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MINISTRY OF PUBLIC HEALTH OF UKRAINE
KHARKOV STATE MEDICAL UNIVERSITY
В.И.Стариков
А.Н.Белый
LUNG CANCER
РАК ЛЕГКОГО
Kharkov KSMU – 2006
УДК 616.024-006.6-07
ISBN 966-7152-05-9
Утверждено ученым советом
Харьковского государственного медицинского университета
Протокол № от
АВТОРЫ:
В.И. Стариков – заведующий кафедрой онкологии
Харьковского государственного медицинского университета, доктор
медицинских наук, профессор
А.Н. Белый – ассистент той же кафедры
РЕЦЕНЗЕНТЫ
Ю.Л. Шальков – заведующий кафедрой онкохирургии и
онкогинекологии
Харьковской
медицинской
академии
последипломного образования, доктор медицинских наук, профессор
Н.Н.Велигоцкий
–
заведующий
кафедрой
торакоабдоминальной хирургии Харьковской медицинской академии
последипломного образования, доктор медицинских наук, профессор
В учебном пособии, изложенном на английском языке, рассмотрены
вопросы эпидемиологии, этиологии, патоморфологии, диагностики рака легкого,
его осложнений. Подробно описана клиническая картина различных форм
заболевания,
проводится
дифференциальная
диагностика
с
наиболее
распространенными заболеваниями легких.
Также
приведены
классификации
рака
легкого.
Освещены
диагностические критерии и подходы при стадировании заболевания.
В пособии подробно изложены вопросы хирургического, лучевого,
химотерапевтического методов лечения и их возможных комбинаций, приведены
стандарты диагностики рака легкого, освещены пути дальнейшего развития науки
по проблеме рака легкого.
Учебное пособие рассчитано на студентов медицинских вузов,
обучающихся на английском языке.
ISBN 966-7152-05-9
© В.И. Стариков, А.Н. Белый
Рак легкого
2004
2
CONTENTS
Epidemiology of the lung cancer…………………………………
Etiology of the lung cancer………………………………………
Pathogenesis and pathomorphology of the lung cancer…………
Manifestation of the lung cancer…………………………………
Local signs………………………………………………...
Secondary signs…………………………………………
General signs…………………………………………….
History and physical examination………………………………..
Additional examinations in case of lung cancer………………….
Diagnostic approach……………………………………………...
Differential diagnostics of the lung cancer and pneumonias…….
Differential diagnostics of the lung cancer and the tuberculosis…
International classification of the lung cancer by TNM and the
stage grouping……………………………………………………
Atypical forms……………………………………………………
Complicated lung cancer…………………………………………
Treatment of the lung cancer……………………………………
Surgical treatment of the lung cancer…………………….
Radiotherapy of the lung cancer………………………….
Chemotherapy of the lung cancer………………………...
Molecular biology of lung cancer: clinical implications…………
Prevention of the lung cancer…………………………………….
Survival…………………………………………………………...
The future………………………………………………………...
Standards of lung cancer treatment………………………………
Treatment of non-small cell lung cancer…………………
Treatment of small cell lung cancer……………………...
References………………………………………………………..
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Lung cancer (LC) is the malignant tumor developing from an epithelium of bronchi mucous or in cicatrix of lung parenchyma. The lung
cancer is the group of tumors differing by a biological nature, clinical
signs, morphological structure, speed of growth and ability to metastasize.
Lung cancer is one of the most important diseases in respiratory
medicine. Worldwide, it is the commonest cancer in men, virtually the
commonest in women, and has a greater total incidence than that of colorectal, cervical, and breast cancer combined.
EPIDEMIOLOGY OF THE LUNG CANCER
Bronchogenic carcinoma remains a major health problem throughout the world. Worldwide it is estimated that 47–52% of men and 10–12%
of women smoke. Compared with women, men started smoking younger,
smoked more and for a longer duration, inhaled more deeply, and bought
cigarettes with a higher tar content. Women took up smoking in the United
States and Western Europe during the second World War. Recent casecontrol studies have shown female smokers to have a higher relative risk
of lung cancer than males, after adjusting for age and average daily consumption.
While the incidence of almost all other malignancies is falling or
remaining stable, the incidence of lung cancer continues to increase dramatically. During 50 years the incidence of LC has grown in 14 times
(Fig. 1). In Ukraine the case rate has increased in 2 times for last 20 years,
thus the annual gain makes 3,8%.
Over the past 20 years, the male preponderance of 5-7 : 1 has fallen
to its current level due to the striking increase in lung cancer among women, which began in 1965 (Fig. 1). Presumably, this changing pattern of
disease is due to the post-World War II increases in cigarette smoking
among the general population, and women in particular, which are only
now being felt.
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The high level of an incidence is marked in England (57,5), Germany (62,7), France (66,2 on 100 thousand population).
Fig. 1. LC death rates per 100,000.
Men are sick with LC in 6-7 times more often, than women. In men
the LC takes first place in structure of an oncologic case rate (22 %). Now
rates of a LC incidence have considerably increased among the female
population.
At the end of the twentieth century, lung cancer had become one of
the world's leading causes of preventable deaths. By 1950, case-control
epidemiologic studies showed that cigarettes were strongly associated
with the risk of lung cancer.
In 1962, the Royal College of Physicians in London intervened in a
public health matter for the first time since 1725 and published a compelling document supporting the evidence that smoking caused lung cancer.
In 2001, lung cancer will have caused more than 1 million deaths
worldwide and this global incidence is rising at 0.5% per annum.
The etiology of the great majority of lung cancers has been known
for nearly 50 years, but we have failed to make serious inroads into the
powerbase of the tobacco industry.
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The elevation of a LC mortality correlates with increasing of its incidence. In the majority of the countries of the world the LC is conducting
reason of deaths among men more than 45 years.
Important LC facts (US data):
• 173,770 estimated new cases in 2004;
• Estimated deaths in 2004: 160,440
– 32% of cancer deaths in men (1st);
– 25% of cancer deaths in women (1st)
• Leading cause of cancer mortality
– Overall 5 year survival rate 15%.
ETIOLOGY OF THE LUNG CANCER
LC is the multifactor disease. There are chemical, physical and genetic theories of a carcinogenesis for today. The role of factors of an environment in a genesis of LC is conventional. The most essential factors are
smoking, professional factors, pollution of atmospheric air and air of living rooms.
Smoking. The majority of scientists count, that 80 % of all cases of
occurrence of a LC are connected with a smoking. There are over 2000
chemicals in cigarette smoke; several of them are either direct carcinogens
or cocarcinogens.
Worldwide it is estimated that 47–52% of men and 10–12% of
women smoke. Compared with women, men started smoking younger,
smoked more and for a longer duration, inhaled more deeply, and bought
cigarettes with a higher tar content. Women took up smoking in the United
States and Western Europe during the second World War. Recent casecontrol studies have shown female smokers to have a higher relative risk
of lung cancer than males, after adjusting for age and average daily
consumption.
Smoking induces a spectrum of histologic changes in the bronchial
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epithelium, which are not seen in nonsmokers. These changes include loss
of bronchial cilia, basal epithelial hyperplasia, and nuclear abnormalities.
The severity of such changes increases in heavy smokers and tends to be
most severe in patients dying from lung cancer. Smoking-induced
alterations in bronchial mucosa may slowly resolve in individuals who
stop smoking.
It precisely fixed, that in persons smoking per day more than 1 pack
of cigarettes the risk of LC in 30 times greater than in nonsmokers.
Results of epidemiological researches specify correlation of a case rate of
a LC with amount of smoked cigarettes and duration of smoking (Fig. 2).
The risk of lung cancer is related to cumulative dose, which for
cigarettes is quantified in "pack-years." One in seven persons who smoke
more than two packs per day will die of lung cancer. The incidence of
death from lung cancer begins to be above that of the nonsmoking population at 10 pack-years.
It is proved, that the tobacco smoke influences equally on smokers
and non-smokers. Smoking cigars or pipes doubles the risk of lung cancer
compared to the risk in nonsmokers.
Nonsmoking wives of husbands-smokers fall ill with a LC in 2
times more often, than wives of nonsmoking husbands. Therefore the
constant presence in a room where someone smokes is dangerous for
nonsmokers.
Passive smoking probably increases the risk of lung cancer about
twofold, but because a proportion of the risk associated with active inhalation is about 20-fold, the actual risk is quite small.
Following the cessation of smoking, the risk steadily declines, approaching but not quite reaching that of nonsmokers after 15 years of abstinence for patients who smoked for less than 20 years. The risk is reduced for patients who smoked for more than 20 years but never approaches that of nonsmokers.
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Mortality (1 on 100 thousands)
300
264,2
229,2
250
200
150
100
50
107,8
95,3
12,8
0
a
b
c
d
e
Groups of nonsmokers and smokers
Fig. 2. Mortality among nonsmokers and smokers (by Hammond & Horn): a
– nonsmokers, b – ½ of pack per day, c – ½-1 pack per day, d – 1-2
packs per day, e – more than 2 packs per day.
Asbestos is causally linked to malignant mesothelioma. Asbestos
exposure also increases the risk of lung cancer, especially in smokers
(three times greater risk than smoking alone). Thus the risk of lung cancer
in smokers who are exposed to asbestos is increased 90-fold.
Radiation exposure may increase the risk of small cell lung cancer
in both smokers and nonsmokers.
Other substances associated with lung cancer include arsenic,
nickel, chromium compounds, chloromethyl ether, and air pollutants. It is
necessary to note, that smoking and professional factors simultaneously
increase risk of LC.
Lung cancer is itself associated with an increased risk of another
lung cancer occurring both synchronously and subsequently.
Other lung diseases. Lung scars and chronic obstructive pulmonary
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disease are associated with an increased risk of lung cancer. Scleroderma
is associated with alveolar carcinoma.
The knowledge of the majority of factors conducting to development of a LC allows to establish groups of the increased risk.
1. Men in the age of more than 45 smoking more than 1 pack of cigarettes per day.
2. People long time suffering from chronic nonspecific lung diseases
(chronic bronchitis, chronic pneumonia, bronchoectatic disease).
3. Workers connected with manufacture of Asbestos, Chromium,
Nickel, radioactive isotopes, extraction of radioelements.
4. People with pulmonary tuberculosis in the past.
5. Contingents, genetically predisposed to initial plurality of malignant tumors (cured from a skin cancer, laryngeal cancer etc.), and
also having three and more cases of malignancies in close relatives.
PATHOGENESIS AND PATHOMORPHOLOGY
OF THE LUNG CANCER
It is possible to divide pulmonary cancerogenesis into three stages:
initiation, promotion (activation) and a tumor progression. The first phase
initiation is the occurrence of pretumor cells with genetically fixed properties: immortality, blocked terminal differentiation, ability to promotion.
The basic condition of initiation is interaction of carcinogen with cellular
DNA, promoting mutational and other changes of DNA of cells-targets.
Following initiation phase is a promotion. This is a phase of a malignant transformation, in which cells under influence of the certain factors (promotors) are transformed and growing as a tumor. Promotors may
be chemical compounds of an exogenous nature and endogenic one.
The third phase of a carcinogenesis is the progression. It is purchase by a tumor during its growth of more malignant properties, simplifi9
cation of structure and function of its cells. The progression of a tumor is
due to heterogeneity of a neoplastic population and it's genetic instability.
Populations of malignant cells of the same tumor differ on metastatic potential, radioresistance, sensitivity to antitumoral therapy.
Malignant lung tumors have great metastatic potential that is caused
by their ability to invasive growth. It is shown in fast local diffusion of a
tumor with infiltration of adjucent anatomic structures: mediastinum, pericardium, diaphragm, ribs etc. (Fig. 3), and also in a rough lymphogenous
and hematogenous innidiation. "Target" organs for distant metastases are
liver, brain, bones, kidneys, opposite lung.
Fig. 3. Main direction of locoregional LC spreading (by K. Mully):
1 – cancer lymphangitis, 2 – pericardium and nervus phrenicus, 3 – oesophagus and vagus nerve, 4 – vena cava superior, 5 – thoracic wall, 6 –
diaphragm, 7 – zone of aortal window and left reccurent laryngeal nerve,
8 – visceral pleura (specific pleuritis), 9 – Pancoast’s cancer (1-st rib,
plexus brahialis, truncus sympaticus).
Favourite zone of a hematogenous innidiation in case of LC is the
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osteal system, which defeat frequency makes about 13,5%. Bones of a
backbone, rib, femoral and humeral bones, clavicle, bones of a skull are
often defeated, bones of phalanxes are defeated less often. Metastases into
the brain are more often in case of undifferentiated histological forms of a
LC especially in case of small cell lung cancer (SCLC). Their frequency
varies from 10 up to 25 %. Metastases into kidneys, according to various
authors, meet in 16,5-25 % of cases. Metastases into a liver are observed
in 42,9 % of cases. Metastases into lung same with a tumor or opposite
lung make 24,8 %.
Now the most widespread is morphological classification of a LC
by N.A. Kraevsky, A.S. Yagubova and I.G. Olhovsky (1982), which is
taking into account a morphological type and grade differentiation.
1. Epidermoid carcinoma:
а) high differentiated;
b) average differentiated;
c) low differentiated.
2. Small cell cancer:
а) oat cell;
b) lymphocyte-similar;
c) spindle-cell;
d) pleomorph.
3. Adenocarcinoma:
а) high differentiated;
b) glandular-solid structure;
c) low differentiated;
d) bronchoalveolar.
4. Large cell carcinoma:
а) giant cell;
b) clear cell.
5. The mixed cancer.
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Specified groups make about 90 % of all cases of a LC: epidermoid
cancer meets in 40 % of patients, adenocarcinoma is in 15-20 %, small
cell lung cancer - in 20-25 %, large cell cancer - in 10-15 %. The other
10% are carcinoid, sarcomas, melanomas, mesothelioma of pleura, etc.
Most classifications, including the one by the World Health
Organization, divide lung cancer into four major types: squamous or
epidermoid, adenocarcinoma, large-cell carcinoma, and small-cell
carcinoma (SCLC) (Fig. 4).
With the exception of the small-cell type, these classifications are
poorly predictive of tumor behavior. As a result, the clinician has been
concerned primarily with the division of lung cancer into SCLC and nonSCLC types.
Fig. 4. Incidence of major histologic types of LC.
For reasons that remain undefined, the incidence of squamous cell
carcinoma has undergone an absolute decline. At the same time, there has
been an absolute increase in the incidence of adenocarcinoma, which is
now the most common histologic subtype, accounting for 40-50% of
primary lung cancers.
Squamous cell carcinoma arises from altered bronchial epithelium
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and is preceded by years of progressive mucosal changes that include
squamous metaplasia, dysplasia, and carcinoma in situ. In its early stages
of growth, the tumor may appear as a small, red, granular plaque or as a
focus of whitish leukoplakia. Later, it may appear as a large intrabronchial
gray-white or yellow mass. Cavitation may occur in the lung distal to the
obstructing mass. Microscopically, there are intercellular bridges
connecting the abnormal neoplastic cells and abundant keratin formation.
Adenocarcinomas are classically peripheral tumors arising from the
peripheral airways and alveoli but may arise proximally from the
epithelium or submucosal glands. When bronchial in origin, they are
almost impossible to distinguish on a cytologic basis from metastatic
pancreatic, renal, breast, and colonic adenocarcinoma. When peripheral,
they may be similarly difficult to distinguish from metastatic
adenocarcinoma or malignant mesothelioma. Peripheral adenocarcinomas
are usually well-circumscribed, gray-white masses that rarely cavitate.
Microscopically, there is a spectrum of well-developed to poorly
developed cuboidal or columnar cells having microvilli and forming
glandlike structures that may or may not produce mucin. In the
bronchoalveolar type, 50% of which secrete mucin, the cylindrical tumor
cells grow along the wall of the alveoli.
Small-cell carcinomas usually develop proximally as large, bulky,
soft, gray-white masses. When bronchial narrowing occurs, it commonly
results from circumferential narrowing by extraluminal tumor.
Microscopically, small-cell carcinomas are composed of fusiform, round,
or polygonal cells about twice the size of lymphocytes with inconspicuous
nucleoli and modest amounts of cytoplasm. The presence of cytoplasmic
dense-core granules has led to the concept that SCLC belongs in a group
of tumors derived from neuroendocrine cells, responsible for the
production and secretion of specific peptide products. Although SCLC is
divided into oat-cell, intermediate cell, and combined cell patterns, it is
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unclear whether these subtypes differ in their natural history or response
to therapy.
Large-cell carcinomas, like adenocarcinomas, are usually located
peripherally. They may be quite large and not infrequently cavitate.
Microscopically, they have large nuclei, prominent nucleoli, abundant
cytoplasm, and distinct cytoplasmic membranes. Large-cell carcinomas
lack evidence of either squamous or glandular differentiation; many may
represent undifferentiated forms of adenocarcinoma or squamous cell
carcinoma.
Clinical picture, choice of treatment and the survival depends on the
form of growth of a bronchogenic cancer.
The most complete and convenient for practical using is clinicalanatomic classification of a LC by A.I. Savitsky:
А. Central cancer (Fig. 5):
1. Endobronchial.
2. Peribronchial nodal.
3. Tree-like.
B. Peripherial cancer:
1. Round tumor.
2. Pneumonia-like cancer.
3. Pancoast's cancer.
4. Cavitary form.
C. Atypical forms:
1. Mediastinal.
2. Miliar carcinosis.
3. Osteal.
4. Cerebral.
5. Cardiovascular.
6. Hepatic.
7. Gastrointestinal etc.
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Fig. 5. Types of central LC growth:
1 – endobronchial, 2 – peribronchial nodal, 3 – tree-like.
In case of the central cancer the tumor affects large bronchi (main,
lobular, segmental) and localised closely from heart, esophagus, large vessels etc. Infringement of bronchial air passage is prevailing in manifestation of disease. Central cancers meet in 80 % of cases.
The peripherial LC develops in bronchi of finer size, that is why tumor is far from the vital organs and a clinical picture of disease is not so
expressed.
It is necessary to note Pancoast's cancer which signs are caused by a
tumor invasion to an adjacent structures. So, in classical variant the tumor
invades first rib, causing its destruction, plexus brahialis and a ganglion
“stellatum” of truncus sympathicus. It is accompanied by a pain in the top
extremity on the side of defeat and development of Horner's syndrome
(ptosis, miosis, enophtalmus).
Peripherial LC with a cavity in center meets more often. It is caused
by fast growth of a malignant tumor and its backlog of vascularisation that
conducts to infringement of trophicity and a necrosis especialy in center.
It is necessary to pay attention to the group of atypical forms of a
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LC. As it was already marked, the tumors reaching 1-2 mm in diameter,
may give lymphogenous and hematogenous metastases. Getting in favorable conditions, in some cases, the metastatic tumor begins to grow much
faster maternal and results in clinical displays of disease as a pathology of
organ with metastase. At the same time the primary lung tumor have small
sizes and frequently is not diagnosticated clinically and with the help of
special examinations.
MANIFESTATION OF THE LUNG CANCER
The clinical picture of a LC is complex and diverse. It depends on
type of a tumor growth, clinico-anatomical form of a LC, rates of growth
and innidiation, accompanying secondary inflammatory changes (Fig. 6).
There are three groups of LC signs: local, secondary and common signs.
Fig. 6. Intrathoracic spread of LC with associated symptoms.
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LOCAL SIGNS
Cough is the most often and, as a rule, the first sign of a LC. Its occurrence is explained by reflex reaction to a boring of a bronchus mucous.
In case of the central cancer frequency of this sign reaches 80-90%.
Cough as a rule is dry, in the beginning transient, then constant. Cough
may be hoarse, excruciating, sometimes it characterizes as "pertussislike".
Especially strong cough happens at transition of a tumor to a trachea or
carina.
Haemoptysis is the second on frequency sign of a LC. It is caused
by disintegration of the tumor, which invades bronchus wall. The haemoptysis meets in 25,3 % of patients with LC. The impurity of a blood in sputum happens more often as small blood particles. Sometimes patients expectorate small blood clots. Oncologists consider that even the small
haemoptysis should be as an indication for radiological and bronchoscopic
examination of the patient and his direction to the thoracic surgeon.
Besides realization of haemostatic therapy is necessary because
haemoptysis may transform at any moment to a profuse pulmonary bleeding and as a result to fatal outcome.
Chest pain is a frequent sign of a LC. The pain meets on the side of
defeat, less often – on the opposite side. Pain meets in 60-77 % of patients
with LC, however frequency of this sign depends on a stage of disease.
