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THE KURSK STATE MEDICAL UNIVERSITY

CANCER OF THE LUNG

Lecture for self-training of 6-th medical course English-speaking students

The chair of surgical diseases № 1 /Chair-head - prof. S.V.Ivanov/

By ass. I.S. IVANOV

KURSK-2003
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Epidemiology of lung cancer

The lung is the major site of cancer in the world today. The annual number of new cases in 1985 was
estimated at 896,000 (11.8% of all new cancers), and the number is increasing at the rate of about 0.5%
per year. About 61% of cases occur in developed countries. Worldwide, lung cancer is by far the
commonest cancer in men (17.6% of all new cancers); it is in first place in all areas of Europe, the former
Russia, North America, the Caribbean, temperate South America, Australia, New Zealand, western and
south-east Asia and Micronesia/Polynesia. In the European Community (EC), lung cancer accounts for
21% of all cancer cases in men, and, because the rate of fatality is high, the disease causes 29% of all
cancer deaths. The corresponding figures for women in the EC are substantially lower: 4 and 8%,
respectively. Incidence is, thus, generally 4-8 times higher in men than in women. Worldwide, lung cancer
is the fifth most frequent cancer in women, but the occurrence has recently shown a steeper increase over
time than in men. It is clear that the predominant risk factor is cigarette smoking. As industrial exposures
also play an important role, lung cancer is largely a preventable disease.

Occurrence and mortality

The incidence rate is the number of new cases that develop in a population at risk (normally per 100,000)
during a calendar year. This measure is widely used in epidemiology because it indicates disease
frequency - or risk; this reflects most directly the burden of disease-causing agents, taking into account the
latency of the disease measured. If exposure of a population to lung carcinogens becomes more prevalent,
lung cancer incidence will eventually increase to a level that is determined simply by specific interactions
between the target tissue and the carcinogens.

Age
In areas of the world where the incidence of lung cancer is high, age is a major determinant of risk, with a
20 fold increase in women and a 100 fold increase in men between the ages of 35 and 75 yrs. This
dependence on age means that it is important to adjust for differences in age composition when comparing
the occurrence of lung cancer in two or more populations. Comparisons are usually made in one of two
ways: 1) by calculating age-adjusted (age-standardized) rates, which are weighted averages of the age-
specific incidence rates using a standard population (normally the World Standard Population (WSP)), or
2 by calculating the cumulative incidence rate between age 0 and, for example, age 74 yrs, which gives a
number (lifetime risk) that indicates the probability that a person will develop the specific cancer within
that age range if he or she does not die from any other cause. These methods are described in more detail
in text books of epidemiology and
in the publication Cancer Incidence in Five Continents. Whilst lung cancer is the commonest cancer
among men in the Nordic countries (closely followed by prostatic cancer), this tumour type ranks third
among Japanese men. Stomach cancer is by far the commonest type of cancer among both men and
women (38.9 per 100,000 per year) in Japan; one man out of 10 develops a stomach cancer before the age
of 75 yrs.

Survival

Many reports are available on the prognosis of patients with lung cancer in clinical trials, the main
purpose of which was to test the impact of new treatments. The outcome does not, therefore, usually
reflect the survival experience of patients with lung cancer in general, nor is it possible on the basis of
trials to evaluate trends in survival over time. The data summarized below on trends in survival rates from
lung cancer in the population of Denmark over a 45 year period, 1943-1987, are considered to be valid for
most parts of Europe and North America.
A more complete understanding of the aetiological basis for the development of lung cancer has long been
the elusive goal of clinicians and basic scientists. The opportunities to make advances in this area have
greatly increased in the last decade as a result of basic research. Molecular changes associated with lung
cancer are increasingly accessible for study, and it is reasonable to expect that we will soon be able to
depict the full process of carcinogenesis, from exposure to a cancer causing agent to the clinical detection
of lung cancer.
This chapter will focus on carcinogenesis, smoking and occupational exposures to industrial carcinogens,
dietary factors and pulmonary diseases that have been associated with lung cancer, and will finally discuss
chemoprevention, an area that is rapidly developing in the 1990s.
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Carcinogenesis
It is generally accepted that the pathogenesis of lung cancer occurs in several steps. This traditional view
of carcinogenesis is derived primarily from studies of animal models, but more recent insight relies on the
molecular analysis of cancer-related genes and growth factors. The well-known clinical observation that
the latent period between exposure to a cancer causing agent and the development of clinical cancer can
be as long as several decades.(the period between onset of cigarette smoking and the first signs of lung
cancer), has led to the assumption that not one but several pathogenic events must have taken place during
this time.
Classically, four major distinct phases have been identified:
1) initiation;
2) promotion;
3) conversion;
4) progression. The initiation phase is described as an early, rapid and largely irreversible change in a
permanently altered cell. Tumour initiation begins through mutation of genetic material following
exposure to carcinogens.

Promotion of carcinogenesis is a more gradual process, during which an initiated cell acquires more and
more malignant characteristics. This complex phase of carcinogenesis, involving a variety of cellular
changes, is thought to last decades in humans. The two final stages of carcinogenesis are conversion and
progression. In contrast to initiation and promotion, which have been studied extensively in experimental
animals, much less is known about tumour conversion and tumour progression, although these are the
aspects of carcinogenesis that most concern clinicians. In both of these processes genetic changes are
involved.

Smoking
The use of tobacco predates the discovery of the New World by Columbus, and tobacco was one of the
major crops of the early American colonies. However, it was not until the end of the 19th century that the
use of tobacco became more widespread and more hazardous. The development of machines for
manufacturing cigarettes and safety matches at the turn of the century set the stage for mass production
and marketing of cigarettes. In the western world, this mass marketing of cigarettes resulted in a rapid rise
in per capita cigarette consumption that began around 1910 and provided one of the first demonstrations
that advertising could create demand for a product where no previous demand existed.
Coincident with the increasing sales of cigarettes, at the beginning of this century, a change was made in
the types of tobacco used to manufacture the cigarettes. The smoke from these tobaccos was milder and so
easier to inhale. It also had a pH that prevented absorption of nicotine across the oral mucosa; users,
therefore, had to inhale the smoke into the lung to absorb the substantial amounts of nicotine they felt they
needed. The deep inhalation and absorption of the smoke's toxic and carcinogenic substances dramatically
enhanced the risk associated with tobacco use, thus resulting in the proliferation of lung cancer and other
smoking-related diseases later in the century.
Evidence linking cigarette smoking with lung cancer began to accumulate in the 1930s, and rapidly
increased in the late 1940s and early 1950s. Four retrospective studies concerning the smoking habits of
lung cancer patients and controls were published in 1950, and each demonstrated a consistent, statistically
significant association between smoking and cancer of the lung.

Sinc then, a considerable number of investigations conducted in different с countries, on different subsets
of the general population have consistently reported an increase in the occurrence of lung cancer among
smoleners in comparison with nonsmokers
All of these studies disclose a clearly visible dose-response relationship between the amount of cigarettes
smoked daily and the subsequent risk for cancer. The association between smoking and lung cancer is
especially strong for squamous and small-cell types of lung cancer.

