1. Optimizing the Delivery of Combined Modality Therapy Philip Bonomi, MD

2. LUNG CANCER STATISTICS 2002 NEW CASES169,000 MEN/WOMEN90,000/79,000 DEATHS155,000 5 YR SURVIVAL15%

3. LUNG CANCER HISTOLOGY NON-SMALL CELL 86% SMALL CELL14%

4. STAGE DISTRIBUTION IN NSCLC 2003 STAGE I-II25% STAGE III30% STAGE IV45%

5. RADIOTHERAPY IN STAGE III NSCLC MST10M 2 YR13% 5 YR5%

6. CHEMOTHERAPY FOR NSCLC STAGE IV RESPONSE - 20%STAGE IV RESPONSE - 20% STAGE III RESPONSE - 40%STAGE III RESPONSE - 40%

8. RT VS SEQUENTIAL CT/RT IN STAGE III SCLC INVESTIGATOR TREATMENT MST 5YR DILLMAN RT 9.7m 7% VP/RT 13.8m 17% VP/RT 13.8m 17% ARRIAGADA RT10m 3% VCPC/RT 12m 6% VCPC/RT 12m 6% SAUSE RT 11.4m 5% VP/RT 13.7m 8% VP/RT 13.7m 8%

9. DAILY CISPLATIN TRIALS IN NSCLC INVESTIGATOR THERAPY PTS 2 YRS pVALUE SCHAAKE- RT 100 13%.009 KONING RT/C 102 26% RT/C 102 26% TROVO RT 88 15%.89 RT/C 85 15% RT/C 85 15%

10. SIMULTANEOUS VS SEQUENTIAL CHEMORADIOTHERAPY IN STAGE III NSCLC REGIMEN RT MST5YR SEQ MVP-RT 56Gy Con 13.3m9% SIM MVP-RT 56Gy Int 16.5m 16% FURUSEJCO 17:2692, 1999

11. SIMULTANEOUS VS SEQUENTIAL CHEMORADIOTHERAPY IN STAGE NSCLC % GRADE 3 TOXICITY TOXICITYSEQ MVRTSIM MVP-RT HEMOGLOBIN 33 10 ESOPHAGUS 2 3 LUNG 1 1 N&V 23 23 FURUSE JCO 17:2692, 1999

12. SIMULTANEOUS VS SEQUENTIAL CT/RT IN STAGE III NSCLC TREATMSTp VALUE SEQ14.6m------------ SIM17.0m.04 SIM - BID15.6m.31 CURRANPASCO 19:1891,2000

13. LAMP TRIAL Paclitaxel 200mg/m 2 Carboplatin AUC6 RT 63Gy Carboplatin AUC6 RT 63Gy Q21 Days X 2 Cycles Q21 Days X 2 Cycles Paclitaxel 200mg/m 2 Paclitaxel 45mg/m 2/wk Paclitaxel 200mg/m 2 Paclitaxel 45mg/m 2/wk Carboplatin AUC6 Carboplatin AUC2/wk Carboplatin AUC6 Carboplatin AUC2/wk Q21 Days X 2 Cycles RT 63Gy Q21 Days X 2 Cycles RT 63Gy Paclitaxel 45mg/m 2 /wk Paclitaxel 200mg/m 2 Paclitaxel 45mg/m 2 /wk Paclitaxel 200mg/m 2 Carboplatin AUC2/wk Carboplatin AUC Carboplatin AUC2/wk Carboplatin AUC RT 63 Gy Q21 Days x 2 Cycles RT 63 Gy Q21 Days x 2 Cycles RANDOMIZE

14. LAMP TRIAL IN STAGE III NSCLC TREATMENT PTS MST 2 YR PC - RT 86 12.5M 31% PC - RT/PC 73 11M 22% RT/PC - PC 92 16.1M 33% CHOY PASCO 21: 291A, 2002

15. LAMP TRIAL % GRADE III TOXICITY DURING RT TOXICITY PC-RTPC-RT/PC RT/PC-PC ESOPHAGUS 3 19 28 LUNG 7 4 16 N&V 0 9 7 ANEMIA 3 7 10

