1. NSCLC

2. NSCLC  85% of lung cancers  Non-squamous  Adenocarcinoma (subtypes based on gene expression) 1.Broncioid (associated with increased survival in early stage) 2.Squamoid (associated with increased survival in advanced disease)  Bronchioloalveolar is subtype of adenocarcinoma  Large-cell  Squamous

3. Mediastinal L.N.  CT scan:  Negative LN by CT  3% +ve by biopsy  May proceed with surgery  1-2cm LN by CT  10-20% +ve by biopsy  >2cm LN by CT  60% +ve by biopsy  >4cm LN  90% +ve by biopsy  PET scan:  94% sensit, 86% specif, 88% accuracy  Does not replace Mediastinoscopy Mediastinoscopy + Biopsy

4. New TNM Staging  International Association of the Study of lung Cancer (IASLC) staging is adopted by AJCC (7 th edition)

5. Changes To TNM staging  T4 pleural and/or pericardial effusion and/or pleural nodules becomes M1a  Additional nodules in the contralateral lung are subclassified as M1a  Distant metastases are subclassified as M1b

6. Sub-classify  T1 into T1a and T1b a. T1a 2 cm and < 3 cm  T2 into T2a and T2b a. T2a > 3 cm and 5 cm and < 7 cm

7. Reclassify  T2 lesions larger than 7 cm as T3  T4 tumors with additional nodules in the primary lobe as T3  M1 by additional nodules in the ipsilateral lung (different lobe) as T4

8. *Red color indicates the changes AJCC 6 th editionAJCC 7 th editionNoN1N2N3 T1 (< 2 cm)T1aIAIIAIIIAIIIB T1 (>2-3cm)T1bIAIIAIIIAIIIB T2 (<5cm)T2aIBIIAIIIAIIIB T2 (>5-7cm)T2bIIAIIBIIIAIIIB T2 (>7cm)T3IIBIIIA IIIB T3 invasionT3IIBIIIA IIIB T4 same lobe noduleT3IIBIIIA IIIB T4 extensionT4IIIA IIIB M1 ipsil lungT4IIIA IIIB T4 p effusionM1aIV M1 cont lungM1aIV M1 distantM1bIV

9. Stages at diagnosis  16% = localized  5YS = 49.5%  25% = regional LN and locally advanced  5YS = 20.6%  51% = metastatic  5YS = 2.8%  8% = unkown  5YS = 8.3%

10. Prognostic and Predictive Biomarkers  Prognostic:  Indicative of survival independent of therapy  Indicates innate tumor aggressiveness  ERCC1 (high expression = better prognosis)  K-ras mutation = poor prognosis  RRM1 (high expression = better prognosis)  Predictive:  Indicative of therapeutic efficaciy  EGFR mutation (E19del, L858R) = response to EGFR TKI  ERCC1 (high expression = poor response to platinum)  K-ras mutation = lack of benefit from EGFR TKI and platinum/vinorelbine  RRM1 (high expression = poor eresponse to Gemzar)

12. TREATMENT 1. Surgery  Lobectomy is preferred over pneumonectomy  Any surgical resection is preferred over ablation 2. Radiation Therapy 3. Chemotherapy

13. SURGERY

14. Surgery  Lobectomy is preferred over pneumonectomy  Any surgical resection is preferred over ablation

15. Segmentectomy (preferred) or Wedge Resection 1. Not good surgical candidates 2. Peripheral nodule < 2cm with at least one of the following 1.Pure BAC histology 2.> 50% ground glass appearance on CT 3.Doubling time > 400 days

16. Video-Assisted Thoracotomy (VAT)  Advantages: 1. Minimal acute/chronic pain 2. Shorter hospitalization 3. Low postop morbidity, mortality 4. Minimal risk of intraop bleeding 5. Minimal locoregional recurrence

17. Mediastinal LND  ACOSOG Z0030 (ongoing)  N0 – N1 disease:  Med LN sampling vs complete Lymphadenctomy  Minimum of three N2 stations sampled

18. Radiation Therapy

19. 1. Adjuvant 2. Primary local treatment 1.Medically inoperable 2.Unresectable 3. Palliative

20. Stereotactic Body RT  Inoperable stage I, N-ve, peripheral lesions <5cm  Provides statistically sig higher 5YS than 3-D RT in stage I  Limited lung mets  Brain mets

