DE LA EPOC AL CANCER DE PULMON

Dr. J. Roig CutillasHospital N. Sra. de Meritxell Servei de PneumologiaANDORRA

I Conferencia Mediterránea sobre Derechos Humanos y TabaquismoCastelló 2009

Concepto y prevalencia de EPOC Riesgo de cáncer de pulmón en EPOC Aumento de riesgo: sexo y raza Implicaciones en programas de screening Implicaciones de esta asociación en la

aproximación terapéutica Perspectivas de futuro

EPOC Y CANCER DE PULMON

¿Qué es la EPOC?

La enfermedad pulmonar obstructiva crónica (EPOC) es una entidad caracterizada por una limitación del flujo aéreo de curso progresivo, poco reversible, pero prevenible y tratable. Esta limitación funcional se asocia a una respuesta inflamatoria anómala del pulmón frente a partículas nocivas o gases, en particular el humo del tabaco.

Espirometría

Prevalencia España

En España 1.300.000 personas entre 40 y 69 años padecen una EPOC. El 78% no estaba diagnosticado.

Leves: 38.3%Mod.: 39.7%Graves: 22%

Sobradillo V et al. Chest. 2000 Oct;118(4):981-9.

Enf cardiaca isquémica Enf cerebrovascularInfección respiratoriaEnf diarreicasTrast perinatalesEPOCEPOCTuberculosisSarampiónAccidentes de tráficoCáncer de pulmón

6ª

3ª

Cáncer gástricoSIDASuicidio

1990 2020

Murray & Lopez. Lancet 1997

Mortalidad Global Prevista

EPOC: factor de riesgo de cáncer de pulmón

Asociación definida de forma incontrovertible Mannino DM. Arch Intern Med 2003 (FEV1 < 80%)

↑ de OR en estudios con ↓ de FEV1 < 60% Kuller LH. Am J Epidemiol 1990

Factor de riesgo independiente de tabaco Skilrud D; Tockman M. Ann Intern Med 1986, 1987 EPOC + ?: población de riesgo con posible

beneficio de screening → problemática CT Mulshine J. NEJM 2005; Mahadevia P. JAMA 2006

Tockman MS. Airways obstruction and the risk for lung cancer. Ann Intern Med 1987

Rabe K. N Engl J Med 2007;356:851-854

Causes of Death in Patients with COPD. TORCH study 2007

Sin DD. Mortality in COPD: role of comorbidities. Eur Respir J 2006

RELATION OF LUNG CANCER MORTALITY TO COPD AMONG NEVER SMOKERS IN THE CANCER PREVENTION STUDY II COHORT, 1982–2002

Previous Lung Disease No. of Lung Cancer Deaths

Person-Years

Death Rate*

Fully Adjusted Hazard Ratio

 (95% CI)  Chronic bronchitis 

Yes 48 210,569 19.0 0.96 (0.72, 1.28)

No 1,711 7,932,210 21.1 1.00

 Emphysema Yes 20 35,418 42.0 1.66 (1.06, 2.59)

 No 1,739 8,107,361 21.0 1.00

Chronic bronchitis and emphysema

 Yes 8 10,585 52.6 2.44 (1.22, 4.90)

 No 1,751 7,907,377 21.1 1.00

Turner MC. COPD is associated with lung cancer mortality in a prospective study of never smokers. AJRCCM 2007

Autofluorescence bronchoscopy: detection of early epithelial abnormalities

Frequency distribution of FEV1 (%) predicted in smoking controls ( ) and lung cancer cases ( ) (n = 602) matched for age, sex and smoking history.

Young RP et al. COPD prevalence is increased in lung cancer, independent of age, sex and smoking history. Eur Respir J 2009; 34:380-386

Screening: otros factores asociados a riesgo alto de cáncer de pulmón en EPOC

↑ riesgo por otros carcinógenos: Ar, asbesto Chen C. JAMA 2004; Smith K. Clin Chest Med 2002

↑ de riesgo por factores raciales-étnicos Haiman C, NEJM 2006; Coté M. JAMA 2005

Son las mujeres más susceptibles? Rivera MP. Clin Ch Med 2004; Patel J. JAMA 2006 ↑ de riesgo por factores genéticos (familiar) Schwartz AG. Familial lung cancer: genetic

susceptibility and relationships to COPD. Am J Respir Crit Care 2006 (cromosomas 6q, 12)

