CES202101 - Clase 12 - Cáncer de pulmón (1/2)

Cáncer de pulmón (lung cancer)

Leading cause of
cancer death
# cases: 2’/yr
worldwide
# deaths: close to
2’/yr worldwide
% surviving 5-yrs:
18% (US)
Tobacco explains
about 90%
Radon
Radiation
Asbestos
Lung cancer (broncus carcinoma)
Risk factors
Some facts
https://www.youtube.com/watch?v=nQQFDvQqw9A

http://bit.ly/2v8zXA3
Tipo Mundo Estados Unidos Colombia
Incidencia Mortalidad Incidencia Mortalidad Incidencia Mortalidad
Todo 201 100.7 362.2 86.3 182.3 84.7
Mama 47.8 13.6 90.3 12.4 48.3 13.1
Próstata 30.7 7.7 72.0 8.2 49.8 11.9
Pulmón 22.4 18.0 33.1 18.9 10.5 9.2
Colo-recto 19.5 9.0 25.6 8.0 16.9 8.2
Cérvix 13.3 7.3 6.2 2.1 14.9 7.4
Estómago 11.1 7.7 4,2 1.7 12.8 9.9
Hígado 9.5 8.7 6.9 4.7 3.5 3.4
Endometrio 8.7 1.8 21.4 3.1 8.1 1.7
Ovario 6.6 4.2 8.1 4.0 7.5 4.5
Esófago 6.3 5.6 2.4 2.8 1.3 1.2
Tiroides 6.6 0.4 11.8 0.3 9.1 0.7
Páncreas 4.9 4.5 8.2 6.6 4.1 4.0
Leucemia 5.4 3.3 11.1 3.2 6.2 4.1
Incidencia y mortalidad por cáncer en el Mundo, Estados
Unidos y Colombia
GLOBOCAN - 2020
/100.000 habitantes-año

http://bit.ly/2v8zXA3
Tipo Mundo Estados Unidos Colombia
Incidencia Mortalidad Incidencia Mortalidad Incidencia Mortalidad
Todo 201 100.7 362.2 86.3 182.3 84.7
Mama 47.8 13.6 90.3 12.4 48.3 13.1
Próstata 30.7 7.7 72.0 8.2 49.8 11.9
Pulmón 22.4(3) 18.0(1) 33.1(3) 18.9(1) 10.5(6) 9.2(4)
Colo-recto 19.5 9.0 25.6 8.0 16.9 8.2
Cérvix 13.3 7.3 6.2 2.1 14.9 7.4
Estómago 11.1 7.7 4,2 1.7 12.8 9.9
Hígado 9.5 8.7 6.9 4.7 3.5 3.4
Endometrio 8.7 1.8 21.4 3.1 8.1 1.7
Ovario 6.6 4.2 8.1 4.0 7.5 4.5
Esófago 6.3 5.6 2.4 2.8 1.3 1.2
Tiroides 6.6 0.4 11.8 0.3 9.1 0.7
Páncreas 4.9 4.5 8.2 6.6 4.1 4.0
Leucemia 5.4 3.3 11.1 3.2 6.2 4.1
Incidencia y mortalidad por cáncer en el Mundo, Estados
Unidos y Colombia
GLOBOCAN - 2020
/100.000 habitantes-año

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

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

YOUR LOGO
Incidencia y mortalidad por de cáncer en Colombia
Registro Poblacional de Cáncer - Cali
http://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

Cell of origin
Small Cell Lung Cancer (SCLC)
15%

Cell of origin
Non-Small Cell Lung Cancer (NSCLC)
85%

Complexities of Lung Cancer Pathogenesis Result in
Diverse Histologic Subtypes
Squamous (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].

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+

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%
BRAF 2%
PIK3CA 2%
HER2
MET AMP
MEK1
NRAS
AKT1

Subjects
55-74 yo
30 ppy
Current or former smoker (<15 years ago)
Procedure
LD-Chest CT q1yr
Outcome
↓20% Lung cancer mortality
(3/1000 screened)

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

Paraneoplastic syndromes
Clinical syndromes involving nonmetastatic systemic effects that accompany
malignant disease.

