#1008 New Strategies in Treatment of Lung Cancer November 9 to 12 Patrick Ross, Jr. MD, PhD Assistant Professor of Surgery Division of Surgical Thoracic Oncology The Ohio State University Medical Center & The James Cancer Hospital and Solove Research Institute Gregory A. Otterson, MD Associate Professor of Internal Medicine Division of Hematology and Oncology The Ohio State University Medical Center & The James Cancer Hospital and Solove Research Institute

Gregory A. Otterson, MD Associate Professor of Internal Medicine Division of Hematology and Oncology The Ohio State University Medical Center & The James Cancer Hospital and Solove Research Institute 1 1

Profile Mr. Perkins 55 year old male Smoker Hemoptosis Photodynamic therapy 2 cycles of chemotherapy Diagnosis: Large T3 N2 tumor Mr. Perkins 55 year old male Smoker Hemoptosis Photodynamic therapy 2 cycles of chemotherapy Diagnosis: Large T3 N2 tumor 2 2

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New Treatment Strategies In The Treatment Of Lung Cancer Multimodality treatment for locally advanced NSCLC - Surgery - Radiation - Chemotherapy Novel agents - SCLC - antisense bcl2 - NSCLC - farnesyltransferase inhibitors Multimodality treatment for locally advanced NSCLC - Surgery - Radiation - Chemotherapy Novel agents - SCLC - antisense bcl2 - NSCLC - farnesyltransferase inhibitors 4 4

Lung Cancer Statistics, 1999 Greatest cause of cancer death worldwide - 921,000 deaths worldwide - 158,900 US deaths (90,900 men, 68,000 women) 28% of US cancer deaths (14% cancer cases) Greatest cause of cancer death worldwide - 921,000 deaths worldwide - 158,900 US deaths (90,900 men, 68,000 women) 28% of US cancer deaths (14% cancer cases) 5 5

Lung Cancer Treatment - Stage And Type Specific Non-small cell lung cancer (NSCLC) - ~80% of lung cancer - Principally surgically treated - Chemotherapy and radiation therapy added in specific circumstances Small cell lung cancer (SCLC) - ~20% of lung cancer - Principally chemotherapy +/- radiation therapy Non-small cell lung cancer (NSCLC) - ~80% of lung cancer - Principally surgically treated - Chemotherapy and radiation therapy added in specific circumstances Small cell lung cancer (SCLC) - ~20% of lung cancer - Principally chemotherapy +/- radiation therapy 6 6

Locally Advanced NSCLC Stage IIIB - Generally unresectable - Either bulky primary tumor involving critical mediastinal structures, pleural effusion or contralateral mediastinal lymph node involvement Chemotherapy added to radiation therapy improves control and survival - Concurrent vs. sequential? Stage IIIB - Generally unresectable - Either bulky primary tumor involving critical mediastinal structures, pleural effusion or contralateral mediastinal lymph node involvement Chemotherapy added to radiation therapy improves control and survival - Concurrent vs. sequential? 7 7

Locally Advanced NSCLC Stage IIIA - Theoretically resectable - Ipsilateral mediastinal lymph nodes involved Surgery is principal modality in most centers - Post-operative radiation improves local controls - Post-operative chemotherapy has not been dramatically successful Stage IIIA - Theoretically resectable - Ipsilateral mediastinal lymph nodes involved Surgery is principal modality in most centers - Post-operative radiation improves local controls - Post-operative chemotherapy has not been dramatically successful 8 8

Stage IIIA NSCLC Questions asked in clinical trials - ? Pre-op chemotherapy - ? Pre-op radiation therapy - ? Pre-op chemo-radiotherapy - ? Role of surgery These questions remain open Questions asked in clinical trials - ? Pre-op chemotherapy - ? Pre-op radiation therapy - ? Pre-op chemo-radiotherapy - ? Role of surgery These questions remain open 9 9

Stage IIIA NSCLC Balance risks with benefits of aggressive treatment - Improved local / systemic control - Increased treatment related morbidity and mortality with combined treatment Prognostic / treatment factors - Weight loss (5-10%), performance status, age, comorbid conditions Balance risks with benefits of aggressive treatment - Improved local / systemic control - Increased treatment related morbidity and mortality with combined treatment Prognostic / treatment factors - Weight loss (5-10%), performance status, age, comorbid conditions 10

