Involved field. Gy/30fr RTOG0617

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1 .1 III Gy Involved field radiotherapy (IFRT) Gy/37 /7 60 Gy/30 /6 74 Gy 60 Gy ( p=0.004) 1) 60 Gy/30fr 2 1) 2) 3) 1) 2)

2 IMRT adaptive 2) hypofraction biomarker 3) meta-analysis 3) 3. おわりに 10 1) Bradley J.D., et al. Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study. Lancet Oncol 16, (2015). 2) Tsujino, K., et al. Combined analysis of V20, VS5, pulmonary fibrosis score on baseline computed tomography, and patient age improves prediction of severe radiation pneumonitis after concurrent chemoradiotherapy for locally advanced non-small-cell lung cancer. J Thorac Oncol 9, (2014). 3) Ohri, N., et al. Radiotherapy protocol deviations and clinical outcomes: a meta-analysis of cooperative group clinical trials. J Natl Cancer Inst 105, (2013).

3 2014Web NSCLC (TNM 7 th ed.) IA IB IIA IIB IIIA (T3N1,T4N0-1) IIIA (N2) IIIB IIIB ( ) IV () : RTOG 7301 P=0.005 CDDP 11 13% 2% Perez CA et al. Cancer , 1980 Non-small Cell Lung Cancer Collaborative Group, BMJ 1995;311: trials1205pts : 6.5 Y G3: 4% vs.18% (p<0.001) Auperin A et al. JCO 28, median survival s RT alone s Seq CT/RT s Conc CT/RT Choy H, PASCO 22, 2003

4 WJTOG0105 OLCSG 0007 MVP MVP IC WJTOG0105 OLCSG 0007 MVP IC PC MST (M) yOS (%) yOS (%) MVP DP MST (M) yOS (%) yOS (%) PC DP Yamamoto N et al JCO28,2010 Segawa Y, et al JCO28,2010 Yamamoto N et al JCO28,2010 Segawa Y, et al JCO28,2010 III 2007/11~2011/11 Consolidation Cx+ Primary endpoint : OS IIINSCLC RANDOMIZE Weekly CBDCA/PTX IFRT 74Gy/7wk Weekly CBDCA/PTX IFRT 60Gy/6wk + Cetuximab - Cetuximab + Cetuximab - Cetuximab Bradley JD et al. Lancet Oncol , 2015 Overall Survival 60Gy 74Gy p MST 28.7M 20.3M Bradley JD et al. Lancet Oncol , 2015 Overall Survival Cet + Cet - p MST 25.0M 24.0M 0.29 Bradley JD et al. Lancet Oncol , 2015 Worst non-hematologic Worst overall Grade 5 events Esophagitis Toxicity (CTCAE Ver.3) 60Gy (n=213) 74Gy (n=206) G3 G4 G5 G3 G4 G5 98 (46%) 99 (46.5%) 15 (7%) 21 (9.9%) 57 (26.8%) (n=2) 1 Pulmonary 1 Sudden death 2 (0.9%) 2 (0.9%) 95 (46.1%) 86 (41.7%) 23 (11.2%) 65 (31.6%) 10 (4.9%) 10 (4.9%) (n=10) 2 Pulmonary 1 Thrombosis 1Upper GI Hemorrhage 1 Pulmonary Hemorrhage 1 Pneumonia NOS 1 Esophageal 1 TE fistula 1 Sepsis 1 Death NOS 43 (21%) Bradley JD et al. ASCO Multivariate Analysis for OS Conclusions (74Gy)60Gy G3 Bradley JD et al. Lancet Oncol , 2015 Bradley JD et al. Lancet Oncol , 2015

5 60Gy D95PTV 9560Gy) 2000PET staging median survival M Isocenter 68Gy s RT alone 1990 s Seq CT/RT 2000 s Conc CT/RT 2010 s Conc CT/RT PET staging MST IMRT?IMRT Never give up! Post Post