Coté M. Risk of lung cancer among white and black relatives of individuals with early –onset lung cancer. JAMA 2005 Early onset LC: diagnóstico edad < 45 años Mayor riesgo en parientes fumadores con historia

familiar en primer grado Familiares de 1er grado de raza negra mayor riesgo

que en raza blanca (OR 2.07) Asociación de EPOC con “early-onset lung cancer”

identificada en familiares blancos (OR 1.48) pero no en los de raza negra después de ajuste para otras variables

Predicted Rates of Lung Cancer among Men Who Currently Smoke 10 Cigarettes per Day (Panel A) or 30 Cigarettes per Day (Panel B) and among Women Who Currently Smoke 10

Cigarettes per Day (Panel C) or 30 Cigarettes per Day (Panel D)

Haiman, C. et al. N Engl J Med 2006;354:333-342

Haiman CA. Ethnic and racial differences in the smoking-related risk of lung cancer. NEJM 2006

FEMALES

Jemal A. Cancer Statistics. CA Cancer J Clin 2003

Wasswa-Kintu S. Relationship between reduced FEV1 and the risk of lung cancer: systematic review and meta-analysis. Thorax 2005

Ben-Zaken Cohen S. The growing burden of COPD and lung cancer in women. Examining sex differences in cigarette smoke metabolism. AJRCCM 2007

Sobreexpresión de enzimas CYP por estrógenos

Mayor frecuencia de mutaciones p53 Mayor depósito de partículas por:

Vías aéreas más pequeñasAumento de reactividad bronquial

Menor capacidad de reparación de DNA

http://ajrccm.atsjournals.org/content/vol176/issue2/images/large/113fig2.jpeg

Autofluorescence bronchoscopy: detection of early epithelial abnormalities

The relationship between progression of lesion and various baseline factors

Variables Odds ratio C-statistic p valueCRP,mg/l 2.59 0.64 0.014Pack-years 2.34 0.62 0.009FEV1,% predicted 0.40 0.69 0.005

Current smoker 2.94 0.57 0.218Age 1.00 0.64 0.990Men 1.22 0.56 0.812

Sin DD. Progression of airway dysplasia and C-reactive protein in smokers at high risk of lung cancer. Am J Respir Crit Care Med 2005

Parimon T. Inhaled corticosteroids and risk of lung cancer among patients with COPD. AJRCCM 2007

Spira A. Multidisciplinary management of lung cancer. NEJM 2004

Sequencial pathogenic changes involved in lung cancer

El inicio de la quimioterapia (1946), basado en la investigación de la guerra química

Cl Cl

N

Aminopterin (1948)

Farber S, et al. N Engl J Med 1948

H2N

N

N N

N

HN

HN

O

OH

OHO

NH2

O

Goodman L, et al. JAMA 1946

Mustine (1946)

1940 1950 1960 1970 1980 1990 2000 20101930

1940 1950 1960 1970 1980 1990 2000 20101930

Nuevos agentes citotóxicos

The first platinum: discovery of cisplatin

NH3NH3

Pt

Cl Cl

The first taxane:discovery of paclitaxel in bark of the Pacific yew

1965 1967

Herbst R and Lippman S. N Engl J Med 2007;356:76-78

Herbst RS. Molecular Signatures of Lung Cancer — Toward Personalized Therapy. NEJM 2007

EPOC ↔ CáncerConsideraciones sobre quimioterapia

Aumento del riesgo de toxicidad pulmonar para diversos agentes como mitomicina

Derrame pleural en síndrome de “fluid retention” (trasudado) con docetaxel

Depresión respiratoria con ifosfamida y metotrexate en EPOC severa-Sleep apnea

Neuropatia (vincristina) puede afectar la función muscular respiratoria

Aldrich T, Clin Chest Med 1990; Klein D, Can Anaesth Soc J 1983; Roig J, Clin Pulm Med 2006

First pneumonectomy performed in a lung cancer patient: 1933 !!

1940 1950 1960 1970 1980 1990 2000 2010

Graham E, et al. JAMA 1933

1930

EPOC ↔ CáncerAlgunas consideraciones quirúrgicas

Función pulmonar y límite de resecabilidadRoig J. SEPAR - FMC 2006 Valor de resección limitada (>70 años)Mery C. Chest 2005 VATS?Muraoka M. Jpn J Thorac Cardiovasc Surg 2006 Esternotomía media?Asaph J. Am J Surg 1984; Miyamoto H. ANZ J Surg 2005 Dolor post-cirugía aumenta riesgo de infecciónBelda J. Chest 2005; Clin Pulm Med 2006

Journal of Thoracic Oncology: Volume 1(9)November 2006pp 960-964

Wedge Resection for Non-small Cell Lung Cancer in Patients with Pulmonary Insufficiency: Prospective

Ten-Year Survival

Griffin, John P. MD*; Eastridge, Charles E. MD†‡; Tolley, Elizabeth A. PhD§; Pate, James W. MD||

Divisions of *Pulmonary and Critical Care Medicine, §Preventive Medicine and Medicine Division of Biostatistics and Epidemiology,

and ||Department of Surgery, University of Tennessee Health Science Center, Memphis, TN; and ‡Thoracic Surgery Section

Surgery Service, VA Medical Center, Memphis, TN.

