医学课件-恶性脑肿瘤的化疗方案教学课件

1、恶性脑肿瘤的化学治疗1.恶性脑肿瘤的化学治疗1.Cerebrum and Cerebellum2.Cerebrum and Cerebellum2.流行病学趋势2005 (US) 18,500* 12,760Incidence 11.47 per 100,000 (annual rate)Adjusted 5 yr survival rate (1995-2000)33% adults73% children 2nd leading cause of cancer deaths in persons 肿瘤,正常脑组织暴露化疗药物高渗性BBB开放31.A/E: 颈动脉灌注高渗溶液, 迅速改变BB

2、B 通透性高渗性32.32.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 procedures P

3、tsCRPRORRM OS(y)MPFS(y)PFS-5(y)1771014180.2%3.11.640%33.Blood brain barrier disruptionA Phase II Trial Involving Patients with Recurrent PCNSL Treated with Carboplatin/BBBD, by Adding Rituxan (Rituximab), an anti CD-20 Antibody, to the Treatment RegimenPhase I/II Study of Carboplatin, Melphalan and

4、Etoposide Phosphate in Conjunction with Osmotic Opening of the Blood-Brain Barrier and Delayed Intravenous Sodium Thiosulfate Chemoprotection, in Subjects with Anaplastic Oligodendroglioma or OligoastrocytomaPhase II Clinical Trial of Patients with High-Grade Glioma Treated with Intra-arterial Carbo

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

6、ts with Brain Malignancies: A Phase I StudyNeuro-Oncology Blood-Brain Barrier ProgramOregon Health & Science UniversityBlood Brain Barrier and Neuro-Oncology Program 34.A Phase II Trial Involving Pat 替尼泊苷联合尼莫司汀治疗转移性脑肿瘤治疗方法：VM26100mg,iv,gtt,D1-3,4周重复ACNU2-3mg/kg,iv,gtt,D1,4-6周重复化疗前20%甘露醇250ml,iv,gtt,

7、DXM10mg,ivACNU共计47周期，平均2.3VM26共计49周期，平均2.5中国癌症杂志Vol9, No2, June,199935. 替尼泊苷联合尼莫司汀治疗转移性脑肿瘤治疗方法：ACNU共计替尼泊苷联合尼莫司汀治疗转移性脑肿瘤研究对象男性： 11例女性： 9例年龄： 33-70岁原发肿瘤病理类型：肺癌 12例乳腺癌 1例恶性淋巴瘤 3例鼻咽癌 1例滑膜肉瘤 1例不明肿瘤 2例中国癌症杂志Vol9, No2, June,199936.替尼泊苷联合尼莫司汀治疗转移性脑肿瘤研究对象中国癌症杂志替尼泊苷联合尼莫司汀治疗转移性脑肿瘤 临床表现症状 例次头痛 13恶心，呕吐 11意识改变6肢体

8、肌力感觉异常 10颅脑神经受损7共济失调1合计 48中国癌症杂志Vol9, No2, June,199937.替尼泊苷联合尼莫司汀治疗转移性脑肿瘤 临床 替尼泊苷联合尼莫司汀治疗转移性脑肿瘤结果：症状缓解率：完全缓解CR：60.4%部份缓解PR：31.6%症状总缓解率：91.7%颅脑CT复查：脑水肿减轻或消失 100%(16/16)完全缓解CR10%(2/20)部份缓解PR50%(10/20)总有效率(CR+PR)60%(12/20)颅脑外病灶缩小52.9%(9/17)中国癌症杂志Vol9, No2, June,199938. 替尼泊苷联合尼莫司汀治疗转移性脑肿瘤结果：中国癌症杂志V替尼泊苷联

9、合尼莫司汀治疗转移性脑肿瘤结果患者存活时间1-17月，平均6.5月超过6个月者11例中国癌症杂志Vol9, No2, June,199939.替尼泊苷联合尼莫司汀治疗转移性脑肿瘤结果中国癌症杂志Vol9避开BBB的方式椎管内化疗：主要用于CNS淋巴瘤，脑膜转移肿瘤，白血病的脑膜侵犯。40.避开BBB的方式椎管内化疗：40.Phase 2 study of BCNU and temozolomide for recurrent glioblastoma multiforme: North American Brain Tumor Consortium studyNeuro-oncol. 2004

10、 January; 6(1): 3337 可评价病人数PRSDMTTP(w)PFS-6MS(w)MPFS(w)OS-61Year532211721%341168%26%41.Phase 2 study of BCNU and temo可评价病人数CRPRMTTP(w)PFS-6(m)42091730.3%Second-line chemotherapy with irinotecan plus carmustine in glioblastoma recurrent or progressive after first-line temozolomide chemotherapy: a pha

11、se II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). J Clin Oncol. 2004 Dec 1;22(23):4779-86 42.可评价病人数42Second-line chemothera2007年ASCO有关Gliomas的文献有36篇病人数可评价病人数PRMPFS(w)MOS(w)PFS-6685959%234043%In grade III patients the median PFS was 42 weeks, the 6 month PFS was 61% the media

