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Non Small Cell Lung Cancer

  1. Non Small Cell Lung Cancer Moderator : Dr. R. Kapoor
  2. Anatomy
  3. Lymphatic Drainage Level 1: Highest Mediastinal nodes Level 2: Upper paratracheal nodes Level 4: Lower paratracheal nodes Level 7: Subcarinal nodes nodes Level 8: Paraesophageal nodes Level 9: Pulmonary ligament nodes Level 10: Hilar nodes Level 11: Interlobar nodes Level 12, 13, 14: Lobar, segmental & subsegmental nodes
  4. Lymphatic Drainage Level 6: Paraaortic nodes Level 5: Subaortic nodes Level 3A and 3P: Prevascular and retrotracheal nodes
  5. Classification & Pathology
  6. Pathology Primary Lung Cancer Non Small cell type (70% - 80%) Small Cell type (20% – 30%) Squamous cell (30 - 50%) Adenocarcinoma (20 - 40%) Large Cell (10 – 15%) Adenosquamous Carcinomas with sarcomatous elements Neuroendocrine Others Bronchial surface epithelial type Goblet cell type Clara cell type Type II alveolar cell type Bronchial gland type
  7. Pathogenesis: Squamous type
  8. Pathogenesis: Adenocarcinoma
  9. Presentation
  10. Incidence & Prevalence
  11. Symptoms Symptoms Cough Central growth Hemoptysis Dyspnea / Wheeze Pneumonitis Peripheral growth Pain Cough Dyspnea Lung abscess Regional Spread Hoarseness Dysphagia Diaphragmatic palsy Horner’s Syndrome SVC syndrome Pancoast syndrome
  12. Chest X ray
  13. Staging & Prognosis
  14. Staging: AJCC 2002 M1 N0-N3 T1-T4 IV M0 N3 T1-T4 M0 N0-N2 T4 IIIB M0 N2 T1-T3 M0 N1 T3 IIIA M0 N0 T3 M0 M0 M0 M0 M N1 N1 N0 N0 N T2 IIB T1 IIA T2 IB T1 IA T TNM Stage
  15. Surgery
  16. Radiotherapy
  17. IMRT : Institutional example
  18. IMRT : Institutional example PTV Esophagus Spinal Cord
  19. Chemotherapy & Targeted therapy
  20. Wayne McLaren as the Marlboro man (1976) Dying from Lung Cancer (1992)
  21. Thank You

Editor's Notes

  1. 10 - hilar nodes; 11 - interlobar nodes; 12 – lobar nodes 13 - segmental; 14 - subsegmental N2 nodes: 1 - highest mediastinal nodes - nodes lying above a horizontal line at the upper rim of the brachiocephalic (left innominate) vein where it ascends to the left, crossing in front of the midline of the trachea 2 - upper paratracheal nodes - nodes lying above a horizontal line drawn tangential to the upper margin of the aortic arch and below the inferior boundary of #1 nodes 4 - lower paratracheal nodes - lie lateral to the midline of the trachea between a horizontal line drawn tangential to the upper margin of the aortic arch and a line extending across the R (or L) main bronchus 7 - subcarinal - caudal to the carina but not associated with the lower lobe bronchi or arteries within the lung 8 - paraesophageal (below carina) - adjacent to the wall of the esophagus, excluding subcarinal nodes 9 - pulmonary ligament - lie within the pulmonary ligament
  2. 3A and 3P - prevascular (3A) and retrotracheal (3P) nodes 5 - subaortic (AP window) - lateral to the ligamentum arteriosum or the aorta or L pulmonary artery and proximal to the first branch of the L pulmonary A 6 - para-aortic nodes - lie anterior and lateral to the ascending aorta and aortic arch beneath a line tangential to the upper margin of the aortic arch
  3. The designation non–small cell carcinoma of the lung refers to a group of commonly observed pulmonary neoplasms that are typically associated with cigarette smoking and share the common property of not being responsive to small cell carcinoma treatment protocols
  4. Tobacco contains over 40 potent carcinogens and among then NNK and PAH are the most important! Murine models indicate that these are known to induce P 53 and K RAS mutation both strongly associated with carcinomas. Asbestos exposure increases the risk of developing lung cancer by as much as 5 times risk of developing lung cancer & persons who currently smoke tobacco and have a history of asbestos exposure approaches 80-90 times that of control populations.