FIGURE 1. Kaplan-Meier plot for a consecutive surgically resected series of patients with non-small cell lung cancer from 1988 to 1992 at Memphis VA Medical Center, based on all-cause mortality.Griffin JP. Wedge resection for NSCLC in patients with pulmonary insufficiency. J Thor Oncol 2006

Sekine I. Association of COPD and tumor recurrence in patients with stage IA lung cancer after complete resection. Ann Thorac Surg 2007

n = 442 Estadio I: lobectomía 362 COPD (FEV1/FVC <70%) Aumento neumonía y traqueostomía COPD No dif. en otras complicaciones postcirugía Supervivencia global peor en COPD

(p<0.001) COPD asociado con recurrencia (p=0.0105)

A-alveolo normal B-enfisema C-bronquiolo y alveolo normales D-enfisema

Ueda K. Computed tomography- diagnosed emphysema, not airway obstruction, is associated with the prognostic outcome of early-stage lung cancer. Clin Cancer Res 2006

EPOC ↔ CáncerConsideraciones sobre radioterapia

Elevado riesgo obliga a optimizar campo a irradiarSpiro SG. Am J Respir Crit Care Med 2005 PET muy útil en atelectasias y PET- CT en la

evaluación de respuesta y predicción evolución?Manus M. J Clin Oncol 2003; Gamez C. J Thor Oncol 2006 Efecto protector de amifostina en ser humano Modelo animal: vitamina A, pentoxifilina, IECA,

Mn superoxide dismutasa gene therapyAbratt RP. Clin Chest Med 2004

Fusion PET- CT scan

Riesgo extravasación intratorácica Hipercoagulabilidad asociada a neoplasia Hipercoagulabilidad por terapia

concomitante como eritropoyetina o acetato de megestrol

TEP asociado a vias centrales y reservorios sc (Portacath)

Hemoptisis en QT intraarterial pulmonar

Domingo C & Roig J. Neglected respiratory toxicity caused by cancer therapy. Open Respir Med Review 2007

Spitz MR et al. The CHRNA5-A3 Region on Chromosome 15q24-25.1 Is a Risk Factor Both for Nicotine Dependence and for Lung Cancer. J Natl Cancer Inst 2008;100: 1552 – 1556.

Common variants in the nicotinic acetylcholine receptor gene cluster on chromosome 15q24-25.1 were associated with lung cancer risk in three recently published independently conducted genome-wide association studies

The variants were associated with higher risks of lung cancer in lower smoking-exposed strata, and in individuals with a strong family history of lung or smoking-related cancers. In contrast, we found no evidence that the variants were associated with elevated risks in 547 lifetime never-smoking lung cancer case subjects

Young RP et al. Lung cancer gene associated with COPD: triple whammy or possible confounding effect? Eur Respir J 2008; 32:1158-1164

Several large genome-wide association studies have identified a putative "lung cancer" locus in the nicotinic acetylcholine receptor subunit genes (nAChR) on 15q25

Comparison of genotype frequencies between three matched smoking cohorts.

The AA genotype was found to be more frequent and was seen in 437 (16%) lung cancer cases and 445 (14%) COPD cases compared with 475 (9%) healthy smoking controls

Granville CA. Identification of a highly effective Rapamycin schedule that markedly reduces in size, multiplicity and phenotypic progression of tobacco carcinogen-induced murine lung tumors. Clin Cancer Res 2007

Inducción de tumores en el modelo animal por el carcinógeno de tabaco NNK

Administración de rapamicina (inhibidor de mTOR) en diferentes esquemas

Administración precoz diaria ↓ tamaño tumoral y multiplicidad (90%)

Aprobación de rapamicina por FDA

1940 1950 1960 1970 1980 1990 2000 20101930

1950: asociación entre cáncer de pulmón y tabaco

‘The risk of developing the disease increases in proportion to the

amount smoked. It may be 50 times as great among those who smoke

25 or more cigarettes a day asamong non-smokers.’

Doll R, et al. Br Med J 1950

Anthonisen NR. The effects of a smoking cessation intervention on 14.5-year mortality. Ann Intern Med 2005

Mortality rates at 14.5 years by cause and smoking status