1. 1 Non–Small-Cell Lung Cancer Diagnosis and Staging EvaluationPurpose Physical examinationIdentify signs Chest x-rayDetermine position, size, number of tumors BronchoscopyDetermine location of tumor, obtain biopsy Fine-needle aspirationCytology CT scanIdentify chest-wall invasion, mediastinal lymphadenopathy, distant metastases PET scanMediastinal, lymph-node and extrathoracic staging Laboratory analysisDetect changes in hormone production, and hematologic manifestations of lung cancer MediastinoscopyVisualize and sample mediastinal lymph nodes

2. 2 TNM Staging of Non–Small-Cell Lung Cancer T = primary tumor; N = nodal involvement; M = distant metastasis. Mountain CF. Chest. 1997;111:1710. Stage IAT1N0M0 Stage IBT2N0M0 Stage IIAT1N1M0 Stage IIB T2 T3 N1 N0 M0

3. 3 TNM Staging of Non–Small-Cell Lung Cancer T = primary tumor; N = nodal involvement; M = distant metastasis. Mountain CF. Chest. 1997;111:1710. Stage IIIA T1–3 T3 N2 N1 M0 Stage IIIB T4 Any T Any N N3 M0 Stage IVAny TAny NM1

4. 4 Early-stage tumor Surgery Surgery Radiation for inoperable patients Radiation for inoperable patients Locally advanced tumor Surgery Surgery Chemoradiation Chemoradiation Surgery + chemoradiation Surgery + chemoradiation Advanced tumor Chemotherapy Chemotherapy Targeted therapy Targeted therapy Chemotherapy + targeted therapy Chemotherapy + targeted therapy NCCN Clinical Practice Guidelines in Oncology. NSCLC. V.I.2007. Available at: http://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf. Accessed May 18, 2007. Overview of NSCLC Treatment Options

5. 5 Postoperative RT 30 – 60 Gy; diverse planning Postoperative RT 30 – 60 Gy; diverse planning Survival data on 2128 patients Survival data on 2128 patients –PORT  21% increase in risk of death PORT Meta-analysis Trialists Group. Lancet. 1998;352:257-263, with permission from Elsevier. Postoperative Radiation Therapy in NSCLC Systematic Review and Meta-analysis of 9 Randomized Controlled Studies Hazard ratio TrialPORTNo PORTO-EVariance Belgium88/9880/10416.0440.67 LCSG 77384/11081/1204.7741.02 CAMS83/153100/1641.0744.88 Lille59/8145/8210.8725.66 EORTC 0886126/5220/545.5311.20 MRC LU11116/154123/154-2.4859.39 GETCB 04CB8669/9959/904.9531.59 Slovenia30/3533/39-2.5615.63 GETCB 05CB88152/274120/26525.1367.08 Total707/1056661/107263.33337.12 No. Events/No. Entered Hazard ratio = 1.21 P =.001 PORT betterNo PORT better 00.51.01.52.0

6. 6 5 Year-Survival According to N Stage 232/840 received radiation after chemotherapy or surgery Doulliard J-Y, et al. Int J Radiat Oncol. 2006;66:S2. Courtesy of Dr. Doulliard. ANITA1: Evaluation of PORT in Patients With Node-Positive Disease N0N1N2 Observation62.3%31.4%16.6% PORT43.8%42.6%21.3% Chemotherapy59.7%56.3%34.0% Chemotherapy + PORT44.4%40.0%47.4%

