Clase de cáncer de pulmón para estudiantes de medicina, con lo mínimo que debe saber uh médco general sobre cáncer del pulmón.

1. CES 2016.02: Neoplasms of the Lung
Mauricio Lema Medina MD

2. Acknowledgments
Diego Morán MD

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

4. 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. Lung cancer

6. Page  6
Cáncer en el mundo
7 millones
Hepatocelular (2x)
Cérvix uterino (2x)
Esófago (2-3x)
11 millones
Pulmón (2x)
Mama (3x)
Próstata (2.5x)
Colon y recto (3x)
Estadísticas en 2002: Prevalencia – 25 millones

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.

13. Smoking cessation and lung
cancer risk over time

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

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

16. 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

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

18. 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

19. 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

20. Clinical findings suggestive of metastatic disease

21. • 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

22. Lung cancer: diagnosis

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].

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

25. 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+

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

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+ TTF1+

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

30. TNM: Lung cancer
AJCC TNM Staging System, 7th Ed. (2010)

31. TNM: Lung cancer
AJCC TNM Staging System, 7th Ed. (2010)

32. TNM: Lung cancer
AJCC TNM Staging System, 7th Ed. (2010)

33. TNM: Lung cancer
AJCC TNM Staging System, 7th Ed. (2010)

34. Lung cancer: anatomic staging
PET-CT +/- Brain MRI
Potentially resectable Nonresectable/metastatic
Extrathoracic metastases
SVCS
Vocal cord / phrenic nerve paralysis
Malignant pleural effusion
Cardiac tamponade
Tumor within 2 cm of the carina
Contralateral lung metastases
Supraclavicular metastases
Contralateral mediastinal LN involvement
Pulmonary artery involvement
Mediastinal LN assessment
ie, Mediastinoscopy
NSCLC
N2/N3 diseaseN0/N1 disease
Unresectable stage III Stage IVPhysiologic staging
Surgery +/- CT Definitive Chemo-RT

35. 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

36. 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

37. 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®
).

38. 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+%

39. 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

40. 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

41. 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

42. HER/erbB familyHER/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:

43. 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

44. EGFR in NSCLC: two distinct
pathways
Nucleus
Adaptor
Survival
PIP2
PI3K
PIP3
PTENPTEN
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

45. EGFR in NSCLC: two distinct pathways
ATP
Nucleus
Adaptor
Survival
PIP2
PI3K
PIP3
PTENPTEN
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

46. 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(%)

47. 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.

48. pTNM 7pTNM 7thth
EditionEdition
0%
20%
40%
60%
80%
100%
0 2 4 6 8 10
YEARS AFTER 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:From: Goldstraw P, Crowley J, Chansky K et al. The IASLC lung cancer project: proposals for theGoldstraw 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 classificationrevision of the TNM stage groupings in the forthcoming (seventh) edition of the TNM classification
of malignant tumours. J Thorac Oncol 2007; 2: 706-714of malignant tumours. J Thorac Oncol 2007; 2: 706-714
TNM Stage Category (Ver 7)

49. Cáncer de pulmón de células
pequeñas - SCLC

50. SCLC

51. 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

52. 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.

53. 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

54. 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

55. Further reading
• Neoplasms of the Lung, in Harrison’s 19th Ed, Chapter 107 (507-523)