21th WCC, Shenzhen, China, Aug 19, 2010 GuoGuo- -Liang JiangLiang Jiang, MD, FACR, MD, FACRMin Fan, MD, Min Fan, MD, JiayanJiayan Chen, MD Chen, MD FudanFudan University Shanghai Cancer Center University Shanghai Cancer CenterCombination of radiation therapy and Combination of radiation therapy and GefitinibGefitinib for non-small cell lung carcinoma for non-small cell lung carcinomaOutcome of non-small cell carcinomaOutcome of non-small cell carcinomaStage and Stage and tmt tmt 5 5-yr survival -yr survival I-II surgeryI-II surgery 48-70% 48-70%I-II inoperable, SBRT I-II inoperable, SBRT 40%40%IIIaIIIa (surgery (surgery other other TmtTmt) 15-27%) 15-27%IIIaIIIa (RT (RTChemo) 14-20%Chemo) 14-20%IIIbIIIb (RT (RTChemo) 5-7%Chemo) 5-7% Predominant failure pattern: Local and distant failuresCombination of radiation therapy and Gefitinib for stage IIIb/IV non-small cell lung carcinoma Clinical phase I trialIrradiation dose escalation (NCT00497250) Gefitinib enhanced radiosensitivity of tumor cells Survival curve of Oral SCC (in vitro) Shintani S. Int J Cancer 2003; 107:1030 37 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 carcinoma) in vivo (tumor re-growth delay) 10Gy/fx4fx + Iressa 2.5mg ip d1-54 wksBianco et al. Clin Cancer Res 2002;8:3250-3258Iressa + RTControlRT IressaThe percentage of S phase decreased after Iressa Iressa+RT (GEO in vivo)Bianco C. Clin Cancer Res 2002;8:3250-3258Mechanism of Gefitinib radiosensitizationGefitinib speeds up apoptosis of tumor cells after RTGEO in vivoBianco C. Clin Cancer Res 2002;8:3250-3258RT+IressaRTIressaGefitinib inhibits RT induced damage repair Oral SCC (Western blot)Shintani S. et al. Int J Cancer 2003; 107:10301037RT damage DNA Need DNA repair enzymeRT 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 And initiates a multistep phosphorylation cascade that leads to activation the pathway, and stimulates cell-cycle progressionShintani S. Int J Cancer 2003; 107:10301037Gefitinib 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 Gefitinibl Decrease percentage of S phase and increase G2/M phases of tumor cellsl Enhance tumor cell apoptosis after RT l Inhibit radiation induced DNA repairl Inhibit multistep phosphorylation of EGFR signaling pathway, so reduce the tumor cell proliferation after RTRationales: 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:Interstitial pneumonitis by GefitinibRadiation pneumonitisGoal of the trialMain endpointSide-effect and toxicity, safety and MTD of concurrent therapy of Gefitinib and RT for advanced non-small cell lung carcinoma.Second endpointAcute response (RECIST) and survivalPatient eligibilityNSCLC histologically or cytologically confirmedIIIb IV: brain mets ECOG 1-2 No contraindication for RT Tolerable for RT and GefitinibTreatmentConcurrent Gefitinib (250mg, qd) and RT and continuously Gefitinib for 2 months after RT. RT target: Gross tumor volume in thorax on CT 2Gy/fx, 5 fx/wk, Total dose escalation 54Gy, 56Gy, 58Gy, 60GyDose limit toxicity (DLT) in 2 months after completion of RT CTCAE V3 =3 for lung CTCAE V3 =4 for others When =2/8 patients occurred DLT, dose escalation terminated and MTD was one dose level before. ResultStatus of dose escalationDose levelNo. pts54Gy856Gy858Gy860Gy8+8One patient in 60Gy occurred interstitial pneumonitis in both lung one week after RT and died of pulmonary failure in 30 days Male/Female28/12 Medium age (yr) Medium cycle of chemo55 (3279) 3.5 (1-5)ECOG 0 1 10 30StageIIIB IV18 22 HistologyAdeno- Sq Poor differentiated 35 (86%) 41 Smoker/non-smoker20/20Clinical characteristics of patients (n=40）Safety (MFT: 9.7 mos)CTCAE 3.0 Incidence Rash 1-224 (60%) 30Pulmonary 1-229 (73%) 3 G50 1 (3%) Espophageal 1-223 (58%)30 Hematological 1-216 (40%) 30OutcomeAt last follow-up visitSD 8 (20%); PD 32 (80%)Median progression-free time: 7 mosMedian survival time: 13.9 mos (11.4-16.4)1-yr OS 62%Conclusion1.IIIB/IV NSCLC patients could tolerate concurrent RT (MTD 60Gy) and Gefitinib.2.There was no excessive toxicity in NSCLC patients treated with concurrent RT and daily Gefitinib, except for pulmonary toxicity, which seemed like increased, especially the low grades (1-2) of CTCAE.3.