Cáncer de pulmón 2 (enfoque inicial post-diagnóstico).

1.  Tissue diagnosis
 Accurate TNM / Stage
 Treatment strategies
 Assess comorbidities
 Performance status
Lung cancer toolkit
What’s needed to treat
2019-01

2. Lung cancer toolkit
What’s needed to treat
Tissue diagnosis
Histology.
Morphology
Squamous
Adeno
NSCLC NOS
SCLC.
IHC
Squamous: p63-p40
Adeno: TTF+, Napsin
PD-L1 expression (mNSCLC)
SCLC: High Ki67, Chromogranin,
synaptophysin
Genotyping
Non-Squamous, advanced NSCLC
EGFR
ALK/EML4
ROS1, and others.

3. 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

4. Lung cancer: “relevant” subgroups
NSCLC SCLC
NSCLC with “Driver”
NSCLC without a
“Driver”
10%
15% 75%
PD-L1
expression
1-50%
25%
PD-L1
expression
≥50%
25%
90%
EGFR: 10%
ALK/EML4: 4%
ROS1: 1%
Mostly, adenocarcinoma
Adenocarcinoma
Squamous
Large-cell
PD-L1
expression
≤1%
25%

5. 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

6. 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:

7. 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

8. 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

9. 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

10. 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+/Citotóxi
co

11. 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+/Citotóxi
co
Receptor de célula T (TCR) MHC II y antígeno
MHC II: Major histocompatibility complex

12. 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
DendríticaLinfocito T
CD8+/Citotóxi
co
Co-estimuladora CD28 Co-estimuladora B7.1

13. En la
periferia...
Mientras tanto...

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

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

16. Extent of diseaseStaging

18. Lung cancer toolkit
What’s needed to treat
Staging procedures
Seek metastatic disease
- Scenario 1: Supected advanced disease
CT Chest
Including liver and adrenal
Brain MRI
Not everyone agrees
Bone-scan
Not everyone agrees.
Indicated if bone pain.

19. Lung cancer toolkit
What’s needed to treat
Staging procedures
Seek metastatic disease
- Scenario 2: Supected early disease
PET-CT
If available
Brain MRI
Not everyone agrees
Mediastinoscopy
Before definitive surgery,
to avoid N3 (unresectable)
disease.

20. Treatment strategies
Tumor side

21. 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

22. N – Regional Lymph Nodes
Regional lymph nodes cannot be assessedNx
No regional lymph node metastasisN0
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 metastasisM0
Distant metastasisM1
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 organM1b
Multiple extrathoracic metastases in one or several organsM1c
International Association for the Study of Lung Cancer, 2015

23. YOUR LOGO
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)

24. N – Regional Lymph Nodes
Regional lymph nodes cannot be assessedNx
No regional lymph node metastasisN0
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 metastasisM0
Distant metastasisM1
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 organM1b
Multiple extrathoracic metastases in one or several organsM1c
International Association for the Study of Lung Cancer, 2015

25. 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

26. Place your patient where she/he belongs
Early Stage NSCLC
 Non-T4.
 Non-N3
 Non-M1
 Mostly, Non-N2
Locally-Advanced NSCLC
 M0 (a must)
 T4
 N3
 Unresectable N2 (ie, bulky)
Advanced-NSCLC
 M1

27. 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 intentMostly unresectable

28. PrinciplesTreatment

29. 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 therapyMultimodal therapy:
(ie, Chemo-Radiation, followed by Immunotherapy)

30. Consider surgery
Pneumonectomy
Lobectomy
+ Mediastinal LN dissection
Assess ability to undergo
surgery
Enough FEV1
Normal arterial CO2
Acceptable cardiac function
Acceptable PS
Early Stage NSCLC
Stages I and II, some stages III
Consider adjuvant platinum-doublet chemotherapy for stage II and III
Consider adjuvant radiotherapy if N+ or R1 resection

31. 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

32. YOUR LOGO
Surgery for lung
cancer

33. Locally Advanced NSCLC
Mostly, stage III disease
2 1
Surgery followed
by chemo and RT
In unexpected N2
disease after surgery
Concurrent
Chemoradiation
Cisplatin + Etoposide +
definitive RT, followed by
immunotherapy.
Sequential chemo-
radiation
First, chemotherapy
followed by RT
Sequential chemo-
followed by surgery
Selected stage IIIa cases

34. Advanced NSCLC
Stage IV (M1, recurrent), PS0/1, first-line
Mutant
EGFR
ALK/EML4
High PD-L1
expression
Intermediate
PD-L1
expression
PS 0/1
No PD-L1
expression

35. mNSCLC with drivers
Stage IV, recurrent, non-squamous, PS 0/1/2
mEGFR
Consider anti EGFR TKI
Osimertinib
Afatinib
Erlotinib
Gefitinib.
50% alive at 2-3 yr
ALK/EML4
Alectinib
Crizotinib
50% alive at 2-3 yr
Others:
ROS1: Crizotinib
BRAF: Dabrafenib + Trametinib

36. 1st-line Osimertinib in
mutant EGFR metastatic
NSCLC (2018)
1st-line Alectinib in
mutant ALK/EML4
metastatic NSCLC (2017)

37. Metastatic NSCLC without actionable mutations
PD-L1 expression
Tumor cell PD-L1
expression
PD-L1 ≥50%
Single-agent Pembrolizumab (2016)
Chemotherapy + Pembrolizumab (2018)
PD-L1 1-50%
Non-squamous:
Platinum / Pemetrexed / Pembrolizumab (2018)
Squamous
Platinum / Paclitaxel / Pembrolizumab (2018)
PD-L1 ≤1%
Adeno:
Platinum doublet +/- Bevacizumab (2006)
Squamous:
Platinum doublet (2008)

38. Cómo se detiene
la respuesta
inmunológica?
Frenos

39. En la sinapsis 2
Células T – Células tumorales

40. 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+/Citotóxi
co
IFN-γ
IFN-
γR
PD-L1
PD-1
- - -
Respuesta inmune
antitumoral
Frenada

41. Célula
T
Célula
tumora
l
MH
C
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

42. Pembrolizumab + Chemotherapy
in Non-Squamous metastatic
KEYNOTE-489
NSCLC (2018)
Pembrolizumab in High-PD-
L1 expression metastatic
KEYNOTE-24
NSCLC (2016)

43. Pembrolizumab + Chemotherapy
in Squamous metastatic
KEYNOTE-407
NSCLC (2018)

44. Pembrolizumab + Chemotherapy
in Squamous metastatic
KEYNOTE-407
NSCLC (2018)

46. Cáncer de pulmón de células
pequeñas - SCLC

47. SCLC

48. 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

49. 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.

50. 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

51. 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

52. Atezolizumab + Chemotherapy in extensive SCLC
IMpower133
NSCLC (2018)

53. “It is easier for the world to
accept a simple lie than a
complex truth.”
Alexis de Tocqueville