The identification of cigarette smoking as the major risk factor of lung cancer has led the tobacco industry
to respond by manufacturing filtered, low tar and low nicotine cigarettes in an attempt to create the illu-
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sion that risk had been eliminated. Such innovations have been readily accepted by consumers, and the
tobacco industry currently heralds health benefits by pushing words such as "light", "ultra light", "mild",
etc. Although there are studies that suggest a greater risk of lung cancer in people who only smoked the
"old fashioned" types of cigarettes, it has now been shown that people who switched to low tar/nicotine
cigarettes often smoke more and inhale more deeply in order to attain the same level of nicotine
satisfaction.

Addiction
The cause of the magnitude of tobacco abuse is multifactorial. Addiction to tobacco has psychological,
behavioural and physiological aspects. The addictive chemical in cigarettes is nicotine, which is a
naturally occurring alkaloid found only in the tobacco plant. Nicotine is a powerful central nervous
stimulant, causing mild arousal and an increased sense of well-being. After being inhaled, nicotine reaches
the brain within seconds, and this rapidity explains why nicotine is as addictive as cocaine or heroin.
Smokers absorb approximately 0.3 mg nicotine per cigarette and become tachyphylactic, requiring
increased intake to achieve a similar effect. Nicotine also increases heart rate. Smokers have a heart rate
approximately 10 beats-min faster than nonsmokers. As a result, smoking causes an increase in metabolic
rate. Smoking cessation, therefore, brings about a weight gain of an average of 6-10 pounds due to a
lowering of the metabolic rate and increased intake of calories. The addiction to nicotine assures a
continual steady intake of a wide variety of carcinogens over a long period of time. Tobacco use is usually
monitored by measuring two chemicals absorbed from smoke: carbon monoxide and cotinine. Both of
these measurements can be useful in the follow-up of persons who have stopped smoking.

Smoking cessation
Smoking is an addiction which is extremely difficult to break. Although there is hardly anyone who has
not been informed about the dangers of smoking, life styles in most countries have only been marginally
Involuntary (passive) smoking
Environmental tobacco smoke (ETS) or secondhand smoke is the combination of sidestream smoke that is
emitted into the air from a burning
Environmental Protection Agency (EPA) also concluded that environmental tobacco smoke is a human
lung carcinogen, and it is estimated that 2,000 deaths per year among nonsmoking men and women are
attributable to passive smoking.

Genetic predisposition
The discussion on abandoning smoking is often clouded by the argument that the majority of heavy
smokers will never acquire lung cancer. This points to the interindividual variability in susceptibility to
carcinogens. There are several lines of evidence that genetic characteristics are able to modify an
individual's risk for lung cancer. Family studies have identified a greater risk in non-smokers who are rel-
atives of lung cancer cases compared with nonsmokers without a family history of lung cancer. In another
study, an increased risk was found among cigarette smoking relatives of lung cancer patients in com-
parison with smoking relatives of control subjects. Familial aggregation has also been found in
bronchioloalveolar carcinoma, a type of lung cancer not traditionally thought to be related to smoking.

Occupational lung cancer

The connection of exposure to industrial agents with lung cancer is a complex subject. Although case
reports, laboratory studies and epidemiological analyses have helped to evaluate the carcinogenic risk of
certain agents, each type of investigation suffers from limitations in distinguishing causal from noncausal
associations.

Asbestos

Asbestos, a naturally occurring rock consisting of magnesium and calcium silicates, is one of the known
causes of human cancer.

Metals
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Arsenic and arsenic compounds are carcinogenic to humans. Several reports have appeared in the
literature concerning occupational exposure to inorganic arsenic and lung cancer. People at risk are
workers in the mining industry, smelter workers and farmers exposed to arsenical pesticides.
Epidemiological studies carried out in Europe, the USA and Japan have shown that workers in the
chromate production industry have an increased risk of lung cancer. This may be due to exposure to
trivalent and hexavalent chromium. The hexavalent compound appears to be the most carcinogenic.
Chromium platers, who are exposed to acid fumes have also been shown to be at increased risk for lung
cancer.
Carcinoma of the nasal sinuses and the lung has been associated with exposure to nickel compounds.
Nickel sulphate and combinations of nickel sulphides and oxides used in the nickel refining industry have
been found to be responsible for this increased risk.

Hydrocarbons

In our industrial society, there are many carbon containing products which derive from coal or petroleum,
and exposure to these products or their byproducts may enhance the risk of lung cancer. One of the earliest
observations of an occupation-related cancer was by POTT, more than two centuries ago. He recorded the
high incidence of scrotal cancer amongst chimney sweeps in England. The coal soot identified as the
cause of these cancers contained polycyclic aromatic hydrocarbons (PAHs), such as dibenzanthracene and
benzo(a)pyrene, both now well-known for their carcinogenic potential. In fact, today benzo(a)-pyrene is
used as the indicator compound for the presence of PAHs in environmental material, since it has been
found consistently in mixtures of such compounds

Radiation
At the end of the nineteenth century, the first report of lung cancer among the miners employed in the
Schneeberg mines appeared. Although initially described as lymphosarcoma, this disease must have been
small-cell-lung cancer. It was shown that the life expectancy of the miners was not more than 50 yrs and
that the time of onset of disease (lung cancer) was about 20 yrs after introduction to the mining environ-
ment. This association is attributed to the contamination by radon gas present in the mines. Radon gas is a
decay product of naturally occurring uranium in the earth, and radon decay products (also called radon
daughters) are thought to cause lung cancer or to contribute to lung cancer risk by forming deposits in the
respiratory system when inhaled and then damaging the respiratory epithelium (and lung parenchyma) by
the emission of X-rays. Malignant epithelial tumours of the lung are often synonymous with the term lung
cancer or "bronchial carcinoma" as most of these tumours histo-genetically derive from epithelial or
neuroendocrine cells (cells of the amine precursor uptake and decarboxylation (APUD) system) of smaller
or central airways within the bronchial system. Less than 10% of these tumours arise within the
bronchioloalveolar region.

Epidemiology

For years, malignant tumours of the lung have been the most frequent fatal neoplasms in men, responsible
for 35% of all cases in men. In North Rhine Westphalia alone, over 8,000 men (97 per 100,000) have died
from malignant tumours of the respiratory organs. A continuous increase in the incidence of lung cancer in
women is seen in Germany, as in the United States. It has been at the top of the list of fatal malignant
tumours since 1980.