21. Radiofrequency Ablation (RFA)  N-ve, isolated peripheral lesion <3cm:  Pt refuse surgery  Medically not fit for surgery  Previously irradiated tissue  palliation

22. PCI (25 Gy in 10 factions)  Controversial  RTOG 0214 (PCI in stage III):  Brain mets 18% vs 7.7%  No survival benefits

23. ADJUVANT CHEMOTHERAPY

24. Surgery  Chemotherapy 1. International Adj Lung Cancer Trial (IALT):  Resected I, II, III (1867 pts)  Adj Cisplatin-based chemo vs observation  5Y f/u:  44.5 vs 40.4% (p<0.03)  DFS 39.4 vs 34.3% (P<0.003)  7.5Y f/u:  More death in the chemo arm  Chemo benefit is decreasing over time

25. Surgery  Chemotherapy 2. NCIC CTG JBR 10 trail:  Stage IB-II (482 pts)  Vinorelbine/Cis vs Observation  OS: 94 m vs 73 m  RFS: not reached vs 46.7m  5YS: 69 vs 54% (p=0.03)  9Y f/u:  Chemo benefits stage II but not IB  Stage II: MS 6.8 vs 3.6 yrs  No increase in death rate

26. Surgery  Chemotherapy 3. ANITA (Adj Navelbine International Trialist Association) trial:  Stage IB, II, IIIA (840 pts)  Vinorelbine/Cis vs Observation  76m f/u: MS 65.7 vs 43.7m  Adj chemo improved 5YS in stage II-IIIA  No benefit in stage I

27. Surgery  Chemotherapy 4. CALGB 9633  Stage IB (344 pts)  Paclitaxel/Carbo vs Observation  3Y OS: 79 vs 70 (P=0.45)  4Y OS: No diff  Subset analysis: Benefit tumor >4cm

28. Surgery  Chemotherapy Summary  Meta-analysis in 4,584 pts (the Lung Adj Cisplatin Evaluation)  Postop Cis-based adj increased survival over 5Y  Absolute benefit 5.4%  No diff among regimens (Vinorelbine, VP, others)  Benefit greater in stage II-III and good PS  Paclitaxel/Carbo if pt cannot tolerates Cisplatin

29. ChemoRadiation

30. Stage IIIA What is the best?!?!?!? SurgeryRT+/-ChemoChemo+/-RT

31. Unresectable IIIA/IIIB  ChemoRT is superior to RT alone  Concurrent chemoRT  Superior to Sequential  Higher rate of G3-4 esophagitis  Initial concurrent chemoRT:  Cis/VP (preferred)  Cis/Vinorelbine (preferred)  Taxol/Carbo (category 2B)

32. Unresectable IIIA/IIIB  Phase II SWOG 9504 (83 pts stage IIIB):  Concurrent Cis/VP+RT  Doce  MS: 26m  5YS: 29%  Phase III, stage III:  Concurrent Cis/VP+RT  Doce  No survival benefit  Increased toxicity  Randomized trial, IIIA/IIIB (203pts):  Induction chemo  RT+/-taxol  MS: 18.7 vs 14.1m (P=0.091)

33. Resected tumor, pN2  NCCN:  Negative margins:  Sequential Chemo  RT  Positive margins:  Postop concurrent ChemoRT +/- chemo

35. Chemotherapy  Stage IV  Good PS  Platinum-based  30-40% 1 Yr survival rates  Doublets superior to single agents

36. ROLE of chemotherapy  No chemotherapy:  10% 1YS, 0% 2YS  Active single agent:  15%RR, 20%1YS, 10%2YS  Active 2 drugs:  25%RR, 35%1YS, 20%2YS

37. Doublets chemo regimens  Cisplatin or Carbo + Taxol  Cisplatin + Vinorelbine  Cisplatin + Gemzar  Cisplatin + Pemetrexed  Cisplatin + docetaxel  Phase III studies:  Similar objective responses and Survival  They differ in Toxicities, Convenience, and Cost  Other options:  Docetaxel + Gemzar  Gemzar + Vinorelbine  Cisplatin + Gemzar  Carboplatin + Pemetrexed  Carboplatin + docetaxel

38. Abraxane (Albumin-bound Taxol)  For patients with hypersensitivity reaction to:  Taxol  Docetaxel  Or if premedications are contraindicated

