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Combination of radiation therapy and Gefitinib for non-small cell lung carcinoma. 21th WCC, Shenzhen, China, Aug 19, 2010 Guo-Liang Jiang, MD, FACR Min Fan, MD, Jiayan Chen, MD Fudan University Shanghai Cancer Center. Outcome of non-small cell carcinoma.
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Combination of radiation therapy and Gefitinib for non-small cell lung carcinoma 21th WCC, Shenzhen, China, Aug 19, 2010 Guo-Liang Jiang, MD, FACR Min Fan, MD, Jiayan Chen, MD Fudan University Shanghai Cancer Center
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 (RT+Chemo) 14-20% IIIb (RT+Chemo) 5-7% Predominant failure pattern: Local and distant failures
Combination of radiation therapy and Gefitinib for stage IIIb/IVnon-small cell lung carcinoma Clinical phase I trial Irradiation 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/fx×4fx + Iressa 2.5mg ip d1-5×4 wks Control RT Iressa Iressa + RT Bianco et al. Clin Cancer Res 2002;8:3250-3258
Mechanism of Gefitinib radiosensitization The percentage of S phase decreased after IressaIressa+RT (GEOin vivo) Bianco C. Clin Cancer Res 2002;8:3250-3258
Gefitinib speeds up apoptosis of tumor cells after RTGEO in vivo RT+Iressa RT Iressa Bianco C. Clin Cancer Res 2002;8:3250-3258
Gefitinib inhibits RT induced damage repairOral SCC (Western blot) RT damage DNA Need DNA repair enzyme RT enzyme DNArepair Gefitinib enzyme DNA repair Shintani S. et al. Int J Cancer 2003; 107:1030–1037
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 Iressa+RT in Oral SCC (Western blot) Gefitinib could inhibit multistep phosphorylation of EGFR signaling pathway, so slow down the tumor cell proliferation and enhance the radiation sterilization. Shintani S. Int J Cancer 2003; 107:1030–1037
Possible mechanisms for radiosensitization of Gefitinib • Decrease percentage of S phase and increase G2/M phases of tumor cells • 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
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: Interstitial 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 histologically 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 escalation54Gy, 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.
Dose level No. pts 54Gy 8 56Gy 8 58Gy 8 60Gy 8+8 ResultStatus of dose escalation One patient in 60Gy occurred interstitial pneumonitis in both lung one week after RT and died of pulmonary failure in 30 days
Outcome At last follow-up visit SD 8 (20%); PD 32 (80%) Median progression-free time: 7 mos Median survival time: 13.9 mos (11.4-16.4) 1-yr OS 62%
Conclusion • IIIB/IV NSCLC patients could tolerate concurrent RT (MTD 60Gy) and Gefitinib. • 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. • MST of 13.9 mos and 62% of 1-yr OS were encouraging. • Clinical phase II trial was warranted, especially for non-smoker and adnocarcinoma (EGFR mutated).
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