CESONCO1901 - Cáncer de pulmón

Generalidades de cáncer de pulmón

1. CES 201 9 .0 1 : Neoplasms of the Lung

2. Solitary pulmonary nodule (SPN) and “ Ground Glass ” opacities (GGO)

3. Variable Low risk Intermediate risk High risk Diameter 1.5 1.5-2.2 2.3+ Age cut -off 45 60 Smoking status Never Current 1pack/d Current 1+ pack/d Smoking cessatin Quit 7+ yrs ago Quit 7- yrs ago Never quit Nodule characteristics Smooth Scalloped Corona radiata or spiculated Solitary pulmonary nodule Radiologic features likely to be benign Stability over 2+ yrs. Benign calcification: central nidus, multiple punctate, “ bulls-eye ” and popcorn SPN/GGO Stable over 2 yrs Benign calcification Less than 4 mm in diameter Stop High- risk of cancer Tissue biopsy Less than 8 mm Repeat CT in 3 mo 8+mm/ Low-Intermediate risk of cancer PET-CT

4. Lung cancer

5. Estimated Lung Cancer Incidence Worldwide in 2012: Men 

6. Estimated Lung Cancer Incidence Worldwide in 2012: Women

7. Cancer New cases (World) Deaths (World) New cases (Colombia) Deaths (Colombia) Breast 2’088.849 (2) 626.679 (5) 13.380 (1) 3.702 (4) Prostate 1’276.106 (4) 358.989 (8) 12.712 (2) 3.166 (5) Lung 2’093.876 (1) 1’761.007 (1) 5.856 (5) 5.236 (2) Stomach 1’033.701 (5) 782.685 (3) 7.419 (4) 5.505 (1) Colon & rectum 1’849.518 (3) 880.792 (2) 9.140 (3) 4.489 (3) Lymphoma (NH) 509.990 (10) 248.724 (11) 4.170 (6) 1.676 (10) Uterine cérvix 569.847 (8) 311.365 (9) 3.853 (7) 1.775 (9) Leukemia 437.003 (12) 309.006 (10) 3.126 (8) 2.192 (7) Ovarian 295.414 (17) 184.799 (14) 2.414 (9) 1.252 (11) Pancreas 458.918 (11) 402.232 (7) 2.311 (10) 2.142 (8) Liver 841.080 (6) 781.636 (4) 2.279 (11) 2.216 (6) Multiple mieloma 159.885 (21) 106.105 1323 (14) 806 (14) Esophagus 572.034 (7) 508.585 (6) 922 (15) 710 (15) Hodgkin 79.999 (25) 26.167 743 (16) 216 Brain 296.851 (16) 241.037 (12) 1884 (12) 1.176 (12) Gallbladder 219.420 (19) 165.087 (17) 1657 (13) 1.104 (13) All 18’078.957 9’555.027 101.893 46.057 http://gco.iarc.fr/today/

8. Cancer New cases (World) Deaths (World) New cases (Colombia) Deaths (Colombia) Breast 2’088.849 (2) 626.679 (5) 13.380 (1) 3.702 (4) Prostate 1’276.106 (4) 358.989 (8) 12.712 (2) 3.166 (5) Lung 2’093.876 (1) 1’761.007 (1) 5.856 (5) 5.236 (2) Stomach 1’033.701 (5) 782.685 (3) 7.419 (4) 5.505 (1) Colon & rectum 1’849.518 (3) 880.792 (2) 9.140 (3) 4.489 (3) Lymphoma (NH) 509.990 (10) 248.724 (11) 4.170 (6) 1.676 (10) Uterine cérvix 569.847 (8) 311.365 (9) 3.853 (7) 1.775 (9) Leukemia 437.003 (12) 309.006 (10) 3.126 (8) 2.192 (7) Ovarian 295.414 (17) 184.799 (14) 2.414 (9) 1.252 (11) Pancreas 458.918 (11) 402.232 (7) 2.311 (10) 2.142 (8) Liver 841.080 (6) 781.636 (4) 2.279 (11) 2.216 (6) Multiple mieloma 159.885 (21) 106.105 1323 (14) 806 (14) Esophagus 572.034 (7) 508.585 (6) 922 (15) 710 (15) Hodgkin 79.999 (25) 26.167 743 (16) 216 Brain 296.851 (16) 241.037 (12) 1884 (12) 1.176 (12) Gallbladder 219.420 (19) 165.087 (17) 1657 (13) 1.104 (13) All 18’078.957 9’555.027 101.893 46.057 http://gco.iarc.fr/today/

9. Trends in incidence of lung cancer - Men GLOBOCAN, 2012 http://globocan.iarc.fr/old/FactSheets/cancers/lung-new.asp

10. Estimated Lung Cancer Mortality Worldwide in 2012: Men 

11. Estimated Lung Cancer Mortality Worldwide in 2012: Women

12. Trends in incidence of lung cáncer - Women GLOBOCAN, 2012 http://globocan.iarc.fr/old/FactSheets/cancers/lung-new.asp

13. Jemal A, Siegel R, Ward E et al. Cancer Statistics, 2009 CA Cancer J Clin 2009 59: 225-249 Mortalidad 1930-2005 USA: Hombres / Mujeres Lung cancer Projected life-time risk of developing lung cáncer is 6% and 8% in females and males, respectively (in the US). Tobacco consumption closely parallels lung cancer incidence 20 years later .

