肺癌放射治療新進展 Recent Advance in Radiation Oncology in Lung Cancer 許峰銘成佳憲國立台灣大學醫學院附設醫院腫瘤醫學部

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1 肺癌放射治療新進展 Recent Advance in Radiation Oncology in Lung Cancer 許峰銘成佳憲國立台灣大學醫學院附設醫院腫瘤醫學部

2 Outline Current status of radiation oncology in lung cancer Focused on stage III non-small cell lung cancer Radiation oncology advances in lung cancer Application of stereotactic body hypofractionated radiotheray / Radiosurgery in lung cancer

3 Role of Radiotherapy (RT) in Lung Cancer Definitive Treatment Early Stage Medical Inoperable NSCLC : RT Alone Advanced Stage NSCLC : Concurrent chemoradiation (CCRT) Limited Stage SCLC : Early CCRT Adjuvant Treatment for NSCLC : Controversy Pancoast tumor : Preoperative CCRT ct3-4n0-2 : Preoperative CCRT pn2, Less than R0 Resection : Postoperative CCRT CNS(Brain) Prophylaxis SCLC : Complete or partial responders NSCLC : Controversy for AJCC Stage IIIA status post neoadjuvant CCRT+Surgery Palliative Treatment Symptoms relief Prevention of neurological or orthopedic events Ablation of oligo-metastasis : Controversy

4 Combined Modalities for Stage III NSCLC Sequential chemoradiation Concurrent chemoradiation Induction chemotherapy followed by concurrent chemoradiation Concurrent chemoradiation followed by consolidation chemotherapy Induction chemotherapy followed by surgery Neoadjuvant chemoradiation followed by surgery

5 CCRT for stage III NSCLC Study Chemotherapy regimen Radiation Dose Design Median Survival 5-Year Survival Acute Esophagitis West Japan Lung Cancer Group Cisplatin, Vindesin, Mitomycin 56Gy/28Fr split course CCRT 16.5 m 15.5% (0.02) 56Gy/28Fr Sequential CRT 13.3 m 8.9% No difference RTOG Cisplatin, Vinblastine 60Gy/30Fr CCRT 17 m 21% (0.046) 60Gy/30Fr Sequential CRT 14.6 m 12% (4-year) 69.6Gy/58Fr/bid CCRT 15.2 m 17% Not Available GLOT-GFPC NPC Cisplatin, Etoposide Cisplatin, Vinorelbine 66Gy/33Fr CCRT 16.3 m 21% (NS) More Grade 3/4 Esophagitis (3% v.s 32%, Sequential CRT 14.5 m 14 % (4-year) p<0.0001) EORTC Daily Cisplatin Cisplatin, Gemcitabine 66Gy/24Fr CCRT 16.5 m 34 % (NS) More Grade 3/4 Esophagitis Sequential CRT 16.2 m 22% (3-year) (5% v.s 14%) Czech Cisplatin, Vinblastine 60Gy/30Fr CCRT 16.6 m 18.6% (0.02) More Grade 3/4 Esophagitis (4% v.s 18%, Sequential CRT 12.9 m 9.5%(3-year) NS)

6 Role of Induction & Consolidation in CCRT Induction Chemotherapy CLGB Median survival Arm A 12 m versus Arm B 14 m, NS Grade 3/5 Pneumonitis Arm A 4% versus Arm B 10% Consolidation Chemotherapy CONSORT Median survival Arm A 23.2 m versus Arm B 21.2 m, NS Grade 3/5 Pneumonitis Arm A 1.4% versus Arm B 9.6%

7 Chemoradiation with or without Surgery Stage IIIA N2 NSCLC Chemo+Surgery versus Chemo+RT Median overall survival 16.4 m versus 17.5 m, NS Median progression-free survival 9 m versus 11.3 m, NS Locoregional recurrence rate 32% versus 55% ChemoRT+Surgery versus ChemoRT Median overall survival 23.6 m versus 22.2 m, NS Median progression-free survival 12.8 m versus 10.5 m, p=0.02 Worse outcome for pneumonectomy Induction Chemotherapy Responders No Progression EORTC-LCG Surgery Randomization RT Gy JNCI 2007 Induction CCRT (45Gy) Surgery Intergroup Randomization CCRT 61Gy Lancet 2009

8 Summary Definitive concurrent chemoradiation and neoadjuvant therapy followed by surgery are options for stage IIIA NSCLC Addition of induction or consolidation chemotherapy with taxane-based regimens to definitive concurrent chemoradiation provides no survival benefit but increases risk of radiation pneumonitis