6 V20G2RP parallel organ DVH V20 31 (n=7) 85% P< D Emami s TD5/5 TD50/5 1/3 2/3 3/3 1/3 2/3 3/3 50Gy Gy cm 2 30cm 2 100cm 2 10cm 2 30cm 2 100cm 2 70Gy 60Gy 55Gy Gy 60Gy 50Gy 45Gy 75Gy 65Gy 60Gy 5cm 10cm 20cm 5cm 10cm 20cm 50Gy 50Gy 47Gy 70Gy 70Gy - 45Gy 30Gy 17.5Gy 65Gy 40Gy 24.5Gy 60Gy 45Gy 40Gy 70Gy 55Gy 50Gy 60Gy 58Gy 55Gy 72Gy 70Gy 68Gy QUANTEC project Emami B, et al. Int J Radiat Oncol Biol Phys 21,1991 (Quantitive Analysis of Normal Tissue Effects in the Clinic) reviewed >70 articles Vdose (%) RP 11 MLDRP % 18% 8% 2630 (n=12) 2125 (n=29) 20 (n=23) Tsujino K, et al. IJROBP 55, 2003 Marks LB, et al. IJROBP 76, 2010 QUANTEC V20,MLDRP parameter range symptomatic RP V20 30% 20% 7Gy 5% 13Gy 10% MLD 20Gy 20% 24Gy 30% 27Gy 40% Marks LB, et al. IJROBP 76, 2010 Hu Y et al Oncol. Letters 2013 Wong S, et al. IJROBP 64: , 2006 DVH + RP G CCRTNSCLC122 RP (%) 0 9 (7.4%) 1 46 (37.7%) 2 53 (43.4%) 3 10 (8.2%) 4 1 (0.8%) 5 3 (2.5%) (11.5%) Tsujino K, et al. J Thorac Oncol 2014;

7 CT score 0 No fibrosis Pulmonary Fibrosis Score (PFS) 1 Interlobular septal thickening; no descrete honeycombing 2 Honeycombing (with or without septal thickening) involving <25% of the lobe 3 Honeycombing involving 25-49% of the lobe 4 Honeycombing involving 50-75% of the lobe 5 Honeycombing involving >75% of the lobe score 1 score 2 score 3 Modified from Kazerooni EA. AJR 169,1997 4PRS RPG3 PRSpredictive risk score 3(if age) +5 (if ) +3(if ) +6 (if VS5 <1500cc) 71.4% 26.6% 7.8% P<0.001 RPG3 -(forward-stepwise logistic regression test)- P value (/ <68) PFS on CT (0-1 / 2-3) V20 (/ <26%) <1500cc) Odds ratio (95%CI) ( ) ( ) ( ) ( ) ( / ) / Tsujino K, et al. J Thorac Oncol 2014; NSCLC (60Gy/30fr) V20 30% MLD 16Gy VS5 1500cc PRS 8 Tsujino K, et al. J Thorac Oncol 2014; serial organ Serial organ D1cc Study Treatment Dose (Gy) Rate of bronchial stenosis (%) Miller b.i.d. EBRT 74 4 (3/67) Miller b.i.d. EBRT 80 5 (1/20) Miller b.i.d. EBRT (4/16) Hayakawa q.d. EBRT (4/5) Speiser q.d. EBRT +endobronchial HDR (HDR) 9 (6/68) Miller KL, et al. IJROBP 61, 2005 :protonhypofx 52.5Gy/15fr Dmean21.0GyE, Dmax55.6GyE 8M 9M Gomez DR, et al. IJROBP 2013;86: NCCN2015-3DCRT- Dmax V20 MLD V5 Mean dose Dmax V40 80% V45 V60 Mean Dmax <66Gy

