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1、老年晚期肺癌患者的药物选择,主要内容,背景,细胞毒药物化疗,分子靶向治疗,总结,4,1,2,3,主要内容,背景,1,背景,肺癌世界范围内: 男性人群:发病率和死亡率居第1位; 女性人群:发病率居第3位,死亡率居第2位1。在美国: 居恶性肿瘤相关死亡第1位2,且47%的肺癌患者年龄70岁3。在我国: 发病率和死亡率居首位4。 随着人口老龄化,老年肺癌患者的比例将持续上升!老年肺癌研究现状 前瞻性研究较少,临床缺乏足够的循证医学证据5。,1Torre LA,et a1CA Cancer J Clin,2015,65(2):871082Siegel R,et a1CA Cancer J Clin,2
2、014,64(1):9293Owonikoko TK,et a1J Clin Oncol,2007,25(35):557055774Chen W,et a1Chin J Cancer Res,2013,25(1):1O一215SacherAG,eta1J Thorae Oncol,2013,8(3):366368,主要内容,细胞毒药物化疗,2,细胞毒药物化疗,单药化疗,长春瑞滨,长春瑞滨单药方案可延长老年NSCLC患者中位生存期(MST),提高1年生存率,但与含铂类两药联合化疗方案相比,没有延长总生存时间。,6Devlin JG, et al. Clin Lung Cancer, 2007,
3、8(5): 319-326.,细胞毒药物化疗,单药化疗,紫杉醇,方法:27名NSCLC患者(B/期),平均年龄73岁(70-83岁),其中16名患者有并发症。给予紫杉醇(80mg/m2,第1、8、15天,每4周1次)方案治疗。结果:平均进展时间为5个月,平均生存时间12个月; 7例出现乏力,1例出现过敏反应,无其他的3/4级毒性反应。结论:紫杉醇每周方案(80mg/m2)疗效确切且安全性高,在老年患者可作为替代长春瑞滨或吉西他滨的一线治疗方案,尤其是存在并发症的患者。,7Rossi D, et al.Clin Lung Cancer, 2008, 9(5): 280-284.,细胞毒药物化疗,
4、单药化疗,吉西他滨,方法:47例NSCLC患者(B-期),平均年龄73岁(70-82岁),第1、8、15天应用吉西他滨(1000mg/m2),每28天为1个周期。结果:总有效率为21.7%,中位生存期8.4个月。 度白细胞减少为19.0%,非血液学毒性少见,无度骨髓抑制。结论:吉西他滨单药用于老年NSCLC患者疗效较好,毒性较低。,8Martoni A,et al.Am J Clin Oncol, 2001, 24(6): 614-617.,细胞毒药物化疗,联合化疗,NCCN指南:成年人宜选用联合化疗方案以达到更高的有效率。常用方案:1.非铂类联合化疗长春瑞滨+吉西他滨或吉西他滨+紫杉醇/多西
5、他赛。2.铂类药物为基础的联合化疗卡铂/顺铂+长春瑞滨/吉西他滨/紫杉类等。,细胞毒药物化疗,非铂类联合化疗,RCT试验,方法:707例老年B、期NSCLC患者随机分为3组,分别给予:A组:长春瑞滨(NVB,30mg/m2);B组:吉西他滨(GEM,1200mg/m2);C组:长春瑞滨(NVB,25mg/m2)+吉西他滨(GEM,1000mg/m2),所有药物均为第1、8天给药,3周为1周期最多6个周期。,9Gridelli C, et al. J Natl Cancer Inst, 2003, 95(5): 362-372.,细胞毒药物化疗,结果1 C组分别与A组、B组比较,与生存期、肿瘤进
6、展时间、客观缓解率均无显著差异(P0.05)。,9Gridelli C, et al. J Natl Cancer Inst, 2003, 95(5): 362-372.,细胞毒药物化疗,非铂类联合化疗,RCT试验,结果2C组与A组比较,血小板减少、肝毒性发生率显著升高(P0.05) ;C组与B组比较,中性粒细胞减少、呕吐、乏力、心脏毒性、便秘等发生率显著升高(P0.05)。,9Gridelli C, et al. J Natl Cancer Inst, 2003, 95(5): 362-372.,细胞毒药物化疗,非铂类联合化疗,RCT试验,结论: 对于老年患者,联合化疗不一定优于单药化疗。,
7、9Gridelli C, et al. J Natl Cancer Inst, 2003, 95(5): 362-372.,方法: 451例70-80岁晚期NSCLC患者随机分为3组,分别给予:A组:长春瑞滨;B组:吉西他滨;C组:紫杉醇+卡铂结果显示:结果显示,采用两药化疗患者的中位生存时间(10.3个月)长于单药化疗(6.2 个月,0.01);两药化疗患者更易发生骨髓抑制和肌无力,但均可耐受,细胞毒药物化疗,铂类联合化疗,1.NCCN指南 以铂类为基础的联合化疗是晚期成年NSCLC患者的一线标准治疗方案,疗效优于单药化疗。2.铂类副作用 明显的胃肠道、肾脏、神经系统毒性,老年人是否耐受较有
8、争议。3.铂类的选择 研究表明10,卡铂和顺铂在晚期NSCLC一线治疗中对总生存无显著差异。4.铂类联合化疗用于老年NSCLC患者的临床试验11 适当降低用药量或采用每周给药方案,结果卡铂联合方案疗效及患者耐受性均较好,因此,推荐一般情况好的老年患者可采用低剂量卡铂、顺铂联合方案化疗,但在用药期间应密切关注可能发生的血液毒性及消化道毒性反应,并及时采取相应的防治措施。,10蒋京伟,等 . 中华医学杂志,2006,86(37):2615-2620.11Hiroshi Takatani, et al. Clin Lung Cancer, 2012 Jan 18.,主要内容,分子靶向治疗,3,分子靶
9、向治疗,厄洛替尼:EURTAC研究,12Resell R,et a1Lancet Once1,2012,3(3):239-246.,分子靶向治疗,EURTAC研究:RCT试验,方法:173例EGFR敏感突变的晚期NSCLC患者(B-期),65岁患者88例,65岁85例。随机分为厄洛替尼组和含铂两药(吉西他滨或多西他赛)化疗组,主要终点事件为PFS。结果:1.厄洛替尼组中位PFS为9.7个月,化疗组仅5.2个月(P0.001);2.3-4度不良反应主要为皮疹(厄洛替尼组13%,化疗组0)和中性粒细胞减少(厄洛替尼组0,化疗组22%)。3. 165岁患者同样获益(HR=0.28,P=0.496)。
10、,基于EURTAC研究:2013年5月美国FDA批准厄洛替尼一线治疗EGFR敏感突变的晚期NSCLC患者13。,13Khozin S,et a1Oncologist,2014,19(7):774-779,分子靶向治疗,贝伐单抗,PCB 方案:贝伐单抗+紫杉醇+卡铂,14SandierA,et a1N Engl J Med,2006,355(24):2542255015Ramalingam SS,et a1J Clin Oneel,2oo8,26(1):60-6516Zhu J,et a1JAMA,2012,307(15):15931601,分子靶向治疗,贝伐单抗,GCB 方案:贝伐单抗+吉西他