OSU Trial For Resectable Stage IIIA NSCLC Pre-operative chemotherapy for three cycles (paclitaxel and carboplatin) Pre-operative radiation (to 4500 cGy) with a novel (Gadolinium-Texaphyrin) radiation sensitizer Curative resection planned after completion of radiation If incomplete resection, post-op radiation Pre-operative chemotherapy for three cycles (paclitaxel and carboplatin) Pre-operative radiation (to 4500 cGy) with a novel (Gadolinium-Texaphyrin) radiation sensitizer Curative resection planned after completion of radiation If incomplete resection, post-op radiation 11

Novel Drug Strategies Apoptosis - many chemotherapeutic drugs induce cell death by initiating a cellular suicide pathway in cancer cells (called apoptosis) Some cancers (including most SCLC) overexpress an oncogene (bcl2) that protects cells from apoptosis Apoptosis - many chemotherapeutic drugs induce cell death by initiating a cellular suicide pathway in cancer cells (called apoptosis) Some cancers (including most SCLC) overexpress an oncogene (bcl2) that protects cells from apoptosis 12

Bcl2 Family Of Proteins Family of proteins that are involved in apoptotic pathways (some pro-, others anti-apoptotic) Bcl2 family members can homo- and hetero-dimerize with each other Susceptibility to programmed cell death (apoptosis) depends on relative ratio of homo- and hetero-dimers Family of proteins that are involved in apoptotic pathways (some pro-, others anti-apoptotic) Bcl2 family members can homo- and hetero-dimerize with each other Susceptibility to programmed cell death (apoptosis) depends on relative ratio of homo- and hetero-dimers 13

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Bcl2 Antisense Therapy Chemotherapy induces cell death through apoptosis Bcl2 protects cells from apoptotic death In theory, chemotherapy should be more effective if bcl2 is inhibited Therefore, use bcl2 antisense (synthetic oligonucleotide directed against the bcl2 messenger RNA molecule) Chemotherapy induces cell death through apoptosis Bcl2 protects cells from apoptotic death In theory, chemotherapy should be more effective if bcl2 is inhibited Therefore, use bcl2 antisense (synthetic oligonucleotide directed against the bcl2 messenger RNA molecule) 15

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Bcl2 Antisense In SCLC Patient population: resistant SCLS (Either progressive disease on treatment or relapse within 3 months) G3139 (bcl2 antisense) via continuous IV infusion X 7 days Paclitaxel 175 mg / m2 over 3 hours, day 6 q 3 weeks Patient population: resistant SCLS (Either progressive disease on treatment or relapse within 3 months) G3139 (bcl2 antisense) via continuous IV infusion X 7 days Paclitaxel 175 mg / m2 over 3 hours, day 6 q 3 weeks 17

Novel Drug Strategies Ras is an oncogene that is mutated in many different cancers (~90% of pancreatic ca, ~50% of colon ca and ~30% of NSCLC) Ras (normal and mutant) requires association with the cell membrane via a cholesterol precurser for activity Ras is an oncogene that is mutated in many different cancers (~90% of pancreatic ca, ~50% of colon ca and ~30% of NSCLC) Ras (normal and mutant) requires association with the cell membrane via a cholesterol precurser for activity 18

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Inhibit Ras Activity Through Its Membrane Association HMG-CoA reductase inhibitors were attempted without remarkable success Inhibition of the farnesyl-transferase enzyme has been pursued with better pre-clinical ad early clinical activity Single agent and combination trials are now underway (including one at OSU) HMG-CoA reductase inhibitors were attempted without remarkable success Inhibition of the farnesyl-transferase enzyme has been pursued with better pre-clinical ad early clinical activity Single agent and combination trials are now underway (including one at OSU) 20

Improvement In Lung Cancer Survival? Better local control - Improved surgical technique - Improved preparation / selection of surgical patients - Improved radiotherapy technique and radiation sensitizers Better local control - Improved surgical technique - Improved preparation / selection of surgical patients - Improved radiotherapy technique and radiation sensitizers 21

Improvement In Lung Cancer Survival? Better control of systemic disease - Application of current chemotherapeutic agents in combination with surgery and / or radiation therapy - Novel chemotherapeutic agents, designed to attack specific genetic defects in tumor cells (for example, bcl2 antisense and farnesyltransferase inhibitors) Better control of systemic disease - Application of current chemotherapeutic agents in combination with surgery and / or radiation therapy - Novel chemotherapeutic agents, designed to attack specific genetic defects in tumor cells (for example, bcl2 antisense and farnesyltransferase inhibitors) 22

