肺癌個(gè)體化精準(zhǔn)治療課件

1、肺癌個(gè)體化精準(zhǔn)治療1. Jemal A, et al. CA Cancer J Clin 2011; 61(2):69-90. 2. Zheng R, et al. China Cancer 2012; 21(1):1-12.2015:中國(guó)肺癌發(fā)病率和死亡率居世界最高2012年新發(fā)中國(guó)腫瘤患者占世界腫瘤患者比例020000040000060000080000010000001200000140000016000001800000食道癌胃癌結(jié)直腸癌肝癌肺癌乳腺癌中國(guó)以外世界中國(guó)52.1%58.8%27.0%35.6%51.2%46.5%其中肺癌治療的療效差別也較大 中美腫瘤5年OS分別為31%

2、vs 68% (IJC-2015)主要是中美兩國(guó)在患者的臨床期別和治療手段的差別所有腫瘤結(jié)直腸癌中樞腫瘤中國(guó)美國(guó)肺癌胃癌肝癌食管癌乳腺癌宮頸癌白血病膀胱癌解除武裝力量：消滅癌細(xì)胞的增殖、血管生成、免疫逃逸等殲滅特種部隊(duì)：腫瘤細(xì)胞、腫瘤干細(xì)胞、微環(huán)境根據(jù)不同戰(zhàn)場(chǎng)設(shè)計(jì)戰(zhàn)術(shù)：原發(fā)灶和轉(zhuǎn)移灶的異質(zhì)性 為何50年抗癌之戰(zhàn)收效不大的反思改變生活方式；早診早治；優(yōu)化治療策略；轉(zhuǎn)化醫(yī)學(xué)研究孫子兵法之謀攻篇：不戰(zhàn)而屈人之兵，要以小代價(jià)取大勝Rethink the war on Cancer. Lancet 2014美國(guó)近15年SCLC療效無(wú)改善; 非小細(xì)胞肺癌5年OS僅提高4%抗癌之戰(zhàn) 前路漫漫 個(gè)體化治療解決

3、肺癌異質(zhì)性 空間異質(zhì)性:Spatial患者個(gè)體異質(zhì)性 時(shí)間異質(zhì)性:Temporal Nature 2013異質(zhì)性是腫瘤遺傳不穩(wěn)定性與環(huán)境因素導(dǎo)致分子多樣性 Science 2012已發(fā)現(xiàn)眾多肺癌相關(guān)分子但？ 基因水平突變肺癌的發(fā)生個(gè)體化治療腫瘤細(xì)胞生成 功能學(xué)改變解剖結(jié)構(gòu)改變需要個(gè)體化精準(zhǔn)與整合醫(yī)學(xué)肺癌治療是復(fù)雜的系統(tǒng)工程 治療現(xiàn)狀:盲人摸象?肺癌治療方案選擇 療效評(píng)價(jià)=Survival;Local Control;Quality 有效 低毒 經(jīng)濟(jì) 肺癌治療的核心是使復(fù)雜的技術(shù)簡(jiǎn)單化 Cost Effective to Cost Toxicity 解決個(gè)體與優(yōu)化 與循證醫(yī)學(xué)依賴(lài)解決標(biāo)準(zhǔn)與平衡但

4、循證不能教條肺癌治療模式進(jìn)展Tr Advances: Art of Oncology循證醫(yī)學(xué)精準(zhǔn)醫(yī)學(xué)個(gè)體醫(yī)學(xué)解決整合與最大更依賴(lài)于大數(shù)據(jù) 治療決策 = 臨床證據(jù)+臨床經(jīng)驗(yàn)肺癌個(gè)體化治療之策略年齡性別身體狀況治療選擇傳統(tǒng)因素(病人因素) 腫瘤位置腫瘤分期病理類(lèi)型傳統(tǒng)因素(腫瘤因素)醫(yī)生水平醫(yī)生責(zé)任治療依從傳統(tǒng)因素(治療因素)影像學(xué)組學(xué)基因?qū)W組學(xué)信息學(xué)組學(xué)新型因素(難以確定) 治療與相關(guān)分子靶點(diǎn)關(guān)系未知已知協(xié)同拮抗無(wú)關(guān)有無(wú) 治 療 相 關(guān) 靶 點(diǎn)Potential Interactions between SBRT & Target drugsRECEL Results: Cut-off 2015

