腫瘤內(nèi)科基本原則現(xiàn)狀進(jìn)展2教學(xué)文稿

1、 Management Strategies for Hard-to-Treat Lymphomas腫瘤內(nèi)科基本原則現(xiàn)狀進(jìn)展220世紀(jì)末21世紀(jì) Cytotoxics繼續(xù)發(fā)展 新的分子靶點(diǎn)藥物(EGFR VEGF) Biotherapy研究 Gene Therapy?細(xì)胞毒化療藥物細(xì)胞毒化療藥物分子靶向藥物分子靶向藥物 細(xì)胞毒藥物缺乏選擇性細(xì)胞毒藥物缺乏選擇性 骨髓抑制：粒細(xì)胞缺乏，感染 血小板減少，出血 免疫抑制：感染 粘膜上皮損傷： 口腔炎，胃腸炎，惡心/嘔吐， 腹瀉，便血 脫發(fā) 器官毒性器官毒性 ADR：心臟毒性 BLM：肺纖維化 DDP：腎毒性 L-OHP、VCR、PTX：神經(jīng)毒性 B

2、CNU：肝毒性細(xì)胞毒化療藥物細(xì)胞毒化療藥物分子靶向藥物分子靶向藥物 人類基因圖譜有10多萬基因,其中3萬多與腫瘤有關(guān):形成網(wǎng)絡(luò)及調(diào)控尤其是細(xì)胞傳導(dǎo)系統(tǒng)的調(diào)控,細(xì)胞傳導(dǎo)系統(tǒng)和網(wǎng)絡(luò)調(diào)控是腫瘤增殖.分化.轉(zhuǎn)移.血管形成.調(diào)亡及和化/放療療效有關(guān)。 人體有518個(gè)蛋白激酶,其中100個(gè)為酪氨酸激酶,50%酪氨酸激酶參與人腫瘤的發(fā)生發(fā)展.酪氨酸酶活化需磷酸化 針對(duì)酪氨酸酪酶的小分子化合物或針對(duì)單個(gè)基因的單抗靶向治療不能解決全部腫瘤的治療問題。 胞外區(qū)：在氮端，為配體結(jié)合區(qū)胞外區(qū)：在氮端，為配體結(jié)合區(qū) 跨膜區(qū)：氨基酸殘基構(gòu)成的疏水區(qū)跨膜區(qū)：氨基酸殘基構(gòu)成的疏水區(qū) 胞內(nèi)區(qū)：由近膜區(qū)、酪氨酸激酶胞內(nèi)區(qū)：由近膜

3、區(qū)、酪氨酸激酶 （TKTK）區(qū)、碳）區(qū)、碳- -末端三個(gè)亞區(qū)構(gòu)成。末端三個(gè)亞區(qū)構(gòu)成。C C端端配體結(jié)合區(qū)配體結(jié)合區(qū)酪氨酸激酶區(qū)酪氨酸激酶區(qū)胞外區(qū)胞外區(qū)跨膜區(qū)跨膜區(qū)胞內(nèi)區(qū)胞內(nèi)區(qū)N N端端TK抑制配體和受體結(jié)合 配體 配體結(jié)合位點(diǎn) 受體受體垮膜區(qū) 細(xì)胞膜酪氨酸激酶區(qū)細(xì)胞核ATP結(jié)合位點(diǎn)ATPDNA 增殖 遷移血管生成 生長因子腫瘤的發(fā)生、腫瘤的發(fā)生、發(fā)展取決于細(xì)發(fā)展取決于細(xì)胞內(nèi)信號(hào)轉(zhuǎn)導(dǎo)胞內(nèi)信號(hào)轉(zhuǎn)導(dǎo)途徑中發(fā)生的途徑中發(fā)生的遺傳突變，阻遺傳突變，阻斷癌細(xì)胞中特?cái)喟┘?xì)胞中特異性增殖異性增殖 的依的依賴性信號(hào)可導(dǎo)賴性信號(hào)可導(dǎo)致腫瘤細(xì)胞增致腫瘤細(xì)胞增殖停止。靶向殖停止。靶向癌癥治療就是癌癥治療就是通過作用于