39. Targeted Therapies  Anti-VEGF  Monoclonal antibody: Bevacizumab (Avastin)  Anti-EGFR  Small molecule: Erltinib (Tarceva)  Monoclonal antibody: Cetuximab (Erbitux)  Anti-Alk  Small molecule: Crizotinib (Xalkori) 

40. Anti-VEGF  Monoclonal antibody: Bevacizumab (Avastin  Unresectable, recurrent, met NON-SQUAMOUS  ECOG 4599: Avastin + Taxol + Carboplatin

41. Anti-EGFR (TKIs)  Small molecule: Erltinib (Tarceva) or Gefitinib  Locally advanced, met NSCLC  After failure of at least one regimen  First-line if EGFR mutation present  Based on Iressa Pan Asia Study (IPASS)

42. Iressa Pan-Asia Study (IPASS)  First-line gefitinib vs chemotherapy in clinically selected patients with EGFR mutation  Sig clinical PFS benefit  No sig OS benefit  Because there was a high rate of cross-over

43. Anti-EGFR  Monoclonal antibody: Cetuximab (Erbitux)  Phase III FELX (Cis/Vin +/- Erbitux)  Slight OS benefit (11.3 vs 10.1m)  Toxic regimen

44. Anti-Alk (Anaplastic Lymphoma Kinase)  Small molecule: Crizotinib (Xalkori)  Phase II:  Advanced progressive NSCLC  >80% RR  Improved pain, dyspnea, cough

46. Definition Treatment beyond 4-6 cycles of 1 st line chemotherapy in the absence of disease progression.  Selection of drug depends on histology and pt P.S.

47. CONCEPT OF MAINTENANCE 1 st Line doublet: Platinum- based Diagnosis Maintenance Response or Stable 2 nd Line therapy Progression

48. TYPES OF MAINTENANCE THERAPY  Continuation Maintenance:  Continuing 1 st line cheotherapy  For a limited number of cycles  Until progression or toxicity  No randomized trial supporting continuation of cytotoxic drugs  Continuing the non-platinum drug  Gemzar  Pemetrexed  Non-squamous, EGFR mutation negative or unknown  Continuing the same targeted therapy  Bevacizumab (FDA appoved)  Cetuximab  Non-squamous, EGFR mutation negative or unknown

49. TYPES OF MAINTENANCE THERAPY  Switch Maintenance:  Switching to a different drug  Pemetrexed (FDA approved)  Targeted: Erlotinib (FDA approved), Gefitinib  Cytotoxic: Vinorelbine,  Adding a second targeted agent after chemo  Erlotinib to Bevacizumab

50. TARCEVA: maintenance SATURN ( Sequential Tarceva in Unresectable NSCLC)  Have two co primary end points:  PFS in the entire intent-to-treat population  PFS in pts with EGFR-positive tumors on the basis of IHC  It was large and well powered,  It was placebo controlled, following 1 st line platinum-based  It met both of its primary end points with:  Significant prolongation of PFS in the intent-to-treat and the EGFR IHC-positive populations.  However, the median PFS prolongation for both populations was of only questionable clinical relevance (despite strong statistical significance) with only 1 month median benefit.  OS also was significantly prolonged in both populations, but once again with only modest absolute improvements.

51.  EGFR mutation status was the most clinically and statistically important marker for PFS benefit in SATURN

52. SATURN CONCLUSION First-line maintenance with erlotinib could be considered in patients who do not progress after four cycles of chemotherapy

53. Prospective Molecular Marker Analyses of EGFR and KRAS From a Randomized, Placebo-Controlled Study of Erlotinib Maintenace Therapy in Advanced NSCLC  patients with activating EGFR mutations derive the greatest PFS benefit from erlotinib maintenance therapy.  Significant PFS benefits were also observed with erlotinib in the wild-type EGFR subgroup  KRAS mutation status was a significant negative prognostic factor for PFS  EGFR IHC–positive KRAS mutations were prognostic for reduced PFS

54. MAINTENANCE THERAPY  Although maintenance therapy may lead to PFS benefit without meaningful survival benefit:  The idea of maintenance therapy is rapidly gaining acceptance in the cancer community  It is difficult to argue against prolongation of time without cancer progression or time without worsening of symptoms, particularly if this can be achieved without significant toxicity, as is the case with EGFR TKIs

55. WHO BENEFIT FROM MAINTENANCE THERAPY?  May use the following to identify the patients who are most likely to benefit:  Clinical characteristics  molecular markers.