Aetiology and pathogenesis

Pathogenetically, ciliary function of the bronchial surface epithelial cells and, thus, the self-cleaning
function of the bronchial mucosa is disturbed by various toxins, mainly the gas phase of tobacco smoking.
The subsequent loss of the natural protective properties of the bronchial mucosa and chronic irritation
cause a transformation of the bronchial surface epithelium with squamous metaplasia. Morphological
findings in bronchial preneoplasia, i.e. dysplasia with epithelial atypia extending to carcinoma in situ and
invasive carcinoma, are suggestive of a multistep process of carcinogenesis.
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Topography and macroscopic findings
Topography of the development of lung cancer is important for early detection, surgical management and
metastatic behaviour. The following growth patterns are distinguished with a predelection for the upper
lobes: 1) central tumours and those close to the hilum (70-80%), originally developing most commonly
peripherally in the intermediate zone, i.e. the areas between subsegmental and segmental bronchi; 2)
peripheral, comparatively well-delineated tumours which may be detected radiologically at an early stage
(20-30%); and 3) tumours growing within the parenchyma or multifocally within the bronchioloalveolar
region of the lung (1.5-2.5%). Histological classification of the lung cancer
The clinician expects the pathologist to give a short, clear-cut diagnosis of the lung tumours, which will
form the basis of therapy. Initially, an internationally approved histological typing scheme of malignant
lung tumours, according to a classification offered by pathologists, has proved to be of value. This World
Health Organization (WHO) classification, last revised in 1982, is based purely on light microscopy
findings. However, the following important aspects must not be neglected when classifying any given
malignant lung tumour: 1) Generally, the evaluation made by the pathologist, which is of utmost
importance for both patient and choice of therapy, is based on only a small biopsy specimen, measuring 1-
3 mm in diameter if taken at fibreoptic bronchoscopy. In some cases, only cytological samples are
available, taken from the margin of a tumour perhaps measuring some centimetres in diameter. 2)
Morphometric, electron microscopic, immunohistochemical, biochemical, and molecular genetic results
collected over the last 10 yrs have shown beyond doubt that there is gross tumour heterogeneity amongst
bronchial carcinomas. 3) Today, the classification of a malignant lung tumour based on only a small
biopsy sample, sometimes also attempting differentiation of the tumour, is to be seen as only a crude
single parameter of the tumour biology for the creation of comparable tumour groups.
Evaluable methods of study will in future assist light microscopy investigation to achieve better diagnostic
features for common lung tumours. These will comprise histological typing and grading, immunohisto-
chemical, cytometric and molecular biological parameters; so-called prognostic factors.

Comparison of the distribution of predominant histological types of malignant lung tumours (typing) in
biopsy, surgical and autopsy samples: 1)squamous cell carcinoma; 2)adenocarcinoma; 3)small-cell
carcinoma; 4)large-cell carcinoma; 5)other types.

Squamous cell carcinoma

Squamous cell carcinomas develop as isolated, nodular, round foci in the lung parenchyma, or
intraluminal and stenosing tumours within the bronchial system. Their cut surface is of crumbly,
sometimes granular and characteristically dry appearance. Tumour necrosis, sometimes visible as large
cavities, is common in advanced stages.
Histologically, squamous cell carcinomas are screen:
1)high differentiation.
2)medium differentiation.
3)poor differentiation.
Microscopically, they develop from uniform epi-dermislike epithelial complexes; sometimes, typical
onion-skin like formations are seen. Characteristic intercellular bridges are frequently demonstrated when
using a green filter. Keratin components are also a characteristic feature, sometimes forming concentric
epithelial pearls

Small-cell carcinoma
The lesions categorized as small-cell carcinoma may be seen as a clinical and pathological entity only
under certain conditions. Both the course of the disease and the morphologically determined criteria reveal
anextremely high grade of malignancy.
Although, in absolute figures, the incidence of small-cell carcinoma in men is still 3.5 times higher than in
women, this tumour type is today the commonest pulmonary tumour in women.
Small-cell lung cancers usually develop centrally in the lung, exhibiting a cuffed, peribronchial and
perivascular growth pattern. On light microscopy they consist of small cells with apparently bare nuclei
with little cytoplasm. The cells resemble lymphocytes and may be spindle-shaped. The histological shift
of the nucleocytoplasmic ratio towards the cell nuclei can also be demonstrated by electron microscopy.
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The small-cell carcinoma may be of the oat-cell type (about 88%) or of intermediate cell type. If an oat-
cell carcinoma also contains significant histological differentiation to squamous cell carcinoma and/ or
adenocarcinoma, it is called "combined oat-cell" carcinoma.
In 20% of all small-cell carcinomas, squamous epithelial or glandular areas can be seen, however,
clinically, these various subtypes of small-cell carcinoma are not considered as an important separate
entity.

Large-cell carcinoma
The WHO classification is still listing large-cell carcinoma as a single entity. Recent investigations,
however, show increasingly that large-cell carcinomas are usually variants of adenocarcinomas, and
sometimes squamous cell carcinomas.
When subdividing large-cell carcinomas on the basis of formation of intracellular bridges, they can be
categorized into two groups: one with a relatively compact growth pattern; and the other with a
comparatively loose growth type. Immunohistochemically, several epithelial markers are expressed.
Significant differences between the two groups are found in the expression of cytoskeletal proteins, such
as keratin, epithelial membrane antigen (EMA). Exocrine and/or neuroendo-crine differentiation can also
be seen in large-cell carcinoma, with patients suffering from carcinoma with neuroendocrine structures
having a poorer prognosis.
Extensive analysis of surgical and autopsy samples can reveal focal areas of large cell differentiation in
tumours with predominantly squamous epithelial or adenoid structures. These findings underline the
problems of classification of malignant lung tumours with comparatively large cells and multinuclear
giant cells into a single tumour group.

Adenocarcinoma
According to reports from the United States, there is evidence that adenocarcinoma of the lungs is
increasing in incidence. In our biopsy collection, they occupy third place at 19%, behind squamous and
small-cell carcinomas. It is not yet clear whether this "change in frequency" is due to more sophisticated
analytical techniques and more differentiated morphological analyses.
Adenocarcinomas develop predominantly within the periphery of the lungs, and consist of atypical
glandular-like structures. Histochemically, mucous substances or secretion vacuoles can be demonstrated
in varying amounts in atypical epithelial cells. Sometimes, psammoma bodies are present and, in over
50%, focal areas of squamous cell growth are seen. "Dedifferentiated" polymorphic structures and giant
cells can be found in an even higher percentage, confirming the sometimes difficult distinction between
poorly differentiated adenocarcinoma and squamous cell tumours.
The average cell size in an adenocarcinoma is 13.2±2.3 цт, and mean nuclear size 8.5±1.3 цт. Based on
cytological-phenotypical criteria, adenocarcinoma can be divided into three groups. When correlating
these grades of malignancy as defined by cytological appearance to the average survival time, differences
were established in a number of studies. Patients with low grade malignant tumours have a 5 yr survival of
87%, as opposed to only 30% for lesions morphologically characterized as highly malignant.
According to the WHO classification, there are four subtypes:
1) acinar adenocarcinoma;
2) papillary adenocarcinoma;
3) solid adenocarcinoma with mucus formation;
4) bronchioloalveolar carcinoma
The WHO classification is still listing large-cell carcinoma as a single entity. Recent investigations,
however, show increasingly that large-cell carcinomas are usually variants of adenocarcinomas, and
sometimes squamous cell carcinomas.
When subdividing large-cell carcinomas on the basis of formation of intracellular bridges, they can be
categorized into two groups: one with a relatively compact growth pattern; and the other with a
comparatively loose growth type. Immunohistochemically, several epithelial markers are expressed.
Significant differences between the two groups are found in the expression of cytoskeletal proteins, such
as keratin, epithelial membrane antigen (EMA) and CEA. Exocrine and/or neuroendo-crine differentiation
can also be seen in large-cell carcinoma, with patients suffering from carcinoma with neuroendocrine
structures having a poorer prognosis.
Extensive analysis of surgical and autopsy samples can reveal focal areas of large cell differentiation in
tumours with predominantly squamous epithelial or adenoid structures. These findings underline the
problems of classification of malignant lung tumours with comparatively large cells and multinuclear
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giant cells into a single tumour group.