4、控通過作用于控制腫瘤細(xì)胞信制腫瘤細(xì)胞信號(hào)轉(zhuǎn)導(dǎo)途徑而號(hào)轉(zhuǎn)導(dǎo)途徑而抑制腫瘤生長。抑制腫瘤生長。 J Clin Oncol, Vol 21, Issue 14 (July), 2003: 2787-2799Adapted from Poon, et al. JCO 2001“En Espaa pendiente de autorizacin de precio y condiciones de reembolso”Stages at which angiogenesis plays a role in tumour progressionPremalignanttumourMalignanttumo

5、urTumourgrowthVascularinvasionMicro-metastasesMetastaticgrowthAngiogenicswitch“En Espaa pendiente de autorizacin de precio y condiciones de reembolso”VEGF = vascular endothelial growth factor; IGF = insulin-like growth factorPDGF = platelet-derived growth factor; EGF = epidermal growth factor1. .腫瘤微

6、血管退變腫瘤微血管退變 3. 3.抑制新生血管形成抑制新生血管形成2. 2.腫瘤血管正?；[瘤血管正?；缙谧饔迷缙谧饔?繼續(xù)作用繼續(xù)作用Baluk, et al. Curr Opin Genet Dev 2005; Inai, et al. Am J Pathol 2004; Erber, et al. FASEB J 2004 Tong, et al. Cancer Res 2004; Jain. Nat Med 2001; Jain. Science 2005; Lee, et al. Cancer Res 2000Willett, et al. Nat Med 2004; Gerber

7、, et al. Cancer Res 2005; Warren, et al. J Clin Invest 19952000200020012001200220022003200320042004200520052006200620072007美羅華美羅華 MabTheraMabThera 赫賽汀赫賽汀 HerceptinHerceptin 格列衛(wèi)格列衛(wèi) GlivecGlivec 易瑞沙易瑞沙 IressaIressa 多吉美多吉美 SorafinibSorafinib 愛必妥愛必妥 ErbituxErbitux 特羅凱特羅凱 TarcevaTarceva n 羅氏羅氏n 諾華諾華n 阿斯利

8、康阿斯利康n 默克默克n 拜爾拜爾 輝瑞輝瑞2008 索坦索坦 Sunitinib 泰欣生泰欣生 Nimotuzumab 百泰百泰恩度恩度 Endostar先聲先聲 2009 2010 2009 2010 安維汀安維汀 Avastin Avastin 易瑞沙 皮疹、痤瘡、皮 膚干燥、瘙癢、惡心、嘔吐、腹瀉、食欲減退、乏力和體重下降 間質(zhì)性肺病特羅凱 皮疹、瘙癢、皮膚干燥、腹瀉、食欲減退、乏力、惡心、嘔吐、口腔炎、結(jié)膜炎、干性 角膜結(jié)膜炎、腹痛。角膜潰瘍 多吉美皮疹、手足皮膚反應(yīng)、粘膜炎/口腔炎、乏力、高血壓、惡心、腹瀉、血液學(xué)毒性高血壓發(fā)燒、腹瀉、感染、寒 戰(zhàn)、過敏反應(yīng)、LVEF下降、心室功能

