Lung Cancer Screening and Molecular Subtypes

CES 2017.02: Neoplasms of the Lung
Mauricio Lema Medina MD

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

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

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

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.

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.

Incidencia/Mortalidad USA: Hombres

Incidencia Mortalidad
Incidencia/Mortalidad USA: Mujeres

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

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

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.

Smoking cessation and lung
cancer risk over time

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

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

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

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

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

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

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

• 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

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

Lung adenocarcinomas subtypes
Adenocarcinoma
Lepidic
Papillar
Acinar
Micropapillar
Solid
Lepidic (adenocarcinoma in-situ)
Lepidic (minimally invasive adenocarcinomas)

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

Lung cancer: “relevant” subgroups
NSCLC SCLC
NSCLC with “Driver” NSCLC without “Driver”
15%
20% 80%
NSCLC (without
“driver”)
Squamous
25%
NSCLC (without
“driver”)
Non-squamous
45%
85%
EGFR: 15%
ALK/EML4: 4%
ROS1: 1%
Mostly, adenocarcinoma
Adenocarcinoma
Squamous
Large-cell

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

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

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

TNM Staging system: Lung Cancer
TNM8

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

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

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

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)

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
N-Stage in lung cancer

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).

2L/2R: Upper paratracheal (R and L)
3A: Prevascular

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.

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.

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.

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)

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.

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.

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.

Stations 10 - 14. N1 lymph-nodes
Hilar, lobar, segmental and subsegmental
Stations 10-14 are NOT mediastinal lymph-nodes.

M-descriptor
Eberhardt W et al. J Thoracic Oncol, 2015, in press
• M1a: as it is
• M1b: single metastasis in a single organ
• M1c: multiple metastases in a single organ or
in several organs

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

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

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
NEW

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
8th Edition of the TNM Classification
for Lung Cancer

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

ARCHIVE
NEJM: LUNG CANCER SCREENING SAVES LIVES – STUDY SHOWS
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

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

NLST: TARGETED SCREENING FOR HIGH-RISK SMOKERS
ARCHIVE
NEJM
NLST
MLM

NLST: SCREENING CT SUPERIOR TO CXR FOR NSCLC
ARCHIVE
NEJM
NLST
MLM
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

NLST: CT IMPROVES EARLY-STAGE NSCLC DETECTION
ARCHIVE
NEJM
NLST
MLM
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%

NLST: CT DECREASES LUNG CANCER MORTALITY BY 20%
ARCHIVE
NEJM
NLST
MLM
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

NLST: CT DECREASES LUNG CANCER MORTALITY BY 20%
ARCHIVE
NEJM
NLST
MLM

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

Lung cancer: anatomic staging
PET-CT +/- Brain MRI
Potentially resectable Unresectable/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 diseaseN0/N1 disease
Unresectable stage III Stage IVPhysiologic staging
Surgery +/- CT Definitive Chemo-RT

Treatment strategies for resectable
NSCLC (Stages I-IIIA)

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

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®).

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

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

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

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

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

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”.

ARCHIVE
ESMO: ADJUVANT RT ONLY INDICATED AFTER R1 RESECTION OF NSCLC
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

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…
08.2014
MLM

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

Treatment strategies for unresectable
NSCLC (Stage III)

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

Ann Oncol
ESMO PG
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

Ann Oncol
ESMO PG
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

Ann Oncol
ESMO PG
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

Ann Oncol
ESMO PG
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

Ann Oncol
ESMO PG
2015;26(8):1573-1588. doi:10.1093/annonc/mdv187.
Heterogeneity in stage III NSCLC
M D T B

Ann Oncol
ESMO PG
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

SURGERY IN STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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

Ann Oncol
ESMO PG
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

Ann Oncol
ESMO PG
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

Ann Oncol
ESMO PG
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

POTENTIALLY RESECTABLE STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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.

Ann Oncol
ESMO PG
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*
Multimodality
Definitive concurrent ChemoRT
Induction Cisplatin + Docetaxel highly effective in downsizing

Ann Oncol
ESMO PG
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
Superior sulcus tumors
Surgery within 4 weeks after RT finished

Ann Oncol
ESMO PG
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

UNRESECTABLE STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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

UNRESECTABLE STAGE III NSCLC ESMO
Ann Oncol
ESMO PG
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

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+%

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

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

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

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:

ProliferationApoptosis Resistance Transcription
TGFα Interleukin-8
bFGF VEGF
MetastasisAngiogenesis
Shc
PI3K
RafMEKK-1
MEKMKK-7
JNK ERK
Ras
mTOR
Grb2
AKT
Sos-1
EGF Pathway
www.clinicaloptions.com

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

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

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(%)

EURTAC: PFS in ITT Population
Erlotinib (n = 86)
Chemotherapy (n = 87)
HR: 0.37 (95% CI: 0.25-
0.54; log-rank P < .0001)
PFSProbability
1.0
0.8
0.6
0.4
0.2
0
0 3 6 9 12 15 18 21 24 27 30 33
Mos
5.2 9.7
Patients at Risk, n
Erlotinib
Chemo
86
87
63
49
54
20
32
8
21
5
17
4
9
3
7
1
4
0
2
0
2
0
0
0
Rosell R, et al. ASCO 2011. Abstract 7503.

pTNM 7th Edition
0%
20%
40%
60%
80%
100%
0 2 4 6 8 10
YEARSAFTER SURGERY
IA
IB
IIA
IIB
IIIA
IIIB
IV
Deaths / N
1168 / 3666
1450 / 3100
1485 / 2579
1502 / 2252
2896 / 3792
263 / 297
224 / 266
MST
119
81
49
31
22
13
17
5 Year
73%
58%
46%
36%
24%
9%
13%
From: Goldstraw P, Crowley J, Chansky K et al. The IASLC lung cancer project: proposals for the
revision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification
of malignant tumours. J Thorac Oncol 2007; 2: 706-714
TNM Stage Category (Ver 7)

Cáncer de pulmón de células
pequeñas - SCLC

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

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.

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

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

Lung Cancer Screening and Molecular Subtypes

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