7. 7 N = 7465; Hazard ratio (HR) <1 = improved overall survival. Lally BE, et al. J Clin Oncol. 2006;24:2998-3006. Reprinted with permission from the American Society of Clinical Oncology. PORT for Stage II or III NSCLC (SEER Database) Conclusion In a population-based cohort, PORT use is associated with an increase in survival in patients with N2 nodal disease but not in patients with N1 and N0 nodal disease. Multivariate Analysis Overall SurvivalDisease-Specific Survival HR95% ClPHR95% ClP 1.1761.005–1.376.04351.3611.134–1.633.0009 1.00 (Ref)1.00 (Ref) 1.0971.015–1.186.01961.0820.990–1.182.0822 1.00 (Ref)1.00 (Ref) 0.8550.762–0.959.00770.8500.748–0.967.0133 1.00 (Ref)1.00 (Ref) Nodal Stage N0 Radiotherapy Observation N1 Radiotherapy Observation N2 Radiotherapy Observation

8. 8 Resection if no progression, then PE x 2 (n = 202) Complete chemoradiotherapy to 61 Gy with PE x 2 (n = 194) INDUCTION CHEMORADIOTHERAPY Cisplatin 50 mg/m 2 IV days 1, 8, 29, 36 + etoposide 50 mg/m 2 IV days 1–5, 29–33 (PE) + RT to 45 Gy starting day 1 Albain KS, et al. J Clin Oncol. 2005;23:16S. Abstract 7014. 10.5 22.2 12.8 23.6 0 5 10 15 20 25 Median PFSMedian OS Months CT/RT/SCT/RT P =.017 HR 0.77 (0.62–0.96) P =.24 HR 0.87 (0.70–1.10) 5-y PFS 22.4% 11.1% 5-y OS 27.2% 20.3% Phase III Trial of Chemoradiation ± Surgery in Stage IIIA pN2 Patients (INT 0139)

9. 9 Overall Survival (%) 0 25 50 75 100 Months from Randomization 01224364860 /// /// / //// /// / / // // / // P =.002 CT/RT/S 57/90 CT/RT 74/90 Deceased/Total Median survival 34 mo 22 mo 34 mo 22 mo 5-y OS 36% 18% CT/RT/S CT/RT CT/RT CT/RT/S Albain KS, et al. J Clin Oncol. 2005;23:16S. Abstract 7014. Courtesy of Dr. K. Albain. INT 0139: Overall Survival of the Lobectomy Subset vs Matched CT/RT Subset

10. 10 Survival Comparison—Chemoradiation Sequencing 0 5 10 15 20 25 30 SequentialInduction- Concurrent WJLCG RTOG 9410 CALGB 39801 BROCAT LAMP GLOT CZECH SWOG 9504 RTOG 9801C RTOG 9801A CALGB 30105A CALGB 30105B Median Overall Survival (%) Concurrent Concurrent- Consolidation 1. Tada T, et al. Radiat Med. 2004;22:163. 2. Curran WJ, et al. Proc Am Soc Clin Oncol. 2003;22:621. Abstract 2499. 3. Vokes EE, et al. J Clin Oncol. 2004;22(suppl):7005. 4. Huber RM, et al. J Clin Oncol. 2006;24:4397. 5. Choy H, et al. Proc Am Soc Clin Oncol. 2002;21:1160. 6. Gournel P, et al. J Clin Oncol. 2005;23:5910. 7. Zatloukal P, et al. Lung Cancer. 2004;46:87. 8. Gandara DR, et al. Clin Lung Cancer. 2006;8:116. 9. Movsas B, et al. J Clin Oncol. 2005;23:2145. 10. Blackstock AW, et al. J Clin Oncol. 2006;24(suppl):7042. 1 2 3 4 5 6 7 8 9 9 10

11. 11 Chemoradiotherapy Induction Cisplatin 50 mg/m 2 days 1, 8, 29, 36 Etoposide 50 mg/m 2 IV days 1–5, 29–33 Concurrent RT 59.4 Gy (1.8 Gy/d) Complete Response, Partial Response, or Stable Disease ECOG PS 0–1 Docetaxel 75 mg/m 2 every 3 weeks  3 Observation Randomize http://www.clinicaltrials.gov/ct/show/NCT00216125?order=1 Confirmation of Consolidation Chemotherapy in Unresectable Stage III NSCLC Hoosier Oncology Group (LUN01-24)