Ther,2017,23(10):1821-1825.
[19]Paterlini-Brechot P.Organ-specific markers in circulating tumor cell screening:an early indicator of metastasis-capable malignancy[J].Future Oncol,2011,7(7):849-871.
[20]Pierga JY,Bidard FC,Autret A,et al.Circulating tumour cells and pathological complete response:independent prognostic factors in inflammatory breast cancer in a pooled analysis of two multicentre phaseⅡtrials(BEVERLY-1and-2)of neoadjuvant chemotherapy combined with bevacizumab[J].Ann Oncol,2016,28(1):103-109.
[21]Lindsay CR,Faugeroux V,Michiels S,et al.A prospective examination of circulating tumor cell profiles in non-small cell lung cancer molecular subgroups[J].Ann Oncol,2017,28(7):1523-1531.
[22]Reeh M,Effenberger KE,Koenig AM,et al.Circulating tumor cells as a biomarker for preoperative prognostic staging in patients with esophageal cancer[J].Ann Surg,2015,261(6):1124-1130.
[23]Qiao Y,Li J,Shi C,et al.Prognostic value of circulating tumor cells in the peripheral blood of patients with esophageal squamous cell carcinoma[J].Onco Targets Ther,2017,3(10):1363-1373.
[2]Chen W,Zheng R,Baade PD,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
[3]张思维,郑荣寿,左婷婷,等.中国食管癌死亡状况和生存分析[J].中华肿瘤杂志,2016,38(9):709-715.
[4]Song Z,Zhang Y.Second line docetaxel based chemotherapy after failure of fluorouracil-based first-line treatment for advanced esophageal squamous cell carcinoma[J].Onco Targets Ther,2014,7:1875-1881.
[5]Li X,Lin W,Wang H,et al.PhaseⅡtrial of second-line chemotherapy with docetaxel and capecitabine in advanced esophageal squamous cell carcinoma[J].Med Oncol,2013,30(4):746.
[6]田晓坤,李玉明,胡宝光,等.胃癌患者外周血Cyttel循环肿瘤细胞检测及临床意义[J].中华实验外科杂志,2017,34(2):208-210.
[7]Zhang H.Apatinib for molecular targeted therapy in tumor[J].Drug Des Devel Ther,2015,13(9):6075-6081.
[8]Roviello G,Ravelli A,Polom K,et al.Apatinib:a novel receptor tymsine kinase inhibitor for the treatment of gastric cancer[J].Cancer Lett,2016,372(2):187-191.
[9]Scott AJ,Messersmith WA,Jimeno A.Apatinib:apromising oral antiangiogenic agent in the treatment of multiple solid tumors[J].Drugs Today(Barc),2015,51(4):223-229.
[10]Wu D,Liang L,Nie L,et al.Efficacy,safety and predictive indicators of apatinib after multilines treatment in advanced nonsquamous nonsmall cell lung cancer:apatinib treatment in nonsquamous NSCLC[J].Asia Pac J Clin Oncol.2018,3(24):1-7.
[11]Ding L,Li QJ,You KY,et a1.The use of apatinib in treating nonsmall cell lung cancer[J].Medicine,2016,95(20):e3598.
[12]高世乐,胡宗涛.阿帕替尼治疗晚期肺腺癌EGFR-TKI耐药后一例报告[J].中华肿瘤防治杂志,2018,25(9):678-680.
[13]曹恒,王静,纪媛媛,等.甲磺酸阿帕替尼治疗晚期非小细胞肺癌临床观察[J].中华肿瘤防治杂志,2017,24(7):468-476.
[14]李春杏,高玲燕,郑丽,等.阿帕替尼对晚期实体恶性肿瘤疗效[J].中华肿瘤防治杂志,2018,25(15):1113-1122.
[15]Li J,Qin S,Xu J,et al.Randomized,double-blind,placebo-controlled phaseⅢtrial of apatinib in patients with chemotherapyrefractory advanced or metastatic adenocarcinoma of the stomach or gastroesophageal junction[J].J Clin Oncol,2016,34(13):1448-1454.
[16]Qin SK,Li J.Experts consensus on the clinical application of apatinib in gastric cancer treatment[J].Chin Clin Oncol,2015,20(9):841-847.
[17]Li J,Wang L.Efficacy and safety of apatinib treatment for advanced esophageal squamous cell carcinoma[J].Onco Targets T-her,2017,7(10):3965-3969.
[18]Song Z,Yu X,Lou G,et al.Salvage treatment with apatinib for advanced non-small-cell lung cancer[J].Onco Targets Ther,2017,23(10):1821-1825.
[19]Paterlini-Brechot P.Organ-specific markers in circulating tumor cell screening:an early indicator of metastasis-capable malignancy[J].Future Oncol,2011,7(7):849-871.
[20]Pierga JY,Bidard FC,Autret A,et al.Circulating tumour cells and pathological complete response:independent prognostic factors in inflammatory breast cancer in a pooled analysis of two multicentre phaseⅡtrials(BEVERLY-1and-2)of neoadjuvant chemotherapy combined with bevacizumab[J].Ann Oncol,2016,28(1):103-109.
[21]Lindsay CR,Faugeroux V,Michiels S,et al.A prospective examination of circulating tumor cell profiles in non-small cell lung cancer molecular subgroups[J].Ann Oncol,2017,28(7):1523-1531.
[22]Reeh M,Effenberger KE,Koenig AM,et al.Circulating tumor cells as a biomarker for preoperative prognostic staging in patients with esophageal cancer[J].Ann Surg,2015,261(6):1124-1130.
[23]Qiao Y,Li J,Shi C,et al.Prognostic value of circulating tumor cells in the peripheral blood of patients with esophageal squamous cell carcinoma[J].Onco Targets Ther,2017,3(10):1363-1373.