The reasons of occurrence of chest pains are various and may be caused
by involving parietal pleura, thoracic wall, diaphragm, pericardium, trachea, nervous trunks and plexuses, and also mediastinal organs. The persistent pain has adverse prognose. Occurrence of a pain outside of a chest
(in the field of a neck, backbone, top and bottom extremities) frequently
testifies to defeat of the specified departments of a skeleton by metastases
of a cancer.
Dyspnea is observed in 30-40 % of patients with the central LC and
expressed more strongly, than larger a diameter of the affected bronchus.
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However in some cases the dyspnea occurs long before an obturation of a
bronchus and, probably, has a reflex or inflammatory genesis. In some
cases the dyspnea may be caused by haemodynamic infringements in lung
due to compression by the tumor of large pulmonary veins and arteries,
and also vessels of a mediastinum (superior vena cava) or a pleural exudate.
The peripherial LC long time proceeds without clinical signs and
determings clinically late. Chest pain occurs at invasion by tumor of a
pleura or a thoracic wall. The haemoptysis and cough at a peripherial LC
are not early signs. The dyspnea is also not characteristic for initial stages
of a peripherial LC.
The peripherial cancer of a lung apex (Fig. 7), which clinical picture
was described in 1924 by the american roentgenologist H. Pancoast has
the brightest clinical picture. Tumor invades first rib, causing its destruction, nerves of plexus brahialis and a sympathetic nerve. It is accompanied
by a pain in the top extremity on the side of defeat and development of
Horner's syndrome (ptosis, miosis, enophtalmus).
Fig. 7. Coronal T1-weighted magnetic resonance imaging showing
subtle Pancoast tumour (open arrow) with extension into the superior sulcus and erosion of the adjacent vertebral body (arrow).
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Cavitary forms of a peripherial LC may have also more expressed
clinical picture that is caused by disintegration of a tumor in its center. If
tumor drained into a bronchus patients have a severe cough with a lot of
purulent sputum.
SECONDARY SIGNS
High temperature concerns to the secondary signs developing as a
result of complications of an inflammatory nature accompanying a bronchogenic cancer. Increase of a temperature, is especial in case of the central LC, is observed almost in all patients. At the beginning of disease tumor partially obturates the bronchus cavity. As a result its drainage function decreases that conducts to a relapsing endobronchitis and a cancer
pneumonitis in the appropriate lung site. The temperature in this period
has subfebrile character. After complete obturation of bronchus by a tumor and development of an atelectasis of obctricted part of the lung there
begins inflammation. In this case high and long rise of temperature (hectic
character) is observed.
Paresis of a recurrent laryngeal nerve in patients with LC develops as a result of metastatic defeat of lymph nodes in the field of an aortal
window, less often as result of a invasion or compression of nerve by a
tumor. For recurrent nerve paresis is typical occurrence of hoarseness.
More infrequent sign is choking during eating of liquid foods. This sign is
caused by absence of complete closing of vocal chords during swallowing
that is accompanied by passing of nutrition in trachea.
The central cancer in some cases may be accompanied by a dysphagia caused by metastatic defeat of paraesophageal group of mediastinal lymph nodes. More often the stenosis develops at a level of a bifurcation of trachea. The direct tumor invasion into an esophagus is possible
also, that also may be complicated by its stenosis.
The liquid in a pleural cavity is observed approximately in 1/3 of
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patients with LC. The mechanism of development of a pleural exudate at
tumoral defeat is not always identical. The isolated infringement of lymphatic outflow conducts to occurrence in a pleural cavity of an exudate
with properties of transsudate. In some cases the cause of an exudate is the
perifocal pneumonia.
But more often it is exudate with a plenty of erythrocytes (hemorrhagic exudate). It is possible to count essential attributes of tumoral pleurites hemorrhagic character of an exudate and its fast accumulation after a
puncture. The hemorrhagic exudate, as a rule, is observed at canceromatosis of pleura.
GENERAL SIGNS
General signs develop owing to influence on an organism of a lung
tumor. The most often general signs: weakness, fatigability, weight loss.
Sometimes patients mark disgust for meat nutrition. The specified sign
develops in some cases long before clinical display of disease.
Under influence of malignant process not oncologic diseases called
"paraneoplastic" may develop. They develop not owing to direct action
of a tumor on tissues and organs, but due to its influence on a metabolism,
immunity and functional activity of regulating systems of an organism.
The paraneoplastic syndromes can be characterized as constitutional, hematologic, skeletal, neuromuscular, cutaneous, and endocrine.
Constitutional symptoms such as weight loss, anorexia, and fatigue
are probably the most common. Their presence or magnitude cannot be
explained by tumor size, and their cause is unknown. Cachexia is a significant prognostic factor in the course of lung cancer. Recent studies suggest
that splenic cytokines such as tumor necrosis factor may influence cachexia, as well as tumor growth. Megestrol acetate, a synthetic progestin, has
been found to improve well-being, as well as allow weight gain, in many
types of lung cancer.
20
A normochromic, normocytic anemia occurs in less than 10% of
patients with bronchogenic carcinoma and is unrelated to marrow
infiltration or therapy. A number of coagulopathies are associated with
lung cancer. They include migratory thrombophlebitis (Trousseau's
syndrome), disseminated intravascular coagulation, chronic hemorrhagic
diathesis, nonbacterial thrombotic endocarditis, and arterial embolization.
Trousseau's syndrome often involves unusual sites such as the upper
extremities or the vena cava and is frequently unresponsive to
anticoagulant therapy.
Hypertrophic pulmonary osteoarthropathy occurs in 4-12% of
patients with lung cancer, most commonly with epidermoid carcinoma
and only rarely with small-cell carcinoma (5%). It consists of periosteal
new bone formation in the long bones, with digital clubbing and
symmetric arthritis. Vasomotor instability is often present with episodic
blanching, swelling, and diaphoresis of the hands and feet. The ankles,
wrists, and long bones can be very painful and tender. Although new bone
growth is present, the syndrome does not seem to be caused by ectopic
human growth hormone production, but it may be mediated by autonomic
reflexes. It usually regresses after tumor removal, vagotomy, or
thoracotomy without tumor resection.
An increasing number of neuromuscular syndromes have been
reported in association with bronchogenic carcinoma, most commonly
small-cell carcinoma. These syndromes may precede the clinical
appearance of the tumor by months to years. The most potentially
devastating are cerebral encephalopathy and cortical cerebellar
degeneration, both of which may occur precipitously. Peripheral
neuropathies, usually sensorimotor and often presenting as pain and
paraesthesias of the lower extremities, occur in up to 15% of patients with
lung cancer. A myasthenia (Eaton-Lambert) syndrome occurs in 6% of
patients with small-cell carcinoma and differs from myasthenia gravis
21
primarily by an increase in the muscle action potential on repetitive
stimulation and the lack of improvement in muscle strength with
anticholinesterases. A symmetric proximal muscle neuromyopathy is also
common and is associated with muscle wasting.
Cutaneous manifestations include features of dermatomyositis,
hyperpigmentation caused by ectopic production of melanocytestimulating hormone, and acanthosis nigricans. The last is a
hyperkeratotic, hyperpigmented dermatosis with small papillomatous
lesions giving the skin a velvety texture. It is symmetric and prominent in
skin folds. When it occurs after age 40, it is almost always associated with
cancer (90% intra-abdominal, 5% lung).
A large number of endocrine and metabolic syndromes are
associated with bronchogenic carcinoma. Many are primarily, but not
exclusively, associated with small-cell carcinoma. It is theorized that lung
cells embryologically derived from neural crest cells with the ability for
amine precursor uptake and decarboxylation (APUD) undergo malignant
derepression and secrete one or more peptide hormones. Overt clinical
syndromes appear in about 10% of patients with lung cancer, although
subclinical hormone production is more common.
The
hormones
produced
are
peptides
and
include
adrenocorticotropic hormone (ACTH), melanocyte-stimulating hormone,
parathyroid hormone, antidiuretic hormone (ADH), human chorionic
gonadotropin, prolactin, serotonin, insulin, glucagon, corticotropinreleasing factor, and calcitonin. Most is known about ectopic ACTH,
parathyroid hormone, and ADH.
ACTH is probably the most commonly produced ectopic hormone
(50% of patients with small-cell carcinoma), although Cushing's
syndrome is rare with bronchogenic carcinoma. Tumors appear to
elaborate both active ACTH (in small amounts) and an immunoreactive,
but biologically weak "big" ACTH, which may be a precursor molecule.
22
Big ACTH was evaluated as a marker for lung cancer, since it is present
in over 80% of all lung cancer patients. It is not, however, specific, since
it also occurs in a significant number of patients with chronic obstructive
pulmonary disease (COPD). When Cushing's syndrome does occur in
association with tumor ACTH secretion, it is a virulent disease with poor
prognosis.
Hypercalcemia occurs in at least 12% of patients with lung cancer,
mainly with epidermoid carcinomas. Although small-cell carcinoma
frequently metastasizes to bone, it rarely causes hypercalcemia. Ectopic
parathyroid hormone production is one cause of hypercalcemia that
usually responds to therapy. Some cases may be caused by tumor-secreted
prostaglandin E. The hypercalcemia in these cases can be suppressed by
aspirin or indomethacin. Other cases may be caused by tumor production
of a peptide with significant structural homology to parathyroid hormone,
but without immunologic cross-reactivity.
The syndrome of inappropriate ADH secretion (SIADH) results
from ectopic ADH secretion. It occurs in 11% of patients with small-cell
carcinoma, and although hyponatremia may be severe, symptoms occur in
only about 25% of patients with tumor-induced SIADH. It usually
resolves within 3 weeks of the initiation of chemotherapy. Occasionally,
severe SIADH can occur in the first 5 days following the start of
chemotherapy, so patients should be monitored carefully during this time.
Preliminary studies have utilized iodine 131-labeled antibodies against
vasopressin-associated neurophysin to localize tumors utilizing
radioimaging.
Gonadotropin production occurs predominantly with large-cell
carcinoma and can cause gynecomastia, which may be unilateral.
Prolactin production by anaplastic tumors may cause lactation in women.
Epidermoid carcinomas have rarely been associated with production of
vasoactive intestinal peptides with a syndrome of watery diarrhea,
23
hypokalemia, and achlorhydria. In addition, bronchogenic carcinomas
have been found to produce small, biologically active amines or peptides
including serotonin, histamine, and a substance resembling eosinophilic
chemotactic factor of anaphylaxis.
At the present time, most of these hormones represent curiosities. In
the future, some may become useful markers of disease or response to
therapy, and the mechanisms of their production may provide insights into
the behavior of carcinoma.
HISTORY AND PHYSICAL EXAMINATION
A detailed history and accurate physical examination remain the
most important steps in assessing a patient with lung cancer. Smoking history, past exposure to environmental carcinogens, and family history may
suggest a higher probability of lung cancer. New symptoms, including a
change in cough, hemoptysis, or history of recurrent respiratory infection,
are suggestive. Symptoms suggesting locoregional spread include chest
pain, symptoms of recurrent nerve palsy, or superior vena cava obstruction. Symptoms suggestive of metastatic disease frequently include cerebral metastases, bone pain, or weight loss. Occasionally, patients suffering
from NSCLC present with symptoms and signs of a paraneoplastic syndrome, but not as frequently as with small cell tumors.
Physical examination should look for signs of partial or complete
obstruction of airways, atelectasis or pneumonia, and pleural effusions.
Examination of the head and neck, including draining regional lymph
node areas, may demonstrate lymphadenopathy, indicating regional lymphatic (N3) spread.
ADDITIONAL EXAMINATIONS IN CASE OF LUNG CANCER
Chest radiograph. The chest radiograph is probably the most valuable tool in the diagnosis of lung cancer. A perfectly normal chest radio24
graph rules out this diagnosis in most instances, except for the rare occult
tumor. Plain chest radiography can reveal peripheral nodules and hilar and
mediastinal changes suggestive of lymphadenopathy or pleural effusions,
all suggestive of possible malignancy. Areas of subsegmental, segmental,
lobar, or lung collapse suggest an endobronchial obstruction.
X-ray inspection of chest:
a) Chest x-ray in two projections (front and lateral);
b) Tomography in a front projection in a section of a bifurcation of a trachea;
c) Tomography of a lung hilar in a lateral projection.
The radiological semeiology of a LC is caused by infringement of
bronchial permeability, complications сonnected with growth of tumors
and metastases. At presence of the preliminary diagnosis of a LC inspection of the patient should be started with multiprojective roentgenoscopy,
which allows to receive the general representation about presence of
pathological process, its localization and about a degree of diffusion.
At a roentgenoscopy it is possible to determine localization of a LC
(central or peripherial) and also to find out connection of a tumor with a
thoracic wall, diaphragm, mediastinum. At a roentgenoscopy condition of
hilar elements and regional lymph nodes are defined. Only with the help
of a roentgenoscopy it is possible to estimate a functional condition of
chest organs and diaphragm: at a sharp inspiration it is possible to notice
jerky shift of mediastinum organs in the affected side (positive sign of
Golkskneht-Yacobson). At invasion of a phrenic nerve as a result is a
phrenasthenia and due to it high location of diaphragm and paradoxical its
mobility is marked at respiration (during an inspiration the diaphragm on
the side of defeat moves upwards, and at an exhalation falls downwards).
Then we need to performe a roentgenogram in frontal and lateral
projections. On the tomograms which made through the hilar, it is possible to receive the image of peribronchial lymph nodes with circular or ex25
centric narrowing of a bronchus. Contours of walls of the affected department of bronchus are rough. Frequently on tomograms the image of a
pencil-point stump of a bronchus is received. At the tree-like form of a LC
on tomograms it is marked uniform narrowing of the affected bronchi, a
thickening of their walls and smoothness of intersegmental and interlobar
carinas. Diagnostics at this form of tumor growth is the most difficult.
The peripherial cancer (Fig. 8) on intact pulmonary background at
the sizes of node of 1-1,5 cm has a polygonal contour with the unequal on
extent sides. Tumors which diameter exceeds 3-4 cm, have mainly ballshaped form. Studying of contours of tumoral unit shows, that they always
are indistinct, have short “rays”, or "spicules", invading environmental
pulmonary tissue. Their length varies from 0,2 up to 1,5 cm and more.
Presence of "spicules" testifies about invasive growth of a tumor in environmental tissues along walls of bronchi, lymphatic and blood vessels.
Fig. 8. A 50-yr-old female with irregular cavitating squamous cell
carcinoma in the right upper lobe (arrows).
Tumoral infiltration of environmental pulmonary tissue results in
formation around of tumoral node original "radiant crown", so-called “corona maligna”. Radiance is sometimes non-uniform and also may be
found out only along one tumor edge.
26
At augmentation of bronchopulmonary lymph nodes on x-ray films
expansion of hilar is determined. Its vascular frame is not differentiated.
An external contour of a root is polycyclic.
The augmentation of upper tracheobronchial lymph nodes gives expansion of a shadow of a mediastinum to the right or to the left. Its contour is convex and polycyclic. The major sign of augmentation of this
group of lymph nodes is loss of shadow of an azigous vein.
Computed tomography. With the introduction of CT scanning in
the late 1970s, a giant step was taken in the ability to diagnose and stage
lung cancer employing noninvasive imaging techniques. CT imaging can
confirm abnormalities seen on plain chest radiographs (Fig. 9), can often
detect lesions that cannot be resolved on chest radiographs, and has played
an important role in staging of lung cancer, especially spread to areas of
the mediastinum undetected on plain films. There is general agreement
that normal mediastinal lymph nodes are less than 1 cm in transverse diameter. Any lymph node larger than this suggests lymphadenopathy and
should be investigated further by more invasive techniques.
Fig. 9. Spiculated mass typical of a carcinoma.
CT scans also suggest possible areas of local invasion of the pri27
mary tumor to chest wall, vertebrae, or mediastinal structures. Small pleural effusions or pleural nodules, often undetected on plain films, may be
evident on CT scans.
The computer tomography is capable to reveal atelectases of small
volume (subsegmentary and segmentary level). Tumoral atelectases on
computer tomograms have equal polygonal or slightly wavy contours,
homogeneous structure and soft-tissue density, which depends on a phase
or a limitation period of a sign. On a computer tomogram reorganization
of an atelectasis frame with sites of disintegration, small air cavities are
clearly determined. High parameters of density of a tumoral conglomerate
clearly allow to define medial border of diffusion.
CT can also identify specific features in lung nodules that are diagnostic, e.g. arteriovenous fistulae, rounded atelectasis, fungus balls, mucoid impaction and infarcts. High-resolution scanning further refines this
diagnostic process. The ability of CT scanning to evaluate the entire thorax at the time of nodule assessment is of further benefit.
An added advantage of CT scanning is the ability to detect abnormalities below the diaphragm, especially metastases to liver and adrenal
glands. For the investigation of lung cancer, CT scanning should include
upper abdominal scanning to the level of the kidneys to include imaging
of the liver and adrenal gland.
Spiral or helical CT is advantageous as small nodules are not
missed between slices as may happen on older, nonspiral machines. It also
increases the detection rate of nodules < 5 mm in diameter, especially
when viewed in cine-format on a workstation. The acquisition of continuous volume data sets permits three-dimensional image reconstruction and
multiplanar (i.e. nonaxial) reformatting. These techniques have been
shown to improve the detection of pleural invasion by tumour and clarify
the origin of peridiaphragmatic tumours respectively.
28
Further manipulation of raw data sets enables the technique of virtual bronchoscopy. An interactive, simulated bronchoscopy can be performed with the added benefit of simultaneous information on adjacent
mediastinal structures. This technique has far reaching potential both as a
teaching tool and as a means of evaluating patients thoracic and bronchial
anatomy prior to interventional procedures and stent placement.
The spiral CT, using a special staging technique, is the mainstay of
staging in lung cancer. This involves an automated bolus injection of contrast 20–30 seconds before the scanning is initiated. This time interval allows optimal enhancement of the mediastinal blood vessels. A maximum
slice thickness of 5 mm is used to prevent errors from partial volume effects. The new multislice CT systems allow the whole thorax to be
scanned with 3-mm slices during a single breath hold.
The recent advent of multislice scanners has seen advances in image resolution with a substantial reduction in both tube loading and scanning time as up to four slices can be acquired simultaneously. Both spiral
and multislice machines suffer less from respiratory motion artefact due to
their shorter scanning times.
Despite advances in CT scanning technology, there remain important limitations for its use in staging, with preoperative predictions differing from operative staging in 35–45% of cases, with patients being both
over- and understaged. CT staging remains unsatisfactory for detecting
hilar (N1) and mediastinal (N2 and N3) lymph node metastases, and for
chest wall involvement (T3) or mediastinal invasion (T4), in which sensitivity and specificity can be less than 65%. These are critical areas that
may make the difference between surgical and nonsurgical management
decisions.
Abnormalities seen on CT scan, unless associated with unequivocal signs of malignancy, should be confirmed by more invasive cytologic
or histologic investigation.
29
Radiological characteristics by cell type.
Adenocarcinoma represents 31% of all lung cancers, including
bronchoalveolar carcinoma. Adenocarcinomas are typically peripherally
located and measure < 4 cm in diameter; only 4% show cavitation. Hila or
hila and mediastinal involvement is seen in 51% of cases on chest radiography and a recent study describes two characteristic appearances on CT:
either a localized ground glass opacity which grows slowly (doubling time
> 1 yr) or a solid mass which grows more rapidly (doubling time < 1 yr).
Bronchoalveolar carcinoma is regarded as a subtype of adenocarcinoma and represents 2–10% of all primary lung cancers. There are three
characteristic presentations: most common is a single pulmonary nodule
or mass in 41%; in 36% there may be multicentric or diffuse disease; finally, in 22% there is a localized area of parenchymal consolidation. Bubble-like areas of low attenuation within the mass are a characteristic finding on CT. Hilar and mediastinal lymphadenopathy is uncommon. Persistent peripheral consolidation with associated nodules in the same lobe or
in other lobes should raise the possibility of bronchoalveolar carcinoma.
Adenosquamous carcinoma represents 2% of all lung cancers. This
cell type is typically identified as a solitary, peripheral nodule. Over onehalf are 1–3 cm in size and cavitation is seen in 13%. Evidence of parenchymal scars or fibrosis in or next to the tumour is seen in 50%.
Squamous cell carcinoma represents 30% of all lung cancers.
These tumours are more often centrally located within the lung and may
grow much larger than 4 cm in diameter. Cavitation is seen in up to 82%.
They commonly cause segmental or lobar lung collapse due to their central location and relative frequency.
