EPIDEMIOLOGY OF LUNG CANCER

This review article presents lung cancer epidemiology, describing main epidemiologic characteristics including epidemiological situation in cancer incidence, mortality and survival in Europe in comparison with situation in the Czech Republic. Influence of environmental and life style risk factors like smoking, passive smoking, risk factors of work environment, ionizing radiation, air pollution, nutrition and genetic and hormonal factors are discussed.


INTRODUCTION
At present, primary lung cancer is a worldwide problem.During the last fifty to sixty years, the incidence of this illness has increased dramatically owing to the increasing prevalence of smoking, urbanization and environment pollution.
Lung cancer is now the most frequent malignant tumorous illness in men in most European countries and is increasing in women as well.Annually, more than 1 million people around the world die from the lung cancer and the incidence is increasing, especially in developing countries 1,2 .Although many etiological factors have been known for years, only during last few years preventive and antismoking programs have been started and that only in some countries.Lung cancer is an illness with a long latency and even with recognizing the causing factors and with knowledge of modern medical procedures, an increase of this illness can be expected in near future, especially in the female population.

SITUATION IN EUROPE
In 1990, approximately 270,000 cases of the lung cancer were diagnosed.With people getting older, the probability of getting lung cancer increases by 4-12 % among European men and by 0.5-3 % among European women, depending on the country.On average, one out of 10-15 European men and one out of 80-90 European women gets the lung cancer before the age of 75 as long as his/her death is not caused by something else.Considering that the incidence of the lung cancer in most of the European countries has an increasing tendency, the risk of getting this illness for young people increases as well.If a fundamental change in risk factors does not occur, after year 2000, we can expect annually 300,000 cases of lung cancer in Europe 3 .
In Great Britain, where until 1970 an increase of lung cancer death rate had been experienced, the increase has leveled off and after a period of plateau, the lung cancer death rate decreased.In comparison, in South European countries, despite a lower death rate, a rapid increase in the lung cancer death rate has been noted in the recent past.In Central European countries, even in the fifties, the death rate was relatively high and since that time, we have been noticing a steady moderate increase in the lung cancer death rate.In Belgium and Holland, the lung cancer death rate was higher than in other countries, and lately, the lung cancer death rate in these countries has been higher than in Great Britain.Among women, the lung cancer death rate in all monitored European countries has been increasing.The highest values are being noticed in Great Britain, Ireland and Denmark.In central and southern Europe, the incidence is still low and varies in the range of 2-5 women out of 100,000 annually.Taking into consideration that among young women, the population prevalence of smoking is increasing, a dramatic increase in lung cancer can be expected in southern and central Europe within the next 2-3 decades 3 .(Tab.

Mortality
Death rate from malignant tumorous illnesses is considered an important yardstick in the struggle against malignant tumorous illnesses.In the Czech Republic, lung cancer is a more frequent cause of death than any other malignant tumorous illness.The death rate of lung cancer in men after the 2 nd world war has been steadily increasing.In 1950-1967 the death rate rose almost ten times 5 and in the second half of the nineteen eighties the lung cancer death rate in men in the Czech Republic remained the highest, worldwide 6 .After peaking out in 1986, we have been noticing a decreasing trend.
Until mid nineteen seventies, the lung cancer death rate in woman was at low level values and 10-12 times lower than the rate in men.Since that time, the lung cancer death rate among women has been steadily increasing and at present it is only 6 times lower than the rate in men and the difference is decreasing.
In 1998, in the Czech Republic, 4,298 (85.8/100,000) men and 1,135 (21.5/100,000) women died of the lung carcinoma, which , compared with the worldwide standard, is 61.0 men out of 100,000 people and 11.5 women out of 100,000 people 7 .
According to the estimate, by 2009, we can expect a decrease in the death rate in men, especially in the 40-60 age group.On the other hand, a steady increase is still expected in women in all age groups 8 .
In men, lung cancer mortality is in the 1st place, in women in the second place, although lung cancer incidence among women is in the 6 th -7 th place.This can be explained by high lethality and relatively short survival time.This is the reason why the death rate is a an excellent indicator on which we can use to draw conclusions regarding incidence changes 9 .(Graph 9, 10)

Survival time
Most people who get lung cancer, succumb to this illness.Five year survival time falls into 10 to 13 % range 10 .
The survival time also depends on the histological type; the small cell lung cancer, five year survival time can be expected only in 5 % patients, while with the localized lung cancer, up to 46 % patients 11 .(Graph  11, 12).