5、/05/31%（n）Erlotinib+RT（n=13）EP+RT（n=12）CR30.8（4）16.7（2）PR15.4（2）16.7（2）SD46.2（6）33.3（4）PD0 (0)8.33（1）NAa7.69（1）25（3）ORR46.2（6）33.3（4）DCR92.3（12）66.7（8）TKI EP PFS: 21.3 m vs 6.2 m CCRT Vs CTRT for IIIm(+)NSCLC個(gè)體醫(yī)學(xué)分子靶向治療新模式Clin Cancer Res 2015;21:151424. (同病異治) (異病同治) 帶有相同基因靶點(diǎn)的不同腫瘤給予相同治療把同一腫瘤所包含不同基因靶點(diǎn)

6、行分類(lèi)研究肺癌個(gè)體化治療理念和實(shí)踐腫瘤3病人療效差且很難預(yù)測(cè) 療效高 損傷小 費(fèi)用低腫瘤 1腫瘤2同樣的治療方案 同樣組織類(lèi)型及同樣臨床分期方案 1腫瘤1腫瘤2腫瘤3分子分型和分期不同同樣組織類(lèi)型及同樣臨床分期方案2方案3 個(gè)體化全程管理與排兵布陣 首先要確定治療目的或目標(biāo)科學(xué)隨訪(fǎng)病理診斷臨床分期與分子分型精準(zhǔn)治療(幾線(xiàn)幾代?） 個(gè)體化治療 與全程管理分子診斷 (集成精準(zhǔn)）精準(zhǔn)醫(yī)學(xué)多學(xué)科會(huì)診Sciences2013十大科學(xué)突破之首 Harnessing the immune system to battle tumors放化療與免疫聯(lián)合:New Paradigm Silvia et al. J

7、 Natl Cancer Inst. 2013免疫指標(biāo)CD8+TILs預(yù)測(cè)PFS和OS過(guò)度放化療破壞機(jī)體免疫Clin Cancer Res 2009；J. Radiat Oncol Biol Phys. 2012; 放療或化療強(qiáng)度不足放療或化療強(qiáng)度過(guò)度放療或化療強(qiáng)度適宜Check-point Signaling in Ca ImmunotherapyJames Allison LASKER 2015Check Mate-017 & 057晚期NSCLC: Success or NotEarly palliative care: 2.7 mons(11.6 vs 8.9)Early suppor

8、tive care: $6000/yr (N Engl J Med)Bevacizumab(ECOG 4599):2 mons(14 vs 12)Bevacizumab: $115,000/yrNivolumab (ASCO 2015): 3.3 monsNivolumab: $140,000/yr 新免疫治療藥價(jià)是黃金4000倍, 治療費(fèi)100萬(wàn)美元/年: Saltz;2015 ASCO Most ExpensiveBest Care:2015 ASCO SBRT Abscopal Effect; Postow et al.N Engl J Med.2012 Combine SBRT wit

9、h Immunotherapy可手術(shù)I期NSCLC: SBRT Vs 手術(shù)STARS & ROSEL Pooled Analysis of 58 ptsChang JY et al. Lancet Oncol, 2015無(wú)復(fù)發(fā)生存總生存SBRT(31 pts)Surgery(27 pts)HRP-value3-yr RFS86%80%0.690.543-yr OS95%79%0.140.037RTOG 3502 Schema: ongoing PI: Jinming Yu, MD, PhD; 目前該研究已經(jīng)成功入組10例病人 放射免疫治療:遠(yuǎn)隔效應(yīng) The abscopal effect: R

10、T-induced tumor regression in lesions distant from a targeted site Kamrava M, et al, Mol Biosyst. 2009 Nov;5:1262-70單純放療對(duì)區(qū)域淋巴結(jié)及遠(yuǎn)隔效應(yīng)影響研究各組單純放療均未見(jiàn)明顯的遠(yuǎn)隔效應(yīng)不同分割模式放療對(duì)腫瘤的局控率不同，引發(fā)的免疫反應(yīng)也不同，但均未見(jiàn)明顯的遠(yuǎn)隔效應(yīng)大分割較常規(guī)分割對(duì)腫瘤的局控率更高，進(jìn)一步激活局部腫瘤、引流淋巴結(jié)及全身免疫反應(yīng)Local plus Systemic Control Lead to Ca Cure沒(méi)有100% Stage I;其中5-10%患者在血

11、液中發(fā)現(xiàn)CTCImmunotherapyBernstein and Chang. Nature Rev Clin OncoI-SBRTPhase III Trial-Study DesignOligometastatic NSCLCChemo and IT naveECOG PS 0-1Pre-tr PD-L1 analysisMPDL3280A(1200mg q3w)+SBRT(50Gy in 4 fraction) Primary Endpoint -OS Additional Endpoint -ORR -PFS -Safety -PD-L1 expressionPemetrexed/D

