Non Small Cell Lung Cancer Introduction Mira Wollner RAMBAM MEDICAL CENTER

Epidemiology Most frequent cause of cancer diagnosed in the US – about 12% of all cancer NSCLC represents ~ 80% of lung cancer In year 2004 ~ 173,770 new cases and 160,440 deaths Leading cause of cancer deaths in both men ( 32%) and women (25%) 75% of new cases present with non resectable disease Overall 5 year survival < 15% American Cancer Society, Cancer Facts & Figures 2005 SEER Cancer Statistics, 1998-2002. http://seer.cancer.gov

Newly Diagnosed NSCLC in Israel 1999 = 1338 2002 = 1450

Etiology Cigarette smoking responsible for > 80% cases Use of filter Tar content Variation of tobacco blends Contains ~ 300 chemicals and up to 40 potent carcinogens (nitrate) Recent changes in histological dominant type (due to changes in tobacco blend and use of filter) American Cancer Society, Cancer Facts & Figures 2005 SEER Cancer Statistics, 1998-2002. http://seer.cancer.gov

Histology Adenocarcinoma ( 45%) Broncho-alveolar carcinoma Atypical Alveolar Hyperplasia ( precursor) Broncho-alveolar carcinoma Squamous cell carcinoma ( 33%) Large cell carcinoma ( 9% ) Adenosquamous carcinoma Pleomorphic carcinoma Carcinoma of salivary gland Carcinoid American Cancer Society, Cancer Facts & Figures 2005 SEER Cancer Statistics, 1998-2002. http://seer.cancer.gov

Diagnosis Medical history Physical exam Labs Imaging studies CXR CT-scan PET-CT scan Bone scan

Diagnosis Bronchoscopy (FOB) Mediastinoscopy Histology Sputum FNA (cytology/biopsy) thoracotomy

Methods of Spread Vascular channels Lymphatic channels Airborne or lymphatic (satellite nodules) Lymphatic spread to regional lymph nodes: bronchopulmonary (segmental and lobar (N1), mediastinal (N2-3) ,supraclavicular (N3) Retrograde lymphatic spread (pleural surface) Direct invasion Systemic dissemination

TNM stage grouping Stage 0 Tis NO MO Stage I T1 NO MO T2 NO MO Stage II T1 N1 MO T2 N1 MO Stage III A T1 N2 MO T2 N2 MO T3 NO MO T3 N1 MO T3 N2 MO Stage III B Any T N3 MO T4 Any N MO Stage IV Any T Any N M1

N0: No lymph node involvement Stage I disease > 2 cm T1 N0 M0 T2 N0 M0 T 3 cm T + visceral pleura involved T + atelectasis T  3 cm OR No lobar bronchus involvement OR N0: No lymph node involvement

N1: Intrapulmonary and/or hilar nodes involved Stage II disease > 2 cm T1 N1 M0 T2 N1 M0 T 3 cm T + visceral pleura involved T + atelectasis T  3 cm OR No lobar bronchus involvement OR N1: Intrapulmonary and/or hilar nodes involved

Stage IIIA disease OR T2 OR OR OR T1 T3 N0 M0 T1 N2 M0 T3 N1 M0 < 2 cm > 2 cm T3 N0 M0 T3 N1 M0 T3 N2 M0 T1 N2 M0 T2 N2 M0 OR T2 T  3 cm T + visceral pleura involved T + atelectasis T  chest wall (or diaphragm) OR OR T  mediastinal pleura (or pericardium) OR T1 T  3 cm No lobar bronchus involvement N1: peribronchial or ipsilateral hilar N2: ipsilateral mediastinal and subcarinal

Stage IIIB disease Any T, N3, M0 Any N, T4, M0 Scalene Supraclavicular Any N T4 Any T N3: lymph nodes involved T4: mediastinal involvement

Mediastinal lymph node map Mountain CF, Dresler CM Mediastinal lymph node map Mountain CF, Dresler CM. Chest 1997; 111:1718-1723