11、滨+顺铂,17 Reek M,et a1Ann Oncol,2010,(9):18041809.18Leighl NB,et a1J Thorac Oncol,2010,5(12):19701976,分子靶向治疗,贝伐单抗,贝伐单抗联合标准化疗方案,19I Crinb L,et a1Lancet 0ncel,2010,1 (8):73374020LynehTJ Jr,et a1J Thorac 0ncol,2014,9(9):13321339,主要内容,总结,4,总结,1.老年肺癌患者的药物治疗需要权衡患者的一般情况评分、考察肝肾功能和患者意愿等,实施个体化治疗,以便为患者更合理的选择化疗药物
12、。 2.可应用长春瑞滨等单药化疗、含铂两药化疗(PS 评分好)、针对 EGFR 敏感突变的小分子靶向药物厄洛替尼、含贝伐单抗的联合治疗(非鳞癌)等。 3.用药过程中需密切观察患者的毒副反应,并及时采取相应的防治措施。,参考文献,1Torre LA,Bray F,Siegel RL,et a1Global cancer statistics,2012JCA Cancer J Clin,2015,65(2):871082Siegel R,Ma J,Zou Z,et a1Cancer statistics,2014JCA Cancer J Clin,2014,64(1):9293Owonikoko
13、TK,Ragin CC,Belani CP,et a1Lung cancelin elderly patients:an analysis of the surveillance, epidemiology, an d end results databaseJJ Clin Oncol,2007,25(35):557055774Chen W,Zheng R, S,et a1Report ofincidence and mortality in China cancer registries,2OO9JChin J Cancer Res,2013,25(1):1O一215SacherAG,Le
14、LW,LeighlNB,eta1Eldedy patientswith advanced NSCLC in phase In clinical trials:are the elderly eXClUded from practicechanging trials in advanced NSCLC?JJ Thorae Oncol,2013,8(3):3663686Devlin JG, Langer CJ. Salvage therapy with vinorelbine in advanced non-small-cell lung cancer: a retrospective revie
15、w of the Fox Chase Cancer Center experience and a review of the literatureJ. Clin Lung Cancer, 2007, 8(5): 319-326.Devlin JG, et al. Clin Lung Cancer, 2007, 8(5): 319-326.7Rossi D, Dennetta D, Ugolini M, et al. Weekly paclitaxel in elderly patients (aged or = 70 years) with advanced non-small-cell l
16、ung cancer: an alternative choice? Results of a phase II studyJ. Clin Lung Cancer, 2008, 9(5): 280-284. Rossi D, et al.Clin Lung Cancer, 2008, 9(5): 280-284. 8Martoni A, Di Fabio F, Guaraldi M, et al. Prospective phase study of single agent gemcitabine in untreated elderly patients with stage B/ non
17、-small-cell lung cancerJ. Am J Clin Oncol, 2001, 24(6): 614-617.Martoni A,et al.Am J Clin Oncol, 2001, 24(6): 614-617.9Gridelli C, Perrone F, Gallo C, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the multicenter Italian lung cancer in the elderly study (MILES) p
18、hase randomized trialJ. J Natl Cancer Inst, 2003, 95(5): 362-372.Gridelli C, et al. J Natl Cancer Inst, 2003, 95(5): 362-372.10蒋京伟,梁晓华,周鑫莉,等 . 卡铂与顺铂治疗晚期非小细胞肺癌疗效的荟萃分析J. 中华医学杂志,2006,86(37):2615-2620.11Hiroshi Takatani, Yoichi Nakamura, Seiji Nagashima, et al. Phase I and II trials of vinorelbine with
19、carboplatin for patients 75 years of age or older with previously untreated nonsmall-cell lung cancerJ. Clin Lung Cancer, 2012 Jan 18.12Resell R,Carcereny E,Gervais R,et a1Erlotinib versus standard chemotherapy as firstline treatment for European patients with advanced EGFR mutation-positive non-sma
20、l1eell lung cancer(EURTAC):a muhicentre,openlabel。randomised phase 3 trialJLancet Once1,2012,3(3):239-246.13Khozin S,Blumenthal GM,Jiang X,et a1USFood and Drug Administration approval summary: Erlotinib for the firstline treatment of metastatic nonsmall eell lung cancer with epidermal growth factor