14. Jemal A Cancer Statistics , 2019 CA Cancer J Clin. Mortalidad USA

15. Jemal A Cancer Statistics , 2019 CA Cancer J Clin. Incidencia / Mortalidad USA

16. Lung Cancer: Incidence and Mortality New cases in 2013: 228,190 40% with stage IV disease at presentation (~ 90,000) ~ 160,000 deaths in 2012, comparable to prostate, pancreas, breast, and colon cancer combined 5-yr relative survival rate: 3.7% for patients with distant-stage disease NCI. Non-small-cell lung cancer treatment (PDQ ® ). ACS. Cancer facts & figures: 2012. CDC. Lung cancer rates by race and ethnicity. Howlader N, et al. SEER cancer statistics review. Estimated Cancer Deaths by Site, 2012 Other Cancers Lung Cancer 180,000 160,000 140,000 120,000 100,000 80,000 60,000 40,000 20,000 Lung cancer Prostate Pancreas Breast Colon

17. Incidencia y mortalidad por de cáncer en Colombia Registro Poblacional de Cáncer - Cali http://rpcc.univalle.edu.co/ Cáncer del pulmón

18. Risk Factors for Lung Cancer Smoking Current: 2000% Former: 900% ETS: 30% 1 new mutation per 15 cigarettes smoked Lung cancer deaths due to smoking ~ 91% males and 80% females [1] Environmental factors [2] Second-hand smoke 3% to 5% Radon 3% to 5% Industrial pollution 0% to 5% Radiation exposure Rare Asbestos, radon, radiation, silicosis, and berylliosis, nickel, chromium, mustard gas, Polycyclic Aromatic Hydrocarbons, bischloromethyl ether Arsenic exposure, talc, obesity, genetic factors 1. CDC. Lung Cancer. 2011. 2. American Cancer Society. Lung Cancer. 2011.

19. Smoking cessation and lung cancer risk over time

20. Alquitrán Oncogenes TSG ras myc telomerasa her2/neu FHIT RB p53 p16 3p- EGFR Creado por: Mauricio Lema Medina - LemaTeachFiles © - 2004

21. ras myc telomerasa her2/neu FHIT RB p53 p16 3p- Hiperplasia Ca in-situ Carcinoma Invasor

22. 55-74 yo, 30 ppy , current or former smokers (up to 15 years ) Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening NLST. N Engl J Med 2011; 365:395-409 R LDCT qy x3 CXR qy x3 LDCT : Low-Dose CT every year x3 CXR: Chest X Rays PA and Lateral every year x3 Enrollment: 8/2002-4/2004 Lung cancer deaths until: 12/2009 n=53.454 n=26.722 n=26.732 Variable LDCT CXR Rate ratio + Screening 24.2% 6.9% False positive 96.4% 94.5% LC detection * 645 (n=1060) 572 (n=941) 1.13 (1.03-1.23, ) LC Mortality * 247 309 LC: Lung cancer; * per 100.000 person/years LDCT decreases lung cancer mortality by 20% (95%CI: 6.8-26.7, p=0.004) in High-Risk patients

23. Lung cancer screening Comments LD CT 15-20% reduction of lung cancer mortality (about 3/1000 screened) Yearly, 55-74, in heavy smokers (30ç ppy) High incidence of incidental findings Radiation exposure CXR Ineffective Harrison’s, 19th Ed, 2015

24. Lung cancer: clinical presentation Cough: 8-75% Dyspnea (3-60%) Thoracic pain: 20-49% Weight loss: 0-68% Hemoptysis: 6-35% Fever: 0-20% Fatigue: 0-68% Dysphagia: 0-2% Bone pain: 6-25% Stridor: 2% SVCS: 2-4%. Clubbing: 0-20% Cardiac tamponade Hoarseness

25. Lung cancer: clinical presentation Cough: 8-75% Dyspnea (3-60%) Weight loss: 0-68% Hemoptysis: 6-35% Fever: 0-20% Fatigue: 0-68% Dysphagia: 0-2% Bone pain: 6-25% Stridor: 2% SVCS: 2-4%. Clubbing: 0-20% Cardiac tamponade Hoarseness Thoracic pain: 20-49% Adrenal gland Lungs Liver Brain Pleura

