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
51、erJJAMA，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)JAnn Oncol，2010，(9)：18041809.18Leighl NB，Zatloukal
52、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，et a1Safety and eficacy of first1ine bevacizumabbas
53、ed 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：final results of the ARIES observational cohort studyJJ Thorac 0ncol，2014，9(9)：13321339,