21、receptor exon 19 deletions or exon 2l (L858R) substitution mutationsJOncologist,2014,19(7):774-77914SandierA,GrayR,PerryMC,et a1Paelitaxelearboplatinalone or with bevacizumab for nonsmall-celI lung cancerf JN Engl J Med,2006,355(24):2542255015Ramalingam SS,Dahlberg SE,Langer CJ,et a1Outcomes for eld
22、erly,advancedstage non small-cell lung cancer patients treated with bevaeizumab in combination with carboplatin and paclitaxel:analysis ofEastern Cooperative Oncology Group al 4599JJ Clin Oneel,2oo8,26(1):60-6516Zhu J,Sharma DB,Gray SW,et a1Carboplatin and paclitaxel with vs without bevacizumab in o
23、lder patients with advanced non-small cell lung cancerJJAMA,2012,307(15):1593160117 Reek M,yon Pawel J,Zatloukal P,et a1Overall survival with cisplatin gemcitabine and bevacizumab or placebo as first1ine thempy for nonsquamous nonsmall-cell lung cancer:results from a randomised phase 11I trial(AVAIL
24、)JAnn Oncol,2010,(9):18041809.18Leighl NB,Zatloukal P,Mezger J,et a1Efficacy and safety of bevacizumabbased therapy in elderly patients with advaneed orrecurrent nonsquamous non-small eell lung cancer in the phase(B017704) study(AVAIL)JJ Thorac Oncol,2010,5(12):1970197619I Crinb L,Dansin E,Garrido P
25、,et a1Safety and eficacy of first1ine bevacizumabbased therapy in advanced nonsquamous nonsmallcell lung cancer(SAiL,MO19390):a phase 4 studyJLancet 0ncel,2010,1 (8):73374020LynehTJ Jr,SpigelDR,Brahmer J,et a1Safetyand effectiveness of bevacizumab-containing treatment for nonsmal1cell langcancer:fin
26、al results of the ARIES observational cohort studyJJ Thorac 0ncol,2014,9(9):13321339,1Torre LA,Bray F,Siegel RL,et a1Global cancer statistics,2012JCA Cancer J Clin,2015,65(2):871082Siegel R,Ma J,Zou Z,et a1Cancer statistics,2014JCA Cancer J Clin,2014,64(1):9293Owonikoko TK,Ragin CC,Belani CP,et a1Lu
27、ng cancelin elderly patients:an analysis of the surveillance, epidemiology, an d end results databaseJJ Clin Oncol,2007,25(35):557055774Chen W,Zheng R, S,et a1Report ofincidence and mortality in China cancer registries,2OO9JChin J Cancer Res,2013,25(1):1O一215SacherAG,Le LW,LeighlNB,eta1Eldedy patien
28、tswith advanced NSCLC in phase In clinical trials:are the elderly eXClUded from practicechanging trials in advanced NSCLC?JJ Thorae Oncol,2013,8(3):3663686Devlin JG, Langer CJ. Salvage therapy with vinorelbine in advanced non-small-cell lung cancer: a retrospective review of the Fox Chase Cancer Cen
29、ter experience and a review of the literatureJ. Clin Lung Cancer, 2007, 8(5): 319-326.Devlin JG, et al. Clin Lung Cancer, 2007, 8(5): 319-326.7Rossi D, Dennetta D, Ugolini M, et al. Weekly paclitaxel in elderly patients (aged or = 70 years) with advanced non-small-cell lung cancer: an alternative ch
30、oice? Results of a phase II studyJ. Clin Lung Cancer, 2008, 9(5): 280-284. Rossi D, et al.Clin Lung Cancer, 2008, 9(5): 280-284. 8Martoni A, Di Fabio F, Guaraldi M, et al. Prospective phase study of single agent gemcitabine in untreated elderly patients with stage B/ non-small-cell lung cancerJ. Am
