惡性腦腫瘤的化學(xué)治療課件

1、惡性腦腫瘤的化學(xué)治療1 惡性腦腫瘤的化學(xué)治療惡性腦腫瘤的化學(xué)治療 四川省腫瘤醫(yī)院內(nèi)科四川省腫瘤醫(yī)院內(nèi)科 張智慧張智慧 惡性腦腫瘤的化學(xué)治療2 Cerebrum and Cerebellum 惡性腦腫瘤的化學(xué)治療3 流行病學(xué)趨勢(shì)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 腫瘤腫

2、瘤, ,正常腦組織暴露化療藥物正常腦組織暴露化療藥物 高滲性高滲性BBBBBB開放開放 惡性腦腫瘤的化學(xué)治療32 惡性腦腫瘤的化學(xué)治療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 instituti

3、ons： 1982-2005， 177 PCNSL BBBD/IA MTX ；2,469 procedures Pts CR PR ORR M OS(y) MPFS(y) PFS-5(y) 177 101 41 80.2% 3.1 1.6 40% 惡性腦腫瘤的化學(xué)治療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 Reg

4、imen Phase I/II Study of Carboplatin, Melphalan and Etoposide 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 wit

5、h High-Grade Glioma Treated with Intra- arterial Carboplatin-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 Conjunctio

6、n with Osmotic Blood-Brain Barrier Disruption in Patients 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)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% 惡性腦腫瘤的化學(xué)治療42 可評(píng)價(jià)病人數(shù)可評(píng)價(jià)病人數(shù) CR PR MTTP(w) PFS-6(

7、m) 42 0 9 17 30.3% Second-line chemotherapy with irinotecan plus carmustine in 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 惡性腦腫瘤的化學(xué)治療43 2007年A

8、SCO有關(guān)Gliomas的文獻(xiàn)有36篇 病人數(shù)病人數(shù) 可評(píng)價(jià)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 III 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

9、 against malignant gliomas. Phase II trial of bevacizumab and irinotecan in the treatment of malignant gliomas 惡性腦腫瘤的化學(xué)治療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 (PFS

10、6) in recurrent, treatment-refractory glioblastoma (GBM). J Clin Oncol 26: 2008 (May 20 suppl; abstr 2010b 惡性腦腫瘤的化學(xué)治療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)可評(píng)價(jià)病人數(shù) PR PFS-6 OS-6 35 57% 46% 77% 惡性腦腫瘤的化學(xué)治療46 Phase II trial of ir

11、inotecan and thalidomide in adults with recurrent glioblastoma multiforme 可評(píng)價(jià)病人數(shù)可評(píng)價(jià)病人數(shù) CR PR SD MPFS(w) MOS(w) 1Year 32 1 11 19 13 36 34% Neuro Oncol. 2008 Feb 26 惡性腦腫瘤的化學(xué)治療47 Bevacizumab and irinotecan for recurrent oligodendroglial tumors. Conclusions: This regimen is effective in recurrent oligod

12、endrogliomas, 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% 惡性腦腫瘤的化學(xué)治療48 惡性腦腫瘤的化學(xué)治療49 惡性腦腫瘤的化學(xué)治療50 惡性腦腫瘤的化學(xué)治療51 惡性腦腫瘤的化學(xué)治療52 惡性腦腫瘤的化學(xué)治療53 惡性腦腫瘤的化學(xué)治療54ASCO 2009,Abstract 2037 2009年ASCO有關(guān)神經(jīng)系統(tǒng)腫瘤的文獻(xiàn)80余篇 惡性腦腫瘤的化學(xué)治療55 A phase II

13、 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 progressive or recurrent GBM. ASCO 2009, Abstract 2047 26Pts. PR SD PD 6-PFS(ms) 38% 35% 27% (9pts