26. Clinical findings suggestive of metastatic disease History Weight loss Skeletal focal pain Headaches , syncope , seizures , extremity weakness , recent changes in mental status Signs Lymphadenopathy Hoarseness Bone tenderness Hepatomegaly Focal neurologic signs Papilledema Soft tissue mass Routine labs Anemia Elevated LFTs

27. Sindromes paraneoplásicos Osteoartropatía pulmonar hipertrófica Hipercalcemia (Escamocelular) Sindrome de secreción inapropiada de hormona antidiurética Sindrome de Cushing Sistema nervioso Presentation with symptoms related to a paraneoplastic Encefalomielitis Neuropatía sensoria subaguda Opsoclonus Mioclonus Neuropatía sensorial Encefalopatía límbica Sindrome de Eaton-Lambert Sistémicos Anorexia Pérdida de peso Debilidad Fatiga Hipercoagulabilidad Dermatomiositis

28. Lung cancer: diagnosis

29. Complexities of Lung Cancer Pathogenesis Result in Diverse Histologic Subtypes SCC (~ 25%) SCLC (~ 15%) LPA (formerly BAC) (~ 5% to 10%) Adenocarcinoma(~ 45%) Large Cell (~ 5% to 10%) NOS (~ 10% to 30%) Reprinted by permission from Macmillan Publishers Ltd: Sun S, et al. Nat Rev Cancer. 2007; 7:778-790. Travis WD, et al. J Clin Oncol. 2013;[Epub ahead of print].

30. Lung adenocarcinomas subtypes Adenocarcinoma Lepidic Papillar Acinar Micropapillar Solid Lepidic (adenocarcinoma in-situ) Lepidic (minimally invasive adenocarcinomas) Excellent prognosis Poor prognosis

31. Lung cancer: IHC Squamous p40 or p63 CK+ Ck 5/6+ Ck 7 unusual PD-L1 Adenocarcinoma CK+ Ck7+ TTF1+ Napsin -A Neuroendocrine (–) PD-L1 Large-cell CK+ TTF1 unusual Neuroendocrine (–) Large-cell neuroendocrine CK+ TTF1+ CD56+ Chromogranin+ Synaptophysin+ Small-cell lung cancer CK+ TTF1+ CD56+ Chromogranin+ Synaptophysin+

32. Lung cancer: “relevant” subgroups NSCLC SCLC NSCLC with “Driver” NSCLC withoud “Driver” 10% 15% 75% NSCLC (without “driver”) Squamous 25% NSCLC (without “driver”) Non-squamous 50% 90% EGFR: 10% ALK/EML4: 4% ROS1: 1% Mostly , adenocarcinoma Adenocarcinoma Squamous Large-cell

33. Kris MG, et al. ASCO 2011. CRA7506. Johnson BE, et al. IASLC WCLC 2011. Abstract O16.01 Lung Cancer Molecular Consortium Analysis in Lung Adenocarcinomas No Mutation Detected KRAS 22% EGFR 17% EML4-AKL 7% Double Mutants 3% BRAF 2% PIK3CA 2% HER2 MET AMP MEK1 NRAS AKT1 Erlotinib Gefitinib Afatinib Selumetinib Crizotinib

34. How to handle small tissue samples in lung cancer p63 and TTF1 H&E SCC Non-SCC ( Adeno ) Genomics SCLC NeuroEndocrine EGFR ALK/EML4 ROS1 BRAF Her2 p63+ TTF1 + PD-L1 by IHC (in advanced NSCLC) PD-L1 by IHC (in advanced NSCLC) Chromogranin Synaptophysin

35. Lung cancer: anatomic staging PET-CT +/- Brain MRI NSCLC

36. TNM Staging system: Lung Cancer TNM8

37. T-descriptor Every cm counts… Previous (TNM 7th) T1a T1a T1b T2a T2a T2b T3 Rami-Porta R, J Thoracic Oncol, 2015 Proposed (TNM 8th) Up to 1 cm: T1a >1-2 cm: T1b >2-3 cm: T1c >3-4 cm: T2a >4-5 cm: T2b >5-7 cm: T3 >7 cm: T4 International Association for the Study of Lung Cancer, 2015

38. T – Primary Tumour Tx Primary tumour cannot be assessed T0 No evidence of primary tumour T1 Tumour 3 cm or less in greatest diameter surrounded by lung or visceral pleura, without evidence of main bronchus T1a(mi) Mininally invasive adenocarcinoma T1a Tumour 1 cm or less in greatest diameter T1b Tumour more than 1 cm but not more than 2 cm T1c Tumour more than 2 cm but not more than 3 cm T2 Tumour more than 3 cm but not more than 5 cm; or tumour with any of the following features: Involves main bronchus (without involving the carina), invades visceral pleura, associated with atelectasis or obstructive pneumonitis that extends to the hilar region T2a Tumour more than 3 cm but not more than 4 cm T2b Tumour more than 4 cm but not more than 5 cm T3 Tumour more than 5 cm but not more than 7 cm or one tha directly invades any of the following: chest wall, phrenic nerve, parietal pericardium, or associated separate tumour nodule(s) in the same lobe as the primary T4 Tumours more than 7 cm or one that invades any of the following: diaphragm, mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina; separate tumour nodule(s) in a different ipsilateral lobe to that of the primary