31、J Clin Oncol, 2001, 24(6): 614-617.Martoni A,et al.Am J Clin Oncol, 2001, 24(6): 614-617.9Gridelli C, Perrone F, Gallo C, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the multicenter Italian lung cancer in the elderly study (MILES) phase randomized trialJ. J Nat
32、l Cancer Inst, 2003, 95(5): 362-372.Gridelli C, et al. J Natl Cancer Inst, 2003, 95(5): 362-372.10蒋京伟,梁晓华,周鑫莉,等 . 卡铂与顺铂治疗晚期非小细胞肺癌疗效的荟萃分析J. 中华医学杂志,2006,86(37):2615-2620.,参考文献,1Torre LA,Bray F,Siegel RL,et a1Global cancer statistics,2012JCA Cancer J Clin,2015,65(2):871082Siegel R,Ma J,Zou Z,et a1Cance
33、r statistics,2014JCA Cancer J Clin,2014,64(1):9293Owonikoko TK,Ragin CC,Belani CP,et a1Lung cancelin elderly patients:an analysis of the surveillance, epidemiology, an d end results databaseJJ Clin Oncol,2007,25(35):557055774Chen W,Zheng R, S,et a1Report ofincidence and mortality in China cancer reg
34、istries,2OO9JChin J Cancer Res,2013,25(1):1O一215SacherAG,Le LW,LeighlNB,eta1Eldedy patientswith advanced NSCLC in phase In clinical trials:are the elderly eXClUded from practicechanging trials in advanced NSCLC?JJ Thorae Oncol,2013,8(3):3663686Devlin JG, Langer CJ. Salvage therapy with vinorelbine i
35、n advanced non-small-cell lung cancer: a retrospective review of the Fox Chase Cancer Center experience and a review of the literatureJ. Clin Lung Cancer, 2007, 8(5): 319-326.Devlin JG, et al. Clin Lung Cancer, 2007, 8(5): 319-326.7Rossi D, Dennetta D, Ugolini M, et al. Weekly paclitaxel in elderly
36、patients (aged or = 70 years) with advanced non-small-cell lung cancer: an alternative choice? Results of a phase II studyJ. Clin Lung Cancer, 2008, 9(5): 280-284. Rossi D, et al.Clin Lung Cancer, 2008, 9(5): 280-284. 8Martoni A, Di Fabio F, Guaraldi M, et al. Prospective phase study of single agent
37、 gemcitabine in untreated elderly patients with stage B/ non-small-cell lung cancerJ. Am J Clin Oncol, 2001, 24(6): 614-617.Martoni A,et al.Am J Clin Oncol, 2001, 24(6): 614-617.9Gridelli C, Perrone F, Gallo C, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the mu
38、lticenter Italian lung cancer in the elderly study (MILES) phase randomized trialJ. J Natl Cancer Inst, 2003, 95(5): 362-372.Gridelli C, et al. J Natl Cancer Inst, 2003, 95(5): 362-372.10蒋京伟,梁晓华,周鑫莉,等 . 卡铂与顺铂治疗晚期非小细胞肺癌疗效的荟萃分析J. 中华医学杂志,2006,86(37):2615-2620.11Hiroshi Takatani, Yoichi Nakamura, Seiji
39、Nagashima, et al. Phase I and II trials of vinorelbine with carboplatin for patients 75 years of age or older with previously untreated nonsmall-cell lung cancerJ. Clin Lung Cancer, 2012 Jan 18.12Resell R,Carcereny E,Gervais R,et a1Erlotinib versus standard chemotherapy as firstline treatment for Eu
40、ropean patients with advanced EGFR mutation-positive non-smal1eell lung cancer(EURTAC):a muhicentre,openlabel。randomised phase 3 trialJLancet Once1,2012,3(3):239-246.13Khozin S,Blumenthal GM,Jiang X,et a1USFood and Drug Administration approval summary: Erlotinib for the firstline treatment of metast
