非小细胞肺癌的放射和吉非替尼综合治疗.ppt

1、第2届广州国际肺癌论坛 2011年8月20日, 广州 蒋国梁 复旦大学附属肿瘤医院,非小细胞肺癌的放射和吉非替尼综合治疗,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%,进一步提高非小细胞肺癌的疗效：放疗靶向药物治疗,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 提高了肿瘤固有的放射敏感性，抑止了肿瘤放射损伤后的修复和增殖,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突变检测周围血:治疗前和治疗后组织切片或细胞涂片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),治疗前,治疗后,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突变检测结果,EGFR突变率: 20% (8/40) EGFR敏感突变率: 17.5% (7/40),EGFR TKI敏感突变和治疗的毒性,治疗毒副作用在有敏感突变和无敏感突变病人之间没有显著差别,EGFR TKI敏感突变和治疗疗效,部分有效率在有敏感突变的病人明显高于无敏感突变病人,EGFR TKI敏感突变和生存,中位生存期: 有敏感突变17.5月（10.9-24.0） 野生型和非敏感突变病人的13.9月（10.7-17.1） （p0.05）,结 论,IIIb期/IV期NSCLC可以耐受放疗同步使用吉非替尼，放疗的最大剂量可达60Gy； 在联合治疗的毒性中，肺的1-2级毒性发生率比单用放疗似有增加； 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，疗效略改善； EGFR TKI敏感突变病人治疗后的PR率显著高于野生型和非敏感突变的病人，中位生存期似有延长，治疗的毒性和副作用在两组病人间无明显差异。,正在进行的放疗和靶向药物综合治疗