39. N-descriptor No changes in the TNM 8th Edition… Exploratory subgrouping (for future validation) - N1a: Single N1 - N1b: Multiple N1 - N2a1: Single N2 (skip metastasis) - N2a2: Single N2 + N1 - N2b: Multiple N2 Asamura H et al. J Thoracic Oncol, 2015, in press International Association for the Study of Lung Cancer, 2015

40. Lymph-node stations in lung cancer: General Plan  Supraclavicular: - Station 1  Superior mediastinal: - Stations 2-4  Aortic: - Stations 5/6  Inferior mediastinal: - Stations 7-9  N1 nodes: - Stations 10-14 http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)

41. M-descriptor • M1a: as it is • M1b: single metastasis in a single organ • M1c: multiple metastases in a single organ or in several organs

42. N – Regional Lymph Nodes Regional lymph nodes cannot be assessed Nx No regional lymph node metastasis N0 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension N1 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s) N2 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene or supraclavicular lymph node(s) N3 M – Distant Metastasis No distant metastasis M0 Distant metastasis M1 Separate tumour nodule(s) in a contralateral lobe; tumour with pleaural or pericardial nodules or malignant pleural or pericardial effusion M1a Single extrathoracic metastasis in a single organ M1b Multiple extrathoracic metastases in one or several organs M1c International Association for the Study of Lung Cancer, 2015

43. STAGE T N M Occult TX N0 M0 Tis N0 M0 IA1 T1a(mi)/T1a N0 M0 IA2 T1b N0 M0 IA3 T1c N0 M0 IB T2a N0 M0 IIA T2b N0 M0 IIB T1a-T2b N1 M0 T3 N0 M0 IIIA T1a-T2b N2 M0 T3 N1 M0 T4 N0/N1 M0 IIIB T1a-T2b N3 M0 T3/T4 N2 M0 IIIC T3/T4 N3 M0 IVA Any T Any N M1a/M1b IVB Any T Any N M1c International Association for the Study of Lung Cancer, 2015

44. 8th Edition of the TNM Classification for Lung Cancer N0 N1 N2 N3 M1a M1b M1c T1a IA1 IIB IIIA IIIB IVA IVA IVB T1b IA2 IIB IIIA IIIB IVA IVA IVB T1c IA3 IIB IIIA IIIB IVA IVA IVB T2a IB IIB IIIA IIIB IVA IVA IVB T2b IIA IIB IIIA IIIB IVA IVA IVB T3 IIB IIIA IIIB IIIC IVA IVA IVB T4 IIIA IIIA IIIB IIIC IVA IVA IVB International Association for the Study of Lung Cancer, 2015

45. 8th Edition of the TNM Classification for Lung Cancer N0 N1 N2 N3 M1a M1b M1c T1a IA1 IIB IIIA IIIB IVA IVA IVB T1b IA2 IIB IIIA IIIB IVA IVA IVB T1c IA3 IIB IIIA IIIB IVA IVA IVB T2a IB IIB IIIA IIIB IVA IVA IVB T2b IIA IIB IIIA IIIB IVA IVA IVB T3 IIB IIIA IIIB IIIC IVA IVA IVB T4 IIIA IIIA IIIB IIIC IVA IVA IVB International Association for the Study of Lung Cancer, 2015 Upfront resection feasible Mostly palliative intent Mostly unresectable

46. 8th Edition of the TNM Classification for Lung Cancer N0 N1 N2 N3 M1a M1b M1c T1a IA1 IIB IIIA IIIB IVA IVA IVB T1b IA2 IIB IIIA IIIB IVA IVA IVB T1c IA3 IIB IIIA IIIB IVA IVA IVB T2a IB IIB IIIA IIIB IVA IVA IVB T2b IIA IIB IIIA IIIB IVA IVA IVB T3 IIB IIIA IIIB IIIC IVA IVA IVB T4 IIIA IIIA IIIB IIIC IVA IVA IVB International Association for the Study of Lung Cancer, 2015 Surgery , followed by adjuvant chemotherapy Systemic therapy Multimodal therapy : ( ie , Chemo-Radiation , followed by Immunotherapy )