14、 received bevacizumab) 惡性腦腫瘤的化學(xué)治療56 腦膠質(zhì)瘤和轉(zhuǎn)移性瘤耐藥的研究腦膠質(zhì)瘤和轉(zhuǎn)移性瘤耐藥的研究 1) 6-1) 6-甲基鳥嘌呤甲基鳥嘌呤DNADNA甲基轉(zhuǎn)移酶甲基轉(zhuǎn)移酶 (MGMT) (MGMT) (6-methylguanine-DNA hyltransferase ) (6-methylguanine-DNA hyltransferase ) 2) P-glycoprotein2) P-glycoprotein 惡性腦腫瘤的化學(xué)治療57 Fruehauf, J. P. et al. Clin Cancer Res 2006;12:4523-4532 腦膠質(zhì)

15、瘤和轉(zhuǎn)移性瘤耐藥的研究腦膠質(zhì)瘤和轉(zhuǎn)移性瘤耐藥的研究 惡性腦腫瘤的化學(xué)治療58 Fruehauf, J. P. et al. Clin Cancer Res 2006;12:4523-4532 惡性腦腫瘤的化學(xué)治療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%) 3

16、0/71(M) 41/71(UM)MGMT methylation M-PFS(ms)48.6 38 p=0.09 ASCO 2009 Abstract 2052 惡性腦腫瘤的化學(xué)治療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. 惡性腦腫瘤的化學(xué)治療61 K1735 cells K1735 cells MDR

17、The biology and mechanism of chemoresistance of brain metastases THE UNIVERSITY OF TEXAS GRAD. SCH. OF BIOMED. SCI. AT HOUSTON 1995 惡性腦腫瘤的化學(xué)治療62 BBBD(blood-brain barrier disruption)BBBD(blood-brain barrier disruption)化療化療 高滲性、緩激肽衍生物：高滲性、緩激肽衍生物：BBBBBB開放開放 選擇性開放血瘤屏障選擇性開放血瘤屏障(blood-tumor barrier, BTB)(

18、blood-tumor barrier, BTB) 克服化療耐藥性克服化療耐藥性 多藥耐藥及逆轉(zhuǎn)多藥耐藥及逆轉(zhuǎn) MGMTMGMT表達(dá)預(yù)測(cè)化療療效，避免無效化療。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)移性瘤耐藥的研究腦膠質(zhì)瘤和轉(zhuǎn)移性瘤耐藥的研究 惡性腦腫瘤的化學(xué)治療63 聯(lián)合化療提高化療敏感性聯(lián)合化療提高化療敏感性 VM-26VM-26和和BCNUBCNU聯(lián)合顯著提高膠質(zhì)瘤對(duì)化療的敏感性聯(lián)合顯著提高膠質(zhì)瘤對(duì)化療的敏感性 機(jī)理：抑制機(jī)理：抑制MDR-IMDR-I或或P-gpP-gp過表達(dá)過表達(dá) PCVPCV方案顯著增強(qiáng)多形膠質(zhì)母細(xì)胞瘤對(duì)方案顯著增強(qiáng)多形膠質(zhì)母細(xì)胞瘤對(duì)BCNUBCNU類藥制的

19、敏類藥制的敏 感性感性 機(jī)理：腫瘤細(xì)胞先暴露于烷化劑類藥物使瘤機(jī)理：腫瘤細(xì)胞先暴露于烷化劑類藥物使瘤 細(xì)胞中細(xì)胞中AGTAGT（O6-O6-烷基鳥嘌呤烷基鳥嘌呤-DNA-DNA烷基化轉(zhuǎn)酶）烷基化轉(zhuǎn)酶） 活性受抑活性受抑 AGTAGT是增強(qiáng)腫瘤細(xì)胞對(duì)是增強(qiáng)腫瘤細(xì)胞對(duì)BCNUBCNU類類 藥物敏感性的主要藥物敏感性的主要靶點(diǎn)靶點(diǎn) 惡性腦腫瘤的化學(xué)治療64 Randomized Comparison of Intra-arterial Versus Intravenous Infusion of ACNU for Newly Diagnosed Patients with Glioblastoma

20、To compare the effectiveness of intra-arterial ACNUwith intravenous ACNU in newly diagnosed patients with supratentorial glioblastoma. ACNU (80mg/m2) once every 6 weeks concomitant with radiotherapy. 病人數(shù)病人數(shù) 可評(píng)價(jià)病人數(shù)可評(píng)價(jià)病人數(shù) MS(w) PFS(w) Toxicity 84 82IA 59 24 - IV 56 45 - Journal of neuro-oncology 2000,

