COPD and Lung Cancer: One agent with two outcomes: or is it?
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COPD and Lung Cancer: One agent with two outcomes:
or is it?
Dr. Juan Pablo de Torres
Servicio de Neumología
Clínica Universidad de Navarra
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ResumenResumen
•La magnitud del problema
•Posibles mecanismos patogénicos
•¿Que podemos hacer?
•Conclusiones
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Top 10 Causes of Death, Years of Life Lost from Premature Death, Years Lived with Disability, and Disability-Adjusted Life-Years (DALYs) in the United States, 2010.
Murray CJ, Lopez AD. N Engl J Med 2013;369:448-457.
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Changes in Rates of Death from Lung Cancer and Chronic Obstructive Pulmonary Disease (COPD) over Time among Current Female and Male Smokers in the Three Time Periods.
Thun MJ et al. N Engl J Med 2013;368:351-364.
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INE: Mortalidad por EPOC y Cáncer de pulmón en 2011 en España
EnfermedadesIsquémicas
EnfermedadesCerebrovasculares
Cáncer de Pulmón
InsuficienciaCardíaca
EPOC
35.260
30.137
20.720
16.025 15.662
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Soriano JB. Lancet 2009;374:721-32.
Prevalencia e infradiagnostico de EPOC en Prevalencia e infradiagnostico de EPOC en España y LatinoaméricaEspaña y Latinoamérica
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Cáncer de PulmónCáncer de Pulmón
•La sobrevida global al momento del diagnóstico es del 5-15%.
•En el último año ya empiezan a aparecer normativas que recomienden estudios de cribado de cáncer de pulmón en pacientes de alto riesgo.
Pirozynscki M. 100 years of lung cancer. Respir Med. 2006
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• 2507 pts mean follow up 60 months
• 215 cases of lung cancer (8,5%)
• Incidence density 1.67/100 persons year
• Most frequent histological type: squamous cell
• 904 died during the follow up time
• 174 due to lung cancer
Lung Cancer in patients with COPD: Incidence and Predicting factors
de Torres JP. Am J Respir Crit Care Med. 2011 ;184:913-9
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Incidencia de cáncer según el estadio de GOLD
de Torres JP. Am J Respir Crit Care Med. 2011 ;184:913-9
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Variables asociadas al diagnostico de cáncer de pulmón en pacientes con EPOC
de Torres JP. Am J Respir Crit Care Med. 2011 ;184:913-9
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Odds Ratio para el diagnóstico de cáncer de pulmón
IC 95%RR
0,79 – 5,582,10COPD
1,01– 6,232,51Emphysema
Adjusted for age, sex and pack-years, emphysema or COPD.
de Torres et al. CHEST 2007; 132: 1932-8
Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest
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95%CIOR
0.87- 2.291.41COPD
1.91– 5.153.14Emphysema
Adjusted for age, sex and smoking and emphysema or COPD
Am J Respir Crit Care Med 2008;178:738
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¿La magnitud del problema?¿La magnitud del problema?
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Brody J and Spira A. State of the art. Chronic obstructive pulmonary disease, inflammation,
and lung cancer.Proc Am Thorac Soc. 2006 Aug;3(6):535-7.
Mecanismos patológicos propuestosMecanismos patológicos propuestos
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McGarry Houghton A. Nature Reviews Cancer 13, 233-245
Mecanismos patológicos propuestosMecanismos patológicos propuestos
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Mechanistic links between COPD and lung cancer
McGarry Houghton A. Nature Reviews Cancer 13, 233-245
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Nature Medicine, Octubre 2008
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Mechanisms involved in Lung Cancer development in COPD
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Ciclo repetitivo de daño y reparación en un ambiente Ciclo repetitivo de daño y reparación en un ambiente inflamatorio crónicoinflamatorio crónico
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Activación del factor de transcripción STAT3 conecta Activación del factor de transcripción STAT3 conecta procesos de inflamación, daño/reparación e hipoxia que procesos de inflamación, daño/reparación e hipoxia que
amplifican la respuesta inflamatoria amplifican la respuesta inflamatoria
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Los receptores de nicotina son activados por la nicotina y Los receptores de nicotina son activados por la nicotina y los carcinógenos del tabaco que activan la vía del PI3K/Akt los carcinógenos del tabaco que activan la vía del PI3K/Akt
PI3K: Phosphoinositide 3 Kinasa
Akt: Protein Kinasa B
Importante señal intracelular
Inhibe la apoptosis y promuevela proliferación celular
Fundamental en el desarrollo del cáncer de pulmón no microcítico
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La vía del Hedgehog regula el desarrollo embrionario de la La vía del Hedgehog regula el desarrollo embrionario de la vía aérea y en los adultos es clave en el proceso de vía aérea y en los adultos es clave en el proceso de
regeneración del epitelio de la vía aérea dañado regeneración del epitelio de la vía aérea dañado
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Nicotinic acetylcholine receptor alpha (nAChR) subunits 3 (CHRNA3) and 5 (CHRNA5), and the 4 nAChR subunit (CHRNB4)
p53 Tumour suppressor genes
p21 wap/C1P1 cell cycle marker
RB1 Tumor supressor protein
Hedgehog interacting protein
Genes potentially involved in lung carcinogenesis and COPD pathogenesis
Adcock IM. Respiration 2011; 81: 265-84
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Diversos eventos epigenéticos son compartidos por la EPOC y el cáncer de pulmón
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Posibles mecanismos patogénicos comunes
Inflamación crónica Factores Epigenéticos
Regulación del ciclo celular
Factores genéticos
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¿Que podemos hacer?
