1、.,1,惡性腦腫瘤的化學(xué)治療,四川省腫瘤醫(yī)院內(nèi)科 張智慧,.,2,Cerebrum and Cerebellum,.,3,流行病學(xué)趨勢(shì),2005 (US) 18,500* 12,760 Incidence 11.47 per 100,000 (annual rate) Adjusted 5 yr survival rate (1995-2000) 33% adults 73% children 2nd leading cause of cancer deaths in persons 39 years (US in 2002) Jemal et al CA: a cancer journal

2、for clinicians 55:10-30, 2005.,new cases deaths (estimated),.,4,流行病學(xué)趨勢(shì),每年以1.2%的速度在增加,.,5,.,6,CNS原發(fā)腫瘤發(fā)病率,Brain Tumor Facts 359(9311):1011-8.,.,20,膠質(zhì)瘤的化療原則,對(duì)高級(jí)別膠質(zhì)瘤(WHO - 級(jí)) 應(yīng)該常規(guī)給予化療 低級(jí)別膠質(zhì)瘤(WHO- 級(jí)) 可以根據(jù)手術(shù)切除程度、病理類型和基因缺失情況考慮是否化療 選擇能通過血腦屏障的脂溶性、小分子藥物（安全-高效）,.,21,Ino et al CCR 2001,.,22,存在于血一腦，血一腦脊液及腦一腦脊液之間

3、 選擇性控制進(jìn)入腦脊液和腦的物質(zhì),作為血與CNS之間的調(diào)節(jié)界面, 對(duì)維持CNS內(nèi)環(huán)境恒定有至關(guān)重要的作用 主要形式: 腦毛細(xì)血管內(nèi)皮細(xì)胞緊密連接 細(xì)胞之間無孔隙, “條焊狀”連接,甚至某種程度重疊 基底部尚有一層連續(xù)的基底膜 內(nèi)皮細(xì)胞內(nèi): 細(xì)胞器, 與物質(zhì)轉(zhuǎn)運(yùn)有關(guān)的酶類 結(jié)構(gòu)為脂性基架, 對(duì)大于3968(40KD)物質(zhì)限制通過 藥物要求 分子量小脂溶性 正常PH時(shí)不電離不與蛋白結(jié)合,血腦屏障(BBB),.,23,血腦屏障(BBB),.,24,腦膠質(zhì)瘤理想化療藥物的特點(diǎn),有效穿透血腦屏障 腦膠質(zhì)瘤細(xì)胞敏感 腦腫瘤內(nèi)維持長時(shí)間有效濃度 骨髓抑制盡量低,毒副作用小 可長期使用,CNS腫瘤的化學(xué)治療,

4、亞硝脲類藥物較容易通過血腦屏障，故被視為治療腦腫瘤的首選藥物。,.,25,Temozolomide (TMZ) development for glioma,Novel oral cytotoxic agent (imidazotetrazine-related to dacarbazine). Rapid absorption with 100% bioavailability. Good CSF penetration (20-40%) Well tolerated with good safety profile 1999 FDA approval for anaplastic astr

5、ocytoma (second line) refractory to nitrosourea and procarbazine. Ref: J Clin Onc 17:2762, 1999 2005 FDA approval for GBM (first line) Stupp et al. Phase III trial NEJM 352:987, 2005 Athanassiou et al Phase III trial ASCO 2005 Stupp et al. Phase II trial J Clin Onc 20:1375, 2002 Lanzetta et al. Phas

6、e II trial Anticancer Res 23:5159, 2003,Clin Cancer Res 11:6767, 2005,.,26,能通過BBB的藥物,亞硝脲類：BCNU,Me-CCNU,ACNU 甲基芐肼（Procarbazine) VM-26,Teniposide MTX/CF Ara-C,Liposomal Ara-c Doxil,Idarubicin Docetaxel Temozolomide,Tamodal,.,27,CNS腫瘤的化學(xué)治療,化療方式： 1，全身化療：IV；IA 2，椎管內(nèi)化療：穿刺化療；置泵 3，間質(zhì)化療：Ommaya, Wafer,.,28,CN

7、S腫瘤的常用化學(xué)治療方案,.,29,間質(zhì)內(nèi)化療: 可避開BBB 機(jī)理: 提高腫瘤局部藥物濃度 減少全身用藥毒副作用 方法: 術(shù)中 術(shù)后,避開BBB的方式,.,30,BBBD治療,Osmotic opening of the blood-brain barrier. When endothelial cells that line capillary walls are exposed to a concentrated sugar solution, the cells shrink, thus opening the tight junctions between them. (Adapte

