非小細胞肺癌的放射和吉非替尼綜合治療.ppt

1、第2屆廣州國際肺癌論壇 2011年8月20日, 廣州 蔣國梁 復旦大學附屬腫瘤醫(yī)院,非小細胞肺癌的放射和吉非替尼綜合治療,Outcome of non-small cell carcinoma,Stage and tmt 5-yr survival I-II surgery 48-70% I-II inoperable, SBRT 40% IIIa (surgery other Tmt) 15-27% IIIa (RTChemo) 14-20% IIIb (RTChemo) 5-7%,進一步提高非小細胞肺癌的療效：放療靶向藥物治療,Gefitinib enhanced radiosensiti

2、vity of tumor cells Survival curve of Oral SCC (in vitro),Shintani S. Int J Cancer 2003; 107:103037,Shoulder of survival curve disappear (inhibition for SLD repair) Slop of survival curve reduced (intrinsic radiosensitivity increased),Gefitinib enhanced radiosensitivity of tumor cells,GEO (rectal ca

3、rcinoma) in vivo (tumor re-growth delay) 10Gy/fx4fx + Iressa 2.5mg ip d1-54 wks,Bianco et al. Clin Cancer Res 2002;8:3250-3258,Iressa + RT,Control,RT,Iressa,The percentage of S phase decreased after IressaIressa+RT (GEO in vivo),Bianco C. Clin Cancer Res 2002;8:3250-3258,Mechanism of Gefitinib radio

4、sensitization,Gefitinib speeds up apoptosis of tumor cells after RT GEO in vivo,Bianco C. Clin Cancer Res 2002;8:3250-3258,RT+Iressa,RT,Iressa,Gefitinib inhibits RT induced damage repairOral SCC (Western blot),Shintani S. et al. Int J Cancer 2003; 107:10301037,RT damage DNA Need DNA repair enzyme,RT

5、 enzyme DNA repair Gefitinib enzyme DNA repair ,Iressa+RT in Oral SCC (Western blot),RT could activate EGFR-TK signaling pathway (Ras-Raf-MAPK). And initiates a multistep phosphorylation cascade that leads to activation the pathway, and stimulates cell-cycle progression,Shintani S. Int J Cancer 2003

6、; 107:10301037,Gefitinib could inhibit multistep phosphorylation of EGFR signaling pathway, so slow down the tumor cell proliferation and enhance the radiation sterilization.,Possible mechanisms for radiosensitization of Gefitinib,Decrease percentage of S phase and increase G2/M phases of tumor cell

7、s Enhance tumor cell apoptosis after RT Inhibit radiation induced DNA repair Inhibit multistep phosphorylation of EGFR signaling pathway, so reduce the tumor cell proliferation after RT,Iressa 提高了腫瘤固有的放射敏感性，抑止了腫瘤放射損傷后的修復和增殖,Combination of radiation therapy and Gefitinib for stage IIIb/IV non-small c

8、ell lung carcinoma Clinical phase I trial Irradiation dose escalation (NCT00497250),Rationales: Gefitinib as radiosensitizer to enhance local tumor sterilization. Inhibit or delay the growth of micrometastases What is concerned most for concurrent RT and Gefitinib for NSCLC? Pulmonary toxicity: Inte

9、rstitial pneumonitis by Gefitinib Radiation pneumonitis,Goal of the trial Main endpoint Side-effect and toxicity, safety and MTD of concurrent therapy of Gefitinib and RT for advanced non-small cell lung carcinoma. Second endpoint Acute response (RECIST) and survival,Patient eligibilityNSCLC histolo

10、gically or cytologically confirmedIIIbIV: brain metsECOG 1-2 No contraindication for RT Tolerable for RT and Gefitinib,TreatmentConcurrent Gefitinib (250mg, qd) and RT and continuously Gefitinib for 2 months after RT. RT target: Gross tumor volume in thorax on CT2Gy/fx, 5 fx/wk,Total dose escalation

11、54Gy, 56Gy, 58Gy, 60GyDose limit toxicity (DLT) in 2 months after completion of RTCTCAE V3 =3 for lungCTCAE V3 =4 for othersWhen =2/8 patients occurred DLT, dose escalation terminated and MTD was one dose level before.,EGFR突變檢測周圍血:治療前和治療后組織切片或細胞涂片ARMS,ResultStatus of dose escalation,One patient in 6

12、0Gy occurred interstitial pneumonitis in both lung one week after RT and died of pulmonary failure in 30 days,Clinical characteristics of patients (n=40）,Safety (MFT: 13.7 mos),治療前,治療后,Outcome,PR 11(28%); SD(55%); PD 7 (18%) Median progression-free time: 6.2 mos (3.4-8.9) Median survival time: 14.2

13、mos (11.7-16.7) 1-yr OS 60%,EGFR突變檢測結果,EGFR突變率: 20% (8/40) EGFR敏感突變率: 17.5% (7/40),EGFR TKI敏感突變和治療的毒性,治療毒副作用在有敏感突變和無敏感突變病人之間沒有顯著差別,EGFR TKI敏感突變和治療療效,部分有效率在有敏感突變的病人明顯高于無敏感突變病人,EGFR TKI敏感突變和生存,中位生存期: 有敏感突變17.5月（10.9-24.0） 野生型和非敏感突變病人的13.9月（10.7-17.1） （p0.05）,結 論,IIIb期/IV期NSCLC可以耐受放療同步使用吉非替尼，放療的最大劑量可達60Gy； 在聯(lián)合治療的毒性中，肺的1-2級毒性發(fā)生率比單用放療似有增加； 中位生存期14.2月和1年生存率60%，在IV期占55%的病人人群中，療效略改善； EGFR TKI敏感突變病人治療后的PR率顯著高于野生型和非敏感突變的病人，中位生存期似有延長，治療的毒性和副作用在兩組病人間無明顯差異。,正在進行的放療和靶向藥物綜合治療