21、 vol. 49, no1, pp. 63-70 惡性腦腫瘤的化學(xué)治療65 20082008年年NCCNNCCN指南指南 成人侵潤(rùn)性低度惡性幕上星形細(xì)胞瘤成人侵潤(rùn)性低度惡性幕上星形細(xì)胞瘤/ /少突膠質(zhì)細(xì)胞瘤少突膠質(zhì)細(xì)胞瘤 輔助化療：高劑量替莫唑胺輔助化療：高劑量替莫唑胺 5/285/28方案方案 復(fù)發(fā)或進(jìn)展：復(fù)發(fā)或進(jìn)展： 一線方案：替莫唑胺一線方案：替莫唑胺 5/285/28方案（初治）方案（初治） 二線方案：二線方案：BCUN210mg/m2 iv 6wBCUN210mg/m2 iv 6w重復(fù)重復(fù);,80mg/m2x3 6w;,80mg/m2x3 6w重復(fù)；重復(fù)； CCNU 110mg/m2

22、 CCNU 110mg/m2 口服口服 6w6w重復(fù)；重復(fù)；PCVPCV聯(lián)合化療聯(lián)合化療 成人室管膜瘤：復(fù)發(fā)用成人室管膜瘤：復(fù)發(fā)用vp-16,vp-16,替莫唑胺替莫唑胺 ，亞硝脲類，鉑及聯(lián)合方案，亞硝脲類，鉑及聯(lián)合方案 原發(fā)性原發(fā)性CNSCNS腫瘤化療指南腫瘤化療指南 惡性腦腫瘤的化學(xué)治療66 多形性膠母細(xì)胞瘤多形性膠母細(xì)胞瘤 輔助化療：輔助化療： 同步替莫唑胺同步替莫唑胺 75mg/m2 daily75mg/m2 daily 替莫唑胺替莫唑胺150-200mg/ m2 5/28150-200mg/ m2 5/28方案方案 復(fù)發(fā)復(fù)發(fā)/ /挽救治療：挽救治療： 替莫唑胺替莫唑胺 5/285/2

23、8方案（初治）方案（初治） Bevacizumab+Irinotecan Bevacizumab+Irinotecan BCUN; CCNU ;PCVBCUN; CCNU ;PCV聯(lián)合化療聯(lián)合化療 間變形星形細(xì)胞瘤間變形星形細(xì)胞瘤/ /少突膠質(zhì)細(xì)胞瘤少突膠質(zhì)細(xì)胞瘤 輔助化療：輔助化療： 替莫唑胺或亞硝脲替莫唑胺或亞硝脲 復(fù)發(fā)復(fù)發(fā)/ /挽救治療：挽救治療： 替莫唑胺替莫唑胺 5/285/28方案（初治）方案（初治） Bevacizumab+Irinotecan Bevacizumab+Irinotecan BCUN; CCNU ;PCVBCUN; CCNU ;PCV聯(lián)合聯(lián)合 原發(fā)性原發(fā)性CNSCNS腫瘤化療原則腫瘤化療原則 20082008年年NCCNNCCN指南指南 惡性腦腫瘤的化學(xué)治療67 轉(zhuǎn)移性腦腫瘤局限轉(zhuǎn)移性腦腫瘤局限1-31-3或多發(fā)或多發(fā)3 3個(gè)以上個(gè)以上 對(duì)原發(fā)腫瘤有效的藥物對(duì)原發(fā)腫瘤有效的藥物 替莫唑胺替莫唑胺 5/285/28方案（器官特異性治療）方案（器官特異性治療） 卡培他賓，大劑量卡培他賓，大劑量MTX(MTX(乳腺癌，淋巴瘤），乳腺癌，淋巴瘤），ToptecanToptecan（肺癌）（肺癌） 癌性腦膜炎癌性腦膜炎 采用對(duì)腦組織穿透能力