47. Lung cancer: anatomic staging PET-CT +/- Brain MRI Potentially resectable Nonresectable/metastatic Extrathoracic metastases SVCS Vocal cord / phrenic nerve paralysis Malignant pleural effusion Cardiac tamponade Tumor within 2 cm of the carina Contralateral lung metastases Supraclavicular metastases Contralateral mediastinal LN involvement Pulmonary artery involvement Mediastinal LN assessment ie, Mediastinoscopy NSCLC N2/N3 disease N0/N1 disease Unresectable stage III Stage IV Physiologic staging Surgery +/- CT Definitive Chemo-RT

48. Treatment strategies for resectable NSCLC (Stages I-IIIA)

49. If surgery is considered Upfront assessment Potentially resectable Potentially resectable with some risk of incomplete resection Not resectable SURGERY IN STAGE III NSCLC Eberhardt WEE, De Ruysscher D, Weder W, et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer. Ann Oncol . 2015;26(8):1573-1588. doi:10.1093/annonc/mdv187.

50. If surgery is considered Optimal pre-op work-up Histopathology for PET- detected isolated single met Primary tumour of >3 cm large axis, central tumours, cN1, CT-enlarged lymph nodes with small axis >1 cm Symptomatic / High Risk (T4N2 PET-CT Assessment of mediastinal disease in PET+ or suspicious lesions Brain MRI or N3) SURGERY IN STAGE III NSCLC Eberhardt WEE, De Ruysscher D, Weder W, et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer. Ann Oncol . 2015;26(8):1573-1588. doi:10.1093/annonc/mdv187.

51. Tratamiento de NSCLC temprano ( Estadíos I-IIIA) CIRUGÍA EN NSCLC Se recomienda cirugía para T resecables (T1-T3), sin compromiso mediastinal (N0-N1) Lobectomía o pneumonectomía (+ disección ganglionar mediastinal). Considerar SBRT en casos selectos (No candidatos a cirugía) No se recomienda cirugía para pacientes con T4, N2 o N3 - Si no hay metástasis, proceder con quimiorradioterapia (Cisplatino + Etopósido)

52. Physiologic staging Appropriate FEV1 Greater than 2L for pneumonectomy Greater than 1.5L for lobectomy VOmax greater than 15 mL/(kg.min) Surgery contraindicated in: AMI within the last 3 months AMI within the last 6 months (relative) Uncontrolled arrhythmias FEV1 less than 1L DLCO less than 40% Severe pulmonary hypertension pCO2 greater than 45 mmHg

53. Surgery for lung cancer

54. NSCLC: Prognostic Factors  Factors correlated with adverse prognosis in resected patients - Presence of pulmonary symptoms - Large tumor size (>3 cm) - Nonsquamous histology - Metastases to multiple lymph nodes within a TNM-defined nodal station - Vascular invasion  For patients with inoperable disease, prognosis is adversely affected by poor performance status, weight loss of more than 10%, male gender  Advanced age alone has not been shown to influence response or survival with therapy NCI. Non-small-cell lung cancer treatment (PDQ ® ).

55. Tratamiento de NSCLC temprano ( Estadíos I-IIIA) RADIOTERAPIA ADYUVANTE Estadíos I, II, IIIA no quirúrgicos Luego de cirugía si márgenes comprometidos Luego de cirugía si ganglios linfáticos mediastinales comprometidos ( estadío IIIA).

56. Tratamiento de NSCLC temprano ( Estadíos I-IIIA) QUMIOTERAPIA ADYUVANTE - Estadíos II-III ( algunos incluyen Ib ) - Dupletas basadas en cisplatino x4 meses

57. Treatment strategies for unresectable NSCLC (Stage III)

58. Incidental N2 (unforeseen N2) Complete resection Adjuvant platinum-based CT Consider RT after CT Incomplete resection Adjuvant platinum-based CT followed by RT Consider definitive chemoRT

59. Potentially resectable IIIA(N2) Multimodality Induction CT followed by Surgery* Induction ChemoRT followed by Surgery Definitive concurrent ChemoRT

60. Potentially resectable stage III, but high risk of incomplete resection Superior sulcus tumors Induction ChemoRT followed by Surgery POTENTIALLY RESECTABLE STAGE III NSCLC

61. Potentially resectable stage III, but high risk of incomplete resection Selected Central T3-T4 tumors Induction ChemoRT followed by Surgery* T4N0-1 Definitive ChemoRT , followed by Durvalumab Surgery within 4 weeks after RT finished POTENTIALLY RESECTABLE STAGE III NSCLC Eberhardt WEE, De Ruysscher D, Weder W, et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer. Ann Oncol . 2015;26(8):1573-1588. doi:10.1093/annonc/mdv187. Eberhardt W, Gauler T, Pöttgen C et al. Phase III study of surgery versus definitive concurrent chemoradiotherapy boost in patients with operable (OP+) stage IIIA(N2)/selected IIIb non-small cell lung cancer (NSCLC) following induction chemotherapy and concurrent CRTx (ESPATUE). J Clin Oncol 2014; 32(5s suppl): abstr

62. Unresectable Stage III disease Unresectable stage III disease Bulky and multiple mediastinal nodal involvement Stage IIIB disease based on unresectable T4 Stage IIIB disease based on N3 Eberhardt WEE, De Ruysscher D, Weder W, et al. 2nd ESMO Consensus Conference in Lung Cancer: locally advanced stage III non-small-cell lung cancer. Ann Oncol . 2015;26(8):1573-1588. doi:10.1093/annonc/mdv187.