• 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
PTHrp

Lung cancer and oncologic
emergencies

Lung cancer is a major cause of oncologic emergencies
Humoral hypercalcemia of
malignancy
Superior vena cava syndrome
Spinal-cord compression
Cardiac tamponade
SIADH

Suspected metastatic
disease
Weight-loss
Bone-pain
Poor PS
Long-standing symptoms
Chest/Abdomen
CT scan
Brain
MRI
Bone-scan
Biopsy: most accessible
lesion

disease
Weight-loss
Bone-pain
Poor PS
Chest/Abdomen
CT scan
Brain
MRI
Bone-scan
lesion
Suspected localized
disease
Incidental finding (ie, screening,
solitary pulmonary nodule)
Single lesion
PS 0
FDG-PET-CT scan
+/- Brain
MRI
Biopsy: lung lesion
No tissue, no issue

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

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 – 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

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

for Lung Cancer
Surgery, followed by adjuvant chemotherapy
Systemic therapy
Multimodal therapy:
(ie, Chemo-Radiation, followed by Immunotherapy)

Suspected localized
disease
Single lesion
PS 0
FDG-PET-CT scan
+/- Brain
MRI
Biopsy: lung lesion
Considering loco-
regional therapy
If non-metastatic NSCLC
No evidence of mediastinal
disease (PET-CT/MRI…)
Mediastinoscopy
Negative (no tumor in
mediastinal LNs)
Patient appropriate for
resection
Lobectomy/Pneumonectomy
+ LN dissection

Preoperative physiologic assessment
Dyspnea Spirometry (FEV1)
Cardiovascular evaluation
Enfermedad pulmonar
difusa
+/- DLCO
FEV1 or DLCO ≥ 80% FEV1 or DLCO < 80%
Post-Op pulmonary reserve estimation
Estimated Post-Op FEV1 or DLCO < 40%
Cardiopulmonary Exercise Testing
Estimated Post-Op FEV1 or DLCO ≥ 40%
Vo(2)max of > 15 mL/kg/min
Surgery
Colice, CHEST, 2007

for Lung Cancer
Upfront resection feasible

Lobectomy/pneumonectomy
+ LN dissection
T1/T2a (≤ 4 cm) N0 M0
(Stages IA, IB)
No adjuvant therapy
required
≥4 cm or N+
Platin-based adjuvant
therapy
Consider RT if: + Margins or +LNs
Oversimplification… I know.

Suspected localized
disease
Single lesion
PS 0
FDG-PET-CT scan
+/- Brain
MRI
Biopsy: lung lesion
Considering loco-
regional therapy
If non-metastatic NSCLC
Overt mediastinal
involvement (N2/N3) or
T4
Chemo-radiation
Surgery, not an option

for Lung Cancer
Multimodal therapy:
(ie, Chemo-Radiation, followed by Immunotherapy)

Immune response: ON
Immune response: OFF
PD-L1
PD-1

Anti PD1 (Pembrolizumab / Nivolumab)
Anti PD-L1 (Durvalumab/Atezolizumab/Avelumab)
Tumor Cell
Immune response: ON

disease
Weight-loss
Bone-pain
Poor PS
Chest/Abdomen
CT scan
Brain
MRI
Bone-scan
lesion
Surgery, NOT an
option
PS 0-1
PS 2
PS 3-4
If metastatic NSCLC

for Lung Cancer
Systemic therapy

disease
Weight-loss
Bone-pain
Poor PS
Chest/Abdomen
CT scan
Brain
MRI
Bone-scan
lesion
Surgery, NOT an
option
PS 0-1
PS 2
PS 3-4
If metastatic NSCLC
BSC
Chemo, targeted, IO… etc
Individualize

Metastatic NSCLC fit
for cancer therapy
Actionable
mutations?
EGFR ALK ROS1
Afatinib
Osimertinib
etc
Alectinib
Crizotinib
Crizotinib
Yes

for cancer therapy
Actionable
mutations?
PD-L1
≥50%
PD-L1
≤50%
Not an IO
candidate
No
Pembrolizumab Pembrolizumab +
Platinum-based CT
Platinum-
based CT +/-
Bevacizumab

for cancer therapy
Actionable
mutations?
EGFR ALK ROS1
Afatinib
Osimertinib
etc
Alectinib
Crizotinib
Crizotinib
Yes
PD-L1
≥50%
PD-L1
≤50%
Not an IO
candidate
No
Pembrolizumab Pembrolizumab +
Platinum-based CT
Platinum-
based CT +/-
Bevacizumab

SCLC
Small Cell Lung Cancer
The tumor is composed of diffuse proliferation of small to
intermediate sized cells (arrow) generally with very scant
cytoplasm and round to oval hyperchromatic nuclei. The tumor
cells are generally larger than small lymphocytes (left
arrowhead) but in some cases the morphologic distinction may
be impossible.

15% of lung cancer
Central mass
Very-early systemic
spread
Higher letality
Tobacco explains
about 99%
Limited-stage
(confined to one
lung)
Extensive-stage
(beyond one lung)
Very high CNS
involvement
SCLC
Neuroendocrine,
small cell
Chromogranin
Synaptophysin

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

CES202101 - Clase 12 - Cáncer de pulmón (1/2)

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