Small cell lung cancer represents 18% of all lung cancers. SCLC
often present with bulky hila and mediastinal lymph node masses. A noncontiguous parenchymal mass can be identified in up to 41% at CT that
very rarely cavitates. They form the malignant end of a spectrum of neu30
roendocrine lung carcinomas with typical carcinoid tumours being at the
more benign end. A mass in or adjacent to the hilum is characteristic of
SCLC and the tumour may well show mediastinal invasion.
Large cell carcinoma represents 9% of all lung cancers. Large or
giant cell carcinoma is a poorly differentiated nonsmall cell carcinoma
and is diagnosed histologically after exclusion of adenocarcinomatous or
squamous differentiation. It may grow extremely rapidly to a large size
but metastasizes early to the mediastinum and brain. It should be noted
that there seems to be a change occurring in the prevalence of the described histological subtypes.
Carcinoid tumour represents 1% of all lung cancers. Atypical carcinoid tumours tend to be larger (typically > 2.5 cm at CT) with typical
carcinoid tumours being more often associated with endobronchial growth
and obstructive pneumonia. Carcinoids tend to be centrally rather than
peripherally located and calcification is seen in 26–33%. The 5-yr survival
for typical carcinoids is 95% against 57–66% for atypical carcinoids.
Magnetic resonance imaging. Magnetic resonance imaging is becoming more available but pressure on MRI scanning time is so intense
that it is usually used for problem solving and where administration of
contrast media is contraindicated. MRI can be more accurate than CT in
separating stage IIIa (resectable) from IIIb (generally unresectable) tumours in selected patients due to its ability to detect invasion of major
mediastinal structures, i.e. T4 disease (fig. 10).
The advantages MRI has over CT include: better soft tissue contrast, multiplanar imaging capability, and therefore useful for superior sulcus tumours and evaluation of the aortopulmonary window, and cardiac
gating which enables excellent delineation of the heart and great vessels
and removes cardiac pulsation artefact.
MRI is also useful in the assessment of mediastinal and chest wall
invasion by virtue of its ability to determine fat-stripe invasion and in31
volvement of the diaphragm and spinal canal. In addition, it has been
shown to aid in differentiating lymph nodes from hila vessels due to the
"flow void" phenomenon.
MRI has disadvantages compared to CT, being slower and more
expensive with poorer spatial resolution and providing limited lung parenchyma information. MRI can overestimate lymph node size because of
respiratory movement, causing the blurring together of discrete nodes into
a larger, conglomerate mass.
MRI is also poorly tolerated by claustrophobic patients and is contra-indicated in patients with indwelling electromagnetic devices and
some prosthetic heart valves. T1-weighted sequences are used for the visualization of fat planes and improved spatial resolution. T2-weighted sequences are useful for detection of high-signal tumour infiltration. Gadolinium enhancement can further enhance the diagnostic yield.
Fig. 10. Coronal magnetic resonance imaging showing an adenocarcinoma in a young male infiltrating the aortopulmonary window. There
is loss of the fat plane against the aorta (arrows) and invasion of the main
pulmonary artery (arrowhead).
Radionuclide scanning. The ability of radionuclide scanning to
32
diagnose and stage lung cancer is limited by its lack of specificity. Scanning with gallium citrate-67 is widespread for an estimation of intrathoracic lymph nodes defeat. It is applied also 99Tc and 131I. . The rate of
incorporation of the radioisotope by the primary tumor and its metastatic
foci is variable, however, and thus has limited its clinical use in both diagnosis and staging. Routine radionuclide bone scanning to rule out
asymptomatic, unsuspecting bone metastases in early-stage disease has
never been shown to be cost-effective but is still advocated by many practitioners. In clinical stage III disease, before considering curative therapy,
bone scans may be more valuable.
Isotope-labeled monoclonal antibodies have been investigated as a
technique for staging and diagnosing lung cancer. Specific monoclonal
antibodies directed to lung cancer cells may prove valuable as diagnostic
and staging modalities in the future.
Positron emission tomography. Positron emission tomography
(PET) scanning is a new imaging modality whose role in the assessment
of lung cancer is still being determined.
Its advantage over other modalities lies in its sensitivity in detecting malignancy and its ability to image the entire body in one examination.
PET is a physiological imaging technique that uses radiopharmaceuticals produced by labelling metabolic markers such as amino acids or
glucose with positronemitting radio nuclides such as fluorine-18. The radiomarker is then imaged by coincidence detection of two 511 KeV photons that are produced by annihilation of the emitted positrons. The radiopharmaceutical, 18F-2-deoxy-D-glucose (FDG) is ideally suited for tumour imaging.
PET performed with this agent exploits the differences in glucose
metabolism between normal and neoplastic cells, allowing accurate, noninvasive differentiation of benign versus malignant abnormalities.
33
Uptake of FDG is known to be proportional to tumour aggressiveness and growth rates. FDG uptake can be assessed visually on PET images by comparing the activity of the lesion with the background or by
semiquantitative analysis using calculated standardized uptake ratios. An
uptake ratio of < 2.5 is considered indicative of a benign lesion.
PET scanning detects malignancy in focal pulmonary opacities
(fig. 11) with a sensitivity of 96%, specificity of 88% and an accuracy of
94% in lesions of more or equal 10 mm. However, compared to CT, PET
has poorer spatial resolution, which precludes it from accurate anatomical
assessment of primary tumour status.
False-positive PET findings in the lung are seen in tuberculous infection, histoplasmosis and rheumatoid lung disease. False negatives are
seen with carcinoid tumours, bronchoalveolar carcinoma and lesions < 10
mm in size.
Fig. 11. Avid uptake of
mour (arrow).
18
F-2-deoxy-d-glucose in left apical tu-
34
PET is more accurate than CT in the detection or exclusion of mediastinal nodal metastases (fig. 12): sensitivity is 67–83% and specificity
is 81–100%. PET has been shown to correctly increase or decrease nodal
staging as initially determined by CT in 21% of presurgical patients.
PET has been shown to detect occult extrathoracic metastases in
11–14% of patients selected for curative resection and alter management
in up to 40% of cases.
PET is more sensitive and specific than bone scintigraphy for the
detection of bone metastases and has a 100% positive predictive value for
the presence of adrenal deposits as against 43% for conventional imaging.
The technique faired poorly in the detection of brain metastases
(60% sensitivity) prompting the authors to recommend the continued use
of conventional imaging for routine staging of the brain.
Fig. 12. Middle-aged-female with a) right hilar mass (arrow) and
b) equivocal precarinal lymph node (arrow). c) PET scan shows increased
uptake in mediastinal nodes (arrows) and small peripheral nodule (open
arrow). Biopsy of hilar mass confirmed nonsmall cell lung cancer.
35
The main disadvantage for PET is the lack of availability and relatively high cost of each examination. However, decision analysis models
indicate that combined use of CT and PET imaging for evaluating focal
pulmonary lesions is the most cost-effective and useful strategy in determining patient management with a pretest likelihood of having a malignant nodule of 0.12–0.69.
PET is more accurate than conventional studies in detecting recurrent lung cancer and appears to be superior in distinguishing persistent or
recurrent tumour from fibrotic scars. However, false-positive studies do
occur secondary to postirradiation inflammatory change and delaying the
examination until 4 or 5 weeks postirradiation is recommended.
The clinical blood test allows to find out in the majority of patients
with LC (75 %) rising ESS more than 30 mm/hour. Change of this parameter is observed in patients with the central and peripherial LC.
Sputum Cytology. Once the disease is suspected, a simple and effective method of obtaining a positive diagnosis of lung cancer is sputum
cytology. It allows to reveal the x-ray-negative cancer and even carcinoma
in situ. The yield from sputum cytology depends on many factors, including the ability of the patient to produce sufficient sputum, the size of the
tumor, the proximity of the tumor to major airways, and to a lesser extent,
the histologic type of the tumor. With three sputum samples, up to 80% of
central tumors can be diagnosed. The yield is much smaller for peripheral
tumors, dropping to less than 20% for peripheral tumors less than 3.0 cms.
in diameter. A 3-day collection of early morning sputa, preserved in Saccamano's solution, appears to be the optimal method of assessment.
Squamous cell tumors are more frequently diagnosed by cytology than
adenocarcinoma or large cell tumors.
Another factor affecting the ability of sputum cytology to diagnose
malignancy is the experience and training of the cytopathologist. Viral
infections and other acute inflammations can produce cellular changes
36
difficult to distinguish from malignancy, especially adenocarcinoma. Frequently, severe dysplasia is misinterpreted as a malignancy, and vice versa. Tockman and colleagues have described a monoclonal antibody staining technique that may more accurately diagnose the presence or absence
of malignancy in severely dysplastic cells. This is being tested prospectively.
Transthoracic needle biopsy. Transthoracic needle biopsy of a
primary lung tumour is controversial when considering a solitary nodule
or mass. A negative biopsy needs repeating and the patient will invariably
proceed to surgery unless a positive benign result is obtained. Biopsy is
useful in determining cell type in inoperable disease to guide further therapy and is essential to confirm the presence of distant metastatic disease.
Needle biopsy is usually performed under either ultrasound or CT
guidance. Ultrasound guided biopsy is quick and allows the operator to
guide the needle under direct vision but can only be used with peripheral
tumours that abut the pleura or invade the chest wall. It is then usually
possible to obtain a tissue core using an 18-gauge cutting needle although
FNA may be used.
CT guided biopsy (fig. 13) takes longer and systemic analgesia and
sedation may be necessary to maintain patient compliance. CT affords
good visualization of all thoracic structures and CT guided biopsy has an
accuracy for diagnosing malignancy of 80–95%. It is the procedure of
choice for sampling peripheral nodules (<2 cm in diameter) as the yield
for transbronchial needle biopsy, in the absence of an endobronchial lesion, falls from 92–95% to 50–80%.
FNA is the preferred sampling method of parenchymal nodules in
order to reduce the incidence of complications and is known to have a
similar sensitivity in detecting malignancy as core biopsy. However, small
tissue fragments for histological evaluation can generally be obtained with
19–22 gauge needles in 40–75% of patients. Such evaluation is valuable
37
because it lends confidence to a cytological diagnosis of cancer, to celltype determination and to the reliability of a negative result.
a
b
Fig. 13. Versatility of transthoracic needle biopsy with needle tip
in a) mediastinal mass (note safe approach) and b) peripheral solitary
nodule.
When a cavitatory or necrotic lesion is encountered, sampling of
the wall is recommended to obtain viable tumour material. A single negative biopsy does not exclude malignancy and should prompt a repeat biopsy. When performing biopsies of mediastinal lesions it is usually possible
to use an 18-gauge cutting needle after selecting a safe route. This is especially important in the diagnosis of lymphomas.
Bronchoscopy. The bronchoscopy is one of main methods in diagnostics of a LC. It visually allows to examine a trachea, main, lobular,
segmentary and subsegmental bronchi, to see directly a tumor and to estimate its sizes and, that it is especially important, localization. Localization
of a tumor frequently allows to define volume of surgery (pneumonectomy, lobectomy, bilobectomy) or impossibility of its performance.
Although rigid bronchoscopy was used for many years to confirm
the diagnosis of lung cancer, the introduction of flexible fiberoptic bronchoscopy more than 20 years ago has revolutionized this approach. The
38
procedure, although invasive, can be performed under local anesthesia
with or without sedation and with minimal morbidity and exceptional
safety. Using flexible fiberoptic instruments, the proximal tracheobronchial tree can be examined up to the second or third subsegmental division, and cytology or histologic specimens can be obtained from abnormal
lesions identified. Diagnostic yield of fiberoptic bronchoscopy with cytology brushing and biopsy for histology when a visible lesion is identified is
higher than 90%. Even with no visible lesion seen, the bronchus draining
the area of suspicion can be irrigated and lavaged, obtaining cytologic material. Using fiberoptic bronchoscopy and image intensification, peripheral
lesions can be reached by cytology brushes, needles, or biopsy forceps,
and specimens can be obtained. This is most effective in lesions larger
than 2 cm in diameter.
The bronchoscope is also valuable for staging. The site of the primary tumor in a major airway may affect its stage (T3 versus T2 versus
T1), and transbronchoscopic needle aspiration through the airway wall
was popularized. Except for intrabronchial diffusion the bronchoscopy
indirectly allows to define extrapulmonary diffusion of metastases of a
tumor (subcarinal and paratracheal lymph nodes).
Fluorescence bronchoscopy is currently being developed as a
method for detecting early lung cancers, carcinoma in situ, and dysplastic
lesions of the tracheobronchial tree. If progress is to be made in the early
detection and treatment of lung cancer then we need to detect lesions before they become invasive. The World Health Organization has published
the third edition of International Histological Classification of Tumors
and lists three main forms of preinvasive lesion in the lung: (1) squamous
dysplasia/carcinoma in situ (SD/CIS), (2) atypical adenomatous hyperplasia (AAH), and (3) diffuse idiopathic pulmonary neuroendocrine cell
hyperplasia (DIPNECH).
SD/CIS is graded into four stages (mild, moderate, severe and
39
CIS). Little is known about the progression of these lesions, but it is generally thought that squamous cell carcinomas have their origin in SD/CIS,
and there is reasonable morphologic evidence that AAH may progress
through low to high grade and then to bronchoalveolar cell carcinoma (a
noninvasive lesion) and finally peripheral adenocarcinoma. DIPNECH is
rare and associated with the development of multiple carcinoid tumors. A
knowledge of these preinvasive lesions and how they might evolve is essential in interpreting the results of studies that aim to detect and treat
them early. Attention has focused on detection of early central squamous
cell lesions (SD/CIS); it is less clear how peripheral lesions such as AAH
might be detected.
The development of fluorescence bronchoscopy is considered to
be one of the most important new initiatives in the detection of early
squamous cell lung cancer. Although traditional white light bronchoscopy
has a yield of greater than 90% for picking up macroscopic lesions, it is
less good at picking up SD/CIS.
It has been recognized for some time that dysplastic and malignant cells exposed to light of a specific frequency will emit light of a
wavelength different from that of normal tissue. Fluorescence bronchoscopy takes advantage of this difference and uses a blue light for illumination. Under this illumination premalignant and malignant tissues give off
slightly weaker red fluorescence but much weaker green fluorescence than
normal tissues, which can be recognized by an experienced operator.
SD/CIS and early invasive lesions detected by fluorescence
bronchoscopy are thought to be the earliest manifestation of lung cancer
and it is hoped that their detection and treatment will improve prognosis in
a subsection of high-risk patients. False-positive abnormal fluorescence
can occur in patients with suction trauma, bronchial asthma, severe mucous gland hyperplasia, or acute purulent bronchitis. Several systems are
available for fluorescence bronchoscopy, of which the best known are the
40
light-induced fluorescence endoscopy (LIFE) device and the SAFE-1000.
Endoscopic ultrasound with fine needle aspiration. Another
technique that is becoming increasingly important in the sampling of mediastinal, but not hilar, lymph nodes is transesophageal lymph node sampling under endoscopic ultrasound guidance (EUS). This has the added
advantage of avoided contamination of lymph node samples with malignant cells from the bronchial tree.
EUS is a technique that has been in use for more than 10 years. It
makes use of a modified endoscope with an ultrasound transducer at the
tip and gives excellent views of the structures that lie adjacent to the gut
lumen. EUS from the esophagus gives access to the subcarinal, aortopulmonary, and posterior mediastinum and is able to resolve nodes as small
as 3 mm.
However, the views of the paratracheal and anterior mediastinal
areas are limited by distortion caused by tracheal air. By using curved
echo-endoscopes it is possible to perform fine needle aspiration (EUSFNA) of abnormal subcarinal and aortopulmonary window nodes with
negligible risk of infection or bleeding. This had a sensitivity of 96% for
malignancy in lymph nodes when bronchoscopy had been unhelpful.
Mediastinoscopy and mediastinotomy. Mediastinoscopy was
developed by Carlens about 35 years ago to facilitate staging of superior
mediastinal lymph nodes (N2 or N3) before consideration of therapy in
patients with lung cancer. It remains the most accurate lymph node staging technique to assess superior mediastinal lymph nodes, which are frequently involved in this disease.
In the future, if early experience proves correct, PET scanning may
replace this invasive procedure as a method of accurately identifying mediastinal involvement.
Thoracoscopy. Video-assisted thoracoscopy has been used in the
diagnosis and staging of lung cancer. Peripheral nodules can be identified
41
and excised using video-assisted minimally invasive techniques, and mediastinal lymph nodes can be sampled for histologic examination. This
technique also can identify suspected pleural disease and has the ability to
assess accurately the status of pleural effusions. The exact indications and
use of this minimally invasive technique await further prospective studies,
but it has been used for assessment of mediastinal nodes and T4 status,
especially effusions.
Thoracotomy. Thoracotomy continues to be used in the diagnosis
and staging of lung cancer. Using less invasive procedures, however,
more than 95% of tumors can be accurately diagnosed and staged without
thoracotomy. Despite this, there remains a small minority of patients in
whom the diagnosis of lung cancer is made only at thoracotomy.
At the time of thoracotomy, the diagnosis can be confirmed by fine-needle aspiration, incisional or preferably excisional biopsy, and frozen-section analysis. All of these techniques can provide tissue that can be
rapidly assessed by pathologists. At the time of thoracotomy, further staging is mandatory by the surgeon using hilar and mediastinal lymph node
sampling or complete lymph node dissection. Not infrequently, unsuspected involvement of adjacent structures is recognized only at the time of
surgery, identifying T3 or T4 tumor.
DIAGNOSTIC APPROACH
The solitary pulmonary nodule
Only 20% of carcinomas are resectable at diagnosis and 50% of
"coin lesions" on chest radiography are malignant: 40% representing primary lung cancers whilst the other 10% are solitary metastases.
However, 20–30% of all cancers present as a solitary pulmonary
nodule (SPN) of which 88% are resectable with a 5-yr survival rate
around 50%. The early identification and correct assessment of such nodules is therefore of the utmost importance.
42
Benign nodules
Chest radiography.A number of findings enable a nodule to be
classed as benign on the basis of chest radiographical findings.
1) age < 35 yrs, no history of cigarette smoking and no history of
extrathoracic malignancy;
2) comparison with old films and establishment of no growth over
at least a 2-yr period;
3) if the nodule contains fat density or a benign pattern of calcification such as central nidustype, popcorn, laminated or diffuse.
Note should be made that eccentric or stippled calcification is seen
in approximately 10% of lung cancers. An appropriate history such as fever or chest pain may promote the likelihood of a benign process such as
focal pneumonia or an infarct presenting as an SPN. A repeat radiograph
should be performed at 2–6 weeks to assess resolution.
Computed tomography scanning, densitometry and enhancement.
CT scanning can further refine the detection of calcification and fat
within nodules. A total 22–38% of noncalcified nodules on chest radiographs appear calcified on CT. Using CT densitometry, a "pixel map" of a
nodule can be created with Hounsfield Unit (HU) values, > 200 being indicative of calcification.
Only characteristic patterns of calcification such as central, diffuse,
laminar or popcorn are indicative of benignity. The presence of fat (-40 – 120 HU) or calcification or a combination of the two has been shown to
correctly identify 64% with hamartomas on 2-mm section CT in one series. However, at least one-third of hamartomas in this series contained
neither fat nor calcium leading to an indeterminate assessment.
Changes in attenuation after intravenous contrast administration at
CT can also be used to distinguish benign from malignant parenchymal
nodules. By retrospectively reducing the cut-off threshold to 10 HU it was
possible to increase the techniques sensitivity in excluding malignancy
43
from 98 to 100%.
Malignant nodules
A nodule size > 3 cm is associated with malignancy in 93–99% of
cases. If the nodule is spiculated 88–94% will be malignant although 11%
of malignant nodules do have distinct margins. The presence of calcification in larger (> 3 cm) and spiculated nodules should not be viewed as indicative of benignity.
Indeterminate nodules
Small size should not be used as a discriminator for exclusion of
malignancy. One in seven nodules < 1 cm in size have been shown to be
malignant and in a recent study of nodules resected at videoassisted thoracoscopic surgery, 31% of nodules < 1 cm in size in patients with no
known malignancy were malignant. Cavitation and lobulation are not
helpful discriminators in favour of malignancy as granulomas and
hamartomas can both have these appearances.
Central tumours
Distinct from the solitary pulmonary nodule, central lung cancers
often present radiographically as a hila mass or as collapse and consolidation of lung beyond the tumour with accompanying volume loss. Air
bronchograms may be seen at CT.