Localization
1. The central cancer
Endobronchial
Exofitic type - quick start, infringement of movement of sputum, tussis (sometimes a blood), pains,
developing of atelectasis.
Endofitic type - later beginning of disease. Th main symptoms: a tussis, sputum (with bloods). Further,
the clinic is similar at exofitic type of cancer.
Peribronchial
Nodal - rise in temperature (36,8-37,5 С), is long asymptomatic current.
Furcal (the tumoral node is absent) – the sputum with blood, clinic of the chronic pneumonia. Diagnostics
is difficult.
2. A peripheric cancer
Intrashare node. At initial stages - it is asymptomatic. Further - rise of temperature, amplification of tussis
and sputum.
Subpleural tumours – The main symptom is pains on the side of demage.
The cavitary form - a necrosis and destruction the center of tumour, long asymptomatic current. Tussis,
with plentiful sputum (with impurity of the blood).
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The miliary form - long asymptomatic current, asymptomatic clinical picture.
Special types of lung tumours and preneoplastic lesions

Early cancer of the lung

Early cancer of the lung is defined as a locally infiltrating carcinoma, which is still confined to the
bronchial wall (with no infiltration of lung or lymphatic tissue). Histologically, this term is only being
used for squamous cell carcinoma. The final diagnosis of "early cancer of the lung" can only be made
from the surgical sample.

Occult carcinoma
Here, tumour cells are found in sputum cytology, but X-ray findings are negative. In these cases,
immediate endoscopic clarification is necessary, which may identify a carcinoma at an early
developmental stage.

Micro carcinoma
The term "microcarcinoma of the lung" is used for primary tumours of the lung, measuring 3-10 mm, with
no clinical disease. Histologically, most pulmonary microcarcinomas are small-cell carcinomas with
already extensive, clinically manifest metastatic spread. At autopsy, the minute primary lesion can in some
cases be detected only after careful preparation of the entire bronchial system.
Tumourlets are atypical epithelial proliferations of the terminal bronchi-oloalveolar segments. They are
frequently found in advanced stages of pulmonary fibrosis, especially asbestosis, and in lung tissue after
cyto-toxic chemotherapy. Tumourlets of the carcinoid type are focal, only microscopically visible,
sometimes multiple. They are thought to be precursors of peripheral small-cell carcinomas.
Lymphatic metastatic spread
Next to light microscopy, phenotypic classification of the lymph node involvement of small-cell and non-
small-cell tumours, is the next important prognostic parameter for patients with pulmonary tumours. Both
criteria are of utmost importance for post-surgical therapeutical management.
Lymphatic spread of lung cancer first affects regional intrapulmonary and hilar lymph nodes. In autopsy
studies, these nodes, which, according to the 4th tumour, node, metastases (TNM) staging classification
(1987), correspond to stage N1, were involved in over 83% of all cases. Mediastinal lymph nodes were
affected in 57%, and the presence of ipsi-lateral mediastinal lymph node metastases, (stage N2), indicates
a much poorer outcome than stage N1 disease [48, 49]. Regardless of the localization of the primary
tumour, contralateral mediastinal lymph node involvement (N3) can be found in over 50% of all autopsy
cases with advanced disease.

Haematogenous metastatic spread

The results of several studies, as well as our own findings, have shown that in almost 40% of cases, the
liver is the most frequent site of haematogenous metastatic spread after the thoracic lymph nodes. Other
organs commonly involved are the skeletal system with 29%, adrenal glands 26%, and the central nervous
system 14%, with differences in the absolute incidence depending on the predominant histological type of
the primary tumour.

Symptoms and signs and staging of lung cancer

Lung cancer usually presents either as an abnormal shadow on a chest radiograph or because the patient
develops a new, or worsening, clinical sign or symptom. In recent years, despite major advances in
biomedical technology the 5 year mortality rate of lung cancer remains at 87-90%, highlighting the fact
that it is usually disseminated at the time of presentation, and current therapy has little efficacy in all but a
small minority of patients. Of 100 new patients presenting with lung cancer, 80 will have inoperable
disease and most of these will die within 3 yrs; only two or three will be alive after 5 yrs. Of the 20
patients with localized disease (mostly non-small-cell tumours) most will go to resection, and 30% of
these will be alive after 5 yrs.
More than 90% of patients with lung cancer are symptomatic at presentation either from local, regional,
metastatic or systemic effects of the tumour. Symptoms usually reflect a manifestation of advanced
disease, as the tumour has been present in the body many years before symptoms develop. It has been
estimated that when lung cancer is first detectable radiographically it has completed three/quarters of its
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natural history. The myriad of symptoms in patients with lung cancer ranges from none to cough,
haemoptysis, dyspnoea, fever, hoarseness, bone pain, weight loss and anorexia, confusion, neuropathic
pain, weakness, headache, and ataxia. Unless a patient has haemoptysis, fever, or a change in cough as the
initial symptom, resectable lung cancer will seldom be diagnosed on the basis of history.

Chest radiography
The chest radiograph plays a central role in the detection of lung cancer in asymptomatic patients, with a
better sensitivity than pooled sputum cytology. Lung cancer arises in the upper lobes more frequently than
in the lower lobes and in the right lung more often than in the left. The most common location of lung
cancer is in the anterior segment of the right upper lobe. Unfortunately, because the upper ribs are
projected closely together and the clavicles also overlie this region, the upper lobes are the most difficult
to evaluate radiographically.

The growth in the lung of the primary tumour may be divided into central and peripheral patterns and
these two types of presentation can be associated with different symptoms due to the local growth of the
tumour. Central tumours appear to arise in mainstem, lobar or proxi-mal segmental bronchi, whereas
peripheral tumours arise in more distant airways. There is a predilection for adenocarcinoma and large cell
carcinoma to occur peripherally and, on the chest radiograph, they appear as intrapulmonary nodules and,
less commonly, as pulmonary infiltrates. Hilar and mediastinal lymphadenopathy are not very common
and, occasionally, pleural effusion may be the first clinical manifestation of the disease. Tumours arising
as peripheral nodules are usually detectable on a chest radiograph when the diameter of the lesion reaches
1 cm.

