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
5. Page 5
Cáncer en el mundo
8.4 millones (2012)
Pulmón: 1.5 millones (2012)
1/5 muertos por cáncer
Hepatocelular (2x)
Cérvix uterino (2x)
Esófago (2-3x)
14.1 millones (2012)
Pulmón: 1.8 millones (2012)
Pulmón (2x)
Mama (3x)
Próstata (2.5x)
Colon y recto (3x)
Estadísticas en 2002: Prevalencia – 32 millones
6. The 10 Most Commonly Diagnosed Cancers: 2012 Estimates
Total Number and Percentage of New Cases Diagnosed per Year, Worldwide
Bowel including anus ICD-10 C18-C21
Please include the citation provided in our Frequently Asked Questions when reproducing this chart: http://info.cancerresearchuk.org/cancerstats/faqs/#How
Prepared by Cancer Research UK
Original data sources:
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray, F.GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide:
IARC CancerBase No. 11 [Internet].Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://globocan.iarc.fr, accessed on 16/01/2014.
7. 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.
8. Jemal A, Siegel R, Ward E et al. Cancer Statistics, 2009 CA Cancer J Clin 2009 59: 225-249
Incidencia/Mortalidad USA: Hombres
9. Incidencia Mortalidad
Jemal A, Siegel R, Ward E et al. Cancer Statistics, 2009 CA Cancer J Clin 2009 59: 225-249
Incidencia/Mortalidad USA: Mujeres
10. 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
0
Lung
cancer
Prostate
Pancreas
Breast
Colon
11. Incidencia y mortalidad por de cáncer en Colombia
Registro Poblacional de Cáncer - Calihttp://rpcc.univalle.edu.co/
Cáncer del pulmón
12. 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.
23. 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].
SCLC: Small-Cell Lung Cancer
SCC: Squamous-Cell Carcinoma
LPA: Lepidic predominant adenocarcinoma
NOS: Not otherwise specified
27. 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
28. How to handle small tissue samples in lung cancer
p63 and TTF1
H&E
SCC Adeno
Genomics
SCLC
NeuroEndocrine
EGFR
ALK/EML4
ROS1
BRAF
Her2
p63 o p40+
PD-L1 expression
TTF1+
PD-L1 expression
31. T-descriptor
Every cm counts…
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
Previous (TNM 7th)
T1a
T1a
T1b
T2a
T2a
T2b
T3
Rami-Porta R, J Thoracic Oncol, 2015
International Association for the Study of Lung Cancer, 2015
32. 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
International Association for the Study of Lung Cancer, 2015
33. 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
34. 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)
35. N-stage in lung cancer
http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)
36. 1. Station 1: Low cervical, supraclavicular, sternal notch lymph-nodes
2. 2L/2R: Upper paratracheal (R and L)
3. 4L/4R: Lower paratracheal
N-Stage in lung cancer
http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)
37. 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)
39. 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)
40. 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)
41. 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)
42. 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)
43. 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)
44. 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)
45. 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)
46. 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)
47. 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)
48. N-Stage in lung cancer
http://www.radiologyassistant.nl/en/p4646f1278c26f/mediastinum-lymph-node-map.html (Accessed 2017)
49. M-descriptor
Eberhardt W et al. J Thoracic Oncol, 2015, in press
International Association for the Study of Lung Cancer, 2015
• M1a: as it is
• M1b: single metastasis in a single organ
• M1c: multiple metastases in a single organ or
in several organs
50. N – Regional Lymph Nodes
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes
and intrapulmonary nodes, including involvement by direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or
contralateral scalene or supraclavicular lymph node(s)
M – Distant Metastasis
M0 No distant metastasis
M1 Distant metastasis
M1a Separate tumour nodule(s) in a contralateral lobe; tumour with pleaural or
pericardial nodules or malignant pleural or pericardial effusion
M1b Single extrathoracic metastasis in a single organ
M1c Multiple extrathoracic metastases in one or several organs
International Association for the Study of Lung Cancer, 2015
51. STAGE T N M
Occult TX N0 M0
0 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
52. STAGE T N M
Occult TX N0 M0
0 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
NEW
53. 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
8th Edition of the TNM Classification
for Lung Cancer
54. ARCHIVE
NEJM: LUNG CANCER SCREENING SAVES LIVES – STUDY SHOWS
Team TNLSTR. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening.