Smoking
Smoking is a risk factor contributing to development of a number of illnesses 12 .
In 1920's and 30's, there was, especially in U.S.A., a tremendous increase in the lung cancer and, based on clinical observations, suspicion arose that smoking could be the inducing factor.A number of studies followed 12,13,14,15 , which confirmed the causal relation between cigarette smoking and developing tumorous illnesses, especially lung cancer.
In 1979, the International Agency for Research on Cancer estimated, that the proportion of lung cancer death caused by smoking is 91.5 % in men and 78.5 % in women 10,16 , with the estimates for England and Wales in 1981 even higher, reaching 94 % values in men and 80 % in women 12 .
Similarly, the estimates for Czech Republic in 1990's were approximately 94% for men and 52 % for women 17 .
Low estimate for women was due to the smaller percentage of women smokers during previous decades in the female population in Czech Republic, as well as in other central and east European countries 18 .
Cigarette smoking is a very serious carcinogenic factor.Cigarettes possess a concentrate of quite a few known genotoxic and carcinogenic agents.Tobacco smoke is a mixture of four to five thousand chemical substances, where the main component is nicotine, but it consists also of other irritative substances like acrolein, aldehydes, ammonia, carbon monoxide, hydrocyanic acid, nitrogen oxides, sulphur oxides, mutagens and approximately 60 carcinogenic agents, aromatic hydrocarbons, aromatic amines, nitrosamines, benzene, cadmium, arsenic, polonium 210 and others 19 .In the metabolic transformation many of these chemical substances, an increase of mutagenic and carcinogenic effects develops, the target tissues and organs sustain oxidation damage and these oxidants create numerous covalent links with DNA.Tobacco smoke consists of the main stream, which is inhaled and partially exhaled by the smoker, and the secondary stream, which is more concentrated, depending on the combustion temperature.A freely burning cigarette stub has a temperature about 300 to 400 °C, during inhaling about 1,000 °C 19,20 .The amount of inhaled substance is higher in the case of a smoker, but exposure in the case of a non-smoker is high as well, because the concentration of carcinogenic agents in the secondary stream is several times higher than in the main stream.This is due to incomplete combustion at lower temperature.An indicator for the solid part of the main stream and gaseous part of the secondary stream is nicotine, which we can evaluate in the environment.In case of an active, but also a passive smoker, exposure to tobacco smoke is evaluated by amount of nicotine and its main metabolite, cotinine 19 .An average smoker absorbs, while actively smoking, 20 to 30 cigarettes a day, 40 mg of nicotine.
Lung cancer development is a long process that takes two, three and even more decades to develop 21 .The daily action of carcinogenic agents, meaning cigarette smoke, is needed for the lung cancer to develop.The bronchial epithelium gradually goes through the stages of metaplasia, dysplasia and carcinoma in situ which are reversible, providing the smoking is stopped before the process gets into the invasive stage.Another significant condition is the number of cigarettes smoked daily, depth of smoke inhalation into lungs 22,23 , age when smoking started, number of smoking years 24 and the amount of tar contained in the cigarettes 25 .Risk of the lung cancer development for smokers who smoke 40 or more cigarettes a day is 20 times greater than for nonsmokers.The situation for women is slightly different.According to the study conducted in 1982-1986 among American women, the risk of lung cancer development was 12.7 for smoking women and this risk increased to 20 and more for women smoking more than 30 cigarettes a day 22,23 .(Graph 13).
Graph 13.Relative risk in relationship to the number of cigarettes smoked per day After quitting smoking, the risk of the lung cancer development decreases, even though, paradoxically, in the first years of abstinence the risk of the lung cancer development for the former smokers can be even higher than for continuing smokers.This can be explained by the fact that some smokers may have stopped smoking because of health problems that have been causing development of their lung cancer.A positive effect of the quitting of smoking can become apparent after 5 years, at the latest, when the relative risk is approximately 6.Further abstinence results in further decrease of the risk which, however, never drops down to the risk level of persons who have never smoked, and even after 20 years of smoking abstinence, the relative risk is in the region of 1.1 to 2 12,26,27 also in the relationship with the smoking period and the age of the smoker.(Graph 14) Smoking promotes lung cancer development of all histological types but a greater effect is manifested with the squamous and small cell lung cancer 28 .
Risk of lung carcinoma development in the case of a non-smoker is rare even though it increases slightly with age 29 and the incidence is up to about 10 %.
Incidence of lung cancer however is not completely explicable only as active smoking.The lung cancer is an illness with a multi-factorial etiology 26,30 .Even though active smoking has decisive importance, the significance of other factors cannot be disregarded, since, beside their independent effects, they can even increase the impact of smoking