Differentiating central tumours from distal collapse can be difficult
but is facilitated by bolus contrast administration followed by prompt CT
scanning at the level of abnormality. The lung is appreciably enhanced
whilst tumour enhancement is minimal and delayed. The most marked
difference between the two is seen from 40 s to 2 min after contrast injection.
Differentiating central lung tumours from mediastinal masses can
also be problematic. Marginal spiculation, nodularity or irregularity between the mass and the surrounding lung almost always indicated the
mass had arisen in the lung. A smooth interface suggested that the mass
44
was mediastinal in location. A notable exception was Hodgkins lymphoma which may occasionally cross the pleura, invade the lung and result in
a poorly marginated mass, mimicking a lung mass.
The following features can be viewed as suspicious for an obstructing neoplasm when associated with pneumonia:
1) the "S" sign of Golden, indicating a fissure deviated around a
central tumour mass;
2) pneumonia confined to one lobe (or more if supplied by a common, obstructed bronchus) especially if > 35-yrs-old and accompanied by
volume loss or mucus filled bronchi with no air bronchograms present;
3) localized pneumonia that persists for > 2 weeks or recurs in the
same lobe. Hila enlargement is a common presenting feature in patients
with lung cancer. The presence of a tumour mass or enlarged lymph nodes
will give a dense hilum. Generally speaking the more lobular the shape
the more likely that adenopathy is present.
Diagnostic staging of nonsmall cell lung cancer
The revised international system for staging lung cancer incorporates the tumour, node, metastasis (TNM) subset system and shows improved survival rates with more accurate staging and appropriate selection
of patients for definitive surgical treatment by distinguishing the IIIa from
the IIIb group.
Survival percentage at 5 yrs by clinical stage for the more advanced stages remains poor, emphasizing the importance of early detection. The overall 5-yr survival of only 5.3% serves to underline the preponderance of advanced-stage disease at presentation.
Precise tumour (T) and nodal (N) staging is imperative as it determines subsequent treatment, especially when considering neo-adjuvant
therapy for IIIa and IIIb disease. Only approximately one-half of the TNM
stages derived from CT agree with operative staging, with patients being
both under and over staged.
45
However, quick access to investigation, high histological confirmation rates (at bronchoscopic/transthoracic biopsy or at thoracotomy),
routine CT scanning and review of every patient by a thoracic surgeon is
known to substantially increase successful surgical resection.
Tumour status
The distinction between T3 and T4 tumours is critical because it
separates conventional surgical and nonsurgical management. T4 tumours
may be readily identified by virtue of their invasion of a vertebral body,
obvious invasion of the mediastinum or heart or the presence of lung
parenchymal metastases. T3 tumours can however be more difficult to
grade principally because of the difficulties of distinguishing simple extension of the tumour into the mediastinal pleura or pericardium (T3) from
actual invasion (T4).
Mediastinal invasion. Minimal invasion of mediastinal fat is considered resectable by many surgeons. Contact with the mediastinum is not
enough to diagnose mediastinal invasion.
The Radiologic Diagnostic Oncology Group compared CT and
MRI in 170 patients with NSCLC, 90% of whom went on to thoracotomy.
There was no significant difference between the sensitivity of the two
modalities (63% and 56% respectively) or the specificity (84% and 80%)
for distinguishing between T3-4 and T1-2 tumours, except when receiver
operating characteristic analysis was performed on the statistics. These
showed that MRI is better than CT at diagnosing mediastinal invasion.
MRI is particularly useful in determining invasion of the myocardium or
tumour extension into the left atrium via the pulmonary veins.
Chest wall invasion. CT assessment of tumour chest wall invasion
is variable with quoted sensitivities ranging from 38–87% and specificities from 40–90%. Invasion of the chest wall by a mass results in a T3
score. This does not mean the mass is irresectable per se but en bloc resection of the mass and adjacent chest wall is necessary which carries an as46
sociated increase in mortality and morbidity. Ultrasound has been cited as
an additional technique for chest wall assessment. MRI is a useful technique in establishing chest wall invasion. It relies on the demonstration of
infiltration or disruption of the normal extra pleural fat plane on T1weighted images or parietal pleural signal hyperintensity on T2 weighting.
The diagnostic yield is further improved by intravenous gadolinium contrast medium. Sagittal and coronal MRI better display the anatomical relationships at the lung apex as opposed to axial CT.
In superior sulcus or Pancoast tumours detection of tumour invasion beyond the lung apex into the brachial plexus, subclavian artery or
vertebral body by MRI has been found to be 94% accurate as opposed to
63% for CT, although multislice CT with nonaxial reconstruction may
improve this figure. Surface coils and thin sections (5 mm) are advised for
MRI of such tumours.
Pleural invasion. Effusions in patients with lung cancer can be benign, especially with a postobstructive pneumonia or malignant due to
pleural metastases, often characterized by pleural nodularity. Such an effusion renders the tumour T4 and irresectable, though this should be confirmed by thoracocentesis or pleural biopsy.
Nodal status
The most important predictor of outcome in the majority of patients with lung cancer limited to the chest is the presence or absence of
involved mediastinal lymph nodes. N3 nodal disease is not an option surgically whilst the management of N2 disease is debatable.
Mediastinoscopy and CT are recognized to be the most valuable
techniques for evaluation of mediastinal lymph node metastases but the
arrival of PET has begun to influence patient management in the limited
number of centres where it is available.
The enthusiasm for the usefulness of CT in assessing nodal status
grew throughout the 1980s. In 1984, LIBSHITZ and MCKENNA demon47
strated CT sensitivity and specificity of 67% and 66% respectively using a
nodal size of 1 cm to distinguish between benign nodes and those seeded
with metastases. In 1988 STAPLES et al. demonstrated 79% sensitivity
and 65% specificity for CT using a 1-cm long axis nodal cut-off measurement. More recently in a study of hila and mediastinal nodes at CT
compared to pathological examination, sensitivities and specifi- cities for
metastatic involvement were only 48% and 53% with an overall accuracy
of 51%.
Despite these statistics, CT is still recommended as the standard
strategy for the investigation of lung cancer, CT and mediastinoscopy in
all patients proving too expensive. It is recommended that mediastinoscopy and biopsy be reserved for nodes with a short axis diameter of > 1 cm
in size. Further refinements of indications for mediastinoscopy have been
recommended with its omission in patients with T1 lesions and negative
nodes at CT, unless the cell type is adeno- or large cell carcinoma.
CT may help to serve as a road map to guide fibreoptic bronchoscopy and biopsy and help identify enlarged nodes that are beyond the
reach of the mediastinoscope. It also alerts the surgeon to the presence of
anatomical anomalies.
No significant difference has been found between the ability of CT
and MRI to detect N2 or N3 mediastinal metastases. The combination of
respiratory movement artefact and poorer spatial resolution inherent with
MRI can mean that small discrete nodes as seen on CT can appear as a
larger, indistinct, single nodal mass on MRI, leading to the erroneous diagnosis of nodal enlargement. MRI is also poor at detecting nodal calcification and may thus misclassify enlarged benign nodes as malignant.
Metastatic status
A meta-analysis of 25 studies evaluating clinical examination and
imaging findings (CT head, abdomen or bone scintigraphy), found the risk
48
of metastases detected by imaging to be < 3% if clinical examination is
normal.
If clinical examination is positive for metastatic disease then metastases will be found by imaging in approximately 50% of patients.
The metastases most commonly affected brain, bone, liver, and adrenal glands in that order. How best to identify these patients preoperatively and prevent a needless thoracotomy is not clear. The literature is divided, with some studies showing that screening all patients for extrathoracic
metastases before thoracotomy is cost-effective and others finding that this
was not the case. It is now standard to include the adrenals and liver as
part of a staging CT of the chest and upper abdomen.
More recently, a multicenter, prospective randomized trial of 634
patients by the Canadian Oncology Group was designed to finally answer
the question concerning whether to search for occult metastases in the
asymptomatic patient with a resectable lung tumor and no clinical suggestion of extrathoracic spread. Although thoracotomy without recurrence
occurred less often in patients who underwent full investigation (bone
scintigraphy and CT of the head, thorax, and abdomen) as opposed to limited investigation (CT of the thorax with mediastinoscopy and other investigations as clinically indicated), the survival results were similar. In the
meantime, we agree with the recommendations of Silvestri, that, before
attempted resection, all patients should have a comprehensive clinical examination and even the subtless of abnormalities should be investigated.
Asymptomatic patients with Stage I disease should not be investigated further, but a routine search for metastases is recommended in any patient
with known or suspected N2 disease.
Diagnostic staging of small cell lung cancer
SCLC is distinguished from NSCLC by its rapid tumour doubling
time, development of early widespread metastases and almost exclusive
occurrence in smokers. It is divided into two stages: limited disease,
49
which is confined to the ipsilateral hemithorax within a single, tolerable
radiotherapy port and extensive disease which covers all other disease including distant metastases. Systemic therapy is required for all patients
with SCLC, even those with limited disease. Mediastinal radiotherapy is
not always indicated in patients with extensive disease making the distinction between the two stages important. To avoid an exhaustive search for
extensive disease (e.g. chest, liver, adrenal and cranial CT, bone scans,
marrow aspirates etc.) an alternative approach is to allow clinical symptoms to direct imaging, terminating on the discovery of extensive disease.
Given the fact that cranial CT in SCLC is positive in 15% of patients at
diagnosis, one-third of whom are asymptomatic and that early treatment
of brain metastases yields a lower rate of chronic neurological morbidity,
it seems reasonable to begin any extrathoracic staging with brain imaging.
DIFFERENTIAL DIAGNOSTICS OF THE
LUNG CANCER AND PNEUMONIAS
The anamnesis of disease is very important. Frequently patients with
acute pneumonia point out the acute beginning with a fever. The important information is the patient is for the first time or repeatedly was ill.
If he was repeatedly ill, radiological inspection before and after treatment
was carried out.
In differential diagnostics of chronic nonspecific pneumonia and the
central cancer crucial importance has X-ray examination. Performance of
chest roentgenograms in two projections, direct and lateral, is necessary in
the beginning and after treatment. It is necessary to note, that segmentary
and lobular forms of a chronic nonspecific pneumonia differ from a LC,
that they extremely seldom have strictly share or segmentary extent. As a
rule, defeat of a part of one lobe is observed. Inflammatory process tends
to be distributed through an interlobar rima to the next lobe. The both
lower lobes, upper right lobe, and 2-nd and 6-th segments are affected
50
more often. Borders of shadow, as a rule, are indistinct and rough.
The spherical form of focuses of a pneumonia are visible usually only in one projection, more often in a direct one. In another projection their
form comes nearer to triangular or wrong oval. The peripherial LC is necessary to differentiate with a ball-shaped chronic nonspecific pneumonia.
As against focuses of a chronic pneumonia the peripherial LC has more
correct spherical form in two projections and more precise tuberous external contours.
At the central LC in most cases there are two groups of attributes:
ones display tumoral process, others – its complications (a pneumonitis,
enlarged lymph nodes of a lung hilar and a mediastinum, an exudate in a
pleural cavity). To the most authentic and convincing attributes displaying
tumoral process are concerned: the image of peribronchial or endobronchial tumoral node, narrowing or a stump of a main, lobular or segmental
bronchi.
In differential diagnostics sputum cytologic examinations on presence of cancer cells helps. It is recommended to carry out not less than 5
examinations.
Big difficulties are connected with differential diagnostics of a cancer of a midlobar bronchus syndrome which obturation is accompanied by
an atelectasis of a lobe. Among patients with the isolated defeat of an average lobe by various pathological processes, the cancer meets at 16-17
%. The isolated cancer defeats of a midlobar bronchus represent the greatest difficulties in differential diagnostics with chronic inflammatory defeats. At a LC in level-by-level pictures in a oblique or lateral projection
the sign of "stump", or "ablation" of a lobar bronchus is taped. The shadow of tumoral node on a background of blackout is sometimes visible.
The final decision of a question on character of a stenosis becomes possible only after a bronchoscopy with a biopsy.
51
DIFFERENTIAL DIAGNOSTICS OF THE
LUNG CANCER AND THE TUBERCULOSIS
Frequently LC has some similar clinical and radiological signs with
pulmonary tuberculosis. Therefore an appreciable part of patients with a
LC is wrongly long time under observation of phthisiatricians with the
diagnosis of various clinical forms of tuberculosis and receives specific
treatment. The cancer mainly amazes persons of elderly and senile age,
while tuberculosis – persons of younger age.
In an anamnesis of patients with a LC are frequently repeated
pneumonias. In patients with tuberculosis there are frequent indications on
contact with a person with tuberculosis at home or at work. In case of LC
tuberculine assays, as a rule, negative while at a tuberculosis they are
positive or sharply positive. Presence of micobacteria of tuberculosis in a
sputum also considerably facilitates differential diagnostics of a LC.
The central LC most frequently is necessary to differentiate with a
tubercular infiltrate in a hilar zone, a tubercular lymphadenitis.
It is especially difficult to differentiate pathology when tubercular
process grasps a lobe or a segment. In these cases cancer focus in lung
will correspond to an atelectasis with all radiological attributes of the last
one, and at tuberculosis it will correspond to a specific pneumonia. Radiologically the shadow of a tubercular infiltrate is less homogenic and intensive, indistinct on edges, less closely connected with a hilar zone and progresses from center to periphery. For tuberculosis is typically bilaterial
defeat of lungs, fibrosis and inclusions of a lime. For infiltrative tuberculosis is more often than for a cancer the acute beginning, high temperature, tussis, chest pain.
Peripherial LC is difficult to differentiate from tuberculoma or caseoma. Incapsulated centers and focuses of a fiber-caseous nature make a
basis of tuberculomas (the original chronic form of a tuberculosis). Tuberculomas make approximately 4-5 % among other forms of the tuberculo52
sis revealed primarily. Tuberculomas as the same as cancer tumors, have
precise borders. They are the centers of a caseous pneumonia and before
break in a bronchus proceed completely asymptomatically. Caseomas are
most frequently localized subpleurally and contain calcinates. Formation
of a cavity is not specific only for these diseases, because this sign also
happens in case of the cavitary form of a peripherial LC.
Around the tuberculomas and caseomas are frequently tuberculous
focuses and calcified lymph nodes near lung hilar are observed. At tuberculosis around the tumor center usually is inflammatory infiltration. At a
peripherial cancer the perifocal phenomena are absent. It is also known,
that tuberculomas are extremely rare (2-3 %) localized in forward segments, and also in the lower lobes. However, last stage of differential diagnostics of these two diseases is the thoracotomy and sometimes only
morphological examination of the removed material.
INTERNATIONAL CLASSIFICATION OF THE LUNG CANCER
BY TNM (6TH EDITION, 2002) AND THE STAGE GROUPING
TNM definitions
Primary tumor (T) (Fig. 14-18)
TX: Primary tumor cannot be assessed, or tumor proven by the presence
of malignant cells in sputum or bronchial washings but not visualized by
imaging or bronchoscopy
T0: No evidence of primary tumor
Tis: Carcinoma in situ
T1: A tumor that is 3 cm or less in greatest dimension, surrounded by lung
or visceral pleura, and without bronchoscopic evidence of invasion more
proximal than the lobar bronchus (i.e., not in the main bronchus)*
T2: A tumor with any of the following features of size or extent:
 more than 3 cm in greatest dimension
 Involves the main bronchus, 2 cm or more distal to the carina;
53


invades the visceral pleura;
associated with atelectasis or obstructive pneumonitis that extends
to the hilar region but does not involve the entire lung
T3: A tumor of any size that directly invades any of the following:
 chest wall (including superior sulcus tumors);
 diaphragm;
 mediastinal pleura;
 parietal pericardium;
 or tumor in the main bronchus less than 2 cm distal to the carina
but without involvement of the carina;
 or associated atelectasis or obstructive pneumonitis of the entire
lung
T4: A tumor of any size that invades any of the following:
 mediastinum;
 heart;
 great vessels;
 trachea;
 esophagus;
 vertebral body;
 carina;
 or separate tumor nodules in the same lobe;
 or tumor with a malignant pleural effusion **
*Note: The uncommon superficial tumor of any size with its invasive
component limited to the bronchial wall, which may extend proximal to
the main bronchus, is also classified as T1.
**Note: Most pleural effusions associated with lung cancer are due to
tumor. However, there are a few patients in whom multiple cytopathologic
examinations of pleural fluid are negative for tumor. In these cases, fluid
is non-bloody and is not an exudate. When these elements and clinical
54
judgement dictate that the effusion is not related to the tumor, the effusion
should be excluded as a staging element and the patient should be staged
as T1, T2, or T3.
Regional lymph nodes (N) (Fig. 19-21)
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis (need to examine more than 6
lymph nodes)
N1: Metastasis to ipsilateral peribronchial and/or ipsilateral hilar lymph
nodes, and intrapulmonary nodes including involvement by direct extension of the primary tumor
N2: Metastasis to ipsilateral mediastinal and/or subcarinal lymph node(s)
N3: Metastasis to contralateral mediastinal, contralateral hilar, ipsilateral
or contralateral scalene, or supraclavicular lymph node(s)
Distant metastasis (M) (Fig. 22)
MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis present
*Note: M1 includes separate tumor nodule(s) in a different lobe (ipsilateral or contralateral).
ABBREVIATIONS FOR M1
BRA = brain
LYM = lymph nodes
OTH = other
PLE = pleura
EYE = eye
MAR = bone marrow
OVR = ovary
PUL = pulmonary
55
HEP = hepatic
OSS = osseous
PER = peritoneal
SKI = skin
Fig. 14. Possible variants of T1 and T2 tumour.
56
Fig. 15. Possible variants of T3 and T4 tumour.
Fig. 16. Possible variants of T4 tumour.
57
Fig. 17. Possible variants of T4 tumour.
58
Fig. 18. Possible variants of T4 tumour.
59
Fig. 19. Possible lymph nodes affection in case of LC: 1 – segmental lymph nodes (LN), 2 – lobal LN, 3 – interlobal LN, 4 – hilar LN, 5
– tracheobronchial LN, 6 – paratracheal L:N, 7 – LN of aortal window
and reccurent laryngeal nerve, 8 – LN of azygous vein, 9 – paraoesophageal LN, 10 – bifurcational LN, 11 – oesophagus, 12 – aorta, 13 – vena
cava superior, 14 – azygous vein, 15 – supraclavicular LN, 16 – LN of
lung ligament, 17 – lung ligament, 18 – left vagus nerve, 19 – left reccurent laryngeal nerve.
Fig. 20. Possible variants of N1
N2.
Fig. 21. Possible variants of
N3 and M1.
60
a
b
c
Fig. 22. a) computed tomography scan of enhancing cerebral
metastasis with marked oedema and mass effect; b) massive left adrenal
(open arrow) and hepatic metastases (arrows); c) vertebral body
metastasis.
STAGE GROUPING
Occult carcinoma
TX, N0, M0
Stage 0
Tis, N0, M0
Stage IA
T1, N0, M0
Stage IB
T2, N0, M0
Stage IIA
T1, N1, M0
Stage IIB
T2, N1,M0
T3, N0, M0
Stage IIIA
T3, N1,M0
T1-3, N2,M0
Stage IIIB
T1-3, N3, M0
T4, N0-3, M0
Stage IV
Any T, Any N, M1
To define the T characteristics of a lesion, chest roentgenography
and fiberoptic bronchoscopy are required. Occasionally, CT or MRI can
be useful in anatomically defining T3 or T4 lesions.
To define the N characteristics of a lesion, some combination of
61
chest roentgenography, CT or MRI scanning, transbronchial needle
aspiration (TBNA), or mediastinoscopy is required.
There is now general agreement that nodal enlargement identified
by CT requires tissue confirmation of metastasis by mediastinoscopy or
alternate biopsy technique, except when gross mediastinal invasion by
tumor (T4) is present. A patient should not be denied potentially curative
surgery based solely on radiographic criteria. Emphasizing this point, a
recent study demonstrated that 37% of lymph nodes measuring 2-4 cm in
short-axis diameter on CT did not contain metastases at the time of
surgery. CT scanning is also useful in identifying the site(s) of mediastinal
node enlargement, especially those that may not be accessible to standard
mediastinoscopy (aortopulmonary nodes, anterior mediastinal nodes,
paraesophageal nodes, and inferior pulmonary ligament nodes). Also,
extension of the CT examination to include the adrenal glands and liver
may often detect the presence of occult metastatic disease. The role of
MRI scanning remains limited due to its poorer spatial resolution
compared to CT, its expense, and its limited ability to detect calcification.
