ces 2016 02 - lung cancer

CES 2016.02: Neoplasms of the LungMauricio Lema Medina MD

AcknowledgmentsDiego Morán 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 benignStability over 2+ yrs.Benign calcification: central nidus, multiple punctate, “bulls-eye” and popcorn

SPN/GGO

Stable over 2 yrsBenign 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

Lung cancer

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

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-EGFRCreado 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 x3LDCT: Low-Dose CT every year x3CXR: Chest X Rays PA and Lateral every year x3

Enrollment: 8/2002-4/2004Lung 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 309LC: 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 (30ç 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 tamponadeHoarseness

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 tamponadeHoarseness

Thoracic pain: 20-49%

Adrenal gland

Lungs

Liver

Brain

Pleura

Clinical findings suggestive of metastatic 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

Lung cancer: diagnosis

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].

Lung adenocarcinomas subtypes

Adenocarcinoma

Lepidic

Papillar

Acinar

Micropapillar

Solid

Lepidic (adenocarcinoma in-situ)

Lepidic (minimally invasive adenocarcinomas)Excellent prognosis

Poor prognosis

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 withoud “Driver”

10%

15% 75%

NSCLC (without “driver”)

Squamous25%

NSCLC (without “driver”)

Non-squamous50%

90%

EGFR: 10%ALK/EML4: 4%ROS1: 1%

Mostly, adenocarcinoma

AdenocarcinomaSquamousLarge-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%

EGFR17%EML4-AKL

7%

DoubleMutants 3%

BRAF 2%PIK3CA 2%HER2MET AMPMEK1NRASAKT1

ErlotinibGefitinibAfatinib

Selumetinib

Crizotinib

How to handle small tissue samples in lung cancer

p63 and TTF1

H&E

SCC Adeno

Genomics

SCLC

NeuroEndocrine

EGFRALK/EML4ROS1BRAFHer2

p63+ TTF1+

Lung cancer: anatomic staging

PET-CT +/- Brain MRI

NSCLC

TNM: Lung cancer

AJCC TNM Staging System, 7th Ed. (2010)

Lung cancer: anatomic staging

PET-CT +/- Brain MRI

Potentially resectable Nonresectable/metastatic

Extrathoracic metastasesSVCSVocal cord / phrenic nerve paralysisMalignant pleural effusionCardiac tamponadeTumor within 2 cm of the carinaContralateral lung metastasesSupraclavicular metastasesContralateral mediastinal LN involvementPulmonary artery involvement

Mediastinal LN assessmentie, Mediastinoscopy

NSCLC

N2/N3 diseaseN0/N1 disease

Unresectable stage III Stage IVPhysiologic staging

Surgery +/- CT Definitive Chemo-RT

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 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 NSCLCEstadíos I, II, IIIA no quirúrgicosConsiderar SBRTComo 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

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®).

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”

NSCLCSquamous*

NSCLCNon-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”

NSCLCSquamous*

NSCLCNon-squamousmEGFT mALK/

ROS1

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 HER/erbB family

Salomon DS, et al. Crit Rev Oncol Hematol 1995;19:183–232Woodburn JR. Pharmacol Ther 1999;82:241–50

HER1EGFRerbB1

HER2erbB2neu

EGFTGF-αAmphiregulinBetacellulinHB-EGFEpiregulin

Heregulins

NRG2NRG3HeregulinsBetacellulin

Cysteine-richdomains

Tyrosine-kinasedomains

HER3erbB3

HER4erbB4

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

PIP3PTEN

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

PIP3PTEN

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

Inci

denc

e (%

)

EURTAC: PFS in ITT Population

Erlotinib (n = 86)Chemotherapy (n = 87)

HR: 0.37 (95% CI: 0.25-0.54; log-rank P < .0001)

PFS

Prob

abili

ty

1.0

0.8

0.6

0.4

0.2

00 3 6 9 12 15 18 21 24 27 30 33

Mos

5.2 9.7

Patients at Risk, nErlotinibChemo

8687

6349

5420

328

215

174

93

71

40

20

20

00

Rosell R, et al. ASCO 2011. Abstract 7503.

pTNM 7pTNM 7thth Edition Edition

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10YEARS AFTER SURGERY

IAIBIIAIIBIIIAIIIBIV

Deaths / N1168 / 36661450 / 31001485 / 25791502 / 22522896 / 3792

263 / 297224 / 266

MST119814931221317

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 the 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 revision 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)

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

Further reading

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

ces 2016 02 - lung cancer

Health & Medicine