Involvement of lymphatic metastatic spread in non-small cell lung cancer accordingly to the primary cancer location Skip metastases to level 10 (hilar) ~ 5% Skip metastases to mediastinal LN ~ 19% Mediastinal LN dissection must be the standard procedure Kotoulas CS et al 2004 Lung Cancer;44:183-191

Patterns of failure after resection of NSCLC CHRIS R. KELSEY,., KIM L. LIGHT, AND LAWRENCE B. MARKS, 2006 Int. J. Radiation Oncology Biol. Phys., Vol. 65, No. 4, pp. 1097–1105

Treatment algorithm Glotocan, Epidemiology Lung Cancer, 2002

Survival and Frequency Mountain Chest 1997; 111:1718-1723 Stage Frequency (%) 5-year survival % Clinical Pathological IA ~ 10 61 67 IB 38 57 IIA ~ 13 34 55 IIB 24 39 IIIA ~ 22 13 25 IIIB ~ 5 IV ~ 32 <1

Surgery Lobectomy = gold standard for early stage Limited recection showed higher local recurrence rate (15%) then lobectomies (5%) for T1N0 tumors Ginsberg RJ et al. Ann Thorac Surg 1995;60:615

Sites of Recurrence Following Complete Surgical Resection Mountain CF, McMurtrey MJ, Frazier OH. Current results of surgical treatment for lung cancer. Cancer Bull 1980;32:105–108

Resected LN-negative Failure Author Stage Pts No Chest % Distant % Feld et all T1N0 162 9 17 T2N0 196 11 30 Pairolero et all 170 6 15 158 23 Thomas et all T1N0 Sq 226 5 7 non-Sq 346

Resected LN-positive Failure Author Stage Pts No Chest % Distant % Feld et all T1N1 32 9 22 Pairolero et all 18 28 39 Martini et all T1-2N1sq 93 16 31 T1-2N1 adeno 114 8 54 T2-3N2sq 46 13 52 T2-3N2 adeno 103 17 61

Completely Resected Stage II or IIIA With Postoperative Adjuvant Therapy (ECOG) Keller SM, Adak S, Wagner H, Herscovic A, et al. New Engl J Med 2000,343;17:1217-1222

Completely Resected Stage II or IIIA With Postoperative Adjuvant Therapy (continuing) Keller SM, Adak S, Wagner H, Herscovic A, et al. New Engl J Med 2000,343;17:1217-1222

Patterns of Failure S. Lee et al. Postoperative adjuvant chemotherapy and radiotherapy for stage II and III non-small cell lung cancer (NSCLC) Lung Cancer 37 (2002) 65/71

Prognostic Factors S. Lee et al. Postoperative adjuvant chemotherapy and radiotherapy for stage II and III non-small cell lung cancer (NSCLC) Lung Cancer 37 (2002) 65/71

Are All T1-2 Tumors the Same. Mulligan CR et al Are All T1-2 Tumors the Same? Mulligan CR et al. Ann Thorac Surg 2006;81(1):220-226 Tumor size (cm) 5 year survival (%) ≤1 48,6 1-2 45,9 2-3 25,6 3-4 27 4-5 14,4 >5 11,6

Outcome After Surgical Resection in Operable NSCLC Stage 5 year survival (%) Relapse Local Distant IA T1N0M0 67 10 15 IB T2N0M0 57 30 IIA T1N1M0 55 IIB T2N1M0 39 12 40 T3N0M0 38 IIIA T3N1M0 25 60 T1N2M0 23 Pisters and Le Chevalier. J Clin Oncol 2005;23:3270-3278

Prognostic factors TNM Stage Tumor size Pathological N2 Extend of LN involvement (single vs multiple) Occult vs Bulky Type of surgery wedge/segmentectomy vs lobectomy LN sampling vs dissection Positive surgical margins age > 60 years PS/QoL