To define the M characteristics of a lesion, the triad of history,
physical examination, and an admission chemistry panel, including liver
function tests, is recommended. Unless an abnormality is identified by
that triad, routine screening by means of multiple organ scans is not
recommended. In the case of radioisotopic liver and bone scans, the
incidence of false-positive scans is appreciable, necessitating an invasive
and costly workup with low yield. Although the evidence remains
somewhat conflicting, certain authors believe that the performance of a
head CT scan in asymptomatic patients with adenocarcinoma of the lung
does represent a prudent preoperative examination.
Combining the TNM elements results in subsets that can be further
grouped to depict stages or extent of disease. Stage I includes only
patients with the best prognostic expectations, those with T1 or T2 tumors
62
and no evidence of metastasis. Stage II disease includes patients with
primary tumor classification of T1 or T2 and metastasis to the
intrapulmonary (including hilar) lymph nodes. Stage IIIA disease
designates those patients with extrapulmonary extension of the primary
tumor or ipsilateral mediastinal lymph node metastasis or both. Stage IIIB
includes patients with more extensive extrapulmonary involvement than in
the potentially operable stage IIIA group, those having malignant pleural
effusion, and those with metastasis to the scalene, supraclavicular, or
contralateral mediastinal or hilar lymph nodes. Stage IV disease is
confined to those patients with metastasis to distant sites.
ATYPICAL FORMS
The mediastinal form of a LC is characterized by defeat of mediastinal lymph nodes. The initial tumor is in bronchi and gives roughly growing metastases in mediastinum, considerably outstripping growth of an
initial tumor. The clinical picture is characteristic by signs of compression
of a superior vena cava: cyanosis and edema of head and neck, phlebectasia of neck and chest. At a palpation of a neck the augmentation of supraclavicular lymph nodes owing to their metastatic defeat is frequently determined.
Miliar carcinosis develops in connection with a rough innidiation
of a tumor by the lymphogenous or hematogenous way in affected or opposite lung. The picture reminds lung tumoral multilocular diffusion by
small "millet-similar" nodules. It is not possible to find the primary tumor
in lung.
The cardial form of a LC is characteristic by the signs reminding
ischemic desease of the heart. Patients address to the theraputist or to the
cardiologist and long time they are treated with the diagnosis "ischemic
desease of the heart". The reason of such manifestation of a LC frequently
is the tumor invasion in a pericardium. Especially at left-sided localization
63
in the lower lobe of left lung the shadow of a tumor long time is near with
a cardiac shadow, and only additional methods of a X-ray examination
allow to determine it.
Osteal, cerebral, hepatic forms etc. are frequent variants of atypical picture of a LC. Each of the listed forms is characterized by dominant
clinic of metastatic defeat of one of the specified organs or systems with
the minimal displays of an initial tumor of a bronchus.
COMPLICATED LUNG CANCER
The compression of vena cava superior (cava-syndrome) develops
as a result of a compression of this vessel directly by a tumor of right lung
or by metastases of a cancer in a mediastinum. Vena cava superior – an
unique vessel by which the blood comes back to heart from a head, neck,
top extremities and the upper half of trunk. Compression or an invasion of
this vein by a tumor may be cause of a decompensation when the blood
from the specified departments of a body may not return to the right auricle, and venous stagnation develops. It is shown by various objective and
subjective attributes: cyanosis of seen mucosas and skin of the face; edema of face or top extremities, expansion of hypodermic veins of neck and
anterior thoracic wall; the venous network reminds a head of a jellyfish
(“Caput medusae”); hum and gravity in a head are marked.
The esophago-bronchial fistula concerns to infrequent, but to the
most severe complications of a LC. The pathological connection between
bronchi and esophagus is formed owing to disintegration or a radial destruction of a LC. Clinically formation of an esophago-bronchial fistula is
shown by fits of severe coughing during eating or drinking. At a X-ray
inspection of an esophagus with use of a contrast agent its passage from
an esophagus to a bronchial tree is taped. The condition of the patient is
quickly worsened in connection with development of aspirational pneumonias. The basic actions should be directed on stop of nutrition passage
64
into bronchi from esophagus and struggle against a pneumonia.
The profuse pulmonary bleeding at a LC comes as a result of disintegration of a tumor and arrosion of branches of bronchial or pulmonary
vessels. The pulmonary bleeding is characterized by the fits of coughing,
accompanying with discharging from a mouth of a scarlet foamy blood.
Sometimes patients choke, not having time to expectorate blood. Paleness
of skin, cold sweat, syncope, tachycardia, arterial hypotension are marked.
Plural atelectasises and the centers of aspirational pneumonias develop in
lung.
The lung atelectasis develops owing to an obturation by a tumor of
a main bronchus. It is accompanied by a short wind, chest pain, tachycardia. Radiologically the massive blackout (lung without air) and shift of a
mediastinum to a side of an atelectasis are taped (Fig. 23).
a
b
Fig. 23. a) collapse of the left lung with mediastinal shift and a right
middle zone nodule (arrow); b) perihilar low attenuation adenocarcinoma
(arrows) with distal enhancing collapsed lung in same patient.
TREATMENT OF THE LUNG CANCER
Surgery and radiotherapy have been used independently to obtain
local control of the primary tumor and regional lymphatic drainage. Until
recently, chemotherapy had been used in an attempt to prolong symptom65
free life in patients with metastatic disease. In the past 20 years, however,
combined-modality therapies have become much more prevalent and have
spurred intensive investigation. All three modalities are now used as primary therapy and, in combination, have been employed to improve disease-free intervals and ultimate survival.
SURGICAL TREATMENT OF THE LUNG CANCER
Unique method of radical treatment of LC is surgical. Once histologic proof of lung carcinoma is obtained, resectability is determined by
the histopathology and extent of the tumor and by operability according to
the overall medical condition of the patient. Age and mental illness per se
are not factors in deciding operability. Approximately 50 percent of patients with NSCLC are potentially operable. About 50 percent of tumors
in operable patients are resectable (25% of all patients) and, approximately 50 percent of patients with resectable tumors survive 5 years (12% of
all patients, or 25% of operable patients).
Signs of unresectable lung cancer.
a. Distant metastases, including metastases to the opposite lung.
b. Persistent pleural effusion, with or without malignant cells (a parapneumonic effusion that clears and may permit subsequent resection).
c. Superior vena cava obstruction.
d. Involvement of the following structures:
1) Supraclavicular or neck lymph nodes (proved histologically).
2) Contralateral mediastinal lymph nodes (proved histologically).
3) Recurrent laryngeal nerve.
4) Tracheal wall.
Cardiac status. The presence of uncontrolled cardiac failure, uncontrolled arrhythmia, or a recent myocardial infarction (within 3-6 months)
makes the patient inoperable.
Pulmonary status. The patient's ability to tolerate resection of part or
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all of a lung must be determined. The presence of pulmonary hypertension
or of abnormalities on certain pulmonary function tests makes the patient
inoperable.
Clinical observation. Any patient who can walk up a flight of stairs
without stopping and without severe dyspnea is likely to tolerate a pneumonectomy.
Routine pulmonary function tests. Arterial blood gases and spirometry should be obtained on all patients before surgery. Pulmonary function
tests must be interpreted in the light of optimal pulmonary toilet and patient cooperation. The patient with test abnormalities should be considered
for therapy with bronchodilators, antibiotics, chest percussion, and postural drainage before inoperability is concluded. The following results suggest inoperability:
1) Forced vital capacity (FVC) less than 40 percent of predicted value, or
2) Maximum voluntary ventilation (MVV) less than 50 percent of predicted value, or
3) Forced expired volume at one second (FEV1.0) < or equal to 1.0 L
Clinical stage grouping defines tumor spread and the potential for
curative resection, thereby determining which patients should or should
not be referred for surgery. Surgical decisions related to staging that are
based on T or M characteristics are clear-cut:
1) all operable patients with stage I or II should have definitive surgery;
2) all patients with stage IIIB or IV disease have nonsurgical disease.
With respect to N characteristics in stage IIIA disease, the issue is
not as clear. Patients with N2 disease discovered at thoracotomy following
a negative mediastinoscopy have been demonstrated to have an improved
survivorship compared to those patients in whom N2 disease is discovered
at mediastinoscopy. Specific characteristics of the node or nodes other
than their location affect the potential for resectability:
1. Number of nodes: Prognosis has been shown to be better for
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single-level nodal metastases than for multilevel nodal involvement.
2. Character of nodal involvement: A number of reports have
suggested that prognosis is related to whether the tumor is contained
within the node (intranodal disease) or has spread beyond the nodal
capsule (perinodal disease).
3. Specific location of nodal involvement: Although still a subject of
controversy, several studies have reported that the survival rate of patients
with subcarinal lymph node metastases was lower than the survival rate of
patients with metastases to lymph nodes in other mediastinal locations.
The data underscore the need for a uniform mapping system of specific
nodal locations to ensure clear and precise definition of the findings at
thoracotomy so that these findings can be correlated with outcome.
The basic standard operations are: lobectomy, pneumonectomy, extended pneumonectomy (removing of a mediastinal fat with lymph
nodes), combined pneumonectomy – removing of a lung with a pericardium site, diaphragm site or thoracic wall site.
Recent years bronchoplastic operations are more often carried out
allowing as much as possible to keep a respiratory lung volume. Removing of the upper lobe with a circular resection of a main bronchus is the
most frequent one.
Surgical resection offers the only definitive means of therapy by
which non-small-cell lung cancer (NSCLC) can be cured. Unfortunately,
less than 30% of patients with newly diagnosed lung cancer fall into a
favorable survival group at the time of diagnosis, thereby accounting for
the barely perceptible increase in 5-year survival rates of 50-60% in stage
I disease, 30-40% in stage II disease, and 10-20% in stage IIIA disease.
The most adverse forecast have undifferentiated cancers (small cell and
giant cellular). Improved patient selection and advances in preoperative
management, anesthetic techniques, and postoperative care have led to a
dramatic decline in mortality rates for pulmonary surgery. Data from the
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Lung Cancer Study Group have demonstrated mortality rates of 6.2% for
pneumonectomy, 2.9% for lobectomy, and 1.4% for lesser procedures.
General 5-year survival rates after surgical treatment of a LC makes
about 30%. At treatment of patients in stage T1-2N0M0 it increases up to
80 %.
RADIOTHERAPY OF THE LUNG CANCER
Radiotherapy for the treatment of LC has experienced significant
changes in a short time with respect to the evolution of appropriate patient
selection, radiobiologic principles, technical innovation, imaging, and the
use and integration of chemotherapy and surgery. Radiotherapy is applied
as an independent method of treatment, and in a combination with a surgery or chemotherapy. The most widespread is application of gammatherapy with a radioactive source 60Co (a radiation energy 1,25 МeV).
Since 1960th high-energy radiations of linear and cyclic particles
accelerators are applied for treatment of malignant tumors. More favourable spatial distribution of high-energy radiation (5-45 MeV) is especially
shown at deeply posed neoplasms, including a LC.
Radical radiootherapy provides reception of long and proof effect as
a result of destruction of all tumor in irradiated volume when at a palliative irradiation there is only partial destruction of tumor. The volume of
the tissues, exposed to radical radial influence, should cover a seen initial
tumor, probable lymphogenous metastases: bronchopulmonary, hilar, upper and lower tracheobronchial, paratracheal lymph nodes. The radical
program of an irradiation at undifferentiated small cell forms of a LC provides a preventive irradiation of supraclavicular areas with the purpose of
destruction of subclinical metastases. The cooperative focal dose necessary for destruction of an initial tumor varies from 50 up to 80 Gy and depends on histological structure of a tumor.
Radiotherapy of a peripherial LC has own features. In a field of an
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irradiation are included a shadow of a tumor, radiological "path" to a lung
hilar (which displays infiltration of a peribronchial and perivascular tissue
by tumor), zones of regional lymph nodes.
In case of mediastinal form of a LC, and also in any other form with
a massive innidiation in lymph nodes of a mediastinum with a compression of the large veins causing development of the mediastinal compressional syndrome, radial treatment is the best one.
Postoperative radiotherapy had been standard treatment after surgical resection of N2 disease. Its ability in moderate doses of 40–55 Gy to
eradicate microscopic residual disease and reduce local recurrent rates is
well established.
Palliative radiotherapy can be effective at relieving local symptoms
of lung cancer. Quality of life data from the British MRC randomized trials of 1 and 2 fractions of treatment versus more conventional treatment
consisting of 10 or 13 fractions have shown improvement in local symptoms, including chest pain, cough, and breathlessness, in more than 50%
of cases, with 90% of those having hemoptysis being controlled. These
showed that shorter schedules using one or two fractions of radiotherapy
are just as effective at obtaining relief of local symptoms without detriment to survival time or an increase in toxicity relative to higher dose,
short courses. The MRC studies (1991, 1992, and 1996) also included
careful assessment of quality of life with daily diary cards, confirming
good durability of palliation and minimal toxicity.
Smaller doses of radiotherapy can be used if delivered directly to the
airway (endobronchial brachytherapy) and are particularly useful in those
patients who have received close to the maximum safe dose of external
beam radiotherapy, and in those with tumor localized to within or close to
the airway lumen. Radical radiotherapy can also be delivered in this way.
Endobronchial brachytherapy has been used in one form or another for at
least 80 years with radium needles and cobalt pearls used commonly in
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1960s and 1970s to destroy local tumor in the upper airways. Iridium has
now become the standard mode of delivery of irradiation via a catheter
placed in the airway through a flexible bronchoscope under radiographic
control. Iridium provides small-volume irradiation with a steep decrease in
radiation isodoses within a few millimeters of the source axis. The target
dose depends on the intent, with 10–15 Gy in 10 mm for palliation, and
20–25 Gy if cure is intended for a localized small lesion. The response to
brachytherapy is slow, over 10 to 20 days, and appears to be safe in doses
of 5 Gy over two to four sessions, even if radical radiotherapy has been
given earlier. In fact, the commonest setting for brachytherapy is for local
relapse after previous radical radiotherapy.
The addition of iridium-192 brachytherapy has been demonstrated
to prolong the duration of palliation substantially, although such complications as hemorrhage or airway fistulization with the esophagus or major
vessels have been reported in 10-15% of treated patients.
The role of laser therapy in endobronchial carcinoma is evolving.
Palliation of airway obstruction can be achieved when obstructing lesions
involve the trachea and mainstem bronchi. Treatment appears most successful when the lesions are short in length, when the distal bronchi are
free of tumor, and when there is functioning lung tissue distal to the obstruction.
One nonsurgical method of treating early lung cancers is by endobronchial photodynamic therapy (PDT) under local anesthesia and sedation. PDT is approved for the endobronchial treatment of microinvasive
NSCLC and for palliation in patients with obstructing tumors. A mixture
of different porphyrin-based oligomers (such as Photofrin [porfimer sodium]) is injected intravenously, with care not to extravasate. The drug is
cleared in 72 hours, but is retained for up to 30 days in tumors, skin, liver,
and spleen. After 48 hours light with a wavelength of 630 nm is shone
71
from a laser onto the tumor and the resulting phototoxic reaction destroys
tumor to a depth of 5 to 10 mm.
The light is delivered through a cylindrical diffuser fiber that is
passed through the working channel of the flexible bronchoscope and the
tip is then embedded into the lesion. The bronchoscopy should be repeated
at 48 hours to clear debris and secretions and prevent compromise of the
airway (a particular problem when treating tracheal lesions, and those requiring high energy levels).
Another complication of PDT is skin photosensitivity. Patients are
kept in special hospital rooms and are given advice before discharge such
as to avoid even normal daylight for 4–6 weeks after the injection. Care
should be taken when using pulse oximeters, which have caused severe
finger-tip burns for monitoring patients during the procedure.
PDT has been used to treat early lung cancers (less than 10 mm in
diameter) with a cure rate of more than 75%. There is some early evidence
that EBUS can be used to select for tumors in the large airways that are
sufficiently localized (i.e., have not extended beyond the airway cartilage)
to be treated by PDT with curative intent, as an alternative to surgery.
PDT has also been assessed for use as a palliative treatment and has been
shown to perform as well as other modalities, in particular the Nd:YAG
laser, in relieving endobronchial obstruction by NSCLC. However, care
must be taken as the time lag between treatment and tissue necrosis means
that PDT is not suitable for emergency relief of obstruction, and in addition, obstruction may worsen because of the intense inflammatory response at 24–72 hours posttreatment, so that bronchoscopy and resuscitation equipment must be available.
CHEMOTHERAPY OF THE LUNG CANCER
For realization of drug treatment of a LC morphological confirmation of the diagnosis, establishment of histological type of a tumor, speci72
fication of prevalence of process in organs and tissues, an estimation of
the general condition of the patient are necessary. Special value in chemotherapy of a LC has the histological type of a tumor, which defines character of chemotherapy, and also the forecast for effect of treatment and
survival.
Chemotherapy has been evaluated as neoadjuvant and adjuvant
treatment around surgery, neoadjuvant and adjuvant around radiotherapy,
and as primary treatment for advanced inoperable disease.
Indications to chemotherapy of a LC:
 Not removable surgically initial lung tumor.
 Impossibility of application of radial treatment.
 The plural remote lymphogenous metastases.
 The specific pleuritis confirmed with cytologic exudate examination.
 Progression of disease in various terms after operation.
 Absence of the effect after radiotherapy.
Contraindications to a chemotherapy:
 Cachexia.
 Serious general condition of the patient.
 Leukopenia.
 Thrombocytopenia.
 Disintegration of a tumor with a pneumorrhagia.
 Infringements of function of a liver and kidneys.
 Metastases in a liver.
Now Cyclophosphanum is one of recognized all over the world the
antitumoral preparation having expressed activity at a LC. It is included in
numerous schemes of a polychemotherapy.
Several new agents, including paclitaxel (Taxol), docetaxel (Taxotere), topotecan, irinotecan, vinorelbine, and gemcitabine have been
shown to be active in the treatment of advanced LC (See table 1).
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Table 1.
Standard agents in case of LC
OLD (pre 1990)
NEW (post 1990)
Cisplatin
Paclitaxel
Etoposide
Docetaxel
Vinblastine
Gemcitabine
Cyclophosphanum
Vinorelbine
Mitomycin-C
Irinotecan
At a chemotherapy the strict control of a peripherial blood condition, a medullar hemopoiesis, function of a liver, kidneys and cardiovascular activity is necessary. Clinical analyses of a blood are carried out not
less often 2 once a week. The hematological control continues also within
7-12 days after end of a course of chemotherapy. The most often complication is oppression of hemopoiesis function: downstroke of amount of
leucocytes and thrombocytes, an anemia.
Chemotherapy of Nonsmall Cell Lung Cancer
A place for chemotherapy before surgery has been controversial for
the last 10 years. There are two issues: first, what is the role for neoadjuvant chemotherapy in conventionally resectable patients, that is, those
with Stage I or II disease (T1, T2, or T3, N0; T1, T2, or T3, N1) and also
limited Stage IIIA disease, that is, unforeseen N2 disease with normal
nodes at CT but microscopic N2 disease at mediastinoscopy? The second
issue is whether chemotherapy can "debulk" more advanced disease, for
example, N2 nodes found on CT, T4 primary tumors, or N3 disease. These
patients would not normally be considered for surgery and are treated by
radical radiotherapy or chemotherapy–radiotherapy. However, if chemotherapy were a really effective treatment, could surgery follow chemotherapy and be more effective than radical radiotherapy? The answer to the
first question is "possibly," and the answer to the second is not at all clear.
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The place of chemotherapy after surgery is likely to emerge clearly
within the next 2 to 3 years. The meta-analysis did not derive a significant
advantage for the addition of chemotherapy after surgery (p < 0.08) and,
therefore, several studies are now in progress, or have recently completed,
that will be expected to answer this question, either as a single study or,
more probably, as a new meta-analysis.
With the lack of any clear advantage for adjuvant chemotherapy or
postoperational radiotherapy in resected N2 lung cancer, the possible benefits of combining chemotherapy with radiotherapy after resection have
been studied. The logic is that radiotherapy decreases local rates of recurrence and chemotherapy may both add to this and treat distant occult disease. There have been four randomized controlled trials of surgery plus
adjuvant chemotherapy–irradiation versus surgery and radiation alone. All
these studies failed to show an advantage in overall survival, with the most
recent failing to demonstrate any improvement in disease-free survival or
overall survival with the addition of chemotherapy to radiotherapy.
Another question concerns the timing of radiation in relation to
chemotherapy. The studies described above all gave chemotherapy before
irradiation (i.e., sequential chemoirradiation). A European Organisation
for Research and Treatment of Cancer (EORTC) three-arm study compared split-course radiotherapy concurrent with daily or weekly cisplatin
versus radiotherapy alone. There was no advantage for the weekly chemotherapy plus radiotherapy arm.