Passive smoking
Passive smoking, meaning inhaling environmental tobacco smoke, is causing health damage and contributes to the increased incidence of the lung cancer among non-smokers 31,32,33 .A non-smoker, living or working in a smoke polluted environment for a prolonged period of time, is exposed to the 20 to 30% greater risk of lung cancer incidence in comparison with non-smokers who are not exposed to passive smoking 34 .
Tobacco smoke environment is mostly created by the secondary stream of smoke, which develops between two inhalations or by spontaneous smouldering of a cigarette stub.The temperature of the stub decreases to 300 °C or less and incomplete combustion of organic substances with chemical reactions under low combustion temperatures starts.In this secondary stream, which accounts for approximately 85% of the total amount of smoke, there is a several times higher concentration of carcinogenic agents than in the main stream.In such a secondary stream, there is for example, as compared with the main stream, 2.7 times more nicotine, 1.7 times more tar, 3.4 times more benzo-Apyran, 57 times more of specific tobacco nitrosamines and a number of other substances.In the case of a nonsmoker, we assess his tobacco smoke exposure by the amount of present nicotine and his main metabolitecotinine 35 .
Even though it is difficult to determine the exact proportion of lung cancer due to passive smoking, it is estimated that the relative risk is 1.3 to 3.5 36 , depending on the time period and intensity of exposure.In the Czech Republic, it is estimated, that approximately 70 non-smokers die annually from the effect of passive smoking 19 .

Risk factors of work environment
Exposure to carcinogenic agents in the environment can affect the incidence of lung cancer independently of tobacco use, but in conjunction with smoking with low intake of protective substances in foodstuffs and in H. Kollárová, V. Janout, L. Čížek Graph 14.Relative risk for former smokers in relationship with the non-smoking period relationship to genetically determined susceptibility and resistance to carcinogenic stimuli, compounds the issue.
Elimination of exposure to carcinogenic agents in the work environment is conditioned by knowledge of sources of risk and compliance with the safety rules in work places, handling materials containing these substances.It is estimated that approximately 15% lung cancer cases are caused by exposure in working environments 37 .
Arsenic and its compounds, including pesticidal, insecticidal and herbicidal substances, for example, are classified as work environment risk factors 38,39 .Another work environment risk factor is asbestos.By this term we denote some types of filamentous mineral fibres differing in shape, length, flexibility and at the same time in aggressiveness of their biological action on organisms.Exposure to asbestos through air is considered one of the greatest risks of contracting the lung cancer and mesothelium in work environment 40 .Persons exposed to asbestos in work environments on a long term basis have up to 20% lung carcinoma death rate.The latency time is in the region of 15 to 20 years 41 .Exposure to chromium, nickel, polycyclic aromatic hydrocarbons 42 , silicone compounds 43 , berylium, formaldehyde, ionizing radiation including radon and a number of others are considered risk factors for development of lung cancer 44 .Exposure to radon in work environment causes a significant increase in risk of development of lung cancer -about 13 times for non-smokers 45 and 20 times for smokers 46 .

Ionizing radiation in the environment and medicine
Lung cancer is one of the main results of exposure to high doses of ionizing radiation 47 .Medicine itself is a source of about 15% of the total radiation load and the current trend rather points to an increase in this load.Therefore it is necessary to carefully consider the suitability and frequency of both X-Ray and isotopic diagnostic examinations.Of natural resources of ionizing radiation , radon, around 50 %, 37,48 and other emission of radioactive agents from subsoil of dwellings, building materials and water represent the largest proportion.Health consequences of radon radiation in dwellings in the Czech Republic are presently estimated 10% of all lung cancer cases, which means approximately 600 deaths annually as a result of radon radiation.The lung cancer caused by radon usually develops at a later age and does not develop at an early age and early adulthood.