9、不全和充血性心力衰竭 愛必妥痤瘡疹、乏力/不適、惡心、發(fā)熱、便秘、 腹痛、頭痛、腹瀉。嚴(yán)重的輸液反應(yīng)（支 氣管痙攣、喘鳴、嘶啞、蕁麻疹、低血壓) 格列衛(wèi) 水腫、惡心、腹瀉、腹痛、肌肉痛性痙攣、 疲勞和皮疹。 肺水腫、胸膜腔積液、充血性 心力衰竭 美羅華發(fā)熱、寒戰(zhàn)、關(guān)節(jié)炎、過敏免疫抑制誘發(fā)病毒性肝炎赫賽汀安維汀高血壓、蛋白尿、出血、皿栓 穿孔、傷口愈合不良動(dòng)脈血栓、腫瘤出血 乳腺癌內(nèi)科治療進(jìn)展乳腺癌內(nèi)科治療進(jìn)展 晚期非小細(xì)胞肺癌內(nèi)科治療進(jìn)展晚期非小細(xì)胞肺癌內(nèi)科治療進(jìn)展 結(jié)腸癌內(nèi)科治療進(jìn)展結(jié)腸癌內(nèi)科治療進(jìn)展 CT-chemotherapyET-endocrine therapyRelative r

10、isk reduction of recurrence (%)01020304017%42%46%31%CEF vs CMFLevine 2005AC T vs AC Henderson 2003CTHerceptin vs CTPiccart 2005Tamoxifen vs placeboFisher 2004DAC vs FACMartin 200528%HER2+HER2+& &HER2-HER2-CT+Herceptin vs CT Romond 20055052%HER2+HER2+ MBCMBC的治療選擇的治療選擇 細(xì)胞毒藥物細(xì)胞毒藥物蒽環(huán)類紫杉類卡培他濱長春瑞濱

11、吉西他濱 新的激素藥物新的激素藥物三苯氧胺芳香化酶抑制劑FulvestrantLHRH類似物生物靶向治療生物靶向治療曲妥株單抗曲妥株單抗 Lapatinib Bevacizumab T-DM1? Pertuzumab? Sutinib? Sorafenib? Iressa? Tarciva?雙磷酸鹽類雙磷酸鹽類支持與姑息治療支持與姑息治療Marty et al. 2005紫杉醇 + 健擇紫杉醇 + 赫賽汀多西紫杉醇+ 健擇多西紫杉醇+ 赫賽汀單藥多西紫杉醇多西紫杉醇希羅達(dá)Slamon et al. 2001Melemed et al. 2007E2100 2007紫杉醇 + 貝伐Jones e

12、t al. 2005Melemed et al. 2007E2100 2007Slamon et al. 2001Jones et al. 2005Marty et al. 2005OShaughnessy et al. 2002OShaughnessy et al. 2002Chan et al. 2005Chan et al. 2005*僅包括有可測量病灶的患者Slamon DJ, et al. N Engl J Med 2001;344:78392; OShaughnessy J, et al. J Clin Oncol 2002;20:281223; Jones SE, et al.

13、J Clin Oncol 2005;23:554251; Marty M, et al. J Clin Oncol 2005;23:426574; Chan S, et al. J Clin Oncol 2005;23(June 1 suppl.):24s (Abstract 581); Melemed AS, et al. Presented at ASCO Breast Cancer 2007; Avastin Summary of Product Characteristics客觀緩解率 (%)單藥紫杉醇010203040506070 DocetaxelChan 1999Doxorubi

14、cinChan 1999PaclitaxelSeidman 2004VinorelbineMuhoz 2006Doxorubicin + paclitaxelJassem 2001Capecitabine + docetaxelOShaughnessy 2002Gemcitabine + paclitaxelAlbain 2004Fluorouracil + epirubicinZielinski 2005Gemcitabine + vinorelbineMuoz 2006Epirubicin + taxanePacilio 2006Avastin + paclitaxelE2100 2005

15、PaclitaxelE2100 200502468101214MonthsMonotherapyCombinationchemotherapyAnti-angiogenic therapy + chemotherapyMedian PFS/TTP9 monthsEMEA Avastin European Public Assessment Report, 2007 ASCO 2006 June 2-6 病人數(shù)病人數(shù)160161進(jìn)展或死亡進(jìn)展或死亡60(38%)78(48%)中位中位PFS(月月)8.44.4 Hazard Ratio (95% CI)0.49 (0.34-0.71) P值值(l