Cough
A productive or dry cough is the most common symptom associated with lung cancer, but it is also a
clinical manifestation of most lung diseases. Since the majority of patients suspected to have lung cancer
are heavy smokers and may have coexistent chronic bronchitis, cough and expectoration may not be
recognized as new symptoms or may tend to be ignored, but any change in the clinical characteristics of
an established cough, or a change in the quality or quantity of expectoration should raise suspicion. Cough
may be caused by a small tumour acting as a foreign body in a large bronchus, or by ulceration of the
bronchial mucosa. Cough occurs with both central and peripheral cancers, but is usually less marked with
peripheral tumours.
Severe paroxysms of coughing may cause rib fractures and even syncope. Rib fractures occur more
commonly in the central portion of the ribs; cough syncope is due to cerebral ischaemia as coughing tends
to diminish venous return with a consequent fall in cardiac output.

Haemoptysis
In a third of cases, haemoptysis is one of the presenting symptoms of lung cancer. It may be the only clue
in a patient whose chest radiographs are normal. Any episode of haemoptysis in a person aged over 40 yrs
should be investigated by radiography and fibreoptic broncho-scopy. About 20% of all cases of
haemoptysis are attributable to lung cancer.
The amount of blood coughed up can range from large volumes, usually associated with the rupture or
erosion of bronchial veins, to blood streaking or flecking of the sputum. Haemoptysis is extremely rare
from metastases to the lung from extrapulmonary cancers. Haemoptysis may also result from coexisting
diseases, such as tuberculosis, chronic bronchitis, mitral stenosis, pulmonary infarction and bronchiectasis.

Dyspnoea, wheezing and stridor

Dyspnoea is usually caused by the tumour obstructing a large bronchus or the trachea. Peripheral tumours
are associated with dyspnoea only when they are so large as to interfere with pulmonary function, or when
complicated by a large pleural effusion, or as a consequence of extensive lymphangitis carcinomatosis.
Wheezing is caused by narrowing of a large bronchus, and it is particularly significant if it is unilateral,
fixed and often of recent origin. Stridor is produced by severe, nearly complete, occlusion of a main
bronchus or the lower part of the trachea, and although it may be obvious clinically, the patient's
complaint is usually of severe dyspnoea and wheeze.

Pyrexia
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Fever and chills may occur due to pneumonia secondary to lung cancer, as tumour may partially or
completely block an airway causing obstructive pneumonitis or atelectasis. Any patient, especially over 40
years old and a current heavy smoker, with recurrent or unresolved pneumonia should be investigated for
the possibility of a lung cancer.
Symptoms and signs due to the intrathoracic spread of lung cancer
Intrathoracic spread of lung cancer, either by direct extension or by the lymphatics, can produce a variety
of symptoms and signs secondary to the involvement of nerves (recurrent laryngeal and phrenic nerves,
brachial plexus, sympathetic nerve trunks and plexus), great vessels (superior vena cava), and viscera
(oesophagus, pericardium, heart), diaphragm and chest wall. In most cases, enlargement of hilar or
mediastinal lymph nodes is by metastatic spread, but it may result from infection distal to an obstructing
cancer located in the central airways. Lymph node enlargement itself seldom causes symptoms unless it is
massive, when it can compress the oesophagus, superior vena cava, or cause retrosternal pressure or pain.
The most common sites of visible or palpable lymph nodes are the supr-aclavicular fossae, which may be
involved in about 15-20% of patients with lung cancer during the course of their disease. The scalene
nodes are much less frequently involved, but are often positive with upper lobe tumours. In the majority of
cases, these findings indicate that the tumour is unresectable.

Pancoast tumour and Horner's syndrome

Pancoast tumours, also called superior sulcus tumours, are usually well-localized neoplasms arising
posteriorly in the apex of the upper lobes near the brachial plexus, causing signs and symptoms related to
the neoplastic infiltration of the eighth cervical, first and second thoracic nerve roots, such as pain,
cutaneous temperature changes and muscle atrophy in the shoulder and the portion of the arm innervated
by the relevant nerve roots. The patient may present to the physician supporting the elbow of the affected
arm to alleviate the pain.

Superior vena caval obstruction

Superior vena caval obstruction (SVCO) is an acute or subacute process that in most cases is caused by an
intrathoracic malignancy, including lung cancer/ lymphoma, primary mediastmal and metastatic tumours,
which are responsible for approximately 90% of cases. Lung cancer accounts for 46% to 75% of all cases.

Recurrent laryngeal and phrenic nerve palsy

In a patient with lung cancer, hoarseness and paralysis of one hemidi-aphragm are relatively uncommon
signs at presentation (5 and 1%, respectively), but they frequently appear later in the natural history of the
disease. Hoarseness is due to recurrent laryngeal nerve entrapment, and is observed more frequently in
cancers arising in the left upper lobe, as the left recurrent laryngeal nerve loops around the aortic arch
whereas the right only loops around the subclavian artery at the apex of the lung.

Chest wall
Chest pain is a common presenting symptom in lung cancer and over half develop this symptom during
the course of the disease. The chest pain is usually dull, intermittent, aching, and lasts from minutes to
hours, unrelated to breathing or coughing, localized to the mid-line or on the same side of the tumour.
When chest pain is particularly severe, persistent, well-localized and disabling, it is commonly related to
direct neoplastic invasion of the parietal pleura or chest wall, with erosion of the ribs.
Shoulder pain may be caused by a Pancoast tumour, or referred by a tumour of the lower lobe invading the
central portion of the diaphragm innervated by the phrenic nerve.

Pleura and diaphragm

In a patient with lung cancer, pleural effusion is a common consequence of the neoplastic invasion of the
visceral pleura, but it may sometimes be associated with mediastinal lymph node obstruction by tumour in
the draining lymphatics or obstructive atelectasis with pneumonia, or less commonly, to coexisting
nonmalignant diseases (congestive heart failure, pulmonary infarction, tuberculosis, etc.). Regardless of
the mechanism of its formation, pleural effusion is associated with a poor prognosis, even when malignant
cells are not discovered cytologically.

Heart
 12
Metastases to the heart and pericardium occur by retrograde lymphatic migration of tumour cells. Other
metastatic pathways may include haematogenous dissemination, direct tumour invasion, or penetration of
lesions to the mediastinal pleura and into the pericardium. Autopsy series show that metastatic
involvement of the heart occurs in about 15% of cases, and of these patients 16% have tamponade. In
primary lung cancer, the pericardium is the most frequent site of metastatic involvement of the heart.

Oesophagus
Dysphagia is an uncommon presenting symptom of lung cancer (2%) despite the fact that enlarged lymph
nodes in the posterior mediastinum commonly affect the oesophagus.