63. Unresectable Stage III disease Unresectable stage III disease Definitive Concurrent ChemoRT , followed bu Durvalumab Sequential ChemoRT Palliative therapy

64. The many faces of stage III NSCLC  Post surgical N2/N3+ disease - Adjuvant CT - Consider adjuvant RT  Known N2/N3+ disease - Definitive chemo RT with platin-based chemotherapy , followed by durvalumab - Consider chemo RT with platin-based chemotherapy followed by surgery (if lobectomy is sufficient) in non-bulky N2 disease.  Superior sulcus tumors - Arise in the apex of the lungs - Invade the 2nd and 3rd ribs, brachial plexus, subclavian vessels, stallate ganglion and vertebral body - Pancoast syndrome: pain in the shoulder or chest wall or radiate to the neck and ulnar aspect of the upper limbs. - Horner ’ s syndrome - Neoadjuvant Chemo-RT followed by surgery (if not N2/N3 disease) - Excellent LT OS: 50+%

65. Stage IV - NSCLC – PS 0-1 NSCLC without “Driver” – PD-L1<50% NSCLC Squamous* NSCLC Non-squamous CT with Platinum + Pemetrexed + Pembrolizumab CT with Platinum+ Paclitaxel + Pembrolizumab *Bevacizumab is contraindicated due to fatal bleeding *Pemetrexed is ineffective in squamous histology

66. Stage IV - NSCLC – PS 0-1 NSCLC without “Driver” – PD-L1≥50% NSCLC Squamous* NSCLC Non-squamous Pembrolizumab Pembrolizumab MLM2018

67. Inmunología tumoral Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Célula Dendrítica Antígeno tumoral Linfocito T CD8+/Citotóxico

68. Inmunología tumoral Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Célula Dendrítica Antígeno tumoral Linfocito T CD8+/Citotóxico Receptor de célula T (TCR) MHC II y antígeno MHC II: Major histocompatibility complex

69. Inmunología tumoral Cebado (priming) y activación de las células T Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Célula Dendrítica Linfocito T CD8+/Citotóxico Co-estimuladora CD28 Co-estimuladora B7.1

70. En la periferia... Mientras tanto...

71. Inmunología tumoral Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Antígeno + MHC-1

72. Inmunología tumoral Activación de la respuesta inmunológica CD8 efectora Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Linfocito T CD8+/Citotóxico Antígeno + MHC-1 Receptor de células T (TCR) +++ Respuesta inmune antitumoral Presente

73. Cómo se detiene la respuesta inmunológica? Frenos

74. En la sinapsis 2 Células T – C élulas tumorales

75. Inmunología tumoral Las células tumorales expresan PD-L1 (PD-L2) cuando hay estimulación continuada del IFN-Gamma, " apagando" al linfocito T Célula tumoral PD-1 PD-L1 PD-L2 Receptor de células T MHC-1 CD28 Shp-2 B7.1 Linfocito T CD8+/Citotóxico IFN-γ IFN-γR PD-L1 PD-1 - - - Respuesta inmune antitumoral Frenada

76. Célula T Célula tumoral MHC TCR PD-1 PD-L1 Cancer cell T-cell Anti-PD-L1 Anti-PD-1 Bloqueo PD-1 Respuesta inmune antitumoral Se restablece Los anticuerpos anti-PD-1 (anti-PD-L1, anti-PD-L2) restablecen la respuesta antitumoral de linfocitos T Interacción Célula T-Célula Tumoral Interaction

77. Reck M, et al. N Engl J Med. 2016;375:1823-1833. Pembro
(n = 154) CT
(n = 151) Median PFS, mos 10.3 6.0 HR (95% CI) 0.50 (0.37-0.68; P < .001) KEYNOTE-024: PFS 10 20 30 40 50 60 70 80 90 100 3 6 9 12 15 18 Mos PFS (%) Pts at Risk, n 62% 50% 48% 15%

78. Stage IV - NSCLC – PS 0-1 NSCLC with “Driver” mEGFT mALK/ROS1 TKIs anti EGFR (Osimertinib or Erlotinib or Gefitinib or Afatinib) TKIs anti ALK/ROS1 (Alectinib or Crizotinib)

79. Extracellular Domain Transmembrane Domain Intracellular Domain EGF Pathway EGFR: transmembrane protein Tyrosine Kinase Domain Adapted from: Ciardiello F, et al. N Engl J Med. 2008;358:1160-1174. www.clinicaloptions.com