9 Radiation Oncology Advances Accuracy GTV (Gross tumor volume) PET scan for target delineation CTV (Clinical target volume) Elective nodal irradiation PTV (Planning target volume) Respiratory motion control Setup error reduction - Image guidance radiotherapy (IGRT) Efficacy Radiation dose escalation (Higher total dose) Radiation dose intensification (Fewer fraction size) Prevention from radiation pneumonitis Particle (Proton or Heavy ion) radiation therapy Combination of target therapy and radiotherapy

10 FDG-PET in GTV Delineation D/D of Primary Tumor from Atelectasis / Collapsed Lung Identify Metastatic Mediastinal Lymphadenopathy Radiology Criteria : Any regional node with diameter > 1.0 cm FDG-PET Criteria : SUV Threshold? Changes in GTV Overall 22%-100% Increase in GTV Avoid Geographic Miss 9-86% of cases Decrease in GTV Spare Normal Tissue 12-66% of cases Lung Cancer 2007;57: J Nucl Med 2007;48:

11 LN withф 1 cm Unclear border between primary tumor and collapsed lung J Thoracic Oncology 2008;3:

12 Elective Nodal Irradiation Increase risk of normal tissue toxicity with radiation dose escalation Elective nodal failure rate < 10% Involved field RT Gy versus Elective nodal RT 60-64Gy American JCO 2007;30:

13 Radiation Dose Escalation Local Failure with Standard Radiation Dose (60Gy/30Fx) CCRT for Stage III NSCLC RTOG 0617 : Randomized Phase III Trial

14 Respiratory Motion Control Required when motion > 5 mm Non-Adaptive Method Internal Target Volume Contour with 4D-CT Simulation Respiratory Motion Restriction with Abdominal Compression Respiratory Motion Control with Active Breath Hold Respiratory Phase Gating Real-Time Adaptive Method Respiratory Motion Tracking

15 Abdominal Compression Active Breath Hold

16 Linear Accelerator Technologies

17 Intensity Modulated / Arc Radiation Therapy IJROBP 2004;58:

18 Cautions of Low Radiation Dose to Lung IJROBP 2006;66:

19 Interaction Between Radiation and EGFR Nature Review Cancer 2006;6:

20 Synergistic Effect of Radiation plus Cetuximab H&N Squamous cell carcinoma NEJM 2006;354:

21 Cetuximab in Lung Cancer : FLEX Study Lancet 2009;373:

22 Integration of EGFR Inhibitors with CCRT Proposed Optimal Trimodality Sequence RTOG 0324 Phase 2 Median survival 22.7 M 7% Grade 3/4 Pneumonitis Five grade 5 events Three pulmonary RTOG 0617 : Randomized Phase III Trial

23 Tyrosine Kinase Inhibitor and RT CALGB Phase 2 : Disappointing East Asian Population? Future clinical trials are warrant

24 Stereotactic Body Radiosurgery Accelerated Hypofractionated Radiotherapy Fraction number 5 Application Early stage NSCLC Oligo-metastases Number of metastasis Brain Bone Lung Liver & Other organs 3

25 Linear Accelerator Technologies

26 Lung metastasis BED10(Gy) : Rusthoven et al, JCO 2009;

27 Early Stage Lung Cancer Study BED10(Gy) Local Control Regional Control Survival Gr.3 Complication Timmerman et al % (2-year) NA 52% (2-year) 11% Baumann et al % (3-year) 95% 52% (3-year) 10% Lagerwarrd et al % (2-year) 92% 64% (2-year) 7.5% Onishi et al % (5-year) 89% 42% (5-year) 2.5% Negata et al % (5-year) 94% 83% (5-year) 0%

28 Radiological Response after SBRT Radiother Oncol 2007;85:

29 Peripheral versus Central Lesions?? 2 cm 60Gy/3Fr Timmerman et al, JCO 2009;

30 Summary Stereotactic body radiotherapy (SBRT) is effective in ablation of primary and metastatic disease The optimal dose fractionation schedule and long term toxicity required further investigation The cost-effectiveness of SBRT for patients with oligo-metastases should be studied

31 Conclusion Definitive concurrent chemoradiation (CCRT) alone is the treatment of choice for patients with inoperable stage III NSCLC PET/CT-based target delineation is beneficial for selective patients Involved field irradiation provides similar outcome with reduced pulmonary toxicity The combination of target therapy and radiation therapy requires further investigation The early results of stereotactic body radiotherapy are promising and worth further investigation

32 Thank You

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