8、d from: SI Rapoport, Blood-Brain Barrier in Physiology and Medicine. Raven Press, 1976.),Blood-Brain Barrier Disruption (BBBD)治療,.,31,A/E: 頸動(dòng)脈灌注高滲溶液, 迅速改變BBB 通透性 20%甘露醇150-250ml, 5-10ml/sec BBB血管內(nèi)皮細(xì)胞收縮 胞間緊密聯(lián)接增寬 腦組織含水量增加1.0%-1.5% 4hr恢復(fù)正常 20世紀(jì)80年代用于臨床 尚未期研究證實(shí) 近年研究: BBB開放無選擇性, 內(nèi)皮細(xì)胞破壞: 正常腦組織腫瘤,正常腦組織暴露化療

9、藥物,高滲性BBB開放,.,32,.,33,Blood brain barrier disruption (BBBD) and intra-arterial methotrexate based therapy for newly diagnosed primary CNS lymphoma: The BBBD Consortium Experience.,2007 ASCO Annual Meeting Proceedings Part I. Vol 25, No. 18S,4 institutions： 1982-2005， 177 PCNSL,BBBD/IA MTX ；2,469 pro

10、cedures,Pts CR PR ORR M OS(y) MPFS(y) PFS-5(y),177 101 41 80.2% 3.1 1.6 40%,.,34,A Phase II Trial Involving Patients with Recurrent PCNSL Treated with Carboplatin/BBBD, by Adding Rituxan (Rituximab), an anti CD-20 Antibody, to the Treatment Regimen Phase I/II Study of Carboplatin, Melphalan and Etop

11、oside Phosphate in Conjunction with Osmotic Opening of the Blood-Brain Barrier and Delayed Intravenous Sodium Thiosulfate Chemoprotection, in Subjects with Anaplastic Oligodendroglioma or Oligoastrocytoma Phase II Clinical Trial of Patients with High-Grade Glioma Treated with Intra-arterial Carbopla

12、tin-based Chemotherapy, Randomized to Treatment with or without Delayed Intravenous Sodium Thiosulfate as a Potential Chemoprotectant against Severe Thrombocytopenia Intra-arterial Melphalan (L-phenylalanine mustard) Administered in Conjunction with Osmotic Blood-Brain Barrier Disruption in Patients

13、 with Brain Malignancies: A Phase I Study,Neuro-Oncology Blood-Brain Barrier Program,Oregon Health 6(1): 3337,可評(píng)價(jià)病人數(shù) PR SD MTTP(w) PFS-6 MS(w) MPFS(w) OS-6 1Year,53 2 21 17 21% 34 11 68% 26%,.,42,可評(píng)價(jià)病人數(shù) CR PR MTTP(w) PFS-6(m),42 0 9 17 30.3%,Second-line chemotherapy with irinotecan plus carmustine i

14、n glioblastoma recurrent or progressive after first-line temozolomide chemotherapy: a phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO).,J Clin Oncol. 2004 Dec 1;22(23):4779-86,.,43,2007年ASCO有關(guān)Gliomas的文獻(xiàn)有36篇,病人數(shù) 可評(píng)價(jià)病人數(shù) PR MPFS(w) MOS(w) PFS-6,68 59 59% 23 40 43%,In grade I

15、II patients the median PFS was 42 weeks, the 6 month PFS was 61% the medial overall survival was 60 weeks Conclusion: The combination of bevacizumab and irinotecan is safe and demonstrates superior activity against malignant gliomas.,Phase II trial of bevacizumab and irinotecan in the treatment of m

16、alignant gliomas,.,44,A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM).,J Clin Oncol 26: 2008 (May 20 suppl; abstr 2

17、010b,.,45,Bevacizumab plus irinotecan in recurrent glioblastoma multiforme,J Clin Oncol. 2007 Oct 20;25(30):4722-9,可評(píng)價(jià)病人數(shù) PR PFS-6 OS-6,35 57% 46% 77%,.,46,Phase II trial of irinotecan and thalidomide in adults with recurrent glioblastoma multiforme,可評(píng)價(jià)病人數(shù) CR PR SD MPFS(w) MOS(w) 1Year,32 1 11 19 13