N Engl J Med. 2011;365(5):395-409. doi:10.1056/NEJMoa1102873
08.2011
NEJM
NLST
LUNG CANCER
SCREENING
MLM
55. ARCHIVE
NEJM: LUNG CANCER SCREENING SAVES LIVES – STUDY SHOWS
Team TNLSTR. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening.
N Engl J Med. 2011;365(5):395-409. doi:10.1056/NEJMoa1102873
08.2011
NEJM
NLSTLUNG CANCER
SCREENING
MLM
• ELEGIBILITY
• Eligible participants were between 55 and 74 years of age at the time of randomization,
• Had a history of cigarette smoking of at least 30 pack-years, and,
• If former smokers, had quit within the previous 15 years.
• EXCLUSION
• Persons who had previously received a diagnosis of lung cancer,
• Had undergone chest CT within 18 months before enrollment,
• Had hemoptysis, or
• Had an unexplained weight loss of more than 6.8 kg (15 lb) in the preceding year were
excluded
56. NLST: TARGETED SCREENING FOR HIGH-RISK SMOKERS
ARCHIVE
NEJM
NLST
MLM
High-risk smokers 55-74 yo
(30 ppy, active smokers
within the last 15 years).
No recent CT, weight-loss or
hemoptysis.
Low-dose Chest CT
Every year
For 3 years
Chest X Rays
Every year
For 3 years
57. NLST: TARGETED SCREENING FOR HIGH-RISK SMOKERS
ARCHIVE
NEJM
NLST
MLM
Team TNLSTR. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening.
N Engl J Med. 2011;365(5):395-409. doi:10.1056/NEJMoa1102873
58. NLST: TARGETED SCREENING FOR HIGH-RISK SMOKERS
ARCHIVE
NEJM
NLST
MLM
Team TNLSTR. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening.
N Engl J Med. 2011;365(5):395-409. doi:10.1056/NEJMoa1102873
59. NLST: SCREENING CT SUPERIOR TO CXR FOR NSCLC
ARCHIVE
NEJM
NLST
MLM
Team TNLSTR. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening.
N Engl J Med. 2011;365(5):395-409. doi:10.1056/NEJMoa1102873
Variable Low-dose CT Chest X Ray Comment
Lung cancer (#) 1060 941
Lung cancer incidence, (per
100.000 person-years)
645 572 RR: 1.13 (CI: 1.03-1.23)
Positive screening, then diagnosis 649 279
Negative screening, then diagnosis 44 137
Diagnosis after screening period 367 525
60. NLST: TARGETED SCREENING FOR HIGH-RISK SMOKERS
ARCHIVE
NEJM
NLST
MLM
Team TNLSTR. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening.
N Engl J Med. 2011;365(5):395-409. doi:10.1056/NEJMoa1102873
61. NLST: CT IMPROVES EARLY-STAGE NSCLC DETECTION
ARCHIVE
NEJM
NLST
MLM
Team TNLSTR. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening.
N Engl J Med. 2011;365(5):395-409. doi:10.1056/NEJMoa1102873
Stage Low-dose CT Chest X Ray
Stage I 50% 31.1%
Stage II 7.1% 7.9%
Stage III 20.2% 24.8%
Stage IV 21.7% 36.1%
62. NLST: CT DECREASES LUNG CANCER MORTALITY BY 20%
ARCHIVE
NEJM
NLST
MLM
Team TNLSTR. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening.
N Engl J Med. 2011;365(5):395-409. doi:10.1056/NEJMoa1102873
Variable Low-dose CT Chest X Ray Comment
Lung cancer deaths (#) 356 443
Lung cancer mortality, (per
100.000 person-years)
247 309 Relative reduction: 20%
(CI: 6.8-26.7%, p=0.004)
NUMBER NEEDED TO SCREEN (TO SAVE ONE LIFE)
320
63. NLST: CT DECREASES LUNG CANCER MORTALITY BY 20%
ARCHIVE
NEJM
NLST
MLM
Team TNLSTR. Reduced Lung-Cancer Mortality with Low-Dose Computed Tomographic Screening.
N Engl J Med. 2011;365(5):395-409. doi:10.1056/NEJMoa1102873
64. MINSALUD
Bogotá
Guía de Práctica Clínica (GPC) para la detección temprana, diagnóstico, estadificación, evaluación pre-quirúrgica y tratamiento de pacientes con
diagnóstico de cáncer de pulmón - http://gpc.minsalud.gov.co/gpc_sites/Repositorio/Conv_563/GPC_c_pulmon/GPC_c_pulmon_profesionales.aspx
MINSALUD (COLOMBIA) RECOMIENDA CRIBADO CON TAC
ARCHIVE
MLM
67. 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
69. 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®).
