This document discusses the relationship between chronic obstructive pulmonary disease (COPD) and lung cancer. It begins by defining COPD and providing statistics on prevalence in Spain. It then discusses several studies that have shown COPD to be an independent risk factor for lung cancer. Certain factors like lower lung function, sex, race, and genetics can further increase the risk. Screening high-risk COPD patients for lung cancer is discussed. The document concludes by considering implications for treatment approaches, like increased toxicity risks from chemotherapy or surgery in COPD patients.

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.  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. ¿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. Espirometría

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

9. Rabe K. N Engl J Med 2007;356:851-854
Causes of Death in Patients with COPD. TORCH study 2007

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

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

14. Autofluorescence bronchoscopy: detection of
early epithelial abnormalities

15. 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

16. 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

17. 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

18. 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

19. FEMALES
Jemal A. Cancer Statistics. CA Cancer J Clin 2003

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

21. 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

23. Autofluorescence bronchoscopy: detection of
early epithelial abnormalities

24. 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

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

26. Spira A. Multidisciplinary management of lung
cancer. NEJM 2004
Sequencial pathogenic changes involved in lung cancer

27. 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

28. 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

29. 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

31. 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

33. First pneumonectomy performed
in a lung cancer patient: 1933 !!
1940 1950 1960 1970 1980 1990 2000 2010
Graham E, et al. JAMA 1933
1930

34. 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

35. 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.

36. 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

37. 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)

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

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

40. 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

41. Fusion PET- CT scan

43.  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

44. 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

45. 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

46. 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

47. 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

48. 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