Chemotherapy in Advanced Disease. Approximately 60% of patients of NSCLC present with Stage IIIB or IV (i.e., advanced) disease.
They have a median survival of 4 to 6 months untreated and 10 to 15%
will remain alive at 1 year. Early studies of single-agent chemotherapy
and combinations of predominantly alkylating agents showed little benefit,
but meta-analyses reported in the mid-1990s suggested a small but definite
benefit with cisplatin-containing regimens compared with best supportive
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care (BSC) alone. These studies, briefly detailed above, do show an undoubtedly better median survival and 1-year survivorship for active treatment and, where available, an improvement in some measures of quality
of life.
The latter is still difficult to quantify and remains "soft" data. Most
studies have taken patient subsets for quality of life analysis, used different measures with no agreed criteria for reporting, and, because of the attrition of the disease itself, the numbers returning questionnaires fall by
30–50% by 6 to 12 weeks, making the data more difficult to interpret.
Most studies show that, if quality of life is to improve, it does so in most
patients after two courses of chemotherapy and worsens after prolongation
of treatment.
Of course, not all patients with advanced disease will benefit from
chemotherapy. Disease stage and performance status are the most important prognostic factors at presentation. Those patients most likely to
respond to chemotherapy and tolerate side effects well are those with a
good performance status, female sex, a single metastatic site, normal calcium and serum lactate dehydrogenase, hemoglobin at more than 11 g/dl,
and the use of cisplatin chemotherapy. Of these, performance status is the
most important factor, and of other variables analyzed, a poor prognosis is
conferred if there are subcutaneous metastases, bone marrow infiltration,
thrombocytosis, and non-large cell histology.
Chemotherapy of Small Cell Lung Cancer
Small cell lung cancer (SCLC) is sensitive to several chemotherapeutic agents, and most if given as single agents will elicit at least a partial
response (50% or greater reduction in tumor size) in more than 30% of
previously untreated patients.
Several new agents have shown similar activity. A plethora of studies in the 1970s showed combinations of agents to be superior to single
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agents both in terms of the response rates and the duration of the response
and prolongation of survival.
Several combination regimens have shown acceptable and fairly
similar activity, producing an objective response rate of 80 to 90%, with
complete response (no tumor detectable on restaging tests) in up to 50% of
patients, depending on the stage of presentation.
Patients presenting with limited stage disease (disease confined to
the hemithorax and including the ipsilateral supraclavicular fossa) do better than those with extensive stage disease. Median survival averages up to
20 months for limited disease and up to 7 to 10 months for extensive disease after treatment compared with 3 months and 6 weeks for untreated
limited disease and extensive disease.
The optimal duration of combination chemotherapy is probably six
to eight cycles. Long-term results after chemotherapy remain disappointing.
Criteria have been identified for patients who have a realistic
chance of living 2 years and those who are likely to die quickly. Apart
from disease extent, performance status, serum alkaline phosphatase,
plasma albumin, and sodium concentrations carry independent prognostic
information. Serum lactate dehydrogenase can be substituted for alkaline
phosphatase.
Taken together, these simple serum analyses and performance status give more prognostic information than disease extent defined by more
detailed and expensive imaging tests. The value of prognostic factors is
that they identify patients with a chance of cure, but also patients with limited disease at risk of early death and patients with extensive disease with
a chance of living 18 months with chemotherapy; and they help to facilitate comparisons between trials.
Although the toxicity from chemotherapy is well understood and to
a considerable extent predictable, the side effects can be a major problem
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and a dose-limiting factor, particularly in an increasingly elderly population of patients.
Dose intensification
In tumor models one of the simplest ways to overcome drug resistance is dose intensification. In the 1970s Cohen and coworkers conducted a series of trials with increasing doses of cyclophosphamide and
lomustine with standard doses of methotrexate. They observed a higher
response rate and prolonged survival in the high-dose arm. Also, longer
term survival was seen only in the high-dose group. By today's standards
the doses used would appear modest, but they introduced the concept of
high-dose chemotherapy for this disease.
Weekly chemotherapy
The concept of increasing intensity by more frequent administration of
chemotherapy has resulted in trials comparing conventional 3-weekly with
weekly regimens. However, one of the difficulties with weekly chemotherapy was in achieving administration of the intended dose, which in our
group's study was only 71% of intended in the weekly group.
Late intensification chemotherapy
There are theoretical advantages for late intensification, as initially
patients are ill and symptomatic as a consequence of the extent of their
disease. Patients achieving a complete response with induction chemotherapy might be good candidates for high-dose consolidation treatment.
However, the results of this approach contain few comparative data as the cases treated tend to be selected from the responders and the attrition rate from toxicity is high, with only a small number of patients
achieving the intended treatment. No useful survival advantage has been
reported from late intensification studies.
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MOLECULAR BIOLOGY OF LUNG CANCER:
CLINICAL IMPLICATIONS
Self-sufficiency of growth signals: proto-oncogenes
and growth stimulation by autocrine and paracrine factors
A number of growth factors and their cognate receptors are expressed by lung cancers or their adjacent stromal cells, thus producing autocrine and paracrine growth stimulation loops. Several are encoded for by
proto-oncogenes which become activated in the course of lung cancer development. The ERBB family is a group of transmembrane receptor tyrosine kinases which, together with their ligands, constitutes a potential
growth stimulatory loop, particularly for NSCLCs.
The two members important for lung cancer are the epidermal
growth factor receptor (EGFR, ERBB1) and HER2/neu (ERBB2), which
are expressed independently of one another in NSCLC. On ligand binding,
ERBB receptors homodimerise or heterodimerise, thereby inducing intrinsic kinase activities that initiate intracellular signal transduction cascades
including the MAP kinases.
EGFR regulates epithelial proliferation and differentiation and can
be overexpressed in lung cancers. Moreover, lung cancer cells also express ligands for EGFR such as epidermal growth factor (EGF) and transforming growth factor (TGF ), thereby producing a potential autocrine
growth loop. Some, but not all, studies have associated EGFR expression
with impaired survival.
Monoclonal antibodies against the EGFR (C225, ImClone) are entering clinical trials in combination with chemotherapy. In addition, tyrosine kinase inhibitors that have some selectivity such as ERBB1 blockers
(CP358774, ZD1839-Iressa, OSI774) are also being tested, most with the
advantage of being orally active.
Another ERBB family member, HER2/neu, is highly expressed in
about 30% of NSCLCs, especially adenocarcinomas. High HER2/neu lev79
els are associated with the multiple drug resistance phenotype and increased metastatic potential in NSCLC, which may help to explain the
poor clinical outcome linked to HER2/neu overexpression reported by
some but not all investigators. Clinical trials investigating chemotherapy
combined with trastuzumab (Herceptin), a monoclonal antibody against
the HER2/neu receptor, are in progress in lung cancer.
The autocrine loop comprising stem cell factor and its tyrosine kinase receptor CD117 is activated in some lung cancers—more often in
SCLC than NSCLC—with resultant growth promotion or chemoattraction.
The recent development of specific tyrosine kinase inhibitors to target this
pathway may translate into novel approaches for this highly lethal subtype.
Similarly, the gastrin releasing peptide (GRP) growth stimulatory
loop is involved in 20–60% of SCLCs. The therapeutic potential of inhibiting this pathway with a neutralising monoclonal antibody directed
against GRP, as well as by antagonists of GRP (also referred to as
bombesin), is being tested in early clinical trials of SCLC. The GRP receptors belong to a G-protein coupled receptor superfamily including
GRP-, neuromedin B- and bombesin subtype-3 receptors; all of these can
be expressed in lung cancers of all histological types and some bronchial
epithelial biopsies from smokers, implying an early pathogenic role for
this family. The GRP receptor is expressed more frequently in women
(where there are two expressed copies of the X linked gene) than in men
in the absence of smoking. Its expression is activated earlier in women in
response to tobacco exposure, which may be a factor in the increased susceptibility of women to tobacco induced lung cancer.
Other putative growth factor systems include insulin-like growth
factors (IGF) I and II, the type I IGF receptor, platelet derived growth factor/receptor, and the hepatocyte growth factor/receptor. Each of these
should be further studied for any potential clinical usefulness. Insulin-like
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growth factor binding protein-6 (IGFBP-6) activated programmed cell
death in NSCLC cells while IGFBP-3 inhibited cell growth in human lung
cancers, suggesting that these binding proteins might potentially be new
treatments. In addition, high levels of blood IGF-I and enhanced mutagen
sensitivity of peripheral blood lymphocytes were individually associated
with an increased risk of lung cancer, which suggests that genetic polymorphisms in IGFs may predispose to the development of lung cancer.
The RAS proto-oncogene family (KRAS, HRAS, and NRAS)
which encodes 21 kD plasma membrane proteins comprises an important
signal transduction pathway. Its members, especially KRAS, can be activated in some lung cancers by point mutations, leading to inappropriate
signalling for cell proliferation. Mutations are found in 15–20% of all
NSCLCs apart from SCLCs, especially adenocarcinomas (20–30%).
KRAS mutations correlate with smoking, often being the G–T transversions associated with polycyclic hydrocarbons and nitrosamines. In mice,
somatic activation of KRAS by spontaneous recombination predisposes
the animals to tumours, predominantly early lung cancer onset. While the
prognostic importance of KRAS mutations is debated, it does not appear to
predict the response to chemotherapy. Two recent large studies in resected
NSCLC showed that KRAS mutations were independent but weak predictors of survival.
The MYC proto-oncogene family encodes nuclear products which
are the ultimate target of RAS signal transduction; the most frequently involved family member is c-MYC in both SCLC and NSCLC, unlike
MYCN and MYCL which are generally activated only in SCLC. Activation occurs as a result of protein overexpression caused by gene amplification or by transcriptional dysregulation. There also appears to be a change
in lung cancers leading to increased stability of MYC mRNA. Approximately 18–31% of SCLCs had amplification of one MYC family member
compared with 8–20% of NSCLCs. MYC amplification appears to occur
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more frequently in chemotherapy treated patients, and the "variant" SCLC
subtype may correlate with adverse survival. Recent studies have suggested that low levels of MYC amplification occur in NSCLC and are associated with impaired survival; the combination of MYC expression with loss
of caspase-3 (an apoptosis inducer) expression results in worse survival.
MYC expression may represent an avenue for therapeutic manipulation.
Evading apoptosis
Tumour cells often escape the normal physiological response
(termed programmed cell death or apoptosis) when challenged by cellular
and DNA damage. Key players include the p53 gene and the BCL2 protooncogene. BCL2 protects against apoptosis and its expression is higher in
SCLC (75–95%) than in NSCLC. These findings are seemingly unexpected as SCLCs are more sensitive to chemotherapy, which often induces
an apoptotic response. In any case, the prognostic value of BCL2 expression is controversial. BCL2 expression in tumours actually predicts increased survival of patients with NSCLC. BAX is a BCL2 related protein
which promotes apoptosis and is a downstream transcription target of p53.
BAX and BCL2 expression is inversely related in neuroendocrine cancers;
high BCL2 and low BAX expression occurs in most SCLCs which are
usually p53 deficient. Expression of the inhibitor of apoptosis protein
(IAP)-1 acts as an important anti-apoptotic protein mediating sensitivity to
deoxynucleotide analogues in NSCLC cells. Among the anti-apoptosis
strategies in preclinical trials are studies of antisense BCL2 in SCLC (to
downregulate BCL2 protein expression), BCL-xL antisense in NSCLC,
and a bispecific BCL2-BCLxL antisense to target both SCLC and
NSCLC.
Insensitivity to anti-growth signals: tumour suppressor genes (TSGs)
TSGs play a critical role in controlling normal cell growth. They
generally inhibit the tumorigenic process but can also be involved in the
response and repair of DNA damage. TSGs are rendered inactive by
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chromosomal loss of one allele (loss of heterozygosity (LOH)) and damage to the other by genetic mutation or the epigenetic hypermethylation of
its promoter. Studies of LOH as a marker of TSG inactivation have shown
that a number of chromosomal regions are damaged in overt lung cancer
cells. For instance, a genome wide search for LOH in 36 lung cancer cell
lines using 400 high resolution polymorphic markers showed that tumours had a mean of 17–22 "hot spots" of chromosomal loss. There were
22 different regions with more than 60% LOH, 13 with a preference for
SCLC, seven for NSCLC, and two affecting both histological types. The
sharing of some LOH regions and the specificity of others may provide an
insight into the genes common to lung cancer development and others
specific to subtype differentiation. The chromosomal arms with the most
frequent LOH were 1p, 3p, 4p, 4q, 5q, 8p, 9p (p16 TSG locus), 9q, 10p,
10q, 13q (RB-retinoblastoma TSG locus), 15q, 17p (p53 TSG locus), 18q,
19p, Xp, and Xq.
There is an intense hunt for the candidate genes in chromosomal
regions with high frequencies of LOH where the precise TSG is not
known. For example, several candidate genes are located on 3p where
LOH can be found in up to 96% of lung cancers and 78% of preneoplastic/preinvasive lesions, as well as by homozygous deletions. The frequency and size of 3p LOH increased with the severity of histopathological preneoplastic/preinvasive changes. There are also TSG candidates at
the 3p21.3 region which appear to suppress the tumorigenic phenotype
when introduced back into lung cancers with numerous other genetic lesions. Expression of wild type but not tumour acquired mutant FUS1 dramatically suppresses the growth in vitro of lung cancer cells, while systemic delivery of FUS1 in an adenovirus vector resulted in regression of
metastatic disease in a lung cancer mouse xenograft model. Wild type
SEMA3B reintroduced into lung cancer cells induces apoptosis, unlike
SEMA3B missense mutants. In addition, transfection of SEMA3B into
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cells results in conditioned media that induce the death of lung cancer
cells, which raises the possibility of using this soluble secreted protein as a
systemic anticancer treatment.
Other chromosomal regions affected by LOH in lung cancers
house known TSGs such as p53, retinoblastoma (RB), and p16, and these
are often found to be abnormal by immunohistochemical examination in
lung cancer. p53 is a key TSG; its protein helps maintain genomic integrity in the face of DNA damage from or UV irradiation and carcinogens.
DNA damage or hypoxia upregulates p53 which acts as a transcription
factor regulating a number of downstream genes including p21, MDM2,
GADD45, and BAX, thereby helping to regulate the G1/S cell cycle transition, G2/M DNA damage check point, and apoptosis. p53 inactivation
occurs in 75% of SCLCs and about 50% of NSCLCs, with mutations correlating with cigarette smoking and comprising the G–T transversions expected of tobacco smoke carcinogens. Missense p53 mutations can prolong the protein half life leading to easily detected mutant p53 protein by
immunohistochemistry. p53 mutations have been linked to response to cisplatinum based chemotherapy in NSCLC and the response to radiotherapy. While there is debate on the prognostic role of p53 abnormalities in
NSCLC, the preponderance of evidence suggests that the presence of such
abnormalities leads to a worse prognosis. p53 is a prototypic model for
gene replacement therapy in lung cancer. Preclinical studies showed that
restoring p53 function resulted in apoptosis of cancer cells, and have progressed to phase II clinical trials where adenoviral mediated p53 gene
transfer delivered by direct tumour injection appeared feasible when given
in conjunction with radiation therapy. Conversely, intratumoral injection
of adenoviral p53 appeared to provide no additional benefit in patients receiving first line chemotherapy for advanced NSCLC. Vaccine trials with
mutant p53 peptides are also being performed. p53 is kept at virtually undetectable levels in normal cells by an autoregulatory loop involving the
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production of HDM2, the human homologue of the murine double minute
2 (MDM2) oncogene which blocks p53 regulation of target genes and enhances its proteasome dependent degradation. Conversely, p53 regulates
(increases) the expression of HDM2 by directly binding and activating the
HDM2 promoter, thereby downregulating itself. The HDM2 protein is
overexpressed in 25% of NSCLCs, thus representing another way of abrogating p53 function. HDM2, in turn, is inactivated by p14ARF, the alternative product of the p16 gene whose downregulation is similarly associated with loss of p53/HDM2/p14ARF pathway function.
p16 is part of the p16-cyclin D1-CDK4-RB pathway that is central
to controlling the G1–S transition of the cell cycle. This critical cell cycle
regulatory pathway is functionally altered or mutated in many cancers including those of lung origin. Each member of the pathway may be rendered dysfunctional during carcinogenesis. Functional loss of the RB gene
can include deletions, nonsense mutations, or splicing abnormalities leading to protein abnormalities in most SCLCs and 15–30% of NSCLCs.
Functionally, in vitro re-introduction into tumour cells of a wild type RB
suppresses SCLC growth. Whereas in SCLC the pathway is usually disrupted by RB gene inactivation, cyclin D1, CDK4 and especially p16 abnormalities are common in NSCLC.
Cyclin D1 inhibits the activity of RB by stimulating its phosphorylation by cyclin dependent kinase 4 (CDK4). Thus, cyclin D1 overexpression is an alternative mechanism for abrogating this pathway and is found
in 25–47% of NSCLC, possibly with a role as a predictor of poor prognosis. Furthermore, transfection of a cyclin D1 antisense construct into lung
cancer cell lines can be shown to destabilise RB and retard growth.
CDK4 expression has also been reported in NSCLCs and an example of potential therapeutic manipulation is flavopiridol. This compound,
which inhibits cyclin dependent kinase, is being tested in clinical trials.
p16 regulates RB function by inhibiting CDK4 and CDK6 kinase activity.
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p16 (or CDKN2) is situated on the short arm of chromosome 9 at
region 21 and undergoes heterozygous and homozygous loss, mutation,
and aberrant promoter hypermethylation in lung cancer, ultimately inactivating its function. Perhaps 30–50% of early stage primary NSCLCs do
not express p16. The p16 locus also encodes a second alternative reading
frame protein, p14ARF, which functions in the p53/HDM2/p14ARF
pathway as discussed above. Interestingly, as an example of their evolutionary deviousness, lung tumours have developed distinct ways of interfering with the two different products from a single genetic locus, each of
which functions in a distinct growth regulatory pathway. Moreover, the
specific mutational targets differ according to lung cancer subtype, indicating the need for efforts to better understand their relative contribution
to tumour differentiation.
Limitless replicative potential: telomerase
Telomerase is the enzyme that adds hexameric TTAGGG nucleotide repeats onto the ends (telomers) of chromosomal DNAs to compensate for losses that occur with each round of DNA replication. Normal somatic cells do not have telomerase activity and stop dividing when the telomeric ends of at least some chromosomes have been shortened to a critical length. Immortalised cells, including nearly all lung cancers, probably
continue to proliferate indefinitely because they express telomerase. While
activation of telomerase is not the earliest step in the pathogenesis of lung
cancer, it does occur early enough to be a potential molecular marker that
can be detected in preneoplastic cells of the bronchial epithelium and in
bronchial lavage specimens. Because all lung cancers express telomerase,
studies of the level of expression in individual tumours will need to be
correlated with prognosis and appear to correlate with the presence of
lymph node metastases. Besides its use as a diagnostic tool, drugs targeting telomerase have therapeutic potential. Several of these involving antisense approaches are nearing entry into clinical trials.
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Sustained angiogenesis
Lung cancers engender angiogenesis, and the expression of a large
number of tumour blood vessels as manifest by tumour microvascularity
counts is generally associated with a poor prognosis, although there are
some dissenting opinions. There are several isoforms of vascular endothelial growth factor (VEGF). The expression ratio of the VEGF189 mRNA
isoform had a greater correlation with tumour angiogenesis, postoperative
relapse time, and survival than those for the VEGF121, VEGF165, and
VEGF206 mRNA isoforms, which suggests that it could be used as a
prognostic indicator for patients with NSCLC. This increase in tumour
neovasculature arises largely because of production of VEGF by lung cancer cells. Part of this dysregulation may arise through loss of p53 function.
Clinically, plasma VEGF levels can predict the degree of angiogenesis in
NSCLC. Some impressive results have recently been presented in abstract
form from clinical trials targeting VEGF with a humanised monoclonal
anti-VEGF antibody. These initial trials were fraught with toxicity related
to unexpected bleeding from large necrotic lung tumour masses, but this
should be approachable by patient selection.