80. HER/erbB family Salomon DS, et al. Crit Rev Oncol Hematol 1995;19:183–232 Woodburn JR. Pharmacol Ther 1999;82:241–50 HER1 EGFR erbB1 HER2 erbB2 neu EGF TGF- α Amphiregulin Betacellulin HB-EGF Epiregulin Heregulins NRG2 NRG3 Heregulins Betacellulin Cysteine- rich domains Tyrosine- kinase domains HER3 erbB3 HER4 erbB4 Ligands:

81. Proliferation Apoptosis Resistance Transcription TGF α Interleukin-8 bFGF VEGF Metastasis Angiogenesis Shc PI3K Raf MEKK-1 MEK MKK-7 JNK ERK Ras mTOR Grb2 AKT Sos-1 EGF Pathway www.clinicaloptions.com

82. EGFR in NSCLC: two distinct pathways Nucleus Adaptor Survival PIP 2 PI3K PIP 3 PTEN AKT Apoptosis regulators Proliferation Adaptor Transcription factors MAPK MEK RAF GTP-RAS GDP - RAS Sordella, et al. Science 2004 ATP ATP Greater signalling through the MAPK pathway producing excessive cell proliferation Higher affinity for ATP than mutant receptor, so greater competition with EGFR TKIs for binding sites; higher concentrations needed to inhibit Successful inhibition of wild-type EGFR reduces proliferation and halts tumour growth Higher incidence of stable disease EGFR wild-type

83. EGFR in NSCLC: two distinct pathways ATP Nucleus Adaptor Survival PIP 2 PI3K PIP 3 PTEN AKT Apoptosis regulators Proliferation Adaptor Transcription factors MAPK MEK RAF GTP-RAS GDP - RAS Sordella, et al. Science 2004 ATP Preferential signalling through the PI3K-mediated anti-apoptotic pathway – ‘oncogene addiction’ Reduced affinity for ATP means EGFR TKIs have less competition for binding sites; lower concentrations sufficient to inhibit Successful inhibition of mutated EGFR produces ‘apoptotic shock’ Higher incidence of complete or partial response EGFR mutation +ve

84. EGFR mutation +ve NSCLC: different epidemiology Majority of mutations are exon 19 deletions or L858R point mutations in exon 21 EGFR Chromosome 7 Shigematsu, et al. JNCI 2005; Murray, et al. JTO 2008 n=3,303 Exons 1–16 Exon 17 Exons 18–24 Exons 25–28 Extracellular domain Transmembrane domain TK domain Regulatory domain EGFR transcript EGF protein Exon 18 Exon 19 Exon 20 Exon 21 50 40 30 20 10 Incidence (%)

85. Cáncer de pulmón de células pequeñas - SCLC

86. SCLC

87. Carcinoma broncogénico de células pequeñas (SCLC) Generalidades Menos común que el NSCLC (1/6, aprox.) Mayor asociación con tabaquismo Diseminación a distancia mucho más precoz en la historia natural El espectro más agresivo de neoplasias neuroendocrinas

88. Carcinoma broncogénico de células pequeñas (SCLC) Patología – Carcinoma de células pequeñas (SCLC) Célula pequeña, redonda y azul. Tiñe positivo para cromogranina y sinaptofisina (marcadores neuroendocrinos) Patrones de diseminación Masa central con extenso compromiso hiliar y mediastinal. Metástasis al: Hueso, Hígado, Cerebro, Pulmón, Adrenales.

89. SCLC Estadificación ESTADÍO LIMITADO: T1-4 (excluyendo derrame pleural) N0-3M0 : Usualmente se puede cubrir en un campo de radioterapia. ESTADÍO EXTENDIDO: Estadío IV: M1, y estadío III con derrame pleural . Supervivencia a 5 años Estadío I : Supervivencia a largo plazo del 70% (luego de cirugía y quimioterapia). Estadío Limitado : Supervivencia mediana 4 meses sin tratamiento, Supervivencia mediana 17 meses Curación en el 5-10%. Estadío Extendido : Supervivencia mediana 2-4 meses sin tratamiento. Se incrementa a 8-10 meses con terapia actual Aproximadamente 3% se curan

90. Small-Cell Lung Cancer: work-up and management CT-Chest/Abdomen + Brain MRI +/- Bone Scan SCLC Stage I All others PET-CT + Brain MRI Confirmed Stage I Surgery + EP Limited-Stage Extended-stage EP + RT + PCI Atezolizumab + Carboplatin + Etoposide +/- PCI EP: Etoposide + Cisplatin x4 months 70% LT survival Median OS: 20 months Median OS: 12.3 months IMpower133

91. Back-up slides

92. Lymph-node stations in lung cancer: General Plan  Supraclavicular: - Station 1  Superior mediastinal: - Stations 2-4  Aortic: - Stations 5/6  Inferior mediastinal: - Stations 7-9  N1 nodes: - Stations 10-14 http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)