Air pollution
Air pollution a suspect risk factor in lung cancer etiology 49,50 .
The main source of contaminating substances emission into the atmosphere are combustion processes, that include electric energy production, thermal energy and transportation.Further sources are industrial and agricultural production.

Epidemiology of lung cancer
Beside the outside atmosphere, a person is exposed to contaminating substances also in environment inside buildings, emitted from subsoil and building materials (radon), furnishing ( coating, formaldehyde) and outside atmosphere.
The proportion of carcinogenic agents in contaminated atmosphere is much smaller than other possible, already mentioned, factors.The seriousness, however, is increasing currently, with an 37,49,51 accumulation of risk factors and thus increase in total load.The impact of polluted environment on total tumorous illnesses death rate is estimated approximately 2 to 3% 50 .

Nutrition
Nutritional factors can intervene in the cancerogenic process at all stages.They interact, on the one hand, with individual chemical substances, and on the other hand through food and food groups in relationship to other outside environmental factors, second they interact within the scope of genetic peculiarities and individual susceptibility.Recent epidemiological studies indicate that dietetic and nutritive factors can positively influence the risk of lung cancer development 52,53,54 .This influence is possible in the sense of both, acceleration and inhibition of cancerogenesis.In cells, peculiar malignant proliferations have been found indicating genes -oncogenes, which can be activated through specific factors in the outside atmosphere.Current knowledge regarding the initiation, maintenance and regulation of oncogenes make it possible to claim that a greater part of malignant tumorous illnesses have an outside cause and can be, at least partially, prevented.The number of tumorous cells increases during the latency period, which can last 5 or more years.Considering the long lung cancer latency period, it is necessary to monitor the relationship between the nutrition and development of the illness during the foregoing 10-20 years before clinical detection of lung cancer.
High consumption of fats, food rich in cholesterol, including full-cream milk and eggs, increase the risk of lung cancer development 54,55 .
Also, consumption of alcohol can increase the risk of lung cancer development 56,57 .Alcoholic beverages have been classified as first class carcinogens for humans 58 .A number of possible mechanisms are responsible for the carcinogenic effect of alcoholic beverages, firstly it is the nutritional deficiency, second an increased permeability of the bronchiol mucosa, leading to, possible penetration of other carcinogenic agents and also the presence of carcinogenic agents in alcoholic beverages.Excessive consumption of alcohol is hazardous primarily in combination with smoking because it strengthens the negative effect.The effect of alcohol itself is difficult to establish, because population groups of non-smoking alcohol users are very small and difficult to identify.
Other important components of food are vitamins and minerals.In vitamins contained in normal food, a protective effect against lung cancer has been confirmed.These are especially carotenoids, vitamins C and vitamins E and trace elements like selenium and zinc 59 .Mechanism of the beta-carotene effect is related to the role of these agents in the cell differentiation and especially their anti-oxidizing effect, when they decrease lipid peroxidation and the creation of free oxygen radicals, this may also cause regression of bronchial dysplasia.
By contrast, vitamins in purified supplementary form appear to be non-effective and some studies, that were supposed to verify the protective effect of vitamin preparations, have found an increased risk of the lung cancer development after beta-carotene had been taken 59,60 .This is the reason why a supplementary carotene is not recommended.
Fruit and vegetables generally decrease the risk of tumorous illnesses and have a positive effect on lung cancer too.We can consider that the positive effect of fruit and vegetables can be achieved by a combination of known nutritional components (fiber, vitamins and mineral substances) and other bioactive agents, so called phytochemicals.This complex of positive factors works together and is not replaceable by isolated preparations.Approximately 20 to 30% of the lung cancer cases are preventable by nutritional factors.
Some studies have pointed to the relationship of the Body Mass Index (BMI) with the risk of development of the lung cancer.A significantly higher incidence of lung cancer in thinner persons, with a lower BMI, has been found 61 .Normal BMI values are considered values in the range of 19-25, the values BMI < 19 mean underweight, the values in the range of 25-30 are considered as overweight and the values BMI > 30 are considered as obesity 62 .