Tissue invasion and metastases
Many of the changes discussed above lead to the ability of lung
cancer cells to invade into tissues and to spread and survive in metastatic
deposits. One of the interesting new candidates to participate in invasion
and metastasis is CRMP-1, a protein involved in mediating the effect of
collapsins. Lung cancer specimens showed that reduced expression of
CRMP-1 is associated with advanced disease, lymph node metastasis, early postoperative relapse, and shorter survival, indicating that CRMP-1 is
involved in cancer invasion and metastasis. Collapsins are part of the semaphorin family, so CRMP-1 may provide another indication of the role of
semaphorins and the pathways they mediate in the pathogenesis of lung
cancer. Laminins and integrins are being intensively studied as key mark87
ers of tissue invasion through the basement membrane and subsequent development of metastases. The expression of laminin chains ( 3 and 5) is
often reduced in lung cancer cells; this might contribute to basement
membrane fragmentation and subsequent proliferation of stromal elements, as well as having a role in the process of cancer cell invasion. The
LAMB3 gene (encoding the laminin ß3 chain, a unique component of laminin-5) was expressed in NSCLC cells and not in SCLC cells. Laminin-5
is a heterotrimeric protein consisting of the 3, ß3, and 2 chains, and another unique component of laminin-5, the 2 chain encoded by the
LAMC2 gene. Since 6ß4-integrin, the specific laminin-5 binding receptor, is known to be expressed only in NSCLCs and not in SCLCs, it appears that laminin-5 is a critical microenvironmental factor for the growth
of NSCLC but not of SCLC cells. Survival analysis revealed that overexpression of laminin-5 was associated with shorter patient survival and was
an independent prognostic factor in NSCLC.
PREVENTION OF THE LUNG CANCER
Prevention of a LC is divided on initial and secondary.
Initial or hygienic prevention assumes system of measures and
medical actions directed to the termination or decrease of influence on an
organism of carcinogenic factors.
Improvement of the ecological situation directed to downstroke of
carcinogenic substances in air, water and nutrition, refusal of smoking.
The last plays the basic role in initial prevention of a LC.
Secondary or clinical prevention is specially organized system of
revealing and treatment of pretumor lung diseases, and also observation
over contingents of groups of the increased oncologic risk. Persons,
сoncerning this category are necessary to undergo 2 times per one year a
chest X-ray and 5 times examination of sputum.
Patients, who underwent radical treatment concerning LC, should be
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under observation of the doctor - oncologist 5 years. Within first 2 years
control surveys are carried out 1 time in 3 months. The next 3 years - 1
time in 6 months.
SURVIVAL
The highest 5-year survival for any cell type is for stage I squamous
cell carcinoma (50%). For stages I and II, the curves are asymptotic at 2
years, and 8-10% of patients with stage IIIA disease survive 5 years. For
stage I adenocarcinoma and large-cell carcinoma, there is little difference
in survival when compared to squamous cell carcinoma. In stages II and
IIIA, patients with squamous cell carcinoma have a better outcome than
those with adenocarcinoma or large-cell carcinoma. The outcome is
similar for all cell types in stage IIIB and IV (See table 2).
Table 2.
Non-small Cell Lung Cancer Survival by Stage
Stage
5- year survival rate
I
47%
II
26%
III
8%
IV
2%
The survivorship data for small-cell carcinoma (SCLC) are poor,
although 5-year survival of 20% has been reported in patients with stage I
disease. In many of these patients, the diagnosis of SCLC was made at the
time of resection for an undiagnosed solitary pulmonary nodule. Patients
with limited disease (tumor confined to one hemithorax and its regional
lymph nodes) have a more favorable prognosis than patients with
extensive disease (See table 3). Weight loss prior to diagnosis, a poor
performance status, failure of SCLC to respond to initial chemotherapy
regimen, and progression of disease after treatment are adverse prognostic
factors.
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Table 3.
Small Cell Lung Cancer Survival by Stage
Stage
Median survival
5-year survival
Limited Disease
18 - 20 months
10%
Extensive Disease
10 - 12 months
1 - 2%
THE FUTURE
The disappointing prognosis for patients with lung cancer has
prompted nihilism on the one hand and determination to improve outcomes on the other. This has led to a search for new agents to complement
the antitumor effects of chemotherapeutic drugs. Several observations of
lung tumor biology have influenced the selection of candidate drugs, many
of which have been designed to affect specific cellular pathways implicated in oncogenesis. Angiogenesis is thought to play an important role in
tumor growth and metastasis. Successful blood vessel formation lies in a
balance between proangiogenic factors, such as the growth factors vascular endothelial growth factor (VEGF), platelet-derived growth factor
(PDGF), transforming growth factor (TGF), and epidermal growth factor
(EGF) acting through their receptor tyrosine kinases; the degradation and
remodeling of the extra cellular matrix by matrix metalloproteinases
(MMPs) and their inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs); and the naturally circulating antiangiogenic molecules
angiostatin and endostatin.
Some observations in lung cancer itself have reinforced the idea that
inhibiting angiogenesis might prove fruitful. For example, in a study of
143 patients with fully resected primary NSCLCs, the median survival of
patients with angiostatin-negative/VEGF-positive tumors was significantly
less than those with angiostatin-positive/VEGF-negative tumors, 52 versus
184 weeks, respectively. Intratumoral microvessel density (IMD) has also
been variably related to a poorer prognosis. Levels of cellular expression
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of VEGF and its receptor (VEGFR), the EGF receptors (EGFR/HER-1/cErb-B1 and HER-2/c-Erb-B2, and MMP-9 have all been found to be increased in certain lung cancers, although how this relates to prognosis is
still contentious.
At present many candidate molecules have been developed to inhibit
angiogenic pathways in the hope of making an impact in cancer treatment,
and this review considers those molecules that have reached Phase III trials.
The growth factors and their receptors are judged to have enormous
potential as novel therapeutic targets. A Phase II trial of a recombinant
humanized anti-VEGF antibody (rhuMAb-VEGF, Bevacizumab; Genentech, San Francisco, CA) in combination with paclitaxel and carboplatin in
NSCLC was sufficiently encouraging that a large Phase III trial involving
metastatic NSCLC is underway.
Even more hope has been invested in the EGFR-blocking agents.
The most extensively studied of these agents are:
1) monoclonal antibodies against the extracellular domain of the receptor, including IMC-C225 (Erbitux; ImClone Systems, Somerville, NJ)
directed against the EGFR and trastuzumab (Herceptin; Genentech) directed against HER-2/c-Erb-B2,
2) inhibitors of the tyrosine kinase region of the receptors such as
ZD 1839 (Iressa; AstraZeneca, Wilmington, DE) and OSI-774 (Tarceva;
OSI Pharmaceuticals, Melville, NY).
So far, only ZD 1839 and OSI-774 have progressed to Phase III
studies in NSCLC. There are currently two multicenter Phase III trials of
chemotherapy (carboplatin plus paclitaxel in one study, and cisplatin plus
gemcitabine in the other) alone or in combination with ZD 1839 in newly
diagnosed patients with advanced Stage III/IV NSCLC. Two similar Phase
III studies are in early stages, and plan to compare chemotherapy (carboplatin plus paclitaxel in one study, and cisplatin plus gemcitabine in the
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other) alone or with OSI-774, again in chemotherapy-naive patients with
advanced stage NSCLC. The primary end point for all four trials is survival.
To date, several potent synthetic inhibitors of MMPs (MMPIs) have
been produced and tested in patients. Many of these made it to Phase III
trials in advanced lung cancer but, disappointingly, most of these trials
were halted following a poorer outcome in the treated group. It is not clear
why the results were so poor, but it has been suggested that MMP inhibition is needed at the time of angiogenesis and not once the tumor microvasculature has been established.
Neovastat (AE-941; Aeterna, Quebec, PQ, Canada), a naturally occurring MMPI extracted from shark cartilage extract, significantly improved survival in patients with inoperable Stage III and IV NSCLC and
recruitment has begun for a Phase III trial in inoperable Stage III NSCLC
in combination with platinum-based chemotherapy (cisplatin and vinorelbine or carboplatin and paclitaxel) and radiotherapy.
Another inhibitor of angiogenesis is carboxyamido-triazole (CAI);
how it works is not entirely clear, although it is known to inhibit calciummediated signal transduction. A randomized Phase III study of oral CAI in
patients with advanced NSCLC, who have received chemotherapy, is recruiting patients and aims to assess the safety of CAI and to collect data on
quality of life and time to progression.
Thalidomide has been shown in preclinical models to be antiangiogenic, and although the exact mechanism is not understood it is thought to
be involve effects on tumor necrosis factor- and VEGF, among others. A
randomized trial of paclitaxel–carboplatin and radiation with or without
thalidomide is open for patients with Stage IIIB NSCLC in the United
States.
Another potential area of interest is that of apoptosis or programmed
cell death and both apoptosis-protective molecules such as Bcl-2, and
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apoptosis-stimulating molecules such as Bax, are being pursued as targets
for inhibition or activation, respectively. Genasense (formerly known as
G-3139; Genta, Berkeley Heights, NJ), is an antisense oligonucleotide
specific for Bcl-2; it is administered as an intravenous infusion and is in
Phase III trials for malignant melanoma and earlier phase studies in
NSCLC.
Another target is protein kinase C (PKC), and some encouraging results have been seen with Isis 3521 (Isis Pharmaceuticals, Carlsbad, CA),
an antisense PKC inhibitor that binds to PKC- RNA and prevents transcription. In Phase II studies, patients with Stage IIIB or IV NSCLC were
treated with carboplatin–paclitaxel alone or with Isis 3521. Those that received Isis 3521 had a median survival of 19 months compared with 8
months for those not receiving the drug. A Phase III study of similar design is underway.
Other strategies have also been developed, such as vaccines directed
against tumor-specific gangliosides; one such anti-idiotypic monoclonal
antibody against the GD3 ganglioside is BEC-2 (Mitumomab; ImClone
Systems). An international randomized Phase III trial is being conducted
to evaluate BEC-2 plus BCG as adjuvant therapy after chemotherapy and
irradiation in limited SCLC. In North America, a bivalent ganglioside
vaccine, MGV (Bristol-Myers Squibb), is under study at the Phase II level. If results are promising, a Phase III trial will be undertaken.
Another attempt at immunomodulation involves the use of Mycobacterium vaccae (SRL172) given as a monthly intradermal injection in
newly diagnosed patients with inoperable NSCLC and mesothelioma. Results from a Phase II trial showed a tendency toward a better response in
patients who received SLR172 compared with those who received chemotherapy alone. A Phase III study is now in progress.
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STANDARDS OF LUNG CANCER TREATMENT
TREATMENT OF NON-SMALL CELL LUNG CANCER
Occult Non-small Cell Lung Cancer
TX, N0, M0
In occult lung cancer, a diagnostic evaluation often includes chest xray and selective bronchoscopy with close follow-up (e.g., computed
tomographic scan), when needed, to define the site and nature of the primary tumor; tumors discovered in this fashion are generally early stage
and curable by surgery. After discovery of the primary tumor, treatment is
determined by establishing the stage of the patient's tumor. Therapy is
identical to that recommended for other non-small cell lung cancer patients with similar stage disease.
Stage 0 Non-small Cell Lung Cancer
Tis, N0, M0
Stage 0 non-small cell lung cancer (NSCLC) is the same as carcinoma
in situ of the lung. Because these tumors are by definition noninvasive and
incapable of metastasizing, they should be curable with surgical resection;
however, there is a high incidence of second primary cancers, many of
which are unresectable. Endoscopic phototherapy with a hematoporphyrin
derivative has been described as an alternative to surgical resection in
carefully selected patients. This investigational treatment seems to be
most effective for very early central tumors that extend less than 1 centimeter within the bronchus. Efficacy of this treatment modality in the management of early NSCLC remains to be proven.
Treatment options:
1. Surgical resection using the least extensive technique possible
(segmentectomy or wedge resection) to preserve maximum normal
pulmonary tissue since these patients are at high risk for second
lung cancers.
2. Endoscopic photodynamic therapy.
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Stage I Non-small Cell Lung Cancer
T1, N0, M0 or T2, N0, M0
Surgery is the treatment of choice for patients with stage I non-small
cell lung cancer (NSCLC). Careful preoperative assessment of the patient's overall medical condition, especially the patient's pulmonary reserve, is critical in considering the benefits of surgery. The immediate
postoperative mortality rate is age-related, but 3% to 5% with lobectomy
can be expected. Patients with impaired pulmonary function may be considered for segmental or wedge resection of the primary tumor. A survival
advantage was noted with lobectomy for patients with tumors greater than
3 centimeters, but not for those with tumors smaller than 3 centimeters.
However, the rate of local/regional recurrence was significantly less after
lobectomy, regardless of primary tumor size. Exercise testing may aid in
the selection of patients with impaired pulmonary function who can tolerate lung resection.
Primary radiation therapy should consist of approximately 60 Gy delivered with megavoltage equipment to the midplane of the known tumor
volume using conventional fractionation. A boost to the cone-down field
of the primary tumor is frequently used to further enhance local control.
Careful treatment planning with precise definition of target volume and
avoidance of critical normal structures to the extent possible is needed for
optimal results and requires the use of a simulator.
Many patients treated surgically subsequently develop regional or distant metastases. Therefore, patients should be considered for entry into
clinical trials evaluating adjuvant treatment with chemotherapy or radiation therapy following surgery. A meta-analysis of 9 randomized trials
evaluating postoperative radiation versus surgery alone showed a 7% reduction in overall survival with adjuvant radiation in patients with stage I
or II disease. Trials of adjuvant chemotherapy regimens have failed to
demonstrate a consistent benefit.
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Smokers who undergo complete resection of stage I NSCLC are also
at risk for second malignant tumors. In the Lung Cancer Study Group trial
of 907 stage T1, N0 resected patients, the rate of nonpulmonary second
cancers was 1.8% per year and 1.6% per year for new lung cancers. A
randomized trial of vitamin A versus observation in resected stage I patients showed a trend toward decreased second primary cancers in the vitamin A arm with no difference in overall survival rates. An ongoing intergroup clinical trial will evaluate the role of isotretinoin in the chemoprevention of second cancers in patients resected for stage I NSCLC.
Treatment options:
1. Lobectomy or segmental, wedge, or sleeve resection as appropriate.
2. Radiation therapy with curative intent (for potentially resectable
patients who have medical contraindications to surgery).
Stage II Non-small Cell Lung Cancer
T1, N1, M0 or T2, N1, M0 or T3, N0, M0
Surgery is the treatment of choice for patients with stage II non-small
cell lung cancer (NSCLC). Careful preoperative assessment of the patient's overall medical condition, especially the patient's pulmonary reserve, is critical in considering the benefits of surgery. The immediate
postoperative mortality rate is age-related, but up to 5% to 8% with
pneumonectomy or 3% to 5% with lobectomy can be expected.
Inoperable patients with stage II disease and with sufficient pulmonary
reserve may be considered for radiation therapy with curative intent.
Among patients with excellent performance status, up to a 20% 3-year
survival rate may be expected if a course of radiation therapy with curative intent can be completed.
Primary radiation therapy should consist of approximately 60 Gy delivered with megavoltage equipment to the midplane of the volume of
known tumor using conventional fractionation. A boost to the cone-down
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field of the primary tumor is frequently used to further enhance local control.
Many patients treated surgically subsequently develop regional or distant metastases. Therefore, patients should be considered for entry into
clinical trials evaluating the use of adjuvant treatment with chemotherapy
or radiation therapy following surgery. Based on these data of many trials,
participation in clinical trials evaluating adjuvant therapy after surgical
resection should be encouraged.
Treatment options:
1. Lobectomy, pneumonectomy, or segmental, wedge, or sleeve resection as appropriate.
2. Radiation therapy with curative intent (for potentially operable patients who have medical contraindications to surgery).
Stage IIIA Non-small Cell Lung Cancer
T1, N2, M0 or T2, N2, M0 or T3, N1, M0 or T3, N2, M0
Depending on clinical circumstances, the principal forms of treatment
that are considered for patients with stage III non-small cell lung cancer
(NSCLC) are radiation therapy, chemotherapy, surgery, and combinations
of these modalities. Although the majority of these patients do not achieve
a complete response to radiation therapy, there is a reproducible long-term
survival benefit in 5% to 10% of patients treated with standard fractionation to 60 Gy, and significant palliation often results. Patients with excellent performance status and those who require a thoracotomy to prove that
surgically unresectable tumor is present are most likely to benefit from
radiation therapy. Because of the poor long-term results, these patients
should be considered for clinical trials. Trials examining fractionation
schedules, endobronchial laser therapy, brachytherapy, and combined modality approaches may lead to improvement in the control of this regional
disease.
The addition of chemotherapy to radiation therapy has been reported
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to improve survival in prospective clinical studies that have used modern
cisplatin-based chemotherapy regimens. A meta-analysis of patient data
from 11 randomized clinical trials showed that cisplatin-based combinations plus radiation therapy resulted in 10% reduction in the risk of death
compared with radiation therapy alone.
Patients with N2 disease apparent on chest radiograph and documented by biopsy or discovered by prethoracotomy exploration have a 5-year
survival rate of only about 2%. The use of preoperative (neoadjuvant)
chemotherapy has been shown to be effective in these clinical situations in
2 small randomized studies of a total of 120 patients with stage IIIa
NSCLC. Two additional single-arm studies have evaluated either 2 to 4
cycles of combination chemotherapy or combination chemotherapy plus
chest irradiation for 211 patients with histologically confirmed N2 stage
IIIa NSCLC. Sixty-five percent to 75% of patients were able to have a resection of their cancer, and 27% to 28% were alive at 3 years. These results are encouraging, and combined-modality therapy with neoadjuvant
chemotherapy with surgery and/or chest radiation therapy should be considered for patients with good performance status who have stage IIIa
NSCLC.
Although most retrospective studies suggest that postoperative radiation therapy can improve local control for node-positive patients whose
tumors were resected, it remains controversial whether it can improve
survival.
No consistent benefit from any form of immunotherapy has been
demonstrated thus far in the treatment of NSCLC.
Treatment options:
1. Surgery with postoperative radiation therapy.
2. Chemotherapy combined with other modalities.
3. Radiation therapy alone.
Superior sulcus tumor (T3, N0 or N1, M0)
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Another category that merits a special approach is that of superior sulcus tumors, a locally invasive problem usually with a reduced tendency
for distant metastases. Consequently, local therapy has curative potential,
especially for T3, N0 disease. Radiation therapy alone, radiation therapy
preceded or followed by surgery, or surgery alone (in highly selected cases) may be curative in some patients, with a 5-year survival rate of 20% or
more in some studies. Patients with more invasive tumors of this area, or
true Pancoast tumors, have a worse prognosis and generally do not benefit
from primary surgical management. Follow-up surgery may be used to
verify complete response in the radiation therapy field and to resect necrotic tissue.
Treatment options:
1. Radiation therapy and surgery.
2. Radiation therapy alone.
3. Surgery alone (selected cases).
4. Chemotherapy combined with other modalities.
5. Brachytherapy.
Chest wall tumor (T3, N0 or N1, M0)
Selected patients with bulky primary tumors that directly invade the
chest wall can obtain long-term survival with surgical management provided that their tumor is completely resected.
Treatment options:
1. Surgery.
2. Surgery and radiation therapy.
3. Radiation therapy alone.
4. Chemotherapy combined with other modalities.
Stage IIIB Non-small Cell Lung Cancer
Patients with stage IIIb non-small cell lung cancer (NSCLC) do not
benefit from surgery alone and are best managed by initial chemotherapy,
chemotherapy plus radiation therapy, or radiation therapy alone, depend99
ing on sites of tumor involvement and performance status. Most patients
with excellent performance status should be considered for combined modality therapy. However, patients with malignant pleural effusion are rarely candidates for radiation therapy, and should generally be treated similarly to stage IV patients. Many randomized studies of unresectable patients with stage III NSCLC show that treatment with neoadjuvant or concurrent cisplatin-based chemotherapy and chest irradiation is associated
with improved survival compared to treatment with radiation therapy
alone.
Patients with stage IIIb disease with poor performance status are candidates for chest irradiation to palliate pulmonary symptoms (e.g., cough,
shortness of breath, or local chest pain). No consistent benefit from any
form of immunotherapy has been demonstrated thus far.
T4 or N3, M0
An occasional patient with supraclavicular node involvement who is
otherwise a good candidate for irradiation with curative intent will survive
3 years. Although the majority of these patients do not achieve a complete
response to radiation therapy, significant palliation often results. Patients
with excellent performance status and those who are found to have advanced-stage disease at the time of resection are most likely to benefit
from radiation therapy. Adjuvant systemic chemotherapy with radiation
therapy has been tested in randomized trials for patients with inoperable
or unresectable locoregional NSCLC. Some patients have shown a modest
survival advantage with adjuvant chemotherapy. The addition of chemotherapy to radiation therapy has been reported to improve long-term survival in some, but not all, prospective clinical studies. The optimal sequencing of modalities remains to be determined and is under study in ongoing clinical trials.