  5. In a study by Doll and Peto a threefold increase in cigarettes smoked per day increased lung cancer risk threefold, whereas a threefold increase in duration of smoking was associated with a 100-fold increase in lung cancer risk.
  6. Estimated global incidence of lung cancer is Lung cancer accounts for 5%-13% of all cancers recorded in population based registries in India.
  7. The NCI-sponsored Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study was a Phase III trial of α-tocopherol and β-carotene to prevent primary lung cancer. The ATBC study involved 29,133 male smokers between 50 and 69 years of age who had smoked an average of one pack of cigarettes a day for approximately 36 years.83 This trial's 2 × 2 factorial design called for α-tocopherol (50 mg/d) and β-carotene (20 mg/d) to be given in a randomized, double-blind, placebo-controlled fashion. The factorial design allowed the study scientists to assess the individual effects of each agent. Significant increases in lung cancer incidence (18% increase, p = .01) and total mortality (8%, p = .02) occurred in the β-carotene-treated subjects after 6.1 years' median follow-up. α-Tocopherol had no significant impact on the lung cancer mortality rate, and there was no evidence of an interaction between α-tocopherol and β-carotene. The β-carotene results from this large-scale Phase III trial are consistent with experimental lung carcinogenesis studies.84,85 These laboratory data and definitive clinical results contradict the epidemiologic data on β-carotene and underscore the need to confirm data of this type53 before public health recommendations are made. The α-tocopherol group had a long-term nonsignificant trend of reduced lung cancer incidence and a significant positive secondary analysis in prostate cancer, a 32% decrease in incidence and 41% decrease in mortality.86 The Beta-Carotene and Retinol Efficacy Trial (CARET) is the other major NCI Phase III lung cancer chemoprevention trial. This trial tested the combination of β-carotene (30 mg/d) plus retinyl palmitate (25,000 IU/d) in 17,000 smokers and asbestos workers.87 It confirmed the major finding of the ATBC study with its primary finding that the β-carotene combination increased lung cancer risk in this high-risk population. There was no evidence from either the ATBC study or the CARET that β-carotene increased lung cancer risk in non-smokers, former, or moderate (less than one pack a day) smokers.
  8. Lung Cancer (2005) 49 , 25—33
  9. As a general guide, the patient can expect to have a 15 per cent reduction in spirometric values if lobectomy proves possible and a 35 to 45 per cent reduction if pneumonectomy is necessary!
  10. 1. Radical radiotherapy for early non small cell lung cancer. Graham PH Int J Radiat Oncol Biol Phys. 1995 Jan 15;31(2):261-6
  11. High energy photons (15MeV, 18MeV, etc) may be preferable when used to treat larger GTV’s (gross tumor volumes) surrounded by consolidated and/or atelectic lung tissue, bulky lymphadenopathy or large blood vessels, thus achieving a better dose distribution and also an improved therapeutic ratio.
  12. In a landmark dose escalation trial, V20 based criteria to select patients for dose escalation, with patients with smaller V20 receiving greater doses! Do we actually need a dose escalation in these patients is anybody’s guess.
  13. The high incidence of intercurrent death unrelated to disease or treatment indicates the extent of medical morbidity in this subgroup of patients!!
  14. Holsti LR, Mattson K. A randomized study of split course radiotherapy of lung cancer: long term results. International Journal of Radiation Oncology, Biology, Physics, 1980; 6: 977–81. Lee RE, Carr DT, Childs DS. Comparison of split-course radiotherapy and continuous radiation therapy for unresectable bronchogenic carcinoma: 5 years results. American Journal of Roentgenology, Radium Therapy, and Nuclear Medicine, 1976; 126: 116–21. Perez CA, et al. Long term observations of the patterns of failure in patients with unresectable non-oat cell carcinoma of the lung treated with definitive radiotherapy. Cancer, 1987; 59: 1874–81. They had used a dose of 40 Gy in 20 # followed by 20 Gy in 10# after 2 weeks rest in the split course arm and in the continuous arm it was 40Gy, 50 Gy and 60 Gy in 2 Gy per #.