Primary non-tumorous lung illnesses
Some primary non-tumorous illnesses (asbestosis, silicosis, tuberculosis, chronic bronchitis, pneumonia, emphysema and others) increase the relative risk of lung cancer development 63,64 , ranging from 1.5 for pneumonia to 2.7 for asthma bronchiale 63 .

Genetic and hormonal effects
Susceptibility and resistance to carcinogenic stimuli and the transformation process from a normal to a tumorous cell has a genetic basis.In susceptible persons, a different process of metabolism of carcinogenic and some other agents has been demonstrated 65,66,67 .Disorder in the ability to repair genic or chromosomal defects can be inherent.
The function of genetic factors is however weakened by strong environmental risk factors like smoking.While searching for genetic susceptibility markers, a genetically regulated enzymatic defect, which change the metabolism of polycyclic aromatic hydrocarbons (PAH) has been indicated.It has however been impossible to demonstrate this defect consistently 68 .In 1991, infor-mation concerning the DNA of polymorphism in a gene for cytochrome P450 (CYP1A1), that is responsible for benzo(a)pyrene, was published.In genetically susceptible persons, small doses of cigarette smoke exposure were sufficient for inducing squamous cell carcinoma of the lung 69 .However, even these findings were not always consistent.Further, in connection with the risk of the lung cancer development, the genetically controlled ability to metabolize anti-hypertensive agent debrisoquine was mentioned.P450 gene ( CYP 2D6), regulating debrisoquin metabolism, can also influence the metabolism of NNK nitrosamine, which is a potential lung carcinogen in experimental animals and which increases the risk of lung cancer development 6 times or more 70 .Also decreased activity of the glutathione S-transferases enzyme, (GST), which catalyzes polycyclic aromatic hydrocarbons (PAH) conjugation is mentioned as a factor which increases the risk of lung cancer development 71 .Recently, the function of polymorphism in the GSTM4 gene in assessing the risk of the lung cancer development, has been indicated 72 .GSTM1 deficit is associated with a relative risk of 1.4 73 .During development of lung cancer, a sequence of genetic changes can occur.Mutation in p53 suppressor gene tumour and in the oncogene ras is commonly found in lung tumorous tissue with the ras mutation limited to small-cell lung cancer 74 .The mutation frequency in lung tumorous tissue is still uncertain, but most tumours express mutated p53 genes and 20 to 30 % of ras genes.Furthermore, p53 and ras mutations are usually found in the same tumour, which supports the idea that one increases the activity of the other in the carcinogenic process 75 .
Hormonal risk factors have been suggested by the observation that among nonsmokers adenocarcinoma affects proportionately more females than males, by the possible role of menstrual variables, particularly menstrual cycle length, and by the finding of sex steroid receptors in lung cancer 76 .It is also necessary to carry out a study of anti-tumour protective ability of an organism 77 .
A synergetic effect of several factors like smoking, exposure to contaminated work environment, polluted atmosphere, genetic pre-disposition and coincidence with previous lungs illness, especially with the lung adenocarcinoma.

Graph 9 .
Lung cancer mortality -male Graph 10.Lung cancer mortality -female Graph 11.Age standardized lung cancer survival time in some European countries in 1995 -male 109 Epidemiology of lung cancer Graph 12. Age standardized lung carcinoma survival time in some European countries in 1995 -female

Table 1 .
Estimate of trachea and lung malignant tumours incidence in selected areas of Europe in 2000 -age standardized incidence (world standard).
Graph 1. Age standardized lung cancer incidence in some European countries in 1995 -male Graph 2. Age standardized lung cancer incidence in some European countries in 1995 -female H. Kollárová, V. Janout, L. Čížek Graph 3. Age standardized lung cancer death rate in some European countries in 1995 -male Graph 4. Age standardized lung cancer death rate in some European countries in 1995 -female Graph 5. Neoplasm death rate by localities in the Czech Republic in 1999 in % -male Graph 6. Neoplasm death rate by localities in the Czech Republic in % -female Graph 8. Lung cancer incidence -female Graph 7. Lung cancer incidence -male