8 Post IMRT VMATboost 3DCRT vs. IMRT 3DCRT IMRT CT/3DCRT vs. 4DCT/IMRT Murshed H, et al. IJROBP 58,2004 G3 MDACC, , CCRT pts, retrospective N=318/3DCRT, 91/IMRT Median dose 63Gy in both groups Liao ZX, et al. IJROBP 2010: 76(3), IMRT 37NSCLCTomotherapyIMRT 4,V5TRD V5 <60% TomotherapySBRTG5RP G5 RP:2/35 (6.7%) - Kyoto prefectural Univ.- TomotherapyG5 RP GTV(p=0.025)V5(p=0.067), PTV (p=0.096) Song CH, et al. IJROBP 2010: 78, Aibe N, et al. J Rad Res 55, DCRT vs. IMRT vs. PSPT(proton) for NSCLC High dose proton with concurrent chemo, phaseii IMRT vs. Proton Unresectable stageiii NSCLC, N=55 74GyE/ 37fr +CBDCA/PTXqw 4D-CT planning, adaptive replanning F/U median21m (32M live pts) 2Y LC 80.8% raiation associated toxicities G3 esophagitis 12.7% G3 pneumonitis 7.3% Roelofs E, et al JTO 2012: 7 Chang JY Cancer 2011;117 Updated at Multidiciplinary Symposium in Thoracic Oncology, 2012

9 Post RTOG stageiii NSCLC, N=474 (short):387(82%)vs. 5(long):87(18%) Overall Survival long short P=0.15 OS: Multivariate analysis Machtay M, IJROBP WJOG3305 Stage III NSCLC CBDCA/PTXqwk+TRTconsolidation CBDCA/PTX IFRT, V20<35% Level Dose No. of patients 1 54Gy/36fr/3.6w, 1.5GyBID Gy/40fr/4w, 1.5GyBID 4-6 (repopulation)sq.c.ca 1(accelerated repopulation) Kim J et al. Nature Reviews Cancer 5, 2005 WJOG3305 Level 472Gy/48Fr/24days 56M, T4N0M0, sq FDG-PET based Adaptive RT Standard plan 40~50GyCT and PET Composite plan with adapted boost based on PET after 46Gy mean decrease tumor volume: CT; 26%, PET; 44% PETboost30-102Gy(mean58Gy) (NTCP<15%) Feng M et al. IJROBP Non-hematologic Hematologic 3 66Gy/44fr/4.4w, 1.5GyBID Gy/48fr/4.8w, 1.5GyBID 4-6 Tada T, et al. IJROBP 2012;83: c WJTOG3305 Toxicities (NCI-CTCAEver.3) and DLTs Level3 (66Gy)II WJOG5710L) Level 1(n=6) Level 2 (n=7) Level 3 (n=5) Level 4 (n=4) grade Neuropathy 1* * Infection 1* Pneumonitis 0 0 1** Esophagitis Nausea/Vomit Leukopenia Neutropenia Anemia Thrombocytopenia DLT 2 (33.3%) 0 1 (20.0%) 0 * DLT, **grade 5 radiation pneumonitis (day 121) MTD was not reached. Tada T, et al. IJROBP 2012;83: Adaptive hypofractionated RT based on PET re-imagingrtog /2~ III NSCLC Hypofraction PET/CT adapted boost RANDOMIZE PET staging, PET based planning IGRT mandatory ArmA (control) CBDCA/PTXqw 50Gy/25fr ArmB (experimental) CBDCA/PTXqw 46.2Gy/21fr During RT PET/CT Continue RT No re-simulation 60Gy/30fr Adaptive RT Re-simulation Gy/9fr Up to 80.4Gy/30fr Individualized to MLD20Gy

10 :EGFR Cetuximub Biomarker RTOG 1306/Alliance /11 II NSCLC stage III Sensitive EGFR mutation Arm 1: induction erlotinib x 12 wk Arm 2: Concurrent chemoxrt, 60 Gy Concurrent chemoxrt (IMRT or 3D-CRT), 60 Gy Cet + Cet - p MST 42.0M 21.2M Stratification Weight loss IIIA vs IIIB Chemo choice ALK translocation Arm 3: Induction crizotinib x 12 wk Arm 4: Concurrent ChemoXRT, 60 Gy Concurrent chemoxrt (IMRT or 3D-CRT), 60 Gy Bradley JD et al. Lancet Oncol , 2015 Post RTOG FUCCRT5-FU/RT 5-FUgemcitabine 416QAPP 216<PP 200 QA QA Abrams RA, et al. IJROBP 2012;82(2): meta-analysis Ohri N, et al. JNCI 2013; Take home message 60Gy IMRTproton adaptivebiomarker