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.
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De la EPOC al Cancer de Pulmón
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.
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.
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
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
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
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
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
30.
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
32.
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)
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
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
Editor's Notes
Figure 1. Causes of Death in Patients with COPD. Among patients with COPD, death can result from causes in a number of disease categories, in part, because of the strong association between COPD and exposure to cigarette smoke. In the Towards a Revolution in COPD Health (TORCH) trial, 35% of deaths were adjudicated as due to pulmonary causes, 27% to cardiovascular disease, and 21% to cancer. Ten percent were attributed to other causes, whereas the primary cause of death could not be determined by the clinical end point committee in 7% of cases.
Figure 1-11. Autofluorescence bronchoscopy has been reported to detect early epithelial abnormalities, as seen in this figure. The system works with helium-cadmium laser light (442-nm wavelength) and an optical multichannel analyzer as the light source attached to the bronchoscope instead of the usual white light [16]. Normal areas have a green coloration, whereas areas that are malignant or premalignant have a reddish coloration. Autofluorescence systems can detect suspicious lesions that are not visible by traditional white light bronchoscopy. Lam et al. [17] found that of 102 intraepithelial lesions, only nine (8.8%) were localized by white light bronchoscopy alone, whereas the addition of autoflouresence bronchoscopy identified 57 sites (56%). Because of conflicting results, further studies are needed to define the role of autofluorescence bronchoscopy in identifying early lung cancer and premalignant lesions.
Figure 1-11. Autofluorescence bronchoscopy has been reported to detect early epithelial abnormalities, as seen in this figure. The system works with helium-cadmium laser light (442-nm wavelength) and an optical multichannel analyzer as the light source attached to the bronchoscope instead of the usual white light [16]. Normal areas have a green coloration, whereas areas that are malignant or premalignant have a reddish coloration. Autofluorescence systems can detect suspicious lesions that are not visible by traditional white light bronchoscopy. Lam et al. [17] found that of 102 intraepithelial lesions, only nine (8.8%) were localized by white light bronchoscopy alone, whereas the addition of autoflouresence bronchoscopy identified 57 sites (56%). Because of conflicting results, further studies are needed to define the role of autofluorescence bronchoscopy in identifying early lung cancer and premalignant lesions.
Figure 1. Development of Personalized Drugs for Lung Cancer, from Identification of Genomic Signatures to Prospective Trials of Personalized Therapy.
Figure 5-11. Molecular imaging. Traditional radiotherapy based on CT scan images (A) is sometimes difficult when tumors are associated with significant amounts of atelectasis or postobstructive pneumonitis, leading to the treatment of larger areas because the precise borders could not be well defined. However, with the advent of molecular based imaging, the fusion of 18-fluorodeoxyglucose positron emission tomography (18FDG PET) images with CT-based imaging permits significant reduction of treated volumes with sparing of normal tissues structures, allowing for the possibility of further dose escalation (B). Note that in both images, the brown line represents the 95% isodose line for coverage of the mass and the red area represents the metabolically active tumor, as detected on PET scan.