• Evitar que los jóvenes adquieran el hábito tabáquico
• Aquellos que fuman ofrecerles tratamiento de deshabituación tabáquica
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Otras opciones (Quimio Prevención)Otras opciones (Quimio Prevención)
• Corticoides inhalados (datos contradictorios)
• Inhibidores de la COX2 (aumento riego CV)
• Prostaciclinas (Iloprost) (datos iniciales prometedores)
• Teofilina (activador de la Histona Acetilasa)
• Estatinas (datos contradictorios)
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¿Que podemos hacer?
EPOC
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Disminución de la mortalidad en EPOC
• Abandono del Tabaco
• Oxigenoterapia crónica domiciliaria
• Rehabilitación pulmonar (ejercicio físico)
Realizar un diagnóstico precozRealizar un diagnóstico precoz
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20%!!
Participants were randomly assigned to undergo three annual screenings with either low-dose CT (26,722 participants) or single-view PA RXTX (26,732).
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Lung cancer screening with low dose computed tomography in patients with mild to moderate COPD: impact on survival
de Torres et al. Respir Med. 2013 May;107(5):702-7.
Low Dose chest CT Anual Protocolo IELCAP
Seguimiento regular EPOC
RXTX basalSeguimiento regular EPOC
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Lung cancer screening with low dose computed tomography in patients with mild to moderate COPD: impact on survival
Tipo Histológico
Reference Group
Adeno 54%
Squamous 37%
Small cell 5%
Screenig Group
Adeno 65%
Squamous 26%
Small cell 5%
Estadio Oncológico TNM
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Lung cancer screening with low dose computed tomography in patients with mild to moderate COPD: impact on survival
Mortalidad por cáncer de pulmón
Mortalidad a 31 meses: 12 grupo control vs 1 grupo screening
Numero Necesario Tratar (hacer TAC): 43
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Young RP Chest. 2013 Oct;144(4):1419-20.
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Criterios de Screening en pacientes con EPOC
Criterios NLST: edad: 55-74 años, ex fumadores <15 años, >30 paquetes año
PLuSS Wilson et al: 1564pts EPOC
Pamplona de Torres et al: 575pts EPOC
70% cumplen NLST
52% cumplen NLST
66% de los DX de cáncer cumplen NLST
75% de los DX de cáncer cumplen NLST
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Acelerated Lung Function Decline increases risk of lung cancer death in COPD patiens
Sánchez P. et al. Submitted
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El Futuro de los fumadoresEl Futuro de los fumadores
Fumadores y ex fumadores: Edad > 30 + Paquetes-año>10
Espirometría y LDCT
Biomarcadores séricos o de esputo ?
Deshabituación Tabáquica
Screening periódico: cada año
Seguimiento de su EPOC anual?
Obstrucción leve + enfisema
Caída acelerada del FEV1
Biomarcadores ↑ ↑ ↑Normal Screening cada 3-5 años??
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ConclusionesConclusiones
• La EPOC y el cáncer de pulmón tienen un enorme impacto en morbimortalidad
• Hay mecanismos patogénicos comunes: inflamación, factores genéticos, epigenéticos y alteraciones ciclo celular
• Diagnóstico precoz es fundamental
• Necesitamos trabajar juntos y ser protagonistas