93. N-stage in lung cancer http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)

94. N-Stage in lung cancer 1. Station 1: Low cervical, supraclavicular, sternal notch lymph-nodes 2. 2L/2R: Upper paratracheal (R and L) 3. 4L/4R: Lower paratracheal http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)

95. N-stage in lung cancer 3. Prevascular and Prevertabral nodes Station 3 nodes are not adjacent to the trachea like station 2 nodes. They are either: 3A anterior to the vessels or 3B behind the esophagus, which lies prevertebrally. Station 3 nodes are not accessible with mediastinoscopy. 3B nodes can be accessible with endoscopic ultrasound (EUS). http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)

96. N-Stage in lung cancer 2L/2R: Upper paratracheal (R and L) 3A: Prevascular

97. N-Stage in lung cancer 4R. Right Lower Paratracheal Upper border : intersection of caudal margin of innominate (left brachiocephalic) vein with the trachea. Lower border :lower border of azygos vein. 4R nodes extend to the left lateral border of the trachea. http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)

98. N-Stage in lung cancer 4R. Lower Paratracheal From the intersection of the caudal margin of innominate (left brachiocephalic) vein with the trachea to the lower border of the azygos vein. 4R nodes extend from the right to the left lateral border of the trachea. 4L. Lower Paratracheal From the upper margin of the aortic arch to the upper rim of the left main pulmonary artery. Aortic Nodes 5-6 5. Subaortic These nodes are located in the AP window lateral to the ligamentum arteriosum. These nodes are not located between the aorta and the pulmonary trunk but lateral to these vessels. 6. Para-aortic These are ascending aorta or phrenic nodes lying anterior and lateral to the ascending aorta and the aortic arch. http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)

99. N-Stage in lung cancer Aortic Nodes 5-6 5. Subaortic These nodes are located in the AP window lateral to the ligamentum arteriosum. These nodes are not located between the aorta and the pulmonary trunk but lateral to these vessels. 6. Para-aortic These are ascending aorta or phrenic nodes lying anterior and lateral to the ascending aorta and the aortic arch. http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)

100. N-Stage in lung cancer 4R. Right Lower Paratracheal Upper border : intersection of caudal margin of innominate (left brachiocephalic) vein with the trachea. Lower border :lower border of azygos vein. 4R nodes extend to the left lateral border of the trachea. 6. Para-aortic These are ascending aorta or phrenic nodes lying anterior and lateral to the ascending aorta and the aortic arch. http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)

101. N-Stage in lung cancer 7. Subcarinal nodes These nodes are located caudally to the carina of the trachea, but are not associated with the lower lobe bronchi or arteries within the lung. On the right they extend caudally to the lower border of the bronchus intermedius. On the left they extend caudally to the upper border of the lower lobe bronchus. On the left a station 7 subcarinal node to the right of the esophagus. 10 Hilar nodes Hilar nodes are proximal lobar nodes, distal to the mediastinal pleural reflection and nodes adjacent to the intermediate bronchus on the right. Nodes in station 10 - 14 are all N1-nodes, since they are not located in the mediastinum. http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)

102. N-Stage in lung cancer 8 Paraesophageal nodes These nodes are below the carinal nodes and extend caudally to the diafragm. On the left an image below the carina. To the right of the esophagus a station 8 node. 10 Hilar nodes Hilar nodes are proximal lobar nodes, distal to the mediastinal pleural reflection and nodes adjacent to the intermediate bronchus on the right. Nodes in station 10 - 14 are all N1-nodes, since they are not located in the mediastinum. http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)

103. N-Stage in lung cancer 7. Subcarinal nodes These nodes are located caudally to the carina of the trachea, but are not associated with the lower lobe bronchi or arteries within the lung. On the right they extend caudally to the lower border of the bronchus intermedius. On the left they extend caudally to the upper border of the lower lobe bronchus. On the left a station 7 subcarinal node to the right of the esophagus. 10 Hilar nodes Hilar nodes are proximal lobar nodes, distal to the mediastinal pleural reflection and nodes adjacent to the intermediate bronchus on the right. Nodes in station 10 - 14 are all N1-nodes, since they are not located in the mediastinum. http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)

104. N-Stage in lung cancer 9. Pulmonary ligament nodes Pulmonary ligament nodes are lying within the pulmonary ligament, including those in the posterior wall and lower part of the inferior pulmonary vein. The pulmonary ligament is the inferior extension of the mediastinal pleural reflections that surround the hila. http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)

105. N-Stage in lung cancer Stations 10 - 14. N1 lymph-nodes Hilar, lobar, segmental and subsegmental Stations 10-14 are NOT mediastinal lymph-nodes. http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)

106. N-Stage in lung cancer http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)