Central nervous system

The anatomical cerebral compartments commonly involved by metastases are the skull, leptomeninges
and parenchymal substance of the brain itself.
Approximate frequencies of metastatic involvement of organs system by lung cancer
Site or type of involvement Approximate frequency %

Central nervous system 20-50

Cervical lymph nodes 15-60

Bone 25
Heart (including pericardium) 20
Kidney 10-15
Gastrointestinal tract 12
Pulmonary embolism, infarcfon 10
Pleura 8-15
Adrenal 2-22
Liver 1-35
Skin and soft tissues 1-3
Choroidal 0.5

Lung cancer, by virtue of its frequency in the general population of western countries, is the most common
metastatic source, accounting for 40-60% of all parenchymal deposits . Ten percent of all lung cancer
patients are found to have central nervous system metastases at the time of initial diagnosis, and another
15-20% develop them during the subsequent course of their disease.

Liver
Liver metastases occur in 1-35% of patients with lung cancer, more commonly in the advanced phase of
the illness. Symptoms and signs include anorexia, epigastric pain, and liver enlargement with hardness and
often a nodular surface. Jaundice and ascites occur less frequently. Liver enzymes (aspartate
aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase and lactate
dehydrogenase) are commonly elevated.

Uncommon sites of metastases

Metastases to the gastrointestinal tract and to the kidney are relatively common but usually clinically
silent. SCLC shows a predilection for the pancreas, occasionally causing obstructive jaundice.
Subcutaneous or intradermal metastases appear as painless, purplish-red, well demarcated masses, rapidly
growing, and usually located on the trunk, neck and skull. Blurred vision and spots before the eyes may be
the consequence of choroidal metastases.

The imaging features of the primary tumour

 13
Peripheral tumours
Approximately 40% of bronchial carcinomas arise beyond the larger segmental bronchi and, in 30%, a
peripheral mass is the sole radio-graphic finding. The mass can be virtually any size, but it is rare for a
bronchial carcinoma to be seen on plain chest radiographs unless it is more than 1 cm in diameter, whereas
computed tomography (CT), because of its better contrast resolution, will demonstrate lesions less than 5
mm diameter. The great majority of peripheral lung cancers assume an approximately spherical or oval
configuration. Lobulation, a sign that indicates uneven growth rates for differing portions of the tumour, is
common. Many tumours have an irregular margin, with one or more strands radiating into the surrounding
lung, but sometimes just a single linear or band-like shadow connects the lesion to the pleura.
Occasionally, a dumb-bell shape is encountered or two nodules are seen next to one another. Tumours at
the lung apex (Pancoast's tumours, superior sulcus tumours) may resemble apical pleural thickening.

Central tumours
The cardinal imaging signs of a central tumour are collapse/consolidation of the lung beyond the tumour
and the presence of hilar enlargement; signs which may be seen in isolation or in conjunction with one
another.Obstruction of a major bronchus often leads to a combination of atelec-tasis and retention of
secretions with consequent pulmonary opacity, but collateral air drift may partially or completely prevent
these postobstructive changes. Secondary infection beyond the obstruction may occur. The following
features suggest that a pneumonia is secondary to an obstructing neoplasm:

1. The shape of the collapsed or consolidated lobe may be altered because of the bulk of the underlying
tumour. In cases with lobar collapse, the fissure in the region of the mass is unable to move in the usual
manner, and, therefore, the fissure appears bulged ("golden S" sign). This sign indicates that the collapse
is the result of an underlying mass and predicts that the mass will be amenable to bronchoscopic biopsy.
2. The presence of pneumonia, in a patient in the cancer age group, confined to one lobe (or more lobes if
there is a common bronchus supplying these lobes) that persists unchanged for more than 3 weeks.

Diagnostic investigations in lung cancer

Sputum cytology
With the ready availability of fibreoptic bronchoscopy, reliance on sputum cytology has diminished.
Nevertheless, it is occasionally useful, particularly in patients unsuitable for fibreoptic bronchoscopy, such
as those with a recent myocardial infarct or very poor lung function.
A single sputum sample gives a positive result in 40% of patients ultimately diagnosed as having lung
cancer. The cumulative yield increases to 56, 69 and 85% with subsequent specimens, but depends both
on the location and size of the tumour, with the highest yields obtained from large central lesions. The best
specimens are obtained from a 'deep cough' early in the morning. Specimens collected 1-4 h after
bronchoscopy and on the following morning can produce a positive yield even if the bronchoscopy is
normal.

Bronchoscopy
The fibreoptic bronchoscopic technique was developed in 1968, and has become the mainstay
investigation in the evaluation of patients suspected of lung cancer. Whilst it is employed mainly as a
diagnostic tool, bronchoscopy has a role in staging the disease, and an extended role in the deciding the
therapeutic choice. It is convenient to perform, safe, and well-tolerated by the patient. The requirement of
only minimal sedation makes it acceptable as an out-patient procedure, and it has, therefore, almost
completely replaced rigid bronchoscopy in the initial assessment of the patient. The major advantage of
the flexible scope is its ability to reach more peripheral bronchi: upper lobe bronchi can be entered and
visualized directly, and almost three quarters of fourth order bronchi and half of sixth order bronchi can be
visualized.
Contraindications to the procedure are few and include: hypoxaemia refractory to supplemental oxygen;
intractable bleeding diathesis; severe pulmonary hypertension; cardiovascular instability; and acute hyper
-capnia. Fibreoptic bronchoscopy may be performed safely in the presence of superior vena caval
obstruction.

Transbronchial biopsy
 14
Transbronchial biopsy (TBB) via the fibreoptic bronchoscope is a widely accepted technique in the
diagnosis of diffuse lung disease of characteristic histopathology, such as sarcoidosis. Several studies have
suggested a role for TBB in the diagnosis of peripheral lung cancers.
Using fluoroscopy, they observed a complication rate of 1.7% for haemorrhage and 0.7% for
pneumothorax. Transbronchial biopsy and brushing under fluoroscopic control, in conjunction with
bronchoalveolar lavage, was the best initial procedure for the investigation of peripherally placed tumours
greater than 2 cm in diameter, and recorded an impressively low incidence of pneumothorax (0.01%) and
haemorrhage (0.01%). The authors recognized that lesions with a diameter of less than 2 cm are best
approached by percutaneous needle aspiration.

Transbronchial needle aspiration

Transbronchial needle aspiration (TBNA) was first introduced by SCHIEPPAT, and then adapted for use
with the fibreoptic bronchoscope by WAN. It involves the insertion of a metal needle into the tissue to be
sam pled, and whilst suction is applied, the needle is moved back and forti to obtain an aspirate for
cytological examination. The technique has been applied to the diagnosis of submucosal endobronchial
disease, a discussed above, but has also proved useful in the investigation о peripheral tumours and as a
means of assessing the mediastinum foi malignant nodes. The technique carries the same limitations on
size a transbronchial biopsy, but for lesions 2 cm or greater in diameter yields of 85% have been quoted,
and the incidence of bleeding appear; lower than with transbronchial biopsy.