12、ocetaxel/Gemcitabin+Cisplatin/Caboplatin探討寡轉(zhuǎn)移者SBRT聯(lián)合免疫治療代替化療可行性Hypothesis:Radiation combined immunotherapy will lead to enhanced anti-tumor immune responses & improved clinical outcomeNot All Stage IV Lung Cancer Are Equal Some stage IV could be curable & some elective olig-mets mOS20monsSelective p

13、ts with mets responded to ChT/TT survive for years Stage Iv=a/b/c disease and gene profiling or CTC based stage in the futureSingle/olig-metsDiffused metsTr sensitive metsCan Stage IV Lung Ca: Have 5 yr OS? Yes If we have targetable genes or ChT sensitive CaIf we can activate immune responseIf resis

14、tant/residual lesion can be wiped out by radiation especially by SBRT If personalized combine modality or precision medision is deliveredIf we could combine immunotherapy & SBRT 免疫與靶向之比較兩者都是有劃時(shí)代意義的革命性貢獻(xiàn)靶向治療可作一線(xiàn)而免疫目前尚不能靶向敏感性高治愈率低而免疫則相反免疫的ORR 僅為20%, 但存在拖尾現(xiàn)象都需要靶點(diǎn)檢測(cè)而靶向的標(biāo)準(zhǔn)更成熟價(jià)格超貴及病人不敏感和耐藥及損傷免疫治療自身免疫與間質(zhì)肺炎

15、等損傷與其他治療手段的聯(lián)合目前都有爭(zhēng)議TKI Vs Immunotherapy個(gè)性化治療方案大數(shù)據(jù)組學(xué)研究精準(zhǔn)治療提高療效、減輕損傷、降低費(fèi)用分子影像精準(zhǔn)腫瘤學(xué):最終目標(biāo)?臨床隊(duì)列和生物樣本庫(kù)Hypoxia PET/CT Imaging Hypoxia FETNIM PET/CT imaging in basic and clinical studies Predict the radiosensitivity and OS using hypoxia imaging Am J Clin Oncol 2006;29:628 Cancer Biol Ther 2006;5:1320 Clin L

16、ung Cancer. 2010;11:335 First reported in 2008 ASCO, be commented in ASCO Daily News “The first study using FETNIM PET to detect the clinical hypoxia & optimize the treatment”A significant correlation between lung cancer hypoxia and overall survival of radiotherapyFETNIM PET/CT uptake positively cor

17、relating with expression of hypoxia markersOverall Survival, % Time, Months HV23.85HV 23.85P=0.041Cancer Sci 2007;98:1413 J Nucl Med 2009;50:303 J Nucl Med 2011 EGFR受體顯像研究獲JNM年度最佳論文通過(guò)細(xì)胞-動(dòng)物-臨床系列研究，創(chuàng)建PD153035 PET/CT EGFR顯像技術(shù)應(yīng)用于臨床，指導(dǎo)肺癌分子靶向治療、療效預(yù)測(cè)及放療靶區(qū)勾畫(huà)意大利博洛尼亞大學(xué)Pantaleo教授在國(guó)際影像學(xué)排名第一的J Nucl Med專(zhuān)題評(píng)述: “國(guó)際率

18、先的臨床研究，在核醫(yī)學(xué)和腫瘤學(xué)研究方面取得突破” EGFR系統(tǒng)顯像技術(shù)15.012.09.06.03.00.0隨訪(fǎng)時(shí)間（月）1.00.20.0總生存率SUV 2.92SUV 2.92P = 0.001EGFR顯像預(yù)測(cè)靶向治療療效Dear Shuanghu Yuan, MD, PhD,On behalf of theAnnual Meeting Scientific Program Committeeof the American Society for Radiation Oncology, I am pleased to inform you that you have b

19、een selected as one of the recipients of a 2015 Annual Meeting Abstract Award. You have won theInternational Abstract Awardfor your abstract titled,“Noninvasive Evaluation of Metabolic Tumor Volume in LLC Tumor Bearing C57 Mice With PET and the Radiotracers 18F-Alfatide and 18F-FDG: A Comparative An

20、alysis.”To honor your achievement, you will receive a$4,000award and acomplimentary registrationto the Annual Meeting. All award winners will be featured in the Annual Meeting Proceedings and in the Final Program, and you will be given a Certificate onsite at the meeting during the International Bre

21、akfast.Your attendance at the meeting is required in order to receive the award benefits.Your award check will be available for pick-up at the Faculty/VIP office at the Henry B. Gonzalez Convention Center when you arrive in San Antonio.The Annual Meeting dates are: October 17 21, 2015Location: Henry B. Gonzalez Convention Center, San Antonio Texas USAAttendance Required - International Breakfast: Sunday, October 18 6:45am 8:00amCongratulation