16、og-rank,1-side) 0.001蒽環(huán)、紫彬、赫賽汀治療失敗患者蒽環(huán)、紫彬、赫賽汀治療失敗患者ORR(95%CI) 28.8% (21.9-36.4) 16.1% (10.8-22.8) p值值(Fisher,s exact, 2-sided) 0.017AVADO多西紫杉醇E2100紫杉醇RIBBON1,2卡培他濱，紫杉類或蒽環(huán)類隨機(jī)入組僅化療化療+貝伐單抗直至進(jìn)展選擇性二線治療：化療+貝伐單抗（AVADO 和RIBBON-1）初治初治的轉(zhuǎn)的轉(zhuǎn)移性移性乳腺乳腺癌癌Joyce OShaughnessy et al, ASCO 2010,abs 1005 OShaughnessy J,

17、et al. ASCO 2010. Abstract 1005.*Assessed in patients with measurable disease at baseline: n = 1105 for chemotherapy plus bevacizumab; n = 788 for chemotherapy alone.Joyce OShaughnessy et al, ASCO 2010,abs 1005 Joyce OShaughnessy et al, ASCO 2010,abs 1005 乳腺癌內(nèi)科治療進(jìn)展乳腺癌內(nèi)科治療進(jìn)展 晚期非小細(xì)胞肺癌內(nèi)科治療進(jìn)展晚期非小細(xì)胞肺癌內(nèi)科治

18、療進(jìn)展 結(jié)腸癌內(nèi)科治療進(jìn)展結(jié)腸癌內(nèi)科治療進(jìn)展 Previously untreated stage IIIb/IV non-squamous NSCLC(n=878)CP 6 (n=444)Bevacizumab (15mg/kg) every 3 weeks + CP 6 (n=434)lPrimary endpoint: overall survivallBevacizumab 15mg/kg i.v. administered every 3 weekslCarboplatin i.v. to AUC 6mg/mL and paclitaxel 200mg/m2 i.v. every 3

19、 weeksPD*PD*No cross over permittedPD = progression of disease; i.v. = intravenous; AUC = area under the curveBevacizumab every 3 weeks until progressionSandler, et al. NEJM 20061.00.80.60.40.200612182430Time (months)ProbabilityCP + AvastinCPHR=0.66 (0.570.77)p 1 implies a greater chance of response

20、 on gefitinibOR and p-value from logistic regression with covariatesPatients (%)(n=659)(n=657)Doulliard et al; Data presented at WCLC 2007 in Seoul, KoreaP=0.1329Doulliard et al; Data presented at WCLC 2007 in Seoul, KoreaP=0.0026P0.0001Doulliard et al; Data presented at WCLC 2007 in Seoul, Koreap-v

21、alues from logistic regression with covariates. Clinically relevant improvement pre-defined as 6 point improvement for FACT-L and TOI; 2 point improvement for LCS, maintained for at least 21 daysEFQ, evaluable for quality of life* Interpret with caution due to open-label study designAE, adverse even

22、t; SAE, serious adverse event; CTC, common toxicity criterian (%)不良事件不良事件嚴(yán)重不良事件嚴(yán)重不良事件不良反應(yīng)導(dǎo)致死亡不良反應(yīng)導(dǎo)致死亡不良反應(yīng)導(dǎo)致停藥不良反應(yīng)導(dǎo)致停藥CTC3-4級(jí)不良反應(yīng)級(jí)不良反應(yīng)GefitinibN=729(%)687 (94.2)161 (22.1)31 (4.3)59 (8.1)272 (37.3)DocetaxelN=715(%)668 (93.4)210 (29.4)28 (3.9)102 (14.3)400 (55.9)GefitinibN=729(%)527 (72.3)28 (3.8) 6 (