18、 36 34%,Neuro Oncol. 2008 Feb 26,.,47,Bevacizumab and irinotecan for recurrent oligodendroglial tumors.,Conclusions: This regimen is effective in recurrent oligodendrogliomas, and the overall tolerance is acceptable.,ASCO 2009,Abstract 2054,25Pts. CR PR M-PFS(d) MOS(d) 6-PFS(ms),20% 52% 174 328 42%,

19、.,48,.,49,.,50,.,51,.,52,.,53,.,54,ASCO 2009,Abstract 2037,2009年ASCO有關(guān)神經(jīng)系統(tǒng)腫瘤的文獻(xiàn)80余篇,.,55,A phase II study of XL184 in patients (pts) with progressive glioblastomamultiforme (GBM) in first or second relapse.,Conclusions: XL184at a dose of 175 mg PO qd, has demonstrated substantial activity in ptswith

20、 progressive or recurrent GBM.,ASCO 2009, Abstract 2047,26Pts. PR SD PD 6-PFS(ms),38% 35% 27%,(9pts received bevacizumab),.,56,腦膠質(zhì)瘤和轉(zhuǎn)移性瘤耐藥的研究,1) 6-甲基鳥嘌呤DNA甲基轉(zhuǎn)移酶 (MGMT) (6-methylguanine-DNA hyltransferase ) 2) P-glycoprotein,.,57,Fruehauf, J. P. et al. Clin Cancer Res 2006;12:4523-4532,腦膠質(zhì)瘤和轉(zhuǎn)移性瘤耐藥的研究

21、,.,58,Fruehauf, J. P. et al. Clin Cancer Res 2006;12:4523-4532,.,59,MGMT methylation status as a prognostic factor in anaplastic astrocytomas.,Conclusions: MGMT methylation status is an independent prognostic factor together with age in AA.,Pts.71/80(88.8%),30/71(M) 41/71(UM),MGMT methylation,M-PFS(

22、ms),48.6 38,p=0.09,ASCO 2009 Abstract 2052,.,60,P-gp expression in brain capillary endothelial cells suggests that P-gp may restrict drug entry into brain tumors and thus be another mechanism of drug resistance.,.,61,K1735 cells,K1735 cells,MDR,The biology and mechanism of chemoresistance of brain m

23、etastases,THE UNIVERSITY OF TEXAS GRAD. SCH. OF BIOMED. SCI. AT HOUSTON 1995,.,62,BBBD(blood-brain barrier disruption)化療 高滲性、緩激肽衍生物：BBB開放 選擇性開放血瘤屏障(blood-tumor barrier, BTB) 克服化療耐藥性 多藥耐藥及逆轉(zhuǎn) MGMT表達(dá)預(yù)測(cè)化療療效，避免無效化療。,腦膠質(zhì)瘤和轉(zhuǎn)移性瘤耐藥的研究,.,63,聯(lián)合化療提高化療敏感性,VM-26和BCNU聯(lián)合顯著提高膠質(zhì)瘤對(duì)化療的敏感性 機(jī)理：抑制MDR-I或P-gp過表達(dá) PCV方案顯著增強(qiáng)多形

24、膠質(zhì)母細(xì)胞瘤對(duì)BCNU類藥制的敏感性 機(jī)理：腫瘤細(xì)胞先暴露于烷化劑類藥物使瘤細(xì)胞中AGT（O6-烷基鳥嘌呤-DNA烷基化轉(zhuǎn)酶） 活性受抑 AGT是增強(qiáng)腫瘤細(xì)胞對(duì)BCNU類 藥物敏感性的主要靶點(diǎn),.,64,Randomized Comparison of Intra-arterial Versus Intravenous Infusion of ACNU for Newly Diagnosed Patients with Glioblastoma,To compare the effectiveness of intra-arterial ACNUwith intravenous ACNU in

25、 newly diagnosed patients with supratentorial glioblastoma.,ACNU (80mg/m2) once every 6 weeks concomitant with radiotherapy.,病人數(shù) 可評(píng)價(jià)病人數(shù) MS(w) PFS(w) Toxicity,84 82,IA 59 24 -,IV 56 45 -,Journal of neuro-oncology2000,vol.49,no1,pp.63-70,.,65,2008年NCCN指南,成人侵潤性低度惡性幕上星形細(xì)胞瘤/少突膠質(zhì)細(xì)胞瘤 輔助化療：高劑量替莫唑胺 5/28方案 復(fù)發(fā)或進(jìn)展： 一線方案：替莫唑胺 5/28方案（初治） 二線方案：BCUN210mg/m2 iv 6w重復(fù);,80mg/m2x3