12、l 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 malignant gliomas43.2007年ASCO有关Gliomas的文献有36篇病人数68A phase II, randomized, no

13、n-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 2010b44.A phase II, randomized, non-coBevacizumab

14、 plus irinotecan in recurrent glioblastoma multiforme J Clin Oncol. 2007 Oct 20;25(30):4722-9可评价病人数PRPFS-6OS-63557%46%77%45.Bevacizumab plus irinotecan inPhase II trial of irinotecan and thalidomide in adults with recurrent glioblastoma multiforme可评价病人数CRPRSDMPFS(w)MOS(w)1Year3211119133634%Neuro Onc

15、ol. 2008 Feb 26 46.Phase II trial of irinotecan aBevacizumab and irinotecan for recurrent oligodendroglial tumors.Conclusions: This regimen is effective in recurrent oligodendrogliomas,and the overall tolerance is acceptable.ASCO 2009,Abstract 205425Pts.CRPRM-PFS(d)MOS(d)6-PFS(ms)20%52%17432842%47.B

16、evacizumab and irinotecan for48.48.49.49.50.50.51.51.52.52.53.53.ASCO 2009,Abstract 20372009年ASCO有关神经系统肿瘤的文献80余篇54.ASCO 2009,Abstract 20372009年ASA phase II study of XL184 in patients (pts) with progressive glioblastomamultiforme (GBM) in first or second relapse.Conclusions: XL184at a dose of 175 mg

17、PO qd, has demonstrated substantial activity in ptswith progressive or recurrent GBM.ASCO 2009, Abstract 204726Pts.PRSDPD6-PFS(ms)38%35%27%(9pts received bevacizumab)55.A phase II study of XL184 in p脑胶质瘤和转移性瘤耐药的研究1) 6-甲基鸟嘌呤DNA甲基转移酶 (MGMT) (6-methylguanine-DNA hyltransferase )2) P-glycoprotein56.脑胶质瘤

18、和转移性瘤耐药的研究1) 6-甲基鸟嘌呤DNA甲基转Fruehauf, J. P. et al. Clin Cancer Res 2006;12:4523-4532脑胶质瘤和转移性瘤耐药的研究57.Fruehauf, J. P. et al. Clin CaFruehauf, J. P. et al. Clin Cancer Res 2006;12:4523-453258.Fruehauf, J. P. et al. Clin CaMGMT methylation status as a prognostic factor in anaplastic astrocytomas.Conclusi

19、ons: 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 methylationM-PFS(ms)48.6 38p=0.09ASCO 2009 Abstract 205259.MGMT methylation status as a p P-gp expression in brain capillary endothelial cells suggests that P-gp may restri

20、ct drug entry into brain tumors and thus be another mechanism of drug resistance. 60. P-gp expression in brain capiK1735 cellsK1735 cellsMDRThe biology and mechanism of chemoresistance of brain metastases THE UNIVERSITY OF TEXAS GRAD. SCH. OF BIOMED. SCI. AT HOUSTON 199561.K1735 K1735 MDRThe biology

21、 andBBBD(blood-brain barrier disruption)化疗高渗性、缓激肽衍生物：BBB开放选择性开放血瘤屏障(blood-tumor barrier, BTB)克服化疗耐药性多药耐药及逆转 MGMT表达预测化疗疗效，避免无效化疗。脑胶质瘤和转移性瘤耐药的研究62.脑胶质瘤和转移性瘤耐药的研究62.联合化疗提高化疗敏感性VM-26和BCNU联合显著提高胶质瘤对化疗的敏感性机理：抑制MDR-I或P-gp过表达PCV方案显著增强多形胶质母细胞瘤对BCNU类药制的敏感性机理：肿瘤细胞先暴露于烷化剂类药物使瘤细胞中AGT（O6-烷基鸟嘌呤-DNA烷基化转酶）活性受抑 AGT是增

22、强肿瘤细胞对BCNU类 药物敏感性的主要靶点63.联合化疗提高化疗敏感性VM-26和BCNU联合显著提高胶质瘤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 newly diagnosed patients with supratentorial g

23、lioblastoma. ACNU (80mg/m2) once every 6 weeks concomitant with radiotherapy. 病人数可评价病人数MS(w)PFS(w)Toxicity8482IA5924-IV5645-Journal of neuro-oncology2000,vol.49,no1,pp.63-70 64.Randomized Comparison of Intra2008年NCCN指南成人侵润性低度恶性幕上星形细胞瘤/少突胶质细胞瘤辅助化疗：高剂量替莫唑胺 5/28方案复发或进展：一线方案：替莫唑胺 5/28方案（初治）二线方案：BCUN210mg/m2 iv 6w重复;,80mg/m2x3 6w重复； CCNU 110mg/m2 口服 6w重复；PCV联合化疗成人室管膜瘤：复发用vp-16,替莫唑胺 ，亚硝脲类，铂及联合方案原发性CNS肿瘤化疗指南65.2008年NCCN指南成人侵润性低度恶性幕上星形细胞瘤/少突多形性胶母细胞瘤辅助化疗：同步替莫唑胺 75m