23、0.8)30 (4.1)62 (8.5)DocetaxelN=715(%)588 (82.2)130 (18.2)15 (2.1) 78 (10.9)291 (40.7)所有不良事件所有不良事件治療相關(guān)治療相關(guān)*Doulliard et al; Data presented at WCLC 2007 in Seoul, Korea Calculations only include patients with a baseline and at least one post baseline value for that lab parameterDoulliard et al; Data p

24、resented at WCLC 2007 in Seoul, KoreaUhm JE, et al. Presented at 2009 WCLC.2009WCLC：前瞻、開放、隨機(jī)、II期研究 (二線治療)厄洛替尼150mg/d，每4周至少滿足以下2項(xiàng)l 腺癌l 女性l 不吸煙或l EGFR突變易瑞沙250mg/d，每4周隨機(jī)分組于第4、8周評(píng)估療效PD或出現(xiàn)不可耐受的毒性PD或出現(xiàn)不可耐受的毒性主要終點(diǎn)：客觀緩解率Uhm JE, et al. Presented at 2009 WCLC.Uhm JE, et al. Presented at 2009 WCLC.無進(jìn)展生存概率(月)24

25、1.00612180.80.60.40.20.0P=0.083Gefitinib(250 mg / day)Carboplatin (AUC 5 or 6) / paclitaxel (200 mg / m2) 3 weekly#1:1 randomisation *Never smokers, 1 implies greater chance of response on gefitinib 71.2% 47.3%1.1%23.5%Gefitinib, HR=0.19, 95% CI 0.13, 0.26, p0.0001No. events M+ = 97 (73.5%)No. event

26、s M- = 88 (96.7%)Carboplatin / paclitaxel, HR=0.78, 95% CI 0.57, 1.06, p=0.1103No. events M+ = 111 (86.0%)No. events M- = 70 (82.4%)04812162024Time from randomisation (months)0.00.20.40.60.81.0Probabilityof PFSGefitinib EGFR M+ (n=132)Gefitinib EGFR M- (n=91)Carboplatin / paclitaxel EGFR M+ (n=129)C

27、arboplatin / paclitaxel EGFR M- (n=85)Mok T, et al. ESMO LBA 2, 2008.110EGFR Mutation +EGFR Mutation -Median OSGefitinib:21.6 monthsC/P:21.9 monthsMedian OSGefitinib:11.2 monthsC/P:12.7 monthsIPASSIPASS：更新的：更新的中位生存期中位生存期吉非替尼吉非替尼(n=115)卡鉑卡鉑+紫杉醇紫杉醇(n=115)IIIB/IV期NSCLCEGFR基因敏感突變既往未化療ECOG PS 0-2=75歲(N=2

28、30)主要終點(diǎn)PFSR突變檢測方法：PNA-LNA PCR Clamp法N Engl J Med 2010;362:2380-8.NEJGSG002主要終點(diǎn)：PFSN Engl J Med 2010;362:2380-8.吉非替尼 10.8M標(biāo)準(zhǔn)化療 5.4MHR(95%CI)=0.30(0.22-0.41) P0.001 NEJGSG002研究：ORRN Engl J Med 2010;362:2380-8.客觀緩解率 (%)P0.001Maemondo M, et al. NEJM 2010; 362:2380-2388.071421283542080204060100生存概率 (%)時(shí)間

29、 (月)P0.3123.630.5易瑞沙易瑞沙 (n=114)(n=114)卡鉑卡鉑/ /紫杉醇紫杉醇 (n=114)(n=114)即使一線化療的患者二線得到高達(dá)即使一線化療的患者二線得到高達(dá)95%95%的易瑞沙交叉治療，的易瑞沙交叉治療，一線使用易瑞沙組，患者總生存仍一線使用易瑞沙組，患者總生存仍延長了延長了6.96.9個(gè)月個(gè)月nEGFR IHC (positive vs negative vs indeterminate)nStage (IIIB vs IV)nECOG PS (0 vs 1)nCT regimen (cis/gem vs carbo/doc vs others)nSmok