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Summary Mr. Perkins Diagnosis: IIIA non-small lung cancer Treatment: - Photodynamic therapy - Chemotherapy - Right pneumonectomy Follow-up: - Operation went smoothly - Further radiation and chemotherapy Prognosis: Good Mr. Perkins Diagnosis: IIIA non-small lung cancer Treatment: - Photodynamic therapy - Chemotherapy - Right pneumonectomy Follow-up: - Operation went smoothly - Further radiation and chemotherapy Prognosis: Good 24

Patrick Ross, Jr. MD, PhD Assistant Professor of Surgery Division of Surgical Thoracic Oncology The Ohio State University Medical Center & The James Cancer Hospital and Solove Research Institute 25

Profile Joseph Tigerina 61 year old male Former smoker Newly identified left upper lobe mass Presented to family physician with left shoulder and back pain Joseph Tigerina 61 year old male Former smoker Newly identified left upper lobe mass Presented to family physician with left shoulder and back pain 26

Profile Joseph Tigerina Symptoms - No cough or hemoptsis - Some fatigue - No weight loss Evaluation - CT scan and CT needle guided biopsy - MRI - PET scan Diagnosis: Non small cell carcinoma Joseph Tigerina Symptoms - No cough or hemoptsis - Some fatigue - No weight loss Evaluation - CT scan and CT needle guided biopsy - MRI - PET scan Diagnosis: Non small cell carcinoma 26-A

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Non Small Cell Lung Cancer Can the tumor be resected? Can the patient undergo resection? What can be done to improve the outcome? Can the tumor be resected? Can the patient undergo resection? What can be done to improve the outcome? 28

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NSCLC: Diagnosis And Staging Chest x-ray CT scan chest Distant metastasis evaluation Bronchoscopy Trans thoracic needle biopsy Mediastinoscopy VATS Chest x-ray CT scan chest Distant metastasis evaluation Bronchoscopy Trans thoracic needle biopsy Mediastinoscopy VATS 30

Solitary Pulmonary Nodule: PET Scan 31

Surgical Management Of Stage 1 And 2 Wedge resection vs lobectomy Node sampling N1 and N2 Refer for adjuvant trials: evaluation of chemotherapy for early stage Appropriate surveillance Wedge resection vs lobectomy Node sampling N1 and N2 Refer for adjuvant trials: evaluation of chemotherapy for early stage Appropriate surveillance 32

Superior Sulcus Tumors Arm pain Arm parathesias Shoulder pain Horner’s syndrome Arm pain Arm parathesias Shoulder pain Horner’s syndrome 33

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NSCLC Induction Therapy: Stage IIIA Surgical staging Chemo or Radiation/chemo Evaluate for distant disease Nutrition Pulmonary rehab Surgical staging Chemo or Radiation/chemo Evaluate for distant disease Nutrition Pulmonary rehab 36

Induction Therapy Radiation alone Chemotherapy alone Radiation and chemotherapy: simultaneous vs sequential Radiation, and / or chemotherapy with PDT Pulmonary rehabilitation Radiation alone Chemotherapy alone Radiation and chemotherapy: simultaneous vs sequential Radiation, and / or chemotherapy with PDT Pulmonary rehabilitation 37

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Pulmonary Resection In The High Risk Patient FEV 1 < 0.8 Hypoxemia Hypercarbia Steroid dependent Elderly Previous pulmonary resection FEV 1 < 0.8 Hypoxemia Hypercarbia Steroid dependent Elderly Previous pulmonary resection 43

Pulmonary Rehabilitation Prepare patient for resection Decrease hospital stay Enhance recovery Promote sense of well being Minimize impact of chronic illness Prepare patient for resection Decrease hospital stay Enhance recovery Promote sense of well being Minimize impact of chronic illness 44

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Summary Joseph Tigerina Surgical procedure - Left upper lobe resection for non small cell cancer - Stage 1b lesion - all nodes were negative Joseph Tigerina Surgical procedure - Left upper lobe resection for non small cell cancer - Stage 1b lesion - all nodes were negative 51

Summary Joseph Tigerina Follow-up treatment Given staging, treatment options are: - Surveillance - Adjunctive chemotherapy within a defined protocol Prognosis: Good Joseph Tigerina Follow-up treatment Given staging, treatment options are: - Surveillance - Adjunctive chemotherapy within a defined protocol Prognosis: Good 51-A

#1009 Evaluation & Management of Atrial Fibrillation November 16 to 19 Stephen F. Schaal, MD Professor of Internal Medicine Division of Cardiology The Ohio State University Medical Center Robert Hoover, MD Assistant Professor of Internal Medicine Division of Cardiology The Ohio State University Medical Center NEXT WEEK