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De la EPOC al Cancer de Pulmón

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I Conferencia Mediterránea sobre Derechos Humanos y Tabaquismo
Castelló 2009

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De la EPOC al Cancer de Pulmón

  1. 1. DE LA EPOC AL CANCER DE PULMON Dr. J. Roig Cutillas Hospital N. Sra. de Meritxell Servei de Pneumologia ANDORRA I Conferencia Mediterránea sobre Derechos Humanos y Tabaquismo Castelló 2009
  2. 2.  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
  3. 3. ¿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.
  4. 4. Espirometría
  5. 5. 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.
  6. 6. Enf cardiaca isquémica Enf cerebrovascular Infección respiratoria Enf diarreicas Trast perinatales EPOCEPOC Tuberculosis Sarampión Accidentes de tráfico Cáncer de pulmón 6ª 3ª Cáncer gástrico SIDA Suicidio 1990 2020 Murray & Lopez. Lancet 1997 Mortalidad Global Prevista
  7. 7. 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
  8. 8. Tockman MS. Airways obstruction and the risk for lung cancer. Ann Intern Med 1987
  9. 9. Rabe K. N Engl J Med 2007;356:851-854 Causes of Death in Patients with COPD. TORCH study 2007
  10. 10. Sin DD. Mortality in COPD: role of comorbidities. Eur Respir J 2006
  11. 11. 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
  12. 12. Autofluorescence bronchoscopy: detection of early epithelial abnormalities
  13. 13. 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
  14. 14. 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
  15. 15. 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
  16. 16. 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
  17. 17. FEMALES Jemal A. Cancer Statistics. CA Cancer J Clin 2003
  18. 18. Wasswa-Kintu S. Relationship between reduced FEV1 and the risk of lung cancer: systematic review and meta-analysis. Thorax 2005
  19. 19. 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 pequeñas Aumento de reactividad bronquial  Menor capacidad de reparación de DNA
  20. 20. Autofluorescence bronchoscopy: detection of early epithelial abnormalities
  21. 21. The relationship between progression of lesion and various baseline factors Variables Odds ratio C-statistic p value CRP,mg/l 2.59 0.64 0.014 Pack-years 2.34 0.62 0.009 FEV1,% predicted 0.40 0.69 0.005 Current smoker 2.94 0.57 0.218 Age 1.00 0.64 0.990 Men 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
  22. 22. Parimon T. Inhaled corticosteroids and risk of lung cancer among patients with COPD. AJRCCM 2007
  23. 23. Spira A. Multidisciplinary management of lung cancer. NEJM 2004 Sequencial pathogenic changes involved in lung cancer
  24. 24. 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 H N H N O OH OHO NH2 O Goodman L, et al. JAMA 1946 Mustine (1946) 1940 1950 1960 1970 1980 1990 2000 20101930
  25. 25. 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
  26. 26. 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
  27. 27. EPOC ↔ Cáncer Consideraciones 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
  28. 28. First pneumonectomy performed in a lung cancer patient: 1933 !! 1940 1950 1960 1970 1980 1990 2000 2010 Graham E, et al. JAMA 1933 1930
  29. 29. EPOC ↔ Cáncer Algunas consideraciones quirúrgicas  Función pulmonar y límite de resecabilidad Roig 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 infección Belda J. Chest 2005; Clin Pulm Med 2006
  30. 30. 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.
  31. 31. 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
  32. 32. 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)
  33. 33. A-alveolo normal B-enfisema C-bronquiolo y alveolo normales D-
  34. 34. Ueda K. Computed tomography- diagnosed emphysema, not airway obstruction, is associated with the prognostic outcome of early-stage lung cancer. Clin Cancer Res 2006
  35. 35. EPOC ↔ Cáncer Consideraciones sobre radioterapia  Elevado riesgo obliga a optimizar campo a irradiar Spiro 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 therapy Abratt RP. Clin Chest Med 2004
  36. 36. Fusion PET- CT scan
  37. 37.  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
  38. 38. 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
  39. 39. 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
  40. 40. 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
  41. 41. 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 as among non-smokers.’ Doll R, et al. Br Med J 1950
  42. 42. 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

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