30、ing history (current vs former vs never)nRegion1:1Chemonave advanced NSCLC(n=1,949)Non-PD(n=889)4 cycles of 1st-line platinum-based doublet*PlaceboPDTarceva150mg/dayPDMandatory tumour sampling*Cisplatin/paclitaxel; cisplatin/gemcitabine; cisplatin/docetaxel cisplatin/vinorelbine; carboplatin/gemcita

31、bine; carboplatin/docetaxel carboplatin/paclitaxelCo-primary endpointsPFS in all patientsPFS in patients with EGFR IHC+ tumoursSecondary endpointsOS in all patients and those with EGFR IHC+ tumours, OS and PFS in EGFR IHC tumours; biomarker analyses; safety; time to symptom progression; QoLSubsequen

32、t therapySubsequent therapyPFS probability1.00.80.60.40.20081624324048566472808896Time (weeks)HR = 0.71 (0.620.82)Log-rank p0.0001PFS is measured from time of randomisation into the maintenance phase; assessments were every 6 weeksTarcivaPlacebo0369121518212427303336Time (months)OS probability 1.00.

33、80.60.40.20OS is measured from time of randomisation into the maintenance phaseHR = 0.81 (0.700.95)Log-rank p=0.0088Tarceva(n=437)Placebo(n=451)OS at 12 mos (%)5045OS at 24 mos (%)2619Median (mos)1211IIIB/IV期NSCLCPS 014周期一線含鉑方案誘導(dǎo)化療后未進(jìn)展隨機(jī)分組培美曲塞BSC N=441治療方安：培美曲塞 500 mg/m2 d1，q3wk 安慰劑 d1， q3wk 患者均接受：V

34、itB12、葉酸、地塞米松治療主要終點(diǎn)：PFS2 1安慰劑BSC N=222PDT. E. Ciuleanu et al. J Clin Oncol 2008;26(20S):Abstr 8011HR=0.59995%CI: 0.49-0.73P0.00001 ASCO 20080369121518212427303336394245480.00.10.20.30.40.50.60.70.80.91.0培美曲塞 13.4 個(gè)月安慰劑 10.6個(gè)月生存率生存率時(shí)間時(shí)間 ( (月月) ) HR=0.79 (95% CI: 0.650.95) P =0.012培美曲塞組52%接受后續(xù)治療安慰劑組67

35、%接受后續(xù)治療, 但僅19%接受了二線培美曲塞治療 ASCO 2009036912 15 18 21 24 27 30 33 36 39 42 45 480.00.10.20.30.40.50.60.70.80.91.0036912 15 18 21 24 27 30 33 36 39 42 45 480.00.10.20.30.40.50.60.70.80.91.0培美曲塞 15.5個(gè)月培美曲塞 9.9個(gè)月安慰劑 10.3個(gè)月安慰劑10.8個(gè)月HR=0.70 (95% CI: 0.56-0.88) P =0.002HR=1.07 (95% CI: 0.491.73) P =0.678生存率生存率時(shí)間時(shí)間(月月) 時(shí)間時(shí)間(月月) ASCO 2009 乳腺癌內(nèi)科治療進(jìn)展乳腺癌內(nèi)科治療進(jìn)展 晚期非小細(xì)胞肺癌內(nèi)科治療進(jìn)展晚期非小細(xì)胞肺癌內(nèi)科治療進(jìn)展 結(jié)腸癌內(nèi)科治療進(jìn)展結(jié)腸癌內(nèi)科治療進(jìn)展1990 5-FU + levamisole1994 5-FU/LV1998 6 months elderly patients2003 CI 5-FU (LV5FU2, PVI 5-FU) 2008 FOLFOX (MOSAIC), CapeOx FOLFOX + bevacizumab