16. CALGB RANDOMIZED PHASE II TRIAL OF CHEMO-RT IN STAGE III NSCLC Paclitaxel 225mg/m 2 Paclitaxel 135 mg/m 2 Cisplatin 80mg/m 2  TRT- Cisplatin 80 mg/m 2 Cisplatin 80mg/m 2  TRT- Cisplatin 80 mg/m 2 66Gy 66Gy Q21 Days Q21 days Q21 Days Q21 days Gem 125mg/m 2 1,8 Gemcitabine 600mg/m 2 1,8 Gem 125mg/m 2 1,8 Gemcitabine 600mg/m 2 1,8 Cisplatin 80 mg/m 2  TRT- Cisplatin Cisplatin 80 mg/m 2  TRT- Cisplatin 66Gy 66Gy Q21 Days Q21 days Q21 Days Q21 days Vin 25mg/m 2 1,8 Vinorelbine 15mg/m 2 1,8 Vin 25mg/m 2 1,8 Vinorelbine 15mg/m 2 1,8 Cisplatin 80mg/m 2  TRT- Cisplatin 80mg/m 2 Cisplatin 80mg/m 2  TRT- Cisplatin 80mg/m 2 66Gy 66Gy Q21 Days Q21 Days Q21 Days Q21 Days RANDOMIZE

17. CALGB RANDOMIZED PHASE II TRIAL OF CHEMO-RT IN STAGE III NSCLC REGIMENMST3 YR PAC-CIS-RT14.8M 28% GEM-CIS-RT18.3M19% VIN-CIS-RT17.7M23% VOKESJCO 20:4191, 2002

18. CALGB RANDOMIZED PHASE II TRIAL OF CHEMO-RT IN STAGE III NSCLC %GR3 TOXICITY DURING RT REGIMEN LUNG ESOPH N&VANEMIA PAC-CIS-RT 14 39 30 4 GEM-CIS-RT 14 52 51 32 VIN-CIS-RT 20 25 27 19 VOKES JCO 20:4191,2002

19. CISPLATIN-VP16-TRT + DOCETAXEL IN STAGE IIIB NSCLC TREATMENT PTS MST 2YR3YR EC-RT 50 16M 34%17% EC-RT-DOC 8327M 54%40% GASPAR PASCO 20: 315a, 2001

20. CHEMORADIOTHERAPY IN STAGE III NSCLC TREATMENTMST5 YR RT 9 mos 5% SEQ - CT/RT14 mos 8% LDSIM - CT/RT13 mos NA HDSIM - CT/RT 16 mos 16%

21. Cellular Dedifferentiation Growth Dysregulation Unlimited Cell Division Angiogenesis Loss of Apoptosis Invasion and Metastasis Natural History of Cancer

22. Molecular Events in Cancer Aberrant Signal Transduction Secretion of Autocrine Growth Factors Secretion of Matrix Metalloproteinases Expression of Oncogenes Loss of Tumor Suppressor Genes Secretion of Angiogenic Growth Factors Dysregulation of Growth Factors or Receptors

23. SINGLE AGENT EGFR TKI’S IN NSCLC INVESTIGATOR AGENT PTS RESPONSE BASELGA Gefitinib 200 18.7% NCI-EORTC 2001 KRIS Gefitinib 216 11.8% PASCO 21:292a, 2002 PEREZ-SOLER Erlotinib 57 12% PASCO 20:310, 2001

24. PHASE III TRIALS OF CHEMOTHERAPY IN STAGE IV NSCLC TRIAL REGIMENRESULTS INTACT I PAC-CARBO+ GefitinibNO DIFF INTACT II GEM-CIS+ GefitinibNO DIFF

25. CHEMO-RT PHASE III TRIALS IN STAGE III NSCLC ECOGON-GOING PACLITAXEL-CARBOPLATIN-RT + THALIDOMIDE CALGBCOMPLETED PAC-CARBO 2 COURSES WEEKLY PAC-CARBO-RT VS VS WEEKLY PAC-CARBO-RT

26. CHEMO-RT PHASE III TRIALS IN STAGE III NSCLC HOGON-GOING VIN-CIS-RT+ DOCETAXEL SWOGON-GOING VP16-CIS-RT- DOCETAXEL + Gefitinib + Gefitinib

27. CHEMO-RT PHASE III TRIALS IN STAGE III NSCLC RTOGCOMPLETED PAC-CARBO 2 COURSES WEEKLY PAC-CARBO-RT + AMIFOSTINE SWOGCOMPLETED VP16-CIS-RT + SURGERY

28. LOCALLY ADVANCED NSCLC 2003 USING 2ND GENERATION CHEMO REGIMENS BEST RESULTS WITH CONCURRENT CT/RT 3RD GENERATION CHEMO NOT GIVEN IN FULL DOSE WITH CONTINUOUS TRT NO PHASE III RESULTS WITH 3RD GENERATION CHEMO AND TRT

29. LOCALLY ADVANCED NSCLC 2003 INDUCTION CHEMOTHERAPY? CONSOLIDATION CHEMOTHERAPY? NEW BIOLOGIC TARGETED THERAPIES? ALTERED RT SCHEDULES? SURGERY?