Bronchoalveolar lavage

The main role of bronchoalveolar lavage (BAL) in patients with lung cancer is the diagnosis of
opportunistic infections in patients undergoing chemotherapy. However, BAL may have an extended role
in the diagnosis of malignancy itself. BAL has been shown to have a high diagnostic yield in the detection
of pulmonary haematological malignancies, to be useful in the assessment of pulmonary infiltrates in
patients with suspected metastatic cancer, in the identification of metastatic adenocarcinoma of breast, and
bronchoalveolar cell carcinoma. In a similar manner to transbronchial biopsy, the diagnostic yield is better
when investigating lesions greater than 2-3 cm in diameter.
The main advantages to BAL are that it is easy to perform, has a high diagnostic yield in diseases other
than cancer, such as pulmonary tuberculosis, and carries a low morbidity. Fever and a transient decline in
lung function are well-recognized but not usually serious. Bleeding and pneumothorax are uncommon.

Endobronchial sonography and pulmonary microvascular cytology

Two novel methods of diagnosing peripheral lung tumours have recently been described: endobronchial
sonography and pulmonary microvascular

Percutaneous fine needle biopsy

Transthoracic aspiration biopsy was first employed by LEYDEN 100 yrs ago to obtain micro-organisms
from a patient with pneumonia, but it was not until 1886 that MENETRIER used the technique to make the
diagnosis of bronchial carcinoma. The substantial morbidity and mortality associated with the procedure
made it increasingly unpopular until the development of narrow gauge, thin-walled needles, image-
intensified fluoroscopy and refined cytological techniques, which have lead to a resurgence of interest in
the last 20 yrs.

Plewal aspiration and biopsy

Pleural effusions are a common manifestation of primary and metastatic tumours of the lung and pleura.
This method is very effectiv.

Thoracoscopy
A substantial number (21-27%) of pleural effusions remain undiagnosed after pleural fluid cytology,
biopsy and other relevant investigations. The need to see and biopsy under direct vision, coupled with
improvements in endoscopic technology and local anaesthesia has led to a resurgence of interest in
thoracoscopy.
The first use of a thoracoscope in the diagnosis of pleural disease was published by JACOBAEUS in 1922.
He emphasized the diagnostic potential of the procedure but the technique was mainly utilized by
 15
phthisiologists to facilitate collapse therapy in patients with tuberculosis ("Jacobaeus operation"). With the
advent of antituberculous chemotherapy, the decline in tuberculosis and validation of closed pleural
biopsy techniques, the use of the thoracoscope as a diagnostic and therapeutic instrument was largely
abandoned. However, the last 20 yrs has seen a resurgence of interest amongst pulmonary physicians and
a revival of the thoracoscope both as a diagnostic and therapeutic instrument. The thoracoscope has been
shown to be superior in diagnosing early and less extensive pleural malignancy, in malignant
mesothelioma, and in identification of nonmalignant pleural disease. The role of surgical thoracoscopy has
been greatly extended to facili-tate, amongst other indications: lung biopsy, evaluation of the
mediastinum, and the staging of lung cancer.

Mediastinoscopy and mediastmotomy

Mediastinoscopy was originally described by CARLENS in 1959. Utilizing a cervical incision, the
mediastinoscope allows access to the structures adjacent to the trachea, carina and superior vena cava,
facilitating assessment of high and low paratracheal, pretracheal, and the most proximal aspects of the
hilar and carinal lymph nodes. Mediastinoscopy cannot reach further than the tip of the subcarinal nodes,
which require a thoracotomy for proper assessment.
Anterior mediastinotomy is performed through a limited thoracotomy incision through the second
intercostal space on either side, and allows assessment of nodes and tumour in the anterior mediastinum. It
is a valuable adjunct to cervical mediastinoscopy in patients with tumours of the left upper lobe or
tumours extending into the left main bronchus, providing access to bidigitally palpate and assess the
subaortic fossa. Both procedures require general anaesthesia.

Surgical treatment and results

Surgery remains the treatment of choice for non-small-cell lung cancer, offering the best prospects for
cure and long-term survival. Since the first pneumonectomies were successfully performed by Nissen
(1931) and Graham (1933) some 60 yrs ago, surgical techniques for the management of bronchial
carcinoma have fundamentally progressed. Twenty years ago, pneumonectomy was the favoured
operation, carried out in 70-80% of all resections. Now, lobectomy, possibly extending to a variety of
broncho- and angioplastic resections, has replaced pneumonectomy as the commoner procedure.
Essentially, this has been achieved by new techniques introduced and perfected to accomplish complete
remission, and simultaneously maintain the maximum possible healthy lung tissue. This allows surgical
cure even in patients with an increased operative risk from reduced lung function, accompanying diseases
or previous damage, who would not have tolerated pneumonectomy.
Appropriate therapy is planned according to the patient's general condition, risk factors, and histological
tumour type. The main determinant, however, is the anatomical extent of the tumour. Unfortunately, two
thirds of all patients already have an advanced stage of lung cancer when evaluated for possible surgical
treatment.

Thoracic incisions
The most popular incisions are posterolateral and anterior thoracotomy. Posterolateral thoracotomy is the
route of choice, providing wide visualization both of the anterior and posterior hilar regions and the medi-
astinum.
The anterior incision has the advantage of speed in opening and closing the chest and is more muscle
sparing, but provides only limited exposure to posterior hilar structures, consequently impairing complete
lym-phadenopathy. Sleeve resections of the bronchial and vascular tree are difficult to perform from this
incision. It is mainly performed for diagnostic open lung biopsy and may also be of use in the treatment of
benign lesions.
Median sterotomy leads to less postoperative pain, but has not been routinely accepted for lung
carcinomas. It requires very elaborate preparatory procedures, especially for resection of the left lower
lobe, and particularly in elderly patients, who often present with an enlarged left ventricle as compression
of the heart may cause arrhythmias. In addition, plastic surgery of the left bronchial tree is not feasible via
this access. Median sternotomy is particularly important in the surgical approach to pulmonary metastases.

Surgical resection
Classic techniques
Until the 1960s, the standard approach to bronchial carcinoma was pneumonectomy. It has been replaced
by lobectomy, which preserves lung parenchyma, has less operative risk, and offers complete remission in
 16
many cases. The intraoperative evaluation of the tumour will be the final arbiter for the extent of resection.