41、atic nonsmall eell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 2l (L858R) substitution mutationsJOncologist,2014,19(7):774-77914SandierA,GrayR,PerryMC,et a1Paelitaxelearboplatinalone or with bevacizumab for nonsmall-celI lung cancerf JN Engl J Med,2006,355(24):2542255
42、015Ramalingam SS,Dahlberg SE,Langer CJ,et a1Outcomes for elderly,advancedstage non small-cell lung cancer patients treated with bevaeizumab in combination with carboplatin and paclitaxel:analysis ofEastern Cooperative Oncology Group al 4599JJ Clin Oneel,2oo8,26(1):60-6516Zhu J,Sharma DB,Gray SW,et a
43、1Carboplatin and paclitaxel with vs without bevacizumab in older patients with advanced non-small cell lung cancerJJAMA,2012,307(15):1593160117 Reek M,yon Pawel J,Zatloukal P,et a1Overall survival with cisplatin gemcitabine and bevacizumab or placebo as first1ine thempy for nonsquamous nonsmall-cell
44、 lung cancer:results from a randomised phase 11I trial(AVAIL)JAnn Oncol,2010,(9):18041809.18Leighl NB,Zatloukal P,Mezger J,et a1Efficacy and safety of bevacizumabbased therapy in elderly patients with advaneed orrecurrent nonsquamous non-small eell lung cancer in the phase(B017704) study(AVAIL)JJ Th
45、orac Oncol,2010,5(12):1970197619I Crinb L,Dansin E,Garrido P,et a1Safety and eficacy of first1ine bevacizumabbased therapy in advanced nonsquamous nonsmallcell lung cancer(SAiL,MO19390):a phase 4 studyJLancet 0ncel,2010,1 (8):73374020LynehTJ Jr,SpigelDR,Brahmer J,et a1Safetyand effectiveness of beva
46、cizumab-containing treatment for nonsmal1cell langcancer:final results of the ARIES observational cohort studyJJ Thorac 0ncol,2014,9(9):13321339,11Hiroshi Takatani, Yoichi Nakamura, Seiji Nagashima, et al. Phase I and II trials of vinorelbine with carboplatin for patients 75 years of age or older wi
47、th previously untreated nonsmall-cell lung cancerJ. Clin Lung Cancer, 2012 Jan 18.12Resell R,Carcereny E,Gervais R,et a1Erlotinib versus standard chemotherapy as firstline treatment for European patients with advanced EGFR mutation-positive non-smal1eell lung cancer(EURTAC):a muhicentre,openlabel。ra
48、ndomised phase 3 trialJLancet Once1,2012,3(3):239-246.13Khozin S,Blumenthal GM,Jiang X,et a1USFood and Drug Administration approval summary: Erlotinib for the firstline treatment of metastatic nonsmall eell lung cancer with epidermal growth factor receptor exon 19 deletions or exon 2l (L858R) substi
49、tution mutationsJOncologist,2014,19(7):774-77914SandierA,GrayR,PerryMC,et a1Paelitaxelearboplatinalone or with bevacizumab for nonsmall-celI lung cancerf JN Engl J Med,2006,355(24):2542255015Ramalingam SS,Dahlberg SE,Langer CJ,et a1Outcomes for elderly,advancedstage non small-cell lung cancer patien
50、ts treated with bevaeizumab in combination with carboplatin and paclitaxel:analysis ofEastern Cooperative Oncology Group al 4599JJ Clin Oneel,2oo8,26(1):60-6516Zhu J,Sharma DB,Gray SW,et a1Carboplatin and paclitaxel with vs without bevacizumab in older patients with advanced non-small cell lung canc