Patients with NSCLC can present with superior vena cava syndrome.
Regardless of stage, this problem should generally be managed with radia100
tion therapy with or without chemotherapy.
Treatment options:
1. Radiation therapy alone.
2. Chemotherapy combined with radiation therapy.
3. Chemotherapy and concurrent radiation therapy followed by resection.
4. Chemotherapy alone.
Stage IV Non-small Cell Lung Cancer
Any T, any N, M1
Cisplatin-containing and carboplatin-containing combination chemotherapy regimens produce objective response rates (including a few complete responses) that are higher than those achieved with single-agent
chemotherapy. Although toxic effects may vary, outcome is similar with
most cisplatin-containing regimens; a randomized trial comparing 5 cisplatin-containing regimens showed no significant difference in response,
duration of response, or survival. Patients with good performance status
and a limited number of sites of distant metastases have superior response
and survival when given chemotherapy when compared to other patients.
Reports of paclitaxel combinations have shown relatively high response
rates, significant 1 year survival, and palliation of lung cancer symptoms.
The combination of cisplatin and paclitaxel was shown to have a higher
response rate than the combination of cisplatin and etoposide. Metaanalyses have shown that chemotherapy produces modest benefits in
short-term survival compared to supportive care alone in patients with inoperable stages IIIb and IV disease.
Radiation therapy may be effective in palliating symptomatic local involvement with NSCLC such as tracheal, esophageal, or bronchial compression, bone or brain metastases, pain, vocal cord paralysis, hemoptysis,
or superior vena cava syndrome. In some cases, endobronchial laser therapy and/or brachytherapy has been used to alleviate proximal obstructing
101
lesions. Such therapeutic intervention may be critical in the prolongation
of an acceptable lifestyle in an otherwise functional patient. In the rare
patient with synchronous presentation of a resectable primary tumor in the
lung and a single brain metastasis, surgical resection of the solitary brain
lesion is indicated with resection of the primary tumor and appropriate
postoperative chemotherapy and/or irradiation of the primary tumor site
and with postoperative whole-brain irradiation delivered in daily fractions
of 180-200 cGy to avoid long-term toxic effects to normal brain tissue.
Treatment options:
1. External-beam radiation therapy, primarily for palliative relief of
local symptomatic tumor growth.
2. Chemotherapy. The following regimens are associated with similar
survival outcomes:
cisplatin plus vinblastine plus mitomycin
cisplatin plus vinorelbine
cisplatin plus paclitaxel
cisplatin plus gemcitabine
carboplatin plus paclitaxel
3.Endobronchial laser therapy and/or brachytherapy for obstructing lesions.
Recurrent Non-small Cell Lung Cancer
Many patients with recurrent non-small cell lung cancer (NSCLC) are
eligible for clinical trials. Radiation therapy may provide excellent palliation of symptoms from a localized tumor mass.
Patients who present with a solitary cerebral metastasis after resection
of a primary NSCLC lesion and who have no evidence of extracranial tumor can achieve prolonged disease-free survival with surgical excision of
the brain metastasis and postoperative whole-brain irradiation. Unresectable brain metastases in this setting may be treated radiosurgically. Because of the small potential for long-term survival, radiation therapy
102
should be delivered by conventional methods in daily doses of 180 to 200
cGy, while higher daily doses over a shorter period of time (hypofractionated schemes) should be avoided because of the high risk of toxic effects
observed with such treatments. Most patients not suitable for surgical resection should receive conventional whole-brain radiation therapy. Selected patients with good performance status and small metastases can be
considered for stereotactic radiosurgery.
Approximately one half of patients treated with resection and postoperative radiation therapy will develop recurrence in the brain; some of
these patients will be suitable for additional treatment. In those selected
patients with good performance status and without progressive metastases
outside of the brain, treatment options include reoperation or stereotactic
radiosurgery. For most patients, conventional radiation therapy can be
considered; however, the palliative benefit of this treatment is limited.
A solitary pulmonary metastasis from an initially resected bronchogenic carcinoma is unusual. The lung is frequently the site of second primary malignancies in patients with primary lung cancers. Determining
whether the new lesion is a new primary cancer or a metastasis may be
difficult. Studies have indicated that in the majority of patients the new
lesion is a second primary tumor, and following resection some patients
may achieve long-term survival. Thus, if the first primary tumor has been
controlled, the second primary tumor should be resected if possible.
The use of chemotherapy has produced objective responses and small
improvement in survival for patients with metastatic disease. In studies
that have examined symptomatic response, improvement in subjective
symptoms has been reported to occur more frequently than objective response. Informed patients with good performance status and symptomatic
recurrence can be offered treatment with a cisplatin-based chemotherapy
regimen for palliation of symptoms.
Treatment options:
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1. Palliative radiation therapy.
2. Chemotherapy alone. For patients who have not received prior
chemotherapy, the following regimens are associated with similar survival
outcomes:
cisplatin plus vinblastine plus mitomycin
cisplatin plus vinorelbine
cisplatin plus paclitaxel
cisplatin plus gemcitabine
carboplatin plus paclitaxel
3. Surgical resection of isolated cerebral metastasis (highly selected
patients).
4. Laser therapy or interstitial radiation therapy for endobronchial lesions.
5. Stereotactic radiosurgery (highly selected patients).
STANDARTS OF TREATMENT
OF SMALL CELL LUNG CANCER
Without treatment, small cell carcinoma of the lung has the most aggressive clinical course of any type of pulmonary tumor, with median survival from diagnosis of only 2 to 4 months. Compared with other cell
types of lung cancer, small cell carcinoma has a greater tendency to be
widely disseminated by the time of diagnosis, but is much more responsive to chemotherapy and irradiation.
Because of its propensity for distant metastases, localized forms of
treatment, such as surgical resection or radiation therapy, rarely produce
long-term survival. With incorporation of current chemotherapy regimens
into the treatment program, however, survival is unequivocally prolonged,
with at least a 4- to 5-fold improvement in median survival compared with
patients who are given no therapy. Furthermore, about 10% of the total
population of patients remain free of disease over two years from the start
104
of therapy, the time period during which most relapses occur. However,
even these patients are at risk of dying from lung cancer (both small and
non-small cell types). The overall survival at 5 years is 5% to 10%.
At the time of diagnosis, approximately 40% of patients with small
cell carcinoma will have tumor confined to the hemithorax of origin, the
mediastinum, or the supraclavicular lymph nodes. These patients are designated as having limited stage disease, and most 2-year disease-free survivors come from this group. In limited stage disease, median survival of
16 to 24 months with current forms of treatment can reasonably be expected. A small proportion of patients with limited stage disease may benefit from surgery with or without adjuvant chemotherapy; these patients
have an even better prognosis. Patients with tumor that has spread beyond
the supraclavicular areas are said to have extensive stage disease and have
a worse prognosis than patients with limited stage. Median survival of 6 to
12 months is reported with currently available therapy, but long-term disease-free survival is rare.
The pretreatment prognostic factors which consistently predict for prolonged survival include good performance status, female gender, and limited stage disease. Patients with involvement of the central nervous system
or liver at the time of diagnosis have a significantly worse outcome. In
general, patients who are confined to bed tolerate aggressive forms of
treatment poorly, have increased morbidity, and rarely attain 2-year disease-free survival. However, patients with poor performance status can
often derive significant palliative benefit and prolongation of survival
from treatment.
Cellular Classification
Review of pathologic material by an experienced lung cancer
pathologist is important prior to initiating treatment of any patient with
small cell lung cancer. The intermediate subtype of small cell carcinoma
and the more readily recognized lymphocyte-like or "oat cell" subtype are
105
equally responsive to treatment.
The current classification of subtypes of small cell lung cancer are:
 small cell carcinoma
 mixed small cell/large cell carcinoma
 combined small cell carcinoma (small cell lung cancer
combined with neoplastic squamous and/or glandular components)
There is increasing evidence that light microscopy has some limitations as a means of classifying bronchogenic carcinomas, particularly
small cell carcinomas. Electron microscopy, which can detect neuroendocrine granules, may help to differentiate between small cell and non-small
cell cancers.
Neuroendocrine carcinomas of the lung represent a spectrum of disease. At one extreme is small cell lung cancer, which has a poor prognosis. At the other extreme are bronchial carcinoids, with an excellent prognosis after surgical excision. Between these extremes is an unusual entity
called well-differentiated neuroendocrine carcinoma of the lung. It has
been referred to as malignant carcinoid, metastasizing bronchial adenoma,
pleomorphic carcinoid, nonbenign carcinoid tumor, and atypical carcinoid. Like small cell lung cancer, it occurs primarily in cigarette smokers, but it metastasizes less frequently. The 5-year survival rate is greater
than 50% in some series, and surgical cure appears possible in most stage
I patients. Careful diagnosis is important, however, since the differential
pathologic diagnosis from small cell lung cancer may be difficult.
Stage Information
Staging procedures are important in distinguishing patients who have
disease limited to their thorax from those who have distant metastases.
Determining the stage of cancer by nonsurgical means allows a better assessment of prognosis and identifies sites of tumor that can be evaluated
for response. Also, the choice of treatment is usually influenced by stage,
particularly when chest irradiation or surgical excision is added to chemo106
therapy for patients with limited stage disease. Staging procedures commonly used to document distant metastases include bone marrow examination, computed tomographic or magnetic resonance imaging scans of
the brain, computerized tomographic scans of the chest and the abdomen,
and radionuclide bone scans.
Because occult or overt metastatic disease is present at diagnosis in
most patients, survival is usually not affected by small differences in the
amount of locoregional tumor involvement. Therefore, the detailed TNM
staging system is not commonly employed in patients with small cell carcinoma. A simple 2-stage system developed by the Veterans Administration Lung Cancer Study Group is more commonly used for staging small
cell lung cancer patients.
Limited stage
Limited stage small cell lung cancer means tumor confined to the hemithorax of origin, the mediastinum, and the supraclavicular nodes, which
can be encompassed within a "tolerable" radiation therapy port. There is
no universally accepted definition of this term, and patients with pleural
effusion, massive pulmonary tumor, and contralateral supraclavicular
nodes have been both included within and excluded from limited stage by
various groups.
Extensive stage
Extensive stage small cell lung cancer means tumor that is too widespread to be included within the definition of limited stage disease above.
Patients with distant metastases (M1) are always considered to have extensive stage disease.
Limited Stage Small Cell Lung Cancer
In patients with small cell lung cancer, combination chemotherapy
produces results that are clearly superior to single-agent treatment, and
moderately intensive doses of drugs are superior to doses that produce only minimal or mild hematologic toxic effects. Current programs yield
107
overall objective response rates of 65% to 90% and complete response
rates of 45% to 75%. Because of the frequent presence of occult metastatic disease, chemotherapy is the cornerstone of treatment of limited stage
small cell lung cancer. Combinations containing two or more drugs are
needed for maximal effect.
Mature results of prospective randomized trials suggest that combined
modality therapy produces a modest but significant improvement in survival compared with chemotherapy alone. Two meta-analyses showed an
improvement in 3-year survival rates of about 5% for those receiving
chemotherapy and radiation therapy compared to those receiving chemotherapy alone. Most of the benefit occurred in patients less than 65 years
of age. Combined modality treatment is associated with increased morbidity and, in some trials, increased treatment-related mortality from pulmonary and hematologic toxic effects; proper administration requires close
collaboration between medical and radiation oncologists. In general, those
studies showing a positive effect for combined modality therapy employed thoracic irradiation early in the course of treatment, concurrently
with chemotherapy.
Studies strongly suggest that minimal tumor doses in the range of 40
to 45 Gy or more (standard fractionation) are necessary to effectively control tumors in the thorax.
The combination of etoposide and cisplatin chemotherapy with concurrent chest radiation therapy has now been used in multiple single institutional studies and in cooperative group studies. These studies have consistently achieved median survivals of 18 to 24 months and 40% to 50%
2-year survival with less than 3% treatment-related mortality. Once-daily
and twice-daily chest radiation schedules have been used in regimens with
etoposide and cisplatin. However, esopohagitis was increased with twicedaily treatment.
The current standard treatment of patients with limited stage small cell
108
lung cancer should be a combination containing etoposide and cisplatin
plus chest radiation therapy administered during the first or second cycle
of chemotherapy administration.
The relative effectiveness of 2- to 5-drug regimens and different
schedules of chest radiation therapy appear to be similar. A representative
selection of regimens incorporating chemotherapy plus chest radiation
therapy are listed below. The use of alternating chemotherapy regimens
has not proven more effective than the consistent administration of a single regimen. The optimal duration of chemotherapy for patients with limited stage small cell lung cancer is not clearly defined but there is no improvement in survival after the duration of drug administration exceeds 3
to 6 months. There is no evidence from randomized trials that maintenance chemotherapy prolongs survival for patients with limited stage
small cell lung cancer.
Patients presenting with superior vena cava syndrome are treated with
combination chemotherapy with or without radiation therapy. A small minority of limited stage patients with adequate pulmonary function and
with tumor pathologically confined to the lung of origin, or the lung and
ipsilateral hilar lymph nodes, may possibly benefit from surgical resection
with or without adjuvant chemotherapy.
Patients with small cell lung cancer treated with chemotherapy with or
without chest irradiation who have achieved a complete remission can be
considered for administration of prophylactic cranial irradiation (PCI).
Patients whose cancer can be controlled outside the brain have a 60%
actuarial risk of developing central nervous system metastases within 2 to
3 years after starting treatment. The majority of these patients relapse only
in their brain and nearly all of those who relapse in their central nervous
system die of their cranial metastases. The risk of developing central
nervous system metastases can be reduced by more than 50% by the administration of PCI in doses of 2400 cGy. A meta-analysis of 7 random109
ized trials evaluating the value of PCI in patients with complete remission
reported improvement in brain recurrence, disease-free survival, and overall survival with the addition of PCI. The 3-year overall survival was improved from 15% to 21% with PCI.
Retrospective studies have shown that long-term survivors of small
cell lung cancer (>2 years from the start of treatment) have a high incidence of central nervous system impairment. However, prospective studies have shown that patients treated with PCI do not have detectably different neuropsychological function than patients not treated. In addition,
the majority of patients with small cell lung cancer have neuropsychological abnormalities present before the start of cranial irradiation and have no
detectable decline in their neurological status up to 2 years after the start
of their cranial irradiation. Patients treated for small cell lung cancer continue to have declining neuropsychologic function after 2 years from the
start of treatment. Therefore, additional neuropsychologic testing of patients beyond 2 years from the start of treatment will be needed before
concluding that PCI does not contribute to the decline in intellectual function.
Treatment options:
Standard:
1. Combination chemotherapy with one of the following regimens and
chest irradiation (with or without PCI given to patients with complete responses):
The following regimens produce similar survival outcomes:
 EC: etoposide + cisplatin + 4000-4500 cGy chest radiation therapy
 ECV: etoposide + cisplatin + vincristine + 4500 cGy chest radiation
therapy
2. Combination chemotherapy (with or without PCI in patients with complete responses), especially in patients with impaired pulmonary function
or poor performance status.
110
3. Surgical resection followed by chemotherapy or chemotherapy plus
chest radiation therapy (with or without PCI in patients with complete responses) for patients in highly selected cases.
Extensive Stage Small Cell Lung Cancer
As in limited stage small cell carcinoma, chemotherapy should be given as multiple agents in doses associated with at least moderate toxic effects in order to produce the best results in extensive stage disease. Doses
and schedules used in current programs yield overall response rates of
70% to 85% and complete response rates of 20% to 30% in extensive
stage disease. Since overt disseminated disease is present, combination
chemotherapy is the cornerstone of treatment of this stage of small cell
lung cancer. Combinations containing two or more drugs are needed for
maximal benefit.
The relative effectiveness of many 2- to 4-drug combination programs
appears similar, and there are a large number of potential combinations.
Therefore, a representative selection of regimens that have been found to
be effective by at least two independent groups has been provided. Some
physicians have administered two of these or other regimens in alternating
sequences, but there is no proof that this strategy yields substantial survival improvement. Optimal duration of chemotherapy is not clearly defined,
but there is no obvious improvement in survival when the duration of drug
administration exceeds 6 months. There is no clear evidence from reported data that maintenance chemotherapy will improve survival duration.
Combination chemotherapy plus chest irradiation does not appear to
improve survival compared with chemotherapy alone in extensive stage
small cell lung cancer. However, radiation therapy plays an extremely important role in palliation of symptoms of the primary tumor and of metastatic disease, particularly brain, epidural, and bone metastases.
Chest irradiation is sometimes given for superior vena cava syndrome,
111
but chemotherapy alone (with irradiation reserved for nonresponding patients) is appropriate initial treatment. Brain metastases are appropriately
treated with whole-brain radiation therapy. However, intracranial metastases from small cell carcinoma may respond to chemotherapy as readily as
metastases in other organs.
Patients with small cell lung cancer treated with chemotherapy with or
without chest irradiation who have achieved a complete remission can be
considered for administration of prophylactic cranial irradiation (PCI).
Many more patients with extensive stage small cell carcinoma have
greatly impaired performance status at the time of diagnosis when compared to patients with limited stage disease. Such patients have a poor
prognosis and tolerate aggressive chemotherapy or combined modality
therapy poorly. Single-agent intravenous, oral, and low-dose biweekly
regimens have been developed for these patients. However, prospective
randomized studies have shown that patients with a poor prognosis who
are treated with conventional regimens live longer than those treated with
the single-agent or low-dose regimens.
Treatment options:
Standard:
1. Combination chemotherapy with one of the following regimens
with or without PCI given to patients with complete responses:
The following regimens produce similar survival outcomes:
 CAV: cyclophosphamide + doxorubicin + vincristine
 CAE: cyclophosphamide + doxorubicin + etoposide
 EP or EC: etoposide + cisplatin or carboplatin
 ICE: ifosfamide + carboplatin + etoposide
Other regimens appear to produce similar survival outcomes but
have been studied less extensively or are in less common use,
including:
 cyclophosphamide + methotrexate + lomustine
112

cyclophosphamide + methotrexate + lomustine + vincristine
 cyclophosphamide + doxorubicin + etoposide + vincristine
 CEV: cyclophosphamide + etoposide + vincristine
 single-agent etoposide
2. Radiation therapy to sites of metastatic disease unlikely to be
immediately palliated by chemotherapy, especially brain, epidural,
and bone metastases.
Recurrent Small Cell Lung Cancer
The prognosis for small cell lung carcinoma that has progressed despite chemotherapy is exceedingly poor regardless of stage. Expected median survival is 2 to 3 months. These patients should be considered for
palliative therapy or clinical trials. Patients who are primarily resistant to
chemotherapy and those who have received multiple chemotherapy regimens rarely respond to additional treatment. However, patients who have
initially responded and relapsed more than 6 months following initial
treatment are more likely to respond to additional chemotherapy. While
no single chemotherapy regimen should be considered standard, those that
have shown activity as second line treatment include oral etoposide,
etoposide/cisplatin, cyclophosphamide/doxorubicin/ vincristine (CAV),
lomustine/methotrexate, and topotecan. A randomized comparison of second line treatment with either CAV or topotecan reported no significant
difference in response rates or survival, but palliation of symptoms was
better with topotecan.
Some patients with intrinsic endobronchial obstructing lesions or extrinsic compression due to tumor have achieved successful palliation with
endobronchial laser therapy (for endobronchial lesions only) and/or
brachytherapy. Expandable metal stents can be safely inserted under local
anesthesia via the bronchoscope, resulting in improved symptoms and
113
pulmonary function in patients with malignant airways obstruction. Patients with progressive intrathoracic tumor after failing initial chemotherapy can achieve significant tumor responses, palliation of symptoms, and
short-term local control with external-beam radiation therapy. However,
only the rare patient will experience long-term survival following "salvage" radiation therapy.
Patients with central nervous system recurrences can often obtain palliation of symptoms with radiation therapy and/or additional chemotherapy. The majority of patients treated with radiation therapy obtain objective
responses and improvement following radiation therapy. A retrospective
review showed that 43% of patients treated with additional chemotherapy
at the time of CNS relapse respond to second-line chemotherapy.
Treatment options:
1. Palliative radiation therapy.
2. Salvage chemotherapy can provide some palliative benefit for patients previously sensitive to standard chemotherapy.
3. Local palliation with endobronchial laser therapy, endobronchial
stents, and/or brachytherapy.
114
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