  15. 1. Arrigada et al. ASTRO plenary: Effect of Chemotherapy on locally advanced non small cell lung carcinoma: A randomized study of 353 patients, GETCB, FNCLCC and the CEBI trialists IJROBP 1991; 20: 1183 2. Sause WT, et al. Radiation Therapy Oncology Group (RTOG) 8808 and Eastern Cooperative Oncology Group (ECOG) 4588: Preliminary results of a phase III trial in regionally advanced, unresectable non small cell lung cancer. Journal of the National Cancer Institute, 1995; 87, 198–205 No patient population was identified who would benefit from CHART. Hyperfractionation is therefore considered to be still an experimental approach.
  16. Preoperative irradiation of cancer of the lung: final report of a therapeutic trial. A collaborative study . Cancer. 1975 Sep;36(3):914-25. Warram J. Between May, 1963 and December, 1966, 17 medical centers cooperated in two separate but integrated therapeutic trials of primary lung cancer. One study was of patients with lesions considered operable at the time of diagnosis, and the other of patients with initially inoperable cancer but who were considered potentially operable after radiotherapy. Patients operable at the time of diagnosis were randomly assigned to receive either immediate surgery (278 patients) or preoperative radiotherapy followed by surgery (290 patients). All but one were followed until death or 5 years survival. Survival to each anniversary after randomization was almost identical for the two groups. At 5 years the survival rate was 14% after preoperative radiotherapy and 16% after immediate surgery. On the basis of the small standard error of the difference between these survival rates, a large advantage or a large disadvantage for preoperative radiotherapy is unlikely. Recurrence of cancer either locally or as distant metastasis was also similar in the two groups. Postoperative mortality was estimated to be 11% in the immediate surgery group, but cannot be estimated in a comparable fashion for the irradiated group. Certain postoperative complications were more frequent in the irradiated group, but survival during the first was not affected. Out of 425 patients initially considered to be inoperable, 152 were considered resectable after radiotherapy. These patients were randomly assigned to have either a thoracotomy and resection of their cancer if possible (78 patients) or no surgery (74 patients). Survival to each anniversary after randomization was very similar. After 5 years the survival rate was 8% for the group assigned to surgery and 6% for the group assigned to no surgery. The difference has a standard error of 4%.
  17. Chemotherapy vs supportive care in advanced non-small-cell lung cancer. Results of a meta-analysis of the literature: P Marino. Chest, Vol 106, 861-865
  18. Cisplatin and paclitaxel, Cisplatin and docetaxel, Cisplatin and Gemcitabine and Carboplatin and paclitaxel Schiller et al. Comparison of Four Chemotherapy Regimens for Advanced Non–Small-Cell Lung Cancer . NEJM Volume 346:92-98 January 10, 2002 Number 2
  19. Induction CCT before radiotherapy has already been discussed.
  20. 1. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomized clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 1995;311:899.  2. Scagliotti GV, Fossati R, Torri V, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer . J Natl Cancer Inst 2003;95:1453. 3. Scagliotti GV, Fossati R, Torri V, et al. Randomized study of adjuvant chemotherapy for completely resected stage I, II, or IIIA non-small-cell lung cancer . J Natl Cancer Inst 2003;95:1453.
  21. We seem to have reached a plateau as far as benefit from CCT is concerned as the results of Scagalotti et al show with similar median survival in three CCT regimens.
  22. Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours.
  23. Women, Japanese, Adenocarcinomas, BAC and non smokers show better response to EGFR inhibitors as they have a higher frequency of EGFR mutations. ISEL Iressa Survival Evaluation in Lung Cancer trial (2004) phase III study showed median survival was 5.6 mo in pts receiving IRESSA and 5 mo in pts receiving placebo In both INTACT 1 & 2 trials which added Iressa with gemcitabine + paclitaxel and carboplatin + paclitaxel showed that the median survival was 10 months and addition of IRESSA did not make an improvement in survival. In Phase III talent trial Tarceva in combination with gemcitabine + cisplatin failed to reveal any significant benefit in median survival when compared to a placebo (301 vs 309 days favoring placebo) Similar results were seen in the TRIBUTE trial where Carboplatin/paclitaxel + (tarceva or placebo) - Phase III was used.