Overall results
Stage I disease. This stage includes subsets with significantly different prognostic long-term survival,
justifying subdivision into Stage IA for Tl tumours, stage IB for T2 tumours.
Five year survival of all patients in Stage I is 59%. Complete surgical remission was achieved in 98% of
patients. For T1NO tumours, the 5 year survival is 71% in 107 patients after radical lobectomy. These
figures confirm data from a trial which reported a 5 year survival between 70 and 83%. In 256 T2NO
patients after radical lobectomy, 5 year survival in 58% is
clearly less good.
Lobectomy is the usual resection; segmentectomies are alternative options for high risk patients. Mortality
after segmental resection was 1%, and after lobectomy 5%. In T2NO tumours extending beyond the lobar
bronchial orifice, bilobec-tomy or pneumonectomy is indicated, or possibly lobectomy plus segmental
resection from the adjacent lobe. In tumour involvement of lobar orifice, sleeve lobectomies are
performed.
Stage II disease. In comparison to Stage I, Stage II disease includes involvement of pulmonary, interlobar
or hilar lymph node stations (N1). The 5 year survival in all patients in this group is 39%. This clearly
demonstrates the significantly worse prognosis for any lymphatic involvement. The overall 30 day
mortality was 7%.
Resection of the primary tumour usually requires lobectomy, if necessary combined with plastic
procedures to the bronchial tree or the pulmonary artery. For tumours of the intermediate bronchus,
bilobectomy is performed (13% of our patients). In lesions extending beyond an interlobar fissure or
involving interlobar nodules, only pneumonectomy may suffice (16%).

Stage IIIa disease. This tumour stage is very heterogeneous. It includes tumours with involvement of
neighbouring organs and structures, such as chest wall, diaphragm, pericardium; endobronchial tumours
located near the bifurcation; and lesions with mediastinal lymph node involvement. Our overall 30 day
mortality was 8.8% in this group. The advanced tumour growth stage required pneumonectomy in 28% of
cases. Lobectomy and bilobectomy performed in 63% and are still the predominant procedures.
Resected T3NO and T3N1 tumours had a 37 and 26% 5 year survival, respectively, and prove the curative
potential of resection. At the same time, it was evident that the prognosis for T3 tumours without lymph
node involvement is very similar to Stage II tumours - the 5 year survival for Stage II was 39% [49]. In
tumours with mediastinal lymph node involvement, 5 year survival varied from 8 to 30%, depending on
multiple factors, such as number and location of the lymphatic metastases, Т category, adjuvant treatment
(table 6, fig. 9) [50-54].
Stage IIIb disease. Indications for surgery in Stage IIIb is disputed. We have resected Stage IIIb lesions
in 15% of patients. Frequently, however, the advanced state was not recognized before intraoperative
exploration. The resection rate is considerably lower for this stage than in Stages I-IIIa, and the 30 day
mortality of 17% is significantly higher. Pneumonectomy was performed in 52% of those who had a
resection. Radical resection, with good prospects for long-term survival, although rarely cure, appears to
be more easily achieved in T4 tumours than in Т IIIb cases with contralateral lymph node involvement.
The 3 year survival was 39% for T4 tumours without lymph node metastases, whereas it is down to 18%
in those with concurrent ipsilateral mediastinal lymph node infiltration (T4N2). Long-term prognosis is
significantly worse, with a 3 year survival of 16% for N3 tumours with infiltration of contralateral
mediastinal lymph node metastases.
Stage IV disease. Stage IV is defined as tumours, irrespective of the extent of the primary and lymph
node metastases, which present with distant metastatic lesions. Surgery is generally not indicated. Some
patients, however, benefit from resection of solitary hepatic, adrenal or cerebral lesions as a life-
prolonging procedure. Palliative pulmonary resection is occasionally also indicated. Particular profit
seems to be gained from resection of isolated synchronous pulmonary spread. The 5 year survival for this
group, without distant spread to other sites, is 29% after complete surgical remission (fig. 10). Prognosis is
related to extent of primary tumour (T) and lymph node involvement (N). Patients with completely
resected metastases at other sites, however, show significantly worse prognosis with 1 year survival of
only 45%.

Radiotherapy of non-small-cell and small-cell lung cancer

 17
Non-small-cell lung cancer (NSCLC) should be treated surgically whenever a complete surgical resection
is possible. The following criteria are generally accepted as contraindications to curative surgery: tumour
extension beyond the hemithorax, including scalene lymph node involvement; presence of large
mediastinal metastases; malignant pleural effusion; distant metasatses, except possibly solitary brain
metastasis; inoperability due to coexisting medical contraindications; and patient refusal. The current
meticulous staging procedures, including magnetic resonance (MR), computed tomography (CT) and
mediastinoscopy, allow only 20-30% of patients to have a high chance of resectability. Finally, only about
20% of all patients presenting with lung cancer are candidates for curative surgery. Of these, at least 50%
will subsequently develop a relapse in the thorax.
At presentation for diagnosis, at least one third of all patients with lung cancer will be inoperable due to
tumour extension (unresectable) or medical contraindication. In this context, radiotherapy, as a
locoregional treatment able to achieve local control, has a major role in management either alone or
combined with surgery and/or chemotherapy.

Radiotherapy in the treatment of NSCLC

Curative radiotherapy for NSCLC and treatment parameters

"Standard" radiotherapy for inoperable NSCLC varies considerably from one country to another, based
more on assumptions and empiricism than on scientific data. Radiation therapy delivered with a curative
intent implies the use of high total doses and may be restricted to a very small group of patients,
presenting with a small tumour confined to the primary site and with limited regional lymph node
involvement.

Chemotherapy in non-small-cell lung cancer

Single agent chemotherapy

Only 25-30% of patients with non-small-cell lung cancer (NSCLC) present with tumour confined to the
lung (stage I-II disease) for whom surgery with curative intent is the treatment of choice. A very large
number of patients are dying, therefore, from advanced NSCLC for whom more effective chemotherapy
offers the only realistic possibility of improving survival. The problem is that relatively few active drugs
have been identified. Ifosfamide, cisplatin, mitomycin С and vinde-sine have overall objective response
(partial and complete responses combined) rates above 15%.

Chemotherapy in small-cell lung cancer

One out of four patients with lung cancer has small-cell carcinoma. It is the most aggressive of the four
common cell types, with very few cases potentially operable at time of diagnosis (<5%). More than 85%
have Stage III disease and the TNM (tumour extent, lymph node involvement, incidence of primary
metastases) classification is, therefore, rarely used. Instead, stage is restricted to two categories: limited or
extensive, corresponding to whether or not disease can be confined within a classical thoracic radiation
field, i.e. no proven cancer beyond primary tumour and regional lymph nodes, including the
supraclavicular nodes, but the pleura or trachea must not be involved.
Staging procedures include chest radiograph, bronchoscopy and iliac crest bone marrow examinations,
plus various imaging procedures, which have changed with developments in techniques over the years but
currently include abdominal computed tomographic (CT) scan or ultra-sonography. In a typical clinical
series, about 55% of patients will have extensive stage disease. The fraction depends on the number of
procedures applied and on selection. Poor performance status and old age may well preclude referral to an
oncological centre and inclusion into treatment trials. Our own trials excluded patients older than 70 yrs of
age, but patients aged 65-70 years were not, however, significantly under-represented as compared to data
on lung cancer notified in the nationwide Danish Cancer Registry. Typical treatment of small-cell lung
cancer (SCLC) in this younger part of the population, is poly-chemotherapy with or without thoracic
radiotherapy, with an intention to cure. Primarily palliative chemotherapy is a relatively new policy
offered to selected elderly patients.