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#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 Profile Mr. Perkins • • • • • 55 year old male Smoker Hemoptosis Photodynamic therapy 2 cycles of chemotherapy Diagnosis: Large T3 N2 tumor 2 3 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 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) 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 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? 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 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 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 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 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 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 13 14 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) 15 16 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 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 18 19 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) 20 Improvement In Lung Cancer Survival? • 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) 22 23 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 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 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 26-A 27 Non Small Cell Lung Cancer • Can the tumor be resected? • Can the patient undergo resection? • What can be done to improve the outcome? 28 29 NSCLC: Diagnosis And Staging • • • • • • • 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 32 Superior Sulcus Tumors • Arm pain • Arm parathesias • Shoulder pain • Horner’s syndrome 33 34 35 NSCLC Induction Therapy: Stage IIIA • 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 37 38 39 40 41 42 Pulmonary Resection In The High Risk Patient • • • • • • 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 44 45 46 47 48 49 50 Summary 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 51-A NEXT WEEK #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