70. ARCHIVE
ESMO: ADJUVANT CT SAVES LIVES IN RESECTED STAGES II AND III NSCLC
Vansteenkiste J, Crinò L, Dooms C, et al. 2nd ESMO Consensus Conference on Lung Cancer: early-stage non-
small-cell lung cancer consensus on diagnosis, treatment and follow-up. doi:10.1093/annonc/mdu089.
08.2014
Annals of Oncology
ESMO
Adjuvant
chemotherapy for
NSCLC
MLM
71. NEJM
JBR.10
Patients 18 years of age or older
with completely resected T2N0,
T1N1, or T2N1 non–small-cell
lung cancer with acceptable
baseline characteristics and an
ECOG performance status of 0 or
1 were eligible
Adjuvant
Cisplatin-Vinorelbine
(16 weeks)
Control
Winton T, Livingston R, Johnson D, et al. Vinorelbine plus Cisplatin vs. Observation in Resected Non–Small-Cell Lung Cancer. N Engl J Med.
2005;352(25):2589-2597. doi:10.1056/NEJMoa043623.
JBR.10: ADJUVANT CHEMOTHERAPY EXPLORED IN STUDY
ARCHIVE
MLM
Patients with clinically significant cardiac dysfunction, active
infection, or neurologic or psychiatric disorders were also
ineligible.
Cisplatin 50 mg/m2 d1 and d8
Vinorelbine 25 mg/m2 qw x16
72. NEJM
JBR.10
Winton T, Livingston R, Johnson D, et al. Vinorelbine plus Cisplatin vs. Observation in Resected Non–Small-Cell Lung Cancer. N Engl J Med.
2005;352(25):2589-2597. doi:10.1056/NEJMoa043623.
JBR.10: 15% ABSOLUTE INCREASE IN SURVIVAL WITH CT
ARCHIVE
MLM
73. NEJM
ANITA
Patients were eligible if they had
stage I (T2N0 only), stage II, and stage
IIIA NSCLC according to the 1986
TNM classification;
Complete resection of the primary
tumour (all margins free of disease:
R0);
Age 18–75 years;
WHO performance status 2 or less;
And adequate biological functions
Adjuvant
Cisplatin-Vinorelbine
(16 weeks)
Control
Douillard J-Y, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB–IIIA non-
small-cell lung cancer ANITA: a randomised controlled trial. Lancet Oncol. 2006;7(9):719-727. doi:10.1016/S1470-2045(06)70804-X.
ANITA: ADJUVANT CHEMOTHERAPY EXPLORED IN STUDY
ARCHIVE
MLM
Cisplatin 100 mg/m2 on days 1, 29, 57 and 85
Vinorelbine 30 mg/m2 qw x16
74. NEJM
ANITA
Douillard J-Y, Rosell R, De Lena M, et al. Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB–IIIA non-
small-cell lung cancer ANITA: a randomised controlled trial. Lancet Oncol. 2006;7(9):719-727. doi:10.1016/S1470-2045(06)70804-X.
ANITA: ALMOST 3% ABSOLUTE REDUCTION IN MORTALITY WITH
ADJUVANT CHEMOTHERAPY
ARCHIVE
MLM
Total patient population: 840
75. JCO
LACE
Pignon J-P, Tribodet H, Scagliotti G V., et al. Lung Adjuvant Cisplatin Evaluation: A Pooled Analysis by the LACE Collaborative Group. J Clin Oncol.
2008;26(21):3552-3559. doi:10.1200/JCO.2007.13.9030.
LACE: Adjuvant cisplatin-based chemotherapy should not be
withheld from elderly patients with NSCLC purely on the basis of age.
ARCHIVE
MLM
“No statistically
significant interaction
(P.26) or test for trend (P
.29) between age and
treatment effect for OS
was observed”.
76. ARCHIVE
ESMO: ADJUVANT RT ONLY INDICATED AFTER R1 RESECTION OF NSCLC
Vansteenkiste J, Crinò L, Dooms C, et al. 2nd ESMO Consensus Conference on Lung Cancer: early-stage non-
small-cell lung cancer consensus on diagnosis, treatment and follow-up. doi:10.1093/annonc/mdu089.
08.2014
Annals of Oncology
ESMO
MLM
• Postoperative radiotherapy in completely resected early-
stage NSCLC is not recommended [I, A].
• In case of R1 resection (positive resection margin, chest
wall), postoperative radiotherapy should be considered [IV,
B].
• Even if such patients were not included in RCTs, adjuvant
chemotherapy should be given to R1 resection regardless
of nodal status [V, A].
• In case chemotherapy and radiotherapy are administered,
radiotherapy should be administered after chemotherapy
[V, C].
Radiation therapy in resected NSCLC
77. Surveillance after Early-Stage NSCLC
Year 1
H&P q6mo
Chest CT
Year 2
H&P q6mo
Chest CT
Year 3 and subsequent
Yearly H&P and Chest CT
(Risk of 2nd primary)
ARCHIVE
ESMO: 6-7% RELAPSE EVERY YEAR FOR THE FIRST 4 YEARS…
Vansteenkiste J, Crinò L, Dooms C, et al. 2nd ESMO Consensus Conference on Lung Cancer: early-stage non-
small-cell lung cancer consensus on diagnosis, treatment and follow-up. doi:10.1093/annonc/mdu089.
08.2014
MLM
78. NSCLC no metastásico: tratamiento
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.
- Se recomienda quimioterapia adyuvante a estadíos II y III
No se recomienda cirugía para pacientes con T4, N2 o N3
- Si no hay metástasis, proceder con quimiorradioterapia (Cisplatino + Etopósido)
RADIOTERAPIA EN NSCLC
Estadíos I, II, IIIA no quirúrgicos
Considerar SBRT
Como parte de terapia multimodal en estadío IIIB (con quimioterapia).
Control de síntomas presentes o potenciales en estadío IV
- Intratorácico
- Cerebral y Sistema Nervioso Central
- Hueso
QUMIOTERAPIA ADYUVANTE
- Estadíos II-III (algunos incluyen Ib)
- Dupletas basadas en cisplatino x4 meses
80. THE MANY FORMS OF STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
Stage III NSCLC
Many presentations, many work-ups
81. THE MANY FORMS OF STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
Challenges of stage III
• Heterogeneity
• Stage migration
– PET-CT
– Brain MRI
• Clinical trials of “another era” may not be
applicable to today’s stage III
• Advances in treatment
– CT, RT and Surgery
82. THE MANY FORMS OF STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
Heterogeneity in histopathology
Squamous cell carcinoma Non-Squamous cell carcinoma
Better outcomes with
multimodality
Higher-risk of loco-regional
relapse
Worse outcomes with
multimodality
Higher-risk of distant/brain
relapse
83. THE MANY FORMS OF STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
Heterogeneity in tumor location
and extension
T4N0 T1-3N3
Less risk of systemic spread Higer risk of systemic spread
Number of LN stations also
may predict patterns of relapse
84. THE MANY FORMS OF STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
Heterogeneity in stage III NSCLC
• Heterogeneity in individual patient risk profile
– Smoking
– Lung disease
– Cardiovascular disease
• Inter-institution diversity
– Ability to perform complex surgeries
– Including partial resection of vital organs
85. THE MANY FORMS OF STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
Heterogeneity in stage III NSCLC
M D T B
86. THE MANY FORMS OF STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
Multi-disciplinary tumor boards
• Pulmonologists
• Thoracic/medical oncologists
• Radiation oncologists and
• Thoracic surgeons
• Rradiologists and
• Nuclear medicine physicians
• Pathologists
87. SURGERY IN STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
If surgery is considered
Upfront assessment
Potentially resectable
Potentially resectable with
some risk of incomplete
resection
Not resectable
88. SURGERY IN STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
If surgery is considered
Optimal pre-op work-up
PET-CT
Assessment of mediastinal
disease in PET+ or suspicious
lesions
Brain MRI
Primary tumour of >3 cm large
axis, central tumours, cN1, CT-
enlarged lymph nodes with
small axis >1 cm
Symptomatic / High Risk (T4N2
or N3)
Histopathology for PET-
detected isolated single met
89. SURGERY IN STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
Platinum is required for CT with curative
intent in stage III disease
• Platinum
– Neoadjuvant
– Adjuvant
– Concurrent chemoRT
– Sequential chemoRT
– Cisplatin preferred
– Contraindication to cisplatin
• Heart failure
• Renal failure
90. SURGERY IN STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
Incidental N2 (unforeseen N2)
Adjuvant platinum-based CT
Consider RT after CT
Complete resection
Adjuvant platinum-based CT followed by
RT
Consider definitive chemoRT
Incomplete resection
91. POTENTIALLY RESECTABLE STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
Potentially resectable IIIA(N2)
Induction CT followed by Surgery*
Induction ChemoRT followed by Surgery
Multimodality
Definitive concurrent ChemoRT
*No scientific evidence in favor of adjuvant RT
Albain KS, Swann RS, Rusch VW, et al. Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III
randomised controlled trial. Lancet. 2009;374(9687):379-386. doi:10.1016/S0140-6736(09)60737-6.
92. POTENTIALLY RESECTABLE STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
Pless M, Stupp R, Ris H et al. Final results of the SAKK 16/00 trial: a randomized phase III trial comparing neoadjuvant chemoradiation to chemotherapy alone in stage
IIIA/N2 non-small cell lung cancer (NSCLC). Ann Oncol 2014; 25(suppl. 4): iv417.
Potentially resectable IIIA(N2)
Induction CT followed by Surgery*
Induction ChemoRT followed by Surgery
Multimodality
Definitive concurrent ChemoRT
Induction Cisplatin + Docetaxel highly effective in downsizing
93. POTENTIALLY RESECTABLE STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
Rusch VW, Giroux DJ, Kraut MJ, et al. Induction Chemoradiation and Surgical Resection for Superior Sulcus Non?Small-Cell Lung Carcinomas: Long-Term Results of
Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Clin Oncol. 2007;25(3):313-318. doi:10.1200/JCO.2006.08.2826.
Potentially resectable stage III, but high
risk of incomplete resection
Induction ChemoRT followed by Surgery
Superior sulcus tumors
Surgery within 4 weeks after RT finished
94. POTENTIALLY RESECTABLE STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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
Potentially resectable stage III, but high
risk of incomplete resection
Induction ChemoRT followed by Surgery*
Selected Central T3-T4 tumors
Surgery within 4 weeks after RT finished
Definitive ChemoRT
T4N0-1
95. UNRESECTABLE STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
Unresectable Stage III disease
Bulky and multiple mediastinal nodal involvement
Unresectable stage III disease
Stage IIIB disease based on unresectable T4
Stage IIIB disease based on N3
96. UNRESECTABLE STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.
Aupérin A, Le Péchoux C, Rolland E, et al. Meta-Analysis of Concomitant Versus Sequential Radiochemotherapy in Locally Advanced Non–Small-Cell Lung Cancer. J Clin
Oncol. 2010;28(13):2181-2190. doi:10.1200/JCO.2009.26.2543.
Unresectable Stage III disease
Definitive Concurrent ChemoRT
Unresectable stage III disease
Sequential ChemoRT
Palliative therapy
97. 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
- 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+%
98. Stage IV - NSCLC – PS 0-1
NSCLC without “Driver”
NSCLC
Squamous*
NSCLC
Non-squamous
CT with Platinum +
Pemetrexed or
Paclitaxel + Bevacizumab
CT with Platinum+
Gemcitabine or Paclitaxel
*Bevacizumab is contraindicated due to fatal bleeding
*Pemetrexed is ineffective in squamous histology
99. Stage IV - NSCLC – PS 0-1
NSCLC with “Driver” NSCLC without “Driver”
NSCLC
Squamous*
NSCLC
Non-squamousmEGFT
mALK/RO
S1
TKIs anti EGFR
(Erlotinib o Gefitinib o Afatinib)
TKIs anti ALK/ROS1
(Crizotinib)
CT with Platinum +
Pemetrexed or
Paclitaxel + Bevacizumab
CT with Platinum+
Gemcitabine or Paclitaxel
*Bevacizumab is contraindicated due to fatal bleeding
*Pemetrexed is ineffective in squamous histology
103. EGFR in NSCLC: two distinct
pathways
Nucleus
Adaptor
Survival
PIP2
PI3K
PIP3
PTEN
AKT
Apoptosis
regulators
Proliferation
Adaptor
Transcription
factors
MAPK
MEK
RAFGTP-RASGDP-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
104. EGFR in NSCLC: two distinct pathways
ATP
Nucleus
Adaptor
Survival
PIP2
PI3K
PIP3
PTEN
AKT
Apoptosis
regulators
Proliferation
Adaptor
Transcription
factors
MAPK
MEK
RAFGTP-RASGDP-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
105. 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
0
Incidence(%)
110. 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
111. 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.
112. 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
113. 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 EP +/- PCI
EP: Etoposide + Cisplatin x4 months
70% LT survival Median OS: 20 months Median OS: 9 months