胸腔外科 副教授 高 英 隆 ( Chest Surgery Associated Professor Kao Eing-Long ) Tel: 3121101 ext: 6306

1. 呼吸系統疾病 ( Respiratory Disease ) 非小細胞肺癌 ( Non Small Cell Lung Cancer ) 胸腔外科 副教授 高 英 隆 ( Chest Surgery Associated Professor Kao Eing-Long ) Tel: 3121101 ext: 6306 E mail: kaeil@cc.kmu.edu.tw

2. 學習目標( Learning Object) • Classification of Lung Cancer : SCLC vs NSCLC. • Diagnosis / Tumor Markers. • Grading / Extent / Staging. • TMN Classification / Performance Status Scales. • Therapeutic Decisions. • Pre-op Pulmonary / Cardiovascular Evaluation. • Surgery Risks / Chemotherapy / Radiation Therapy. • New Diagnostic Tolls & Treatment Strategies.

3. New Diagnostic Tools & Treatment Strategies TOPICS - New Diagnostic Tools Molecular Biology / Biomarkers Early detection. Prediction of sensitivity to CT/RT Detection of minimal residual disease / relapse Results of low dose spiral CT scan screening programs New diagnostic tools PET, LIFE Bronchoscopy, ( Lung Imaging Fluorescence Endoscope ) Virtual CT bronchoscopy

4. TOPICS - Treatment Strategies Role of Surgery Minimally invasive thoracic approaches. Surgical staging. Nodal sampling / radical dissection. Sentinel node. Limited resection for very early disease. Management of spiral CT scan lesions below 1 cm

5. Role of Radiotherapy 3D Conformal Radiotherapy, Intensity Modulated Radiation Therapy ( IMRT ). Images Guided Radiation Therapy ( IGRT ). DIBH. Stereotactic Precision Radiotherapy. Proton Therapy

6. Chemopreventive agents COX-2 inhibitors, Glucorticoids. Retinoid resistance and new retinoids, Gene strategies, Bioadjuvant therapies, Systemic vs. Pulmonary delivery

7. New treatment approaches Pharmacogenomic. New cytotoxic agents, ( Paclitaxel - Taxol ) Targeted ( EGFR ) biologic therapies. Apoptotic agents, ( p53-cs17, Rb-cs13,… ) Hybrid cytotoxic-cytostatic approach, Modulators ( Interferon, Cytokin ) and revertants of drug resistance, Vaccines

8. Laboratory Tests • Special biochemical studies • Blood survey • Calcium • LDH • Hormone – ACTH, AVP, ADH (SIADH), PTH • Tumor marker • CEA TPA CYFRA21 SCC NSE • p34 Biology, Genetic Changes p35 Oncogens, • Tumor Suppressor Genes, • p36 Growth Factors.., p37 & p38遺傳, 突變, • 不活化腫瘤抑制基因, 活化Oncogenes & GH不正常分泌.

9. Pre-op Pulmonary / Cardiovascular Evaluation Evaluation Of The Respiratory System Clinical Evaluation, Exercise Capacity, Spirometry, Arterial Blood Gas Analysis, Regional Pulmonary Studies ( Including LPT ), Pulmonary Circulation (TUPAO).. Evaluation Of Cardiovascular System Other Perioperative Therapeutic Considerations Prevention Of CV Complications Prevention Of Respiratory Complications

10. Risk Factors Age, Respiratory Diseases, Abnormal Pulmonary Function, CV Disease ( Cardiac Function Test ) Extent of Resection, General Risk Factors ( Nutrition, Alcohol & Smoking, Obesity ) Common Physiologic Disturbance Increased Pulmonary Arterial Venous Shunting Atelectasis Uneven Disturbance of Ventilation & Perfusion Increased Lung Water Diffusion Block Increased Pulmonary Dead Space Increased Work of Breathing Decrased oxygen Transport in The Blood Decreased Resistance to Infection

11. PREOPERATIVE ASSESSMENT OF PATIENTS UNDERGOING LUNG RESECTION FOR CANCER SURGERY FOR NSCLC SURGICAL ADJUVANT THERAPY OF NSCLC NSCLC: DEFINITIVE RADIOTHRAPY & COMBINED MODALITY THERAPY THE ROLE OF CHEMOTHERAPY IN THE MANAGEMENT OF DISSEMINATED NSCLC ∮ TREATMENT OF SCLC SUPERIOR SULCUS TUMORS SVC SYNDROME: AN ONCOLOGIC EMERGENCY

12. The Surgery Procedure vs. Risk Factors Dependent On The Nature, Conduct, And Extent Of Operation Normal Lung Function After Operation Lung Volumes And Ventilatory Patterns Gas Exchange Pulmonary Defense Mechanisms Dependent On The Conduct Of The Procedure Will Suffer Respiratory Complications. Airway Defense Abolish / Reduce; 需Airway Monitor ARDS ( Fluid Overload / Blood Massive Transfuse ) Dependent On The Extent Of The Operation Lung Function After Pneumonectomy Risk Of Concomitant Cardiac & Pulmonary Operations

14. CANCER PATIENT MANAGEMENT • The diagnosis of cancer requires a histological proof of malignancy • The treatment is mostly based on the extension of the disease and on the histology. Performance status, age and history are also critical factors for establishing the treatment strategy.

16. TUMOR EXTENT STAGING • The extent of the disease is one of the key parameters for treatment orientation. In case of localized disease the resectability of the tumor and the operability of the patient are also pivotal.

17. TNM CLASSIFICATION • The U.I.C.C (Union Internationale Contre le Cancer) has set up on international classification based on tumor size (T), lymph node involvement (N) and the presence (or not) of distant metastasis (M). The prognosis is better if the tumor id small and if there is no lymph node involvement and no distant metastasis.

18. TUMOR MARKERS/EXAMPLES • In some tumors, the evolution of tumor markers over time should allow the assessment of treatment efficacy and the early detection of relapse.

20. PERFORMANCE STATUS SCALES • There are several performance status scales. The Karnofsky goes from 100 (normal) to 0 (dead). The E.C.O.G. from 0 (normal) to 5 (dead). These scales evaluate the degree of autonomy for current activities.

22. RADIATION THERAPY / DEFINITION OF VOLUME • The target volume encompasses the tumor volume plus a margin to take into account the possibility of microscopic extension. • The treatment volume encompasses the target volume plus a security margin.

24. TYPES OF IONIZING RADIATIONS • Gamma Rays (=photons, =X rays) are the most penetrating rays. The maximum dose of these rays is delivered 0.5 cm beneath the skin surface. B particules are electrons. The dose of radiation delivered by electrons diminishes rapidly with tissue depth. A particules are helium nuclei. They deliver their radiation dose at a defined tissue depth.

26. CANCER RADIATION SENSITIVITY • The tumors are classified in different categories based on their sensitivity to radiation. The goal of radiotherapy is to deliver enough radiation to sterilize every tumor type whatever the radiation sensitivity is . The dose depends also on the tumor extent and the histological nature of the cancer.

27. Guidelines on Treatment of Stage IIIB Non-small Cell Lung Cancer2003;123;211S-225S Chest • Introduction • Stage IIIB – T4 tumors, any N, M0 N3 tumors, any T, M0 • 10-15% of the patient at the time of diagnosis • 5 year survival 3~7% for patients with Stage IIIB

28. Guidelines on Treatment of Stage IIIB Non-small Cell Lung Cancer • Treatment options depend on the extent of disease • Surgery alone in selected patients • Surgery after induction therapy in selected patients • Combination of chemotherapy and radiotherapy • Evidence based guidelines is based on an extensive review of medical literatures • 8 guidelines, 1 randomized phase III trail in England and abstracts

29. Limited role of Surgery • Surgery alone may be indicated for carefully selected situations • T4N0-1 satellite tumor nodule within a primary tumor lobe  20% 5 year survival • T4N0-1 main carinal involvement, carinal resection with or without pulmonary resection  incrased risk of local recurrence but 20% 5 year survival

30. Surgical Recommendation • 1.Patients with clinical T4N0 NSCLC due to either satellite tumor nodule(s) in the same lobe or carinal involvement should be evaluated by a thoracic surgeon for possible resection. (Fair/B) • 2. For patients with stage IIIB NSCLC due to T4 (excluding Pancoast tumors) or N3 disease, treatment with neoadjuvant chemotherapy or chemoradiotherapy followed by surgery has been explored in limited phase II trials.

31. Combination Chemoradiotherapy Recommendation At this time, there are no phase III trial data available to document that surgery adds to survival; therefore, this approach should not be considered as standard therapy. (Poor/I) • 3. For patients with stage IIIB disease without malignant effusions, PS 0 or 1, and minimal weight loss ( 5%), combined chemoradiotherapy should be the standard of care. (Good/A) • 4. In patients with stage IIIB NSCLC and PS 2 or those with substantial weight loss ( 10%), combined modality treatment could be used after careful consideration. (Poor/C)

32. Altered Fractions Of Radiotherapy • 5. For epithelial tumors. The clinical effectiveness of radiation: total dose /unit time. Multiple daily fractionsreduction in late tissue damage. • 6. Hyperfractionation= the use of 2 or more fractions daily of smaller-than-conventional fraction size. • 7. Accelerated RT: the use of 2 or more fractions of standard fraction size daily to the same conventional total dose, increasing the numbers of fractions per week, shortening the overal treatment time. • 8. Hyperfractionated accelerated RT:2 or 3 fractions of smaller fraction size daily, delivered over a shorter period of time than conventional therapy. To reduce long-term normal tissue damage.

33. Altered Fractions Of Radiotherapy • A randomized phase III trail in England: • Continuous hyperfractionated accelerated RT (CHART) VS standard RT(60 Gy/ 30 Fx) • 1-year survival: 63% : 55%; 2-year survival: 29%: 20% • Overall: 22% reduction in the relative risk of death. • Acute esphagitis. No difference at late morbidity. • Phase III trial of HART: stopped. • No data are available concerning the combination of CHART and chemotherapy.

34. 摘要 ( Summary ) Non Small Cell Lung Cancer (NSCLC ) • Diagnosis / Tumor Markers / TMN Classification. • Pre-op Pulmonary / Cardiovascular Evaluation. • Role of Surgery vs Risks / Pulmonary Defense Mechanisms • Role of Radiotherapy / Combination Chemoradiotherapy. • SUPERIOR SULCUS TUMORS. New Diagnostic Tolls & Treatment Strategies • Chemopreventive agents / Bioadjuvant therapies / Pharmacogenomic. ◎ 下課了，請發問！？ http://www.kmuh.org.tw/www/thorax/index.htm