腫瘤內(nèi)科基本原則現(xiàn)狀進展2教學文稿

1、 Management Strategies for Hard-to-Treat Lymphomas腫瘤內(nèi)科基本原則現(xiàn)狀進展220世紀末21世紀 Cytotoxics繼續(xù)發(fā)展 新的分子靶點藥物(EGFR VEGF) Biotherapy研究 Gene Therapy?細胞毒化療藥物細胞毒化療藥物分子靶向藥物分子靶向藥物 細胞毒藥物缺乏選擇性細胞毒藥物缺乏選擇性 骨髓抑制：粒細胞缺乏，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：肝毒性細胞毒化療藥物細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:形成網(wǎng)絡及調(diào)控尤其是細胞傳導系統(tǒng)的調(diào)控,細胞傳導系統(tǒng)和網(wǎng)絡調(diào)控是腫瘤增殖.分化.轉移.血管形成.調(diào)亡及和化/放療療效有關。 人體有518個蛋白激酶,其中100個為酪氨酸激酶,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 針對酪氨酸酪酶的小分子化合物或針對單個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，為配體結合區(qū)胞外區(qū)：在氮端，為配體結合區(qū) 跨膜區(qū)：氨基酸殘基構成的疏水區(qū)跨膜區(qū)：氨基酸殘基構成的疏水區(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- -末端三個亞區(qū)構成。末端三個亞區(qū)構成。C C端端配體結合區(qū)配體結合區(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抑制配體和受體結合 配體 配體結合位點 受體受體垮膜區(qū) 細胞膜酪氨酸激酶區(qū)細胞核ATP結合位點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)展取決于細發(fā)展取決于細胞內(nèi)信號轉導胞內(nèi)信號轉導途徑中發(fā)生的途徑中發(fā)生的遺傳突變，阻遺傳突變，阻斷癌細胞中特斷癌細胞中特異性增殖異性增殖 的依的依賴性信號可導賴性信號可導致腫瘤細胞增致腫瘤細胞增殖停止。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胞信制腫瘤細胞信號轉導途徑而號轉導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?；[瘤血管正常化早期作用早期作用 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、結膜炎、干性 角膜結膜炎、腹痛。角膜潰瘍 多吉美皮疹、手足皮膚反應、粘膜炎/口腔炎、乏力、高血壓、惡心、腹瀉、血液學毒性高血壓發(fā)燒、腹瀉、感染、寒 戰(zhàn)、過敏反應、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。嚴重的輸液反應（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、傷口愈合不良動脈血栓、腫瘤出血 乳腺癌內(nèi)科治療進展乳腺癌內(nèi)科治療進展 晚期非小細胞肺癌內(nèi)科治療進展晚期非小細胞肺癌內(nèi)科治療進展 結腸癌內(nèi)科治療進展結腸癌內(nèi)科治療進展 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 細胞毒藥物細胞毒藥物蒽環(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進展或死亡進展或死亡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)類隨機入組僅化療化療+貝伐單抗直至進展選擇性二線治療：化療+貝伐單抗（AVADO 和RIBBON-1）初治初治的轉的轉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)科治療進展乳腺癌內(nèi)科治療進展 晚期非小細胞肺癌內(nèi)科治療進展晚期非小細胞肺癌內(nèi)科治

18、療進展 結腸癌內(nèi)科治療進展結腸癌內(nèi)科治療進展 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重不良事件嚴重不良事件不良反應導致死亡不良反應導致死亡不良反應導致停藥不良反應導致停藥CTC3-4級不良反應級不良反應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治療相關*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、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周隨機分組于第4、8周評估療效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：客觀緩解率Uhm JE, et al. Presented at 2009 WCLC.Uhm JE, et al. Presented at 2009 WCLC.無進展生存概率(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：PFSN Engl J Med 2010;362:2380-8.吉非替尼 10.8M標準化療 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即使一線化療的患者二線得到高達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個月個月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化療后未進展隨機分組培美曲塞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：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 個月安慰劑 10.6個月生存率生存率時間時間 ( (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個月培美曲塞 9.9個月安慰劑 10.3個月安慰劑10.8個月HR=0.70 (95% CI: 0.56-0.88) P =0.002HR=1.07 (95% CI: 0.491.73) P =0.678生存率生存率時間時間(月月) 時間時間(月月) ASCO 2009 乳腺癌內(nèi)科治療進展乳腺癌內(nèi)科治療進展 晚期非小細胞肺癌內(nèi)科治療進展晚期非小細胞肺癌內(nèi)科治療進展 結腸癌內(nèi)科治療進展結腸癌內(nèi)科治療進展1990 5-FU + levamisole1994 5-FU/LV1998 6 months elderly patients2003 CI 5-FU (LV5FU2, PVI 5-FU) 2008 FOLFOX (